SECTION 1: CHRONIC MYELOID LEUKEMIA (CML)
CONCEPTUAL SUMMARY
Definition and Pathophysiology:
CML is a myeloproliferative disorder defined by the t(9;22) translocation — the Philadelphia chromosome (Ph+) — which produces the BCR::ABL1 fusion gene present in more than 95% of CML cases. The resulting fusion protein is a constitutively active tyrosine kinase that drives cytokine-independent proliferation and blocks apoptosis. The most common fusion protein is p210 (CML); p190 is associated with Ph+ ALL; p230 is rare. The Philadelphia chromosome originates in the hematopoietic stem cell and is therefore present in all myeloid lineages, B-cells, and a small proportion of T-cells.
Epidemiology and Presentation:
CML is more common in adults than children. Classic labs include markedly elevated WBC (can exceed 300×109/L), normal or elevated platelets, and variable hemoglobin. Thrombocytopenia is NOT a routine finding at diagnosis. Basophilia is universal; eosinophilia occurs in approximately 90% of cases. Symptoms include fatigue, night sweats, weight loss, early satiety, and splenomegaly. Hyperleukocytosis causing leukostasis with CNS symptoms (headache, stroke-like) is treated with hydroxyurea + allopurinol ± leukapheresis.
Phases of CML:
- Chronic phase (CP): blasts < 10%, most TKI-responsive.
- Accelerated phase (AP): blasts 10–19%, goal is to induce back to chronic phase.
- Blast crisis (BP): blasts ≥ 20%, AML-like or ALL-like, poorest prognosis.
Risk Scoring Systems:
The Sokal score uses spleen size, blast %, age, and platelet count only — no basophils or eosinophils. The Hasford score adds basophils and eosinophils to the Sokal variables. The EUTOS score uses only basophil % and spleen size. The ELTS score is the current preferred score with low, intermediate, and high risk categories.
Treatment Response Milestones (ELN 2020): The gold standard at 12 months is CCyR (complete cytogenetic response = 0% Ph+). MMR (major molecular response) = BCR-ABL ≤ 0.1%. A warning at 3 months means BCR-ABL > 10% — continue TKI and reassess at 6 months; do NOT switch yet. Failure at any milestone requires BCR::ABL1 mutational analysis before switching.
First-Line TKI Selection:
For low-risk CP-CML, imatinib, dasatinib, nilotinib, or bosutinib are all acceptable. For intermediate/high-risk CP-CML, second-generation TKIs (dasatinib, nilotinib, bosutinib) are Category 1 preferred. Key comorbidity rules: avoid dasatinib in COPD/pulmonary disease (pleural effusion risk ~70%) and atrial fibrillation; use only imatinib in patients on PPIs who cannot switch; use interferon alfa in pregnancy; prefer second-generation TKIs in younger women for faster deep response and TFR potential.
TKI Administration Rules: Imatinib is taken with food and a large glass of water — no PPI restriction, 400 mg daily in CP. Nilotinib is the ONLY TKI dosed twice daily and must be taken on an empty stomach — avoid PPIs. Dasatinib is taken once daily, 100 mg in CP and 140 mg in AP/BP — avoid PPIs. Bosutinib is taken with food once daily at 400 mg in CP — avoid PPIs. Ponatinib is taken once daily at 45 mg; reduce to 15 mg when BCR-ABL ≤ 1% — FDA black box for vascular occlusion.
T315I Gatekeeper Mutation: Occurs in approximately 15% of imatinib-resistant patients. Confers resistance to ALL first- and second-generation TKIs. Treatment of choice is ponatinib (third-generation TKI). Alternative is omacetaxine (acts independently of BCR-ABL binding). The ultimate option is allogeneic HSCT.
Blast Crisis Management: Treatment of choice is allogeneic HSCT. Bridge to transplant uses dasatinib 140 mg daily or ponatinib. TKI + high-dose chemotherapy before transplant improves outcomes. Autologous HSCT has NO role in any phase of CML.
Treatment-Free Remission (TFR): Criteria require chronic phase only (no prior AP/BP), TKI therapy ≥ 3–5 years, and stable MR4 or better (BCR-ABL ≤ 0.01%) for ≥ 2 years. TFR requires MR4, NOT just MMR (≤ 0.1%).
PRACTICE QUESTIONS — CML
PK is a 65-year-old female with a history of chronic obstructive pulmonary disease, psoriasis, and seasonal allergies. Her blood work reveals WBC of 94,000 cells/mm³, platelets of 197,000 cells/mm³, and Hgb of 13.1 g/dL. Cytogenetic analysis is positive for t(9;22), confirming chronic phase CML. She is considered intermediate-risk according to her ELTS score. Given this information, which of the following is the most appropriate initial therapy for PK?
A. Imatinib
B. Bosutinib
C. Ponatinib
D. Dasatinib
Explanation: For intermediate-risk CP-CML, second-generation TKIs are recommended— bosutinib, dasatinib, or nilotinib. Second-generation TKIs achieve faster and deeper molecular responses compared to imatinib. PK has a history of COPD, which is the deciding comorbidity factor. Dasatinib is associated with pleural effusions (~70%) and pulmonary arterial hypertension, making it inappropriate for a patient with underlying pulmonary disease. Bosutinib is the safest second-generation TKI for pulmonary patients. Imatinib is not Category 1 for intermediate-risk disease. Ponatinib is reserved for patients who have failed at least two prior TKIs or harbor the T315I mutation.
[/expand]PK is started on bosutinib 400 mg PO daily. After 12 months of therapy, she has not achieved a complete cytogenetic response. Drug interactions and non-adherence with therapy have been ruled out. What is the most appropriate intervention for PK at this point in time?
A. Increase bosutinib to twice daily
B. Change to high-dose imatinib
C. Order BCR::ABL mutational analysis
D. Change to asciminib
Explanation: Failure to achieve CCyR within 12 months classifies the response as TKI-resistant disease — the failure category in consensus guidelines. Before switching therapy, BCR::ABL kinase domain mutational analysis must be performed because identifying a specific mutation is critical to selecting the next TKI. For example, the T315I mutation would render all first- and second-generation TKIs ineffective, necessitating ponatinib or asciminib. Increasing bosutinib to twice daily has no clinical evidence of benefit in CP-CML. Switching back to imatinib from a second-generation TKI is inappropriate — never switch backward to a first-generation agent. Asciminib is indicated for patients who have failed two or more TKIs; since PK has failed only one TKI and her mutational status is unknown, testing must precede agent selection.
[/expand]Which of the following counseling points regarding any TKI therapy for CML would be most important to stress to PK during your discussions with her?
A. Food does not impact the effectiveness of TKIs
B. She can miss one dose of TKI per week without a difference in treatment outcome
C. TKIs should be taken once daily to maintain serum steady state concentration
D. TKIs may be discontinued if MMR is sustained for 2 years
Explanation: Treatment-free remission (TFR) is a key counseling point — advances in TKI therapy have made cessation of therapy a realistic goal for eligible patients. Outside of a clinical trial, patients may consider stopping their TKI if they meet specific criteria including being at least 18 years old, no history of advanced-phase disease, TKI therapy for at least 3–5 years, and maintaining a stable deep molecular response (MR4 or better, BCR-ABL ≤ 0.01%) for at least 2 years. Food significantly impacts several TKIs: nilotinib must be taken on an empty stomach; bosutinib and imatinib should be taken with food. Missing doses is dangerous — adherence ≤ 85% carries a 27% probability of losing CCyR within 2 years versus only 1.5% with > 85% adherence. Not all TKIs are dosed once daily — nilotinib must be taken twice daily.
[/expand]VM is a 46-year-old male diagnosed with Ph+ CP-CML four years ago with no genetic mutations. He failed imatinib, then developed a pleural effusion on dasatinib, and cannot take nilotinib due to a major drug interaction. His most recent bloodwork revealed t(9;22) plus trisomy 8 and isochromosome 20q, confirming conversion to accelerated phase. What is the most appropriate therapy for VM at this point in time?
A. Interferon alfa
B. Omacetaxine
C. Ponatinib
D. Allogeneic stem cell transplantation
E. Autologous stem cell transplantation
Explanation: VM has failed or is intolerant to three TKIs (imatinib, dasatinib, nilotinib). Omacetaxine is recommended for patients who progress to accelerated phase due to resistance or intolerance to two or more TKIs. Its antileukemic effect is independent of BCR-ABL binding — it acts as a reversible ribosomal protein synthesis inhibitor — making it active in patients resistant to multiple TKIs. The primary goal in AP-CML is to induce the patient back into a second chronic phase. Interferon alfa has no standard role in current practice except in pregnancy. Ponatinib for AP-CML is generally reserved for patients with the T315I mutation, which VM does not have. Allogeneic HSCT should be considered after the patient is induced back into a second chronic phase — it is not the immediate first intervention. Autologous HSCT has NO role in any phase of CML.
[/expand]LP is a 42-year-old female who takes no medications. Her blood work reveals WBC of 94,000 cells/mm³, platelets of 197,000 cells/mm³, and Hgb of 13.1 g/dL. Cytogenetic analysis is positive for t(9;22), confirming chronic phase CML. She is considered intermediate-risk according to her ELTS score. Which of the following is the most appropriate initial therapy for LP?
A. Imatinib
B. Bosutinib
C. Ponatinib
D. Allogeneic stem cell transplant
Explanation: For intermediate-risk CP-CML, the NCCN Guidelines provide a Category 1 recommendation for second-generation TKIs. Bosutinib, dasatinib, and nilotinib all achieve faster and deeper molecular responses than imatinib. For a younger woman such as LP, second-generation TKIs are preferred to achieve a rapid deep molecular response, which is a prerequisite for potentially discontinuing therapy for family planning. LP has no comorbidities that would favor one second-generation TKI over another — bosutinib is an appropriate first choice. Imatinib is not Category 1 for intermediate-risk disease. Ponatinib is reserved for patients who have failed at least two prior TKIs or harbor the T315I mutation. Allogeneic HSCT is a second- or third-line intervention or is used for advanced-phase disease.
[/expand]LP is started on bosutinib 400 mg PO daily. After 12 months of therapy, she has not achieved a complete cytogenetic response. Drug interactions and non-adherence have been ruled out. What is the most appropriate second-line treatment for LP at this point in time?
A. Increase bosutinib to twice daily
B. Change to high-dose imatinib
C. Change to dasatinib
D. Change to ponatinib
Explanation: When a second-generation TKI is used in the first-line setting and the patient fails to achieve CCyR at 12 months, the appropriate next step is to switch to an alternate second-generation TKI. Dasatinib or nilotinib are appropriate second-line options after bosutinib failure. Increasing bosutinib to twice daily has no clinical evidence of benefit in CP-CML. Switching from a second-generation TKI back to imatinib (even at high dose) is inappropriate — never switch backward. Ponatinib is a third-generation TKI generally reserved for patients who have failed or are intolerant to at least two prior TKIs or who harbor the T315I mutation. Before initiating dasatinib, BCR::ABL1 mutational analysis should be performed to confirm no resistance mutations are present.
[/expand]LP's therapy is changed from bosutinib to dasatinib. Which of the following counseling points regarding any TKI therapy for CML would be important to stress to LP during your discussion with her?
A. Food does not impact the effectiveness of TKIs
B. Adherence with TKI therapy is directly associated with outcome
C. TKIs should be taken once daily to maintain serum steady state concentration
D. TKIs will be discontinued if MMR is sustained for 2 years
Explanation: Adherence is the single most critical factor in the successful management of CML and the only independent predictor for achieving a complete molecular response on standard-dose therapy. Patients with an adherence rate ≤ 85% have a 27% probability of losing their CCyR within two years, compared to only 1.5% for those with an adherence rate > 85%. Nearly 30% of CML patients are non-adherent — counseling on this is essential, especially when the patient is asymptomatic. Food significantly impacts several TKIs: nilotinib must be taken on an empty stomach; imatinib and bosutinib should be taken with food. Not all TKIs are dosed once daily — nilotinib must be taken twice daily. The criteria for TFR require a stable MR4 (BCR-ABL ≤ 0.01%) for at least 2 years, not just MMR (≤ 0.1%) — making option D less precise than option B.
[/expand]A 41-year-old male was recently diagnosed with chronic phase Ph+ CML. He has a prior history of GERD, for which he takes pantoprazole 20 mg PO once daily. H2 blockers and antacids do not work for him, and he has found that only pantoprazole adequately controls his GERD. Which one is the best TKI agent to start for this patient?
[expand] Answer: 1. Imatinib 400 mg dailyExplanation: The primary factor determining TKI selection here is the patient's concurrent use of pantoprazole, a PPI, which cannot be substituted. Dasatinib, nilotinib, and bosutinib all have pH-dependent absorption that is severely compromised by acid-reducing agents, including PPIs — these drugs must be avoided altogether in patients requiring PPIs. Imatinib does not have a listed restriction regarding PPI use, making it the only appropriate TKI for this patient. The standard first-line dose for CP-CML is imatinib 400 mg PO daily, taken with food and a large glass of water to improve tolerability.
[/expand]TK is a 52-year-old female who presents with symptoms consistent with the diagnosis of CML. Cytogenetic work-up has been ordered. Which of the following cytogenetic abnormalities is most likely in TK?
- Translocation 9;22
- Translocation 8;21
- Translocation 4;14
- Translocation 15;17
Explanation: CML is defined by the t(9;22) translocation — the Philadelphia chromosome — which results in the juxtaposition of the ABL1 gene from chromosome 9 and the BCR gene from chromosome 22. The resulting BCR::ABL1 fusion protein produces a constitutive proliferative signal leading to continuous cell cycling and lack of apoptosis. Up to 95% of CML patients possess this fusion gene at diagnosis. The other translocations are hallmarks of other malignancies: t(15;17) is the hallmark of APL; t(8;21) is common in AML; t(4;14) is a high-risk marker in multiple myeloma.
[/expand]A 50-year-old female on imatinib for 12 months for CML diagnosis now has disease progression to blast phase CML. Her oncologist ordered a BCR-ABL mutation panel and found her to be T315I mutation positive. Which CML agent would be the best for this patient at this time?
A. Dasatinib
B. Bosutinib
C. Ponatinib
D. Omacetaxine
Explanation: The T315I "gatekeeper" mutation replaces threonine with isoleucine in the ATP-binding pocket of BCR-ABL1, creating steric hindrance that prevents most TKIs from binding effectively. This mutation confers resistance to ALL first-generation (imatinib) and second-generation TKIs including dasatinib and bosutinib — making those options clinically ineffective. Ponatinib is a third-generation TKI specifically designed to be active against the T315I mutation and is the preferred treatment in any phase of disease with this mutation. In blast phase, a TKI should be combined with high-dose combination chemotherapy. While omacetaxine acts independently of BCR-ABL binding and has activity against T315I, ponatinib is explicitly designated as the preferred pharmacologic agent for T315I-mutated disease. When initiating ponatinib, monitor closely for cardiovascular risks — the FDA has issued black box warnings for life-threatening blood clots and vascular occlusion. The recommended starting dose is 45 mg PO daily, reduced to 15 mg when BCR-ABL ≤ 1%.
[/expand]Which agent is a first-line option for a newly diagnosed chronic phase CML in a 52-year-old woman with a WBC < 20,000/mm³?
A. Rituximab
B. Busulfan
C. Dasatinib
D. Interferon
Explanation: Dasatinib is a second-generation TKI with an NCCN Category 1 recommendation for first-line treatment of CP-CML across all risk groups. The DASISION trial demonstrated faster and deeper cytogenetic and molecular responses compared to imatinib. For a younger patient like this 52-year-old woman, a second-generation TKI may be preferred to achieve rapid deep molecular response — a prerequisite for attempting TFR in the future. Rituximab is a monoclonal antibody used in CLL and NHL but has no role in CML management. Busulfan is a historical alkylating agent replaced by TKI therapy due to inferior outcomes and transplant complications. Interferon has no standard role in current CML management except during pregnancy.
[/expand]If a patient presents with CNS symptoms such as severe headaches or stroke-like symptoms from leukocytosis, which type of leukemia would they most likely have if treated with hydroxyurea, allopurinol, and leukapheresis?
A. ALL
B. CLL
C. CML
D. Plasma cell leukemia
Explanation: The triad of hydroxyurea (rapid cytoreduction), allopurinol (prevents tumor lysis syndrome), and leukapheresis (mechanical WBC removal) is the classic management approach for CML with hyperleukocytosis. CML patients can present with WBC counts exceeding 100–300 × 109/L. Immature myeloid blasts in CML are large, rigid, and adhesive — they physically occlude cerebral microvasculature, causing CNS symptoms including severe headaches and stroke-like symptoms. CLL causes leukostasis only rarely because mature lymphocytes are small and deformable and do not plug microvasculature the way immature myeloid cells do. ALL can cause leukostasis but lymphoblasts are less viscous; hydroxyurea is not a primary agent in ALL. Plasma cell leukemia causes hyperviscosity via immunoglobulins — a different mechanism from leukostasis.
[/expand]Tyrosine kinase inhibitors (TKIs) have changed how we manage patients with CML. Interferon-based therapy is no longer standard practice. Which of the following agents are appropriate to consider as first-line treatment options for patients with CML?
A. Nilotinib, dasatinib, sorafenib
B. Sorafenib, sunitinib, imatinib
C. Imatinib, nilotinib, dasatinib
D. Imatinib, dasatinib, sunitinib
Explanation: The established first-line TKIs for CP-CML are imatinib (first-generation, Category 1 for low-risk), dasatinib (second-generation, Category 1 for all risk groups), nilotinib (second-generation, Category 1 for all risk groups), and bosutinib (second-generation, Category 1 — not listed in options). Sorafenib and sunitinib are multi-kinase inhibitors used in solid tumors but they do not inhibit BCR-ABL and have no role in CML management. The available TKIs for CML are specifically restricted to imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and asciminib.
[/expand]A 62-year-old white female with suspected leukemia comes to the hospital. Labs: WBC = 72.2, Hgb = 8.1, Hct = 24.7, Platelets = 333, Uric Acid = 12.9, LDH = 1933. Symptoms include weight loss over the past 6 months with occasional fevers at night. Which drug is preferred for maintenance treatment of this disease?
A. Tretinoin
B. Imatinib
C. Sunitinib
D. Interferon-alfa
Explanation: The patient's presentation — significant leukocytosis (WBC 72.2 k/mm³), anemia (Hgb 8.1 g/dL), and constitutional symptoms (weight loss and fevers) — is highly characteristic of CML. The extremely high LDH and uric acid are markers of high cell turnover consistent with a large myeloid tumor burden. Imatinib is a first-generation TKI specifically designed to target the BCR-ABL1 fusion protein — the hallmark oncogene of CML. In CML management, the goal of continuous TKI therapy is to achieve and maintain hematologic, cytogenetic, and molecular remission, which is established by the landmark IRIS trial. Tretinoin is used for APL, not CML. Sunitinib is a multi-kinase inhibitor not used in CML. Interferon-alfa is a historical treatment now reserved only for CML during pregnancy.
[/expand]Cytogenetics were completed on the peripheral blood of a patient, which eventually demonstrated a t(9;22). What disease is typically seen with this chromosomal abnormality?
A. Chronic lymphocytic leukemia
B. Plasma cell leukemia
C. Acute promyelocytic leukemia
D. Chronic myelogenous leukemia
Explanation: The t(9;22) translocation — the Philadelphia chromosome — is the diagnostic hallmark of CML. This reciprocal translocation between chromosomes 9 and 22 results in the BCR::ABL1 fusion gene, which produces a constitutively active tyrosine kinase that drives CML pathogenesis. Up to 95% of CML patients possess this fusion gene at diagnosis. CLL involves cytogenetic changes such as del(13q), del(11q), trisomy 12, and del(17p) — not t(9;22). APL is defined by t(15;17). Plasma cell leukemia involves plasma cell proliferation with different cytogenetic profiles.
[/expand]CD is a 59-year-old patient diagnosed with chronic phase CML. She was started on imatinib about 16 months ago. Today she has BCR-ABL FISH result confirming progression on imatinib. Her oncologist has decided to change her therapy to dasatinib. Which of the following is the most appropriate dosing of dasatinib?
A. 70 mg twice daily
B. 50 mg twice daily
C. 100 mg once daily
D. 140 mg once daily
Explanation: CD is diagnosed with chronic phase CML (CP-CML). The established dose for dasatinib in the chronic phase is 100 mg PO once daily. It is critical to distinguish between doses used for different phases: 100 mg once daily is the standard for chronic phase, while 140 mg once daily is preferred for the accelerated phase. Historical dosing included twice-daily regimens such as 70 mg BID, but current standards favor once-daily dosing — twice-daily dosing is actually a risk factor for the development of pleural effusions, a common adverse effect of dasatinib.
[/expand]Which of the following statements is true concerning CML?
A. It is more common in children than adults
B. The presence of t(9;22) is diagnostic for CML
C. Bone marrow transplantation is not curative
D. Patients routinely have thrombocytopenia on diagnosis
Explanation: CML is defined by the t(9;22) translocation — the Philadelphia chromosome — and cytogenetic analysis positive for t(9;22) is used to confirm the diagnosis. CML is a disease of adults, not more common in children. Allogeneic HSCT is considered a recommended treatment for patients in advanced phases or those who fail TKI therapy and is potentially curative. Thrombocytopenia is NOT a routine finding at CML diagnosis — platelet counts are typically normal or elevated, as evidenced by patients PK and LP who both presented with platelets of 197,000 cells/mm³. The Sokal and Hasford risk scores use platelet count as a variable, reflecting that counts can be high or low.
[/expand]The treatment of choice for CML blast crisis is:
A. Imatinib 800 mg once daily
B. Dasatinib 70 mg twice daily
C. Cytarabine plus interferon
D. Allogeneic stem cell transplantation
Explanation: Allogeneic HSCT is the treatment of choice for CML blast crisis. Evaluation for allogeneic HSCT is recommended for all patients who present with or progress to blast crisis. The ultimate goal is to bridge the patient to transplant once a second chronic phase is achieved using a TKI in combination with high-dose induction chemotherapy. Without definitive intervention, median survival in blast crisis is only 6–12 months. Imatinib 800 mg is specifically listed as a recommendation for the accelerated phase, not blast crisis, where a second- or third-generation TKI is preferred. Dasatinib 70 mg twice daily is historical dosing — current guidelines prefer 140 mg once daily for advanced phase disease, and twice-daily dosing increases pleural effusion risk. Cytarabine plus interferon is a historical regimen evaluated in the IRIS trial and has been replaced by TKI-based therapy.
[/expand]Treatment of a patient with the T315I mutation includes which of the following?
A. Imatinib 800 mg
B. Nilotinib 400 mg twice daily
C. Dasatinib 70 mg twice daily
D. Allogeneic stem cell transplantation
Explanation: Based on the options provided, allogeneic stem cell transplantation is the correct answer. The T315I mutation confers resistance to imatinib, dasatinib, nilotinib, and bosutinib — making options A, B, and C clinically ineffective. Allogeneic HSCT should be considered for patients with TKI-resistant disease, and the T315I mutation is a specific indication for transplant evaluation. While ponatinib is the preferred pharmacologic treatment for T315I-mutated disease and is not listed among the choices here, allogeneic HSCT remains the standard curative approach in the absence of effective TKI options. Asciminib and omacetaxine are also alternatives not listed.
[/expand]True about CML are all EXCEPT:
A. Basophilia is universal
B. Eosinophilia is seen in about 90% of cases
C. Fusion protein p190 is most common, though p210 is also seen in some cases
D. All of the above
Explanation: This statement is false — the relationship is exactly the opposite. The most common BCR::ABL1 fusion protein in CML is p210, not p190. The p210 form contains the active tyrosine kinase region of ABL1 and is the hallmark transcript for the vast majority of CML cases. p190 is associated primarily with Ph+ ALL, not CML. Basophilia is universal in CML and eosinophilia is present in approximately 90% of cases — both statements A and B are true. Because option C is the false statement, it is the correct answer for "all except."
[/expand]The Sokal score for CML includes all EXCEPT:
A. Spleen size
B. Blast percent
C. Basophil percent
D. Age
E. Platelet count
Explanation: The Sokal score is calculated using only four clinical variables: patient age, spleen size, platelet count, and percentage of blasts in the peripheral blood. Basophil percent is NOT included in the Sokal score. It is the Hasford model (EuroSCORE) that adds eosinophils and basophils to the same four Sokal variables. The ELTS score also uses age, spleen size, platelet count, and blast percentage but weights these criteria differently. The memory hook is: Sokal = Spleen, Blasts, Age, Platelets only — Hasford adds Basophils + Eosinophils.
[/expand]Imatinib is capable of inhibiting which of the following?
A. Tyrosine kinase
B. c-KIT
C. Platelet-derived growth factor receptor
D. All of the above
Explanation: Imatinib inhibits BCR-ABL1 tyrosine kinase, c-KIT, and platelet-derived growth factor receptor (PDGFR). Because of its inhibition of c-KIT and PDGFR in addition to BCR-ABL, imatinib is also used in the treatment of malignancies where these targets are overexpressed, such as gastrointestinal stromal tumors (GIST). This broad spectrum of tyrosine kinase inhibition distinguishes imatinib from being purely a CML-specific agent.
[/expand]A pregnant patient with CML should be treated with:
A. Imatinib
B. Nilotinib
C. Dasatinib
D. Interferon
Explanation: All TKIs — imatinib, nilotinib, dasatinib, and bosutinib — are contraindicated during pregnancy due to teratogenicity. Interferon alfa is the only agent with a current standard role in the management of CML during pregnancy. It does not cross the placenta and has demonstrated approximately 70% 10-year survival in low Sokal risk patients. The management of young women with CML often prioritizes achieving a rapid and deep molecular response with TKIs so that they can eventually discontinue therapy for family planning — with the understanding that if pregnancy occurs, interferon alfa will be used.
[/expand]The Hasford system is related to:
A. Hodgkin's disease
B. NHL
C. CML
D. Cutaneous lymphoma
Explanation: The Hasford system (also known as the Hasford model or EuroSCORE) is a prognostic risk stratification tool used specifically for patients with CML. It uses the same four variables as the Sokal score — age, spleen size, platelet count, and percentage of blasts — but additionally includes the percentages of eosinophils and basophils. Patients are stratified into low, intermediate, or high risk groups. While contemporary references advocate for the more modern ELTS score, the Hasford and Sokal scores remain established systems for CML initial treatment selection and clinical trial stratification.
[/expand]The following are common side effects of imatinib, EXCEPT:
A. Skin rashes
B. Leg edema
C. Diarrhea
D. Renal dysfunction
Explanation: Imatinib's common toxicities include skin rash (managed with topical or systemic steroids), fluid retention/edema (particularly periorbital edema, but also pleural effusion and ascites — managed with loop diuretics), and diarrhea. Renal dysfunction is NOT a side effect caused by imatinib. It is a pre-existing condition that must be monitored — dose reductions are required for patients who have baseline renal impairment, but imatinib does not cause renal dysfunction. Additional notable imatinib toxicities include nausea, muscle cramps, bone pain, and elevated LFTs. Notably, imatinib does NOT cause hair loss (alopecia) — a common exam distinction.
[/expand]In CML, the BCR-ABL transcript seen most commonly is:
A. p230
B. p190
C. p210
D. p240
Explanation: The most common BCR::ABL1 fusion protein in CML is p210. This p210 form contains the active tyrosine kinase region of ABL1. While normal ABL1 carefully regulates cell proliferation and survival, the p210 fusion protein produces a constitutive, cytokine-independent proliferative signal — the hallmark feature of CML pathogenesis leading to continuous cell cycling, altered differentiation, and loss of apoptosis. The p190 transcript is associated primarily with Ph+ ALL. The p230 transcript is associated with a rare variant of CML called neutrophilic CML. p240 is not a recognized CML transcript.
[/expand]In CML, the Philadelphia chromosome is present in:
A. Myeloid cells
B. B-lymphocytes
C. T-lymphocytes
D. All of the above
Explanation: CML results from an acquired mutation — the t(9;22) translocation — that affects hematopoietic stem cells (HSCs). Because the Philadelphia chromosome originates in the multipotent HSC, which is the common ancestor for all blood cell lineages, it is passed down to all progeny including myeloid cells, B-lymphocytes, and T-lymphocytes. This is clinically evidenced by the lymphoid variant of blast crisis (BP-CML), where the disease transforms into a Ph+ acute leukemia that behaves like ALL and requires induction regimens similar to those used for ALL. The Ph+ mutation is therefore present in myeloid cells, B-cells, and a small proportion of T-cells.
[/expand]Imatinib acts by which of the following mechanisms?
A. Phosphorylation
B. Dephosphorylation
C. Demethylation
D. Methylation
Explanation: Imatinib is an ABL1 tyrosine kinase inhibitor that binds to and occupies the ATP-binding pocket of the ABL1 kinase component of the BCR-ABL1 protein. By acting as a synthetic ATP mimic — displacing ATP from the binding pocket — it blocks the enzyme's capacity to phosphorylate downstream effector molecules. The result is dephosphorylation of downstream targets, which blocks the proliferative signal driving CML. Imatinib rapidly reverses clinical and hematological abnormalities and induces major cytogenetic responses in over 80% of previously untreated CML chronic-phase patients.
[/expand]All are side effects of imatinib therapy EXCEPT:
A. Edema
B. Hair loss
C. Rashes
D. Bone pains
Explanation: Hair loss (alopecia) is NOT a side effect of imatinib and is not listed in the comprehensive toxicity tables for this agent. Edema (particularly periorbital edema) is a hallmark side effect of imatinib — a key distinguishing feature from other TKIs. Rash is listed as a unique toxicity for imatinib, managed with topical or systemic steroids. Bone pain and musculoskeletal pain are also frequently associated with imatinib, along with hypophosphatemia and associated changes in bone and mineral metabolism. The absence of hair loss and renal dysfunction are important distinguishing features of imatinib's toxicity profile.
[/expand]SN is a 55-year-old woman with medium-risk CML. She was started on dasatinib 100 mg daily 3 months ago and underwent assessment. Her TLC = 8,000/mm³, PLTs = 200,000/mm³, BCR-ABL1 = 20%, and 65% Ph+ metaphases of baseline value. Which of the following is correct?
- We should start a different TKI immediately
- Continue on dasatinib 400 mg and monitor response 3 months later; if she lost CHR, BCR-ABL > 10%, or Ph+ metaphases > 35%, start a different TKI
- CCyR should be achieved at 6 months maximum
- Continue on dasatinib 400 mg and monitor response 3 months later; if BCR-ABL > 10% or Ph+ metaphases > 65%, start a different TKI
- CCyR should be achieved at 12 months maximum
Explanation: At 3 months, SN has achieved a CHR (TLC and platelets within normal range) but has BCR-ABL1 of 20% (goal ≤ 10%) and 65% Ph+ metaphases. Per ELN guidelines, BCR-ABL > 10% at 3 months is classified as a "warning" — not failure — meaning the clinician should evaluate adherence and drug interactions or perform mutational analysis before deciding to switch, but should NOT switch immediately. The gold standard milestone is CCyR (0% Ph+ metaphases) within 12 months — this is the definitive deadline most strongly associated with improved long-term survival. Options B and D are pharmacologically incorrect because the established dose for dasatinib in chronic phase is 100 mg daily, not 400 mg — 400 mg is the standard imatinib dose. Increasing the dose of a second-generation TKI for an inadequate response is also not supported. CCyR at 6 months is achievable but 12 months is the established gold standard milestone.
[/expand]SECTION 2: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
CONCEPTUAL SUMMARY
Definition and Overview: CLL is an indolent B-cell malignancy characterized by the progressive accumulation of small, mature-appearing lymphocytes in the peripheral blood, bone marrow, spleen, and lymph nodes. It is primarily a geriatric disease with a median age at diagnosis of 72 years. CLL is currently INCURABLE — patients will universally relapse after primary treatment. Survival ranges from 1 to 20 years. Richter's transformation — transformation into aggressive NHL (usually DLBCL) — occurs in 2–16% of patients with a median survival of 8–12 months.
Staging: Rai staging ranges from Stage 0 (lymphocytosis only, lowest risk) to Stage IV (lymphocytosis + thrombocytopenia, highest risk). Binet staging: Stage A (< 3 lymphoid areas involved), Stage B (≥ 3 lymphoid areas), Stage C (anemia and/or thrombocytopenia).
Prognostic Factors: Poor prognosis markers include unmutated IGHV (≤ 2% mutated), del(17p)/TP53 mutation (ultra-high risk; resistant to chemoimmunotherapy), del(11q), ZAP-70 ≥ 20%, CD38 ≥ 30%, CD49D ≥ 30% (strongest single predictor of OS and treatment-free survival among flow cytometry markers), and high β-2-microglobulin. Favorable prognosis markers include mutated IGHV (> 2%), del(13q14) as a SOLE abnormality (BEST prognosis — NOT adverse, a common exam trap), and low β-2-microglobulin.
Indications for Treatment:
- Watch and wait is the standard for asymptomatic early-stage disease (Rai stage 0, Binet stage A) — there is NO survival benefit from early treatment. Treatment is indicated for progressive marrow failure, massive or symptomatic lymphadenopathy/splenomegaly, lymphocyte doubling time < 6 months or ≥ 50% increase in ALC over 2 months, or disease-related symptoms.
First-Line Treatment:
- Acalabrutinib ± obinutuzumab (Category 1 preferred, continuous therapy; preferred if patient has CKD or age ≥ 65).
- Zanubrutinib (Category 1 preferred; fewer cardiac effects than ibrutinib, preferred BTKi in patients with pre-existing AF).
- Venetoclax + obinutuzumab (Category 1 preferred; fixed-duration ~1 year; best for patients wanting time-limited therapy; also preferred in patients with cardiac comorbidities).
- FCR is ONLY for young (< 65–70), fit, mutated IGHV patients without CKD or del(17p)/del(11q).
- Ibrutinib has been moved to "other recommended" due to cardiac toxicities (AF up to 16%).
- Alemtuzumab in first-line is ONLY for del(17p) patients — NOT without del(17p).
Relapsed/Refractory CLL:
- Venetoclax + rituximab (Category 1; MURANO trial; fixed-duration 2 years; preferred in patients with AF or cardiac comorbidities).
- Acalabrutinib, zanubrutinib (continuous). Pirtobrutinib (non-covalent BTKi; overcomes resistance to prior covalent BTKi). Repeat FCR at relapse is NOT preferred. Bendamustine + rituximab + idelalisib is NOT recommended (toxicity concerns).
Key Drug Toxicities: Ibrutinib: most common toxicity is minor bleeding (up to 66%); AF in up to 16%; hypertension in > 75% over 30 months; NOT associated with TLS or periorbital edema. Acalabrutinib: most common toxicity is headache (up to 40%); hypertension ~3%; NOT associated with TLS. Zanubrutinib: similar to ibrutinib but fewer cardiac effects; AF rate 2.5% vs ibrutinib 10.1%. Venetoclax: major toxicity is TLS (potentially fatal); 5-week ramp-up required; TLS prophylaxis mandatory. Idelalisib: severe diarrhea/colitis (~10% grade ≥ 3); black box warnings for hepatotoxicity, severe diarrhea/colitis, pneumonitis, intestinal perforation; available through REMS program; causes redistribution lymphocytosis (same as ibrutinib — it is FALSE to say idelalisib does NOT cause lymphocytosis). Both ibrutinib AND idelalisib cause treatment-induced lymphocytosis — does NOT signify disease progression.
Supportive Care: PJP prophylaxis (SMX-TMP): required for purine analogs, bendamustine, idelalisib, duvelisib, alemtuzumab — NOT required for acalabrutinib or zanubrutinib alone. Acyclovir: herpes prophylaxis for idelalisib and alemtuzumab patients. Shingrix (recombinant zoster vaccine) is recommended for BTKi patients and treatment-naive CLL — Zostavax (live vaccine) is STRICTLY AVOIDED. IVIG: only if IgG < 500 mg/dL AND recurrent sinopulmonary infections ≥ 2 in 6 months requiring IV antibiotics — NOT routine.
Richter's Transformation: Rapid-onset (days to weeks) bulky lymphadenopathy, fevers, splenomegaly, and weight loss — typically within first 1–2 years of BTKi treatment. Ibrutinib/zanubrutinib resistance onset is INSIDIOUS — key distinction. Redistribution lymphocytosis is an EARLY treatment effect (peaks week 2, resolves by week 12) — would NOT occur after 18 months of BTKi therapy.
ITP Treatment Ladder: First-line: corticosteroids. Second-line: IVIG (rapid platelet rise) or rituximab. Third-line: cyclosporine, thrombopoietin agents (romiplostim, eltrombopag, avatrombopag), fostamatinib.
Venetoclax TLS Risk and Monitoring: HIGH risk = any node ≥ 10 cm OR (ALC ≥ 25 × 10⁹/L AND any node ≥ 5 cm) → inpatient monitoring at 20 mg and 50 mg doses, then outpatient pre-dose, 6–8h, and 24h for subsequent dose escalations.
PRACTICE QUESTIONS — CLL
JF is a retired 68-year-old male with a history of chronic kidney disease, hypertension, and hypercholesterolemia. Flow cytometry confirmed the diagnosis of CLL. He is diagnosed with Binet stage B disease. His cytogenetic analysis reveals del(13q) mutation and unmutated IGHV. He is medically fit to receive treatment and is interested in receiving a regimen that can be completed in a short amount of time. Given this information, which of the following treatment regimens is the most appropriate first-line therapy for JF?
A. Acalabrutinib
B. Chlorambucil + ofatumumab
C. Fludarabine, cyclophosphamide and rituximab (FCR)
D. Venetoclax + obinutuzumab
Explanation: JF specifically requested a regimen that can be completed in a short amount of time. While acalabrutinib is a Category 1 preferred first-line option, it must be taken continuously until disease progression. In contrast, venetoclax + obinutuzumab is a fixed-duration regimen completed in approximately one year — specifically addressing his preference. JF is over 65 with CKD, making him ineligible for FCR since creatinine clearance is the primary predictor of fludarabine toxicity. Venetoclax + obinutuzumab is a Category 1 preferred regimen that has demonstrated superior PFS in patients with unmutated IGHV and other high-risk markers. Ofatumumab is no longer recommended for CLL in any line of therapy.
[/expand]JF will be receiving venetoclax + obinutuzumab for his newly diagnosed CLL. Which of the following statements about venetoclax is correct?
A. Pancreatitis is common
B. Tumor lysis syndrome prophylaxis is required
C. Lower extremity edema often occurs
D. Visual changes are frequent
Explanation: TLS is a potentially deadly adverse effect of venetoclax due to its high potency and rapid induction of tumor cell death. All patients starting venetoclax must follow a 5-week stepwise ramp-up schedule (20 → 50 → 100 → 200 → 400 mg daily) and must receive TLS prophylaxis including oral hydration (1.5–2 L) and allopurinol initiated 2–3 days before the first dose. JF has an ALC of 27,000 cells/mm³ placing him at medium risk — outpatient monitoring with blood chemistry checks is required. Pancreatitis is associated with nilotinib and ponatinib in CML — not venetoclax. Lower extremity edema is more commonly associated with imatinib (periorbital edema). Visual changes are not common adverse effects of venetoclax.
[/expand]JF is a retired 68-year-old male with CKD, hypertension, and hypercholesterolemia. Flow cytometry confirmed CLL. He is diagnosed with Binet stage B disease. His cytogenetic analysis reveals del(13q) and unmutated IGHV. He is medically fit to receive treatment (no time-limited preference specified in this version).
Which of the following treatment regimens is the most appropriate first-line therapy for JF?
A. Acalabrutinib +/- obinutuzumab
B. Chlorambucil + ofatumumab
C. Fludarabine, cyclophosphamide and rituximab (FCR)
D. Alemtuzumab + rituximab
Explanation: For patients aged 65 or older with significant comorbidities such as CKD, acalabrutinib +/- obinutuzumab is a Category 1 preferred regimen. The ELEVATE-TN trial demonstrated significantly longer PFS with acalabrutinib-containing arms compared to chlorambucil + obinutuzumab. JF is 68 years old with CKD — creatinine clearance is the primary predictor of fludarabine toxicity, making him ineligible for FCR regardless of perceived fitness. His unmutated IGHV indicates more aggressive disease — targeted therapies like acalabrutinib have shown consistent benefit across high-risk subgroups including unmutated IGHV. Ofatumumab is no longer recommended for first-line CLL. Alemtuzumab is not recommended for patients without del(17p) — JF has del(13q), not del(17p).
[/expand]JF has been receiving ibrutinib for 18 months. Over the past two weeks, he has noted rapidly enlarging cervical, axillary, and inguinal lymphadenopathy. He also reports new fevers, splenomegaly, and unintentional weight loss. Which of the following is the most likely cause of JF's new complaints?
A. Richter's transformation
B. Ibrutinib resistance
C. Redistribution lymphocytosis
D. Tuberculosis infection
Explanation: The rapid onset (over just two weeks), nature, and severity of symptoms — rapidly growing lymphadenopathy, new fevers, splenomegaly, and unintentional weight loss — are hallmark signs of Richter's transformation (RT), the transformation of CLL into aggressive NHL (most commonly DLBCL). RT typically occurs within the first 1–2 years of treatment. Ibrutinib resistance does occur, but its onset is typically insidious rather than the rapid, explosive lymph node growth seen here. Redistribution lymphocytosis is an early treatment effect that peaks at week 2 and resolves by week 12 — it would NOT occur after 18 months of therapy. Tuberculosis infection is not associated with ibrutinib therapy.
[/expand]DG is a 63-year-old male with CLL with del(11q), well-controlled atrial fibrillation, hypothyroidism, and GERD. He received FCR three years ago and achieved a complete response. He has recently been diagnosed with relapsed CLL. Which of the following regimens is most appropriate for DG at this point in his course?
A. Repeat FCR
B. Chlorambucil + ofatumumab
C. Zanubrutinib
D. Bendamustine, rituximab + idelalisib
Explanation: Zanubrutinib is a Category 1 recommendation for second-line CLL and has demonstrated superior overall response rates and improved PFS compared to ibrutinib. DG has a history of atrial fibrillation — zanubrutinib has a statistically significantly lower rate of AF (2.5%) compared to ibrutinib (10.1%), making it the preferred BTKi for a patient with pre-existing cardiac rhythm issues. Del(11q) patients respond well to initial FCR but novel agents are preferred at relapse — repeating FCR is not the most appropriate choice when more effective novel therapies are available. Chlorambucil + ofatumumab is incorrect because ofatumumab is no longer recommended for CLL. Bendamustine + rituximab + idelalisib is not recommended due to toxicity concerns.
[/expand]DG has now been receiving zanubrutinib for 18 months. Over the past two weeks, he has noted rapidly enlarging cervical, axillary, and inguinal lymphadenopathy. He also reports new fevers, splenomegaly, and unintentional weight loss. Which of the following is the most likely cause of DG's new complaints?
A. Richter's transformation
B. Zanubrutinib delayed hypersensitivity reaction
C. Redistribution lymphocytosis
D. Tuberculosis infection
Explanation: The rapid onset, nature, and severity of DG's symptoms — rapid lymph node enlargement, fevers, splenomegaly, and weight loss after 18 months of BTKi therapy — are hallmark features of Richter's transformation into aggressive lymphoma (most commonly DLBCL). There are no documented reports of BTKi delayed hypersensitivity reactions. Redistribution lymphocytosis is an early treatment effect that would NOT occur after 18 months of therapy. Tuberculosis infection is not associated with zanubrutinib.
[/expand]DG is a 63-year-old male with relapsed CLL, del(11q), and atrial fibrillation. He received FCR three years ago. Which of the following regimens is most appropriate for DG at this point in his course?
A. Repeat FCR
B. Chlorambucil + obinutuzumab
C. Venetoclax + rituximab
D. Bendamustine, rituximab + idelalisib
Explanation: Venetoclax + rituximab is an NCCN Category 1 recommendation for second-line treatment of relapsed or refractory CLL. Its preferred status is based on the MURANO study, which demonstrated statistically significant improvements in both PFS and OS compared to bendamustine + rituximab. DG has atrial fibrillation — ibrutinib is associated with AF in up to 16% of patients; venetoclax-based therapy is preferred in patients with significant cardiac comorbidities to avoid exacerbating cardiac risk. Del(11q) patients initially respond well to FCR, but repeating chemoimmunotherapy at relapse is generally less effective than novel agents. Chlorambucil + obinutuzumab is a first-line option not recommended for relapsed disease. Bendamustine + rituximab + idelalisib is Category 2B and not appropriate due to toxicity concerns.
[/expand]DG is a 63-year-old male with relapsed CLL, del(11q), and atrial fibrillation. He received FCR three years ago without lenalidomide maintenance and has been on observation. He has recently been diagnosed with relapsed CLL. Which of the following regimens is most appropriate for DG at this point in his course?
A. Repeat FCR
B. Ibrutinib
C. Venetoclax + rituximab
D. Bendamustine, rituximab + idelalisib
Explanation: Venetoclax + rituximab is the Category 1 preferred recommendation for second-line relapsed/refractory CLL based on the MURANO study. DG has a history of atrial fibrillation — ibrutinib is well-documented to increase the risk of AF (up to 16%), making ibrutinib less appropriate despite being a Category 1 choice. Ibrutinib has also been moved to "other recommended" due to cardiac toxicity concerns. Venetoclax-based therapy is specifically preferred in patients with significant cardiac comorbidities. Repeating FCR is not preferred when more effective novel therapies are available. Bendamustine + rituximab + idelalisib is Category 2B and not recommended due to toxicity.
[/expand]DG is a 63-year-old male with relapsed CLL who is not a candidate for ibrutinib. He cannot afford venetoclax + rituximab, so he will initiate idelalisib + rituximab instead. Which of the following statements about idelalisib is correct?
A. Pancreatitis is common
B. Diarrhea may be severe
C. Lower extremity edema often occurs
D. Visual changes are frequent
Explanation: Idelalisib is associated with significant immune-mediated adverse effects, most notably severe diarrhea or colitis. Diarrhea is common and follows two peaks: lower-grade diarrhea early in therapy (~30% of patients) and severe diarrhea/colitis in approximately 10% of patients with a median onset of 9.5 months. Because this toxicity is immune-mediated, it must be managed promptly with steroids such as budesonide or systemic corticosteroids. Pancreatitis is associated with nilotinib and ponatinib in CML — not idelalisib. Lower extremity edema is a hallmark toxicity of imatinib — not idelalisib. Visual changes are not listed as common adverse effects of idelalisib.
[/expand]DG is a 63-year-old male receiving idelalisib + rituximab for relapsed CLL. He has no known drug allergies. What supportive care measures should DG receive to prevent complications from his underlying disease and/or treatment regimen?
A. Sulfamethoxazole-trimethoprim
B. Zostavax
C. Ganciclovir
D. IVIG
Explanation: PJP prophylaxis with sulfamethoxazole-trimethoprim (or an equivalent) is recommended for all patients receiving idelalisib. Because DG is receiving idelalisib as part of his relapsed CLL treatment, initiating this antibiotic is the standard of care to prevent a potentially life-threatening opportunistic infection. Prophylaxis continues until the CD4+ T-cell count is greater than 200 cells/µL. Zostavax is a live vaccine and must be strictly avoided in all CLL patients — Shingrix (recombinant) is the preferred alternative. Prophylactic ganciclovir is not warranted unless confirmed CMV viremia is present at the initiation of therapy. IVIG is only appropriate if DG has recurrent sinopulmonary infections (≥ 2 in 6 months requiring IV antibiotics) AND documented serum IgG < 500 mg/dL — not routine.
[/expand]DG is a 63-year-old male receiving idelalisib + rituximab for relapsed CLL. What additional supportive care measure should DG receive?
A. Acyclovir
B. Zostavax
C. Ganciclovir
D. IVIG
Answer: A. Acyclovir
Explanation: Patients receiving idelalisib are at increased risk for herpes virus infections. Clinical guidelines recommend acyclovir (or equivalent) for herpes/VZV prophylaxis during idelalisib treatment and for a period thereafter. Zostavax is a live vaccine — strictly avoided in all CLL patients. Prophylactic ganciclovir is not warranted unless CMV viremia is confirmed — the standard approach for most patients is regular monitoring via PCR. IVIG is not a routine supportive measure; it is only indicated with documented IgG < 500 mg/dL and a history of recurrent sinopulmonary infections requiring hospitalization or IV antibiotics.
[/expand]MB is a 71-year-old female with newly diagnosed CLL who will be initiating therapy with acalabrutinib. Which of the following adverse effects are frequently seen with acalabrutinib and should be discussed during your counseling session with MB?
A. Hypotension
B. Tumor lysis syndrome
C. Headache
D. Periorbital edema
Explanation: Headache is the most commonly reported adverse effect of acalabrutinib, occurring in up to 40% of patients. It typically occurs early in the treatment course and usually resolves spontaneously within 4 to 8 weeks. Counseling for MB should include mitigation strategies such as hydration, caffeine supplementation, and use of analgesics like acetaminophen. Acalabrutinib is associated with hypertension (~3%) — NOT hypotension. TLS is specifically associated with venetoclax initiation — not acalabrutinib. Periorbital edema is a unique toxicity of imatinib (CML) — not acalabrutinib.
[/expand]MB is a 71-year-old female with newly diagnosed CLL. She has no known drug allergies and will be initiating therapy with acalabrutinib. What supportive care measure should MB receive to prevent complications from her underlying disease and/or treatment regimen?
A. Zoster vaccine recombinant, adjuvanted
B. Dapsone
C. Valganciclovir
D. IVIG
Explanation: The recombinant, adjuvanted zoster vaccine (Shingrix) is specifically recommended for patients who are treatment-naïve or being treated with a BTK inhibitor such as acalabrutinib. All live vaccines (such as Zostavax) must be strictly avoided in CLL patients. Dapsone is used for PJP prophylaxis in patients with a sulfa allergy, but PJP prophylaxis is not recommended for acalabrutinib — it is recommended for purine analogs, PI3K inhibitors, and alemtuzumab. Valganciclovir is for CMV prophylaxis only if CMV viremia is confirmed — there is no indication of CMV viremia for MB. IVIG is only indicated if IgG < 500 mg/dL AND recurrent sinopulmonary infections ≥ 2 in 6 months — not routine.
[/expand]FB is a 71-year-old male diagnosed with Binet stage B disease. His cytogenetic analysis reveals del(13q) mutation and unmutated IGHV. He is considered medically fit to receive treatment. Which of the following treatment regimens is the most appropriate first-line therapy for FB?
A. Ibrutinib
B. Chlorambucil and ofatumumab
C. Fludarabine, cyclophosphamide and rituximab (FCR)
D. Alemtuzumab and rituximab
Explanation: FB is 71 years old. FCR is specifically preferred for younger fit patients (typically < 65 years) with mutated IGHV — the benefit of improved PFS with FCR was not seen in patients > 65 years, and age combined with renal status typically makes fludarabine-based regimens inappropriate. Ibrutinib is a Category 1 recommendation for patients age ≥ 65 years without del(17p) or TP53 mutation, demonstrated through the RESONATE-2 trial. FB has unmutated IGHV (more aggressive disease) — ibrutinib shows consistent benefit including in high-risk subgroups. Chlorambucil + ofatumumab is incorrect because ofatumumab is no longer recommended. Alemtuzumab is NOT recommended for patients without del(17p) — FB has del(13q), a favorable prognostic marker.
[/expand]FB is a 71-year-old male with CLL who has been receiving ibrutinib for 18 months. Over the past two weeks, he has noted rapidly enlarging cervical, axillary, and inguinal lymphadenopathy. He also reports new fevers, splenomegaly, and unintentional weight loss. Which of the following is the most likely cause of FB's new complaints?
A. Richter's transformation
B. Ibrutinib resistance
C. Redistribution lymphocytosis
D. Tuberculosis infection
Answer: A. Richter's transformation
Explanation: The rapid onset, nature, and severity of FB's symptoms suggest transformation to a more aggressive malignancy — Richter's transformation (RT) into aggressive NHL (most commonly DLBCL). While ibrutinib resistance does occur, the onset is often insidious rather than the rapid explosive growth seen here. Redistribution lymphocytosis occurs early in treatment (peaks week 2, resolves by week 12) and would not occur after 18 months of therapy. Tuberculosis infection is not associated with ibrutinib.
[/expand]FB is a 71-year-old male with newly diagnosed CLL who will be initiating therapy with ibrutinib. Which of the following adverse effects are frequently seen with ibrutinib and should be discussed during your counseling session with FB?
A. Hypotension
B. Tumor lysis syndrome
C. Minor bleeding
D. Periorbital edema
Explanation: Minor bleeding is an extremely common side effect of ibrutinib, reported in up to 66% of patients. The mechanism involves selective inhibition of platelet signaling and platelet adhesion on von Willebrand factor. The risk of bleeding is highest during the first 3 to 6 months of treatment. Patients should be advised to avoid vitamin E, fish oils, flaxseed, and NSAIDs, which can further increase bleeding risk. Ibrutinib is associated with hypertension (develops or worsens in > 75% of patients over 30 months) — NOT hypotension. TLS is specifically associated with venetoclax or bendamustine-based therapy — not BTK inhibitors. Periorbital edema is a toxicity of imatinib (CML) — not ibrutinib.
[/expand]A 75-year-old man presents with recently diagnosed asymptomatic CLL Rai stage 0. Which option is recommended?
A. Alemtuzumab
B. Chlorambucil
C. Fludarabine
D. Observation only — no therapy
Explanation: An "active surveillance" or "watch and wait" approach is the standard of care for asymptomatic patients with early-stage, low-risk disease — specifically Rai stage 0 or Binet stage A. Multiple Phase III studies and meta-analyses have demonstrated no statistically significant survival difference between patients who receive early treatment for asymptomatic early-stage CLL and those whose treatment is deferred until a clinical indication arises. Treatment is initiated based on the development of symptoms or disease progression — not the diagnosis itself. Starting alemtuzumab, chlorambucil, or fludarabine for this asymptomatic Rai stage 0 patient would offer no proven survival benefit and would subject him to unnecessary toxicities.
[/expand]BR is a 62-year-old male who presents with fever and night sweats and is subsequently diagnosed with CLL. His cytogenetic analysis reveals a del(17p) mutation. BR is physically active and has no comorbidity. Which of the following is the most appropriate for BR at this time?
A. Alemtuzumab + Rituximab
B. Chlorambucil
C. Idelalisib + Rituximab
D. Observation only — no treatment
Explanation: BR has disease-related constitutional symptoms (fever and night sweats) — these are clear indications to initiate therapy rather than observation. BR has the del(17p) mutation — the single most important adverse prognostic factor in CLL, resulting in ultra-high risk disease that responds poorly to standard chemotherapy. Alemtuzumab ± rituximab is explicitly listed as a recommended first-line treatment option specifically for patients with del(17p)/TP53 mutation. Standard chemoimmunotherapy like chlorambucil is associated with very low response rates and short median survival (< 3 years) in del(17p) patients. Idelalisib + rituximab is categorized as second-line or subsequent therapy for these high-risk patients, rather than a primary first-line choice. Observation is inappropriate because the patient is symptomatic.
[/expand]KR is a 52-year-old patient with fever, chills, and night sweats. He has cervical and axillary lymphadenopathy, splenomegaly, WBC of 63,000, Hgb of 9.8 g/dL, Hct of 30%, and Platelets of 165,000. WBC flow cytometry revealed a diagnosis of CLL with poor cytogenetics. Which of the following is the best treatment option for KR?
A. Watch and wait
B. Pentostatin/Rituximab
C. Bendamustine
D. Fludarabine/Cyclophosphamide/Rituximab (FCR)
Explanation: KR is 52 years old — a younger, physiologically fit patient (< 65 years) — and is symptomatic with constitutional symptoms (fever, chills, night sweats), massive lymphadenopathy, and splenomegaly — definitive indications to initiate therapy. KR has poor cytogenetics. In younger fit CLL patients, del(11q) responds well to FCR. The CLL10 study demonstrated FCR produced significantly improved PFS compared to bendamustine + rituximab in younger, fit patients < 65 years. Watch and wait is inappropriate because KR is symptomatic with bulky disease. Pentostatin/rituximab is not the standard-of-care first-line choice for CLL — pentostatin is more commonly used in hairy cell leukemia. Bendamustine alone is inferior to FCR in fit young patients per the CLL10 study.
[/expand]Which of the following statements is FALSE concerning idelalisib?
A. Idelalisib is only available through the REMS program
B. It has a black box warning for hepatotoxicity, severe diarrhea/colitis, pneumonitis, and intestinal perforation
C. Unlike ibrutinib, idelalisib does not lead to a treatment-induced lymphocytosis
D. Idelalisib should be used with rituximab in patients with relapsed CLL who cannot tolerate aggressive chemotherapy
Explanation: This statement is FALSE. Redistribution lymphocytosis — a transient increase in ALC caused by CLL cells moving from lymph nodes into the peripheral blood — can occur with ALL kinase inhibitors used to treat CLL, including idelalisib. In the pivotal Study 116 trial for idelalisib, isolated lymphocytosis was observed, typically peaking at week 2 and resolving by week 12. While the addition of rituximab blunted but did not eliminate this effect, idelalisib absolutely DOES cause treatment-induced lymphocytosis. This lymphocytosis does not signify disease progression and therapy should be continued. The other statements are all true: idelalisib is available through the REMS program; it has black box warnings for hepatotoxicity, severe diarrhea/colitis, and pneumonitis; and its FDA approval was based on Study 116 in patients unable to receive cytotoxic chemotherapy.
[/expand]FR is a 59-year-old female who is started on a fludarabine-based combination chemotherapy regimen for Rai stage IV CLL. Which of the following supportive care medications should be initiated concurrently?
A. Sulfamethoxazole/trimethoprim
B. Amoxicillin/clavulanate
C. Leucovorin
D. Pyridoxine
Explanation: Fludarabine is a purine analog, and patients receiving purine analogs are at significantly increased risk for opportunistic infections due to treatment-induced immunosuppression. PJP prophylaxis with sulfamethoxazole-trimethoprim (or an equivalent such as dapsone for sulfa-allergic patients) is explicitly recommended for all patients receiving purine analogs. Prophylaxis is generally continued until the CD4 count is > 200 cells/µL. Amoxicillin/clavulanate is not the specific standard of care for preventing PJP associated with purine analogs. Leucovorin and pyridoxine are not recommended supportive care measures for fludarabine-based chemotherapy in CLL.
[/expand]KT is a 56-year-old female who presents with newly diagnosed Rai stage 3 CLL. Further workup shows IGHV mutations and del(13q) mutation. Which of the following statements is TRUE?
A. KT has several good prognostic factors: young age, unmutated IGHV, and del(13q)
B. KT should be started on ibrutinib and needs to be counseled on the common side effects of thrombocytopenia, diarrhea, and bruising
C. Rituximab should not be added to KT's regimen since it has not been shown to improve response rates, PFS, or OS
D. Since KT is young and does not have comorbidities, she should be started on chemoimmunotherapy
Explanation: KT is 56 years old (a young, fit patient) with Rai stage 3 disease (a definitive indication for treatment) and has mutated IGHV, which is a highly favorable prognostic marker. FCR is specifically preferred for young, fit patients with mutated IGHV — these patients can achieve durable long-term remissions that may not require continuous therapy. Del(13q) as the sole abnormality is a favorable prognostic marker associated with the longest median survival. Statement A incorrectly identifies unmutated IGHV as a good prognostic factor — unmutated IGHV is actually poor prognosis. Statement B is less appropriate than D for a young patient with mutated IGHV; ibrutinib's common toxicities are bleeding and AF — not thrombocytopenia and diarrhea specifically. Statement C is incorrect — adding rituximab (FC → FCR) demonstrated improved OS and PFS in younger fit patients.
[/expand]Adverse prognostic features in CLL are all EXCEPT:
A. ZAP-70
B. CD38
C. Unmutated immunoglobulin Vh genes
D. del(13q14)
Explanation: Del(13q14) when it occurs as the sole cytogenetic abnormality is associated with a FAVORABLE prognosis and the longest median survival among CLL patients — it is NOT an adverse feature. This is a common exam trap. ZAP-70 expression ≥ 20% is an unfavorable (adverse) prognostic factor associated with shorter PFS and OS. CD38 expression ≥ 30% is an unfavorable (adverse) prognostic factor. Unmutated IGHV (≤ 2% mutated) is associated with a poor prognosis and significantly decreased survival compared to mutated IGHV. Only del(13q14) is favorable among the listed options.
[/expand]The cause of anemia in CLL is:
A. Gastrointestinal blood loss
B. Hypersplenism
C. Marrow suppression secondary to the use of alkylating agents
D. Hemolytic anemia
E. Red blood cell aplasia
F. All of the above
Explanation: Anemia in CLL has multiple contributing causes, all of which are documented complications of the disease or its standard treatments. Hemolytic anemia (AIHA) is the most common cause — AIHA occurs when non-malignant B cells produce antibodies directed against red blood cell antigens. Red blood cell aplasia (PRCA) occurs in approximately 1% of CLL patients when the bone marrow stops producing red blood cells. Bone marrow infiltration and alkylating agents (such as cyclophosphamide in FCR) cause progressive marrow failure and myelosuppression. Hypersplenism — the enlarged spleen sequesters and destroys red blood cells prematurely. Gastrointestinal blood loss — especially from ibrutinib-associated bleeding (up to 66% of patients) — can lead to iron-deficiency anemia. All of the listed causes contribute to anemia in CLL patients.
[/expand]Which of the following biomarkers is associated with poor prognosis in CLL?
A. Low β-2-microglobulin
B. ZAP70
C. CD49D
D. Mutated IGHV
Explanation: ZAP-70 expression ≥ 20% is an unfavorable prognostic factor associated with shorter PFS and OS, though ZAP-70 flow cytometry lacks standardization and is not recommended outside clinical trials. CD49D expression ≥ 30% is also an unfavorable prognostic marker — it is the STRONGEST single predictor of OS and treatment-free survival among flow cytometry markers in CLL. Low β-2-microglobulin is a FAVORABLE prognostic marker — it is elevated levels that predict poor survival. Mutated IGHV (> 2%) is a FAVORABLE prognostic marker associated with better outcomes — it is unmutated IGHV (≤ 2%) that is poor prognosis. When asked to choose one single answer, CD49D is the strongest predictor, but both B and C represent poor prognosis markers.
[/expand]KL is a 70-year-old patient with uncontrolled DM, asthma, and MI, diagnosed 2 days ago with CLL Binet Stage A. What type of treatment should he receive?
A. Acalabrutinib +/- obinutuzumab
B. Alemtuzumab + rituximab
C. Zanubrutinib
D. No treatment, only surveillance
Explanation: KL has Binet Stage A CLL — early-stage, low-risk disease diagnosed only 2 days ago. The standard approach for asymptomatic Binet Stage A (or Rai Stage 0) CLL is active surveillance. Multiple Phase III studies and meta-analyses have demonstrated no statistically significant survival difference between patients treated immediately and those whose treatment is deferred until a clinical indication arises. KL has no mentioned constitutional symptoms, lymphadenopathy requiring intervention, or markers of progressive bone marrow failure — there are currently no indications to initiate therapy. His comorbidities (MI, asthma) do not change the initial recommendation for surveillance in Stage A CLL. If his disease were to progress in the future, his history of MI would make ibrutinib a poor choice due to cardiac toxicities — acalabrutinib or zanubrutinib would be preferred if a BTKi were chosen at that time.
[/expand]FJ is a 55-year-old patient diagnosed with CLL 3 weeks ago. He started ibrutinib but relapsed after 12 months and is planned to start second-line venetoclax + rituximab. His ALC = 30 × 10⁹/L, largest lymph node measures about 7 cm, serum K = 3.5 mEq/L, Mg = 1.8 mmol/L, and CrCL = 60 mL/min. What monitoring plan should he undergo?
- Outpatient: Pre-dose, 6–8 hours and 24 hours at first dose of 20 mg and 50 mg, then pre-dose before subsequent doses
- Outpatient: Pre-dose, 4, 8, 12, and 24 hours at first dose of 20 mg and 50 mg, then pre-dose before subsequent doses
- Inpatient: Pre-dose, 4, 8, 12, and 24 hours at first dose of 20 mg and 50 mg, then outpatient: pre-dose before subsequent doses
- Inpatient: Pre-dose, 4, 8, 12, and 24 hours at first dose of 20 mg and 50 mg, then outpatient: pre-dose, 6–8 hours and 24 hours at subsequent doses
Explanation: FJ's ALC = 30 × 10⁹/L (≥ 25 × 10⁹/L) AND his largest lymph node = 7 cm (≥ 5 cm). The HIGH tumor burden definition is: any node ≥ 10 cm OR (ALC ≥ 25 × 10⁹/L AND any node ≥ 5 cm). Because FJ meets both the ALC threshold AND the nodal size threshold, he is classified as HIGH BURDEN. For HIGH burden patients, the first doses of 20 mg and 50 mg require INPATIENT hospitalization with blood chemistry monitoring (K⁺, uric acid, phosphorus, calcium, creatinine) pre-dose and at 4, 8, 12, and 24 hours post-dose. For subsequent ramp-up doses (100 mg, 200 mg, 400 mg), monitoring shifts to the outpatient setting with required checks at pre-dose, 6–8 hours, and 24 hours after the dose. His CrCL of 60 mL/min does not change the high-burden classification or monitoring requirement.
[/expand]Which of the following is used in first-line treatment of ITP (Immune Thrombocytopenic Purpura)?
A. Corticosteroids
B. Cyclosporine
C. IVIG
D. Rituximab
Explanation: The management of ITP in the context of CLL begins with corticosteroids as first-line therapy. IVIG is reserved for second-line use when a rapid platelet rise is needed. Rituximab is also a second-line option. Cyclosporine is a third-line option for refractory cases. Additional third-line options include synthetic thrombopoietin-like agents (romiplostim, eltrombopag, avatrombopag) and fostamatinib. The treatment ladder progresses from corticosteroids → IVIG or rituximab → cyclosporine or TPO agents.
[/expand]SECTION 3: MULTIPLE MYELOMA (MM)
CONCEPTUAL SUMMARY
Definition and Pathophysiology: Multiple myeloma is a malignant proliferation of plasma cells in the bone marrow that produces monoclonal immunoglobulin (M-protein) or light chains, leading to bone destruction, renal impairment, anemia, and immunodeficiency. MM is currently INCURABLE — the goal of therapy is disease control, prolonging survival, and improving quality of life.
Precursor States: MGUS (Monoclonal Gammopathy of Undetermined Significance) requires serum M-protein < 3 g/dL, BMPC < 10%, and absence of CRAB symptoms — progresses to MM at ~1% per year. Smoldering Multiple Myeloma (SMM) requires serum M-protein ≥ 3 g/dL and/or BMPC 10–59%, still without CRAB symptoms — progression risk is ~10% per year for the first 5 years. Both MGUS and SMM generally require OBSERVATION only — chemotherapy is reserved for active MM.
Diagnostic Criteria (IMWG 2014): Active MM requires ≥ 10% clonal plasma cells plus CRAB criteria: hyperCalcemia (> 11 mg/dL), Renal dysfunction (SCr > 2 mg/dL or CrCl < 40 mL/min), Anemia (Hgb < 10 g/dL), Bone lesions; OR SLiM biomarkers: ≥ 60% plasma cells, FLC ratio ≥ 100, > 1 focal lesion on MRI.
Risk Stratification: High-risk cytogenetics include del(17p), t(4;14), t(14;16). Standard risk includes t(11;14) and hyperdiploidy. The R-ISS (Revised International Staging System) uses β2-microglobulin, albumin, LDH, and cytogenetics. R-ISS Stage I: β2M < 3.5 mg/L AND albumin ≥ 3.5 g/dL AND normal LDH AND no high-risk cytogenetics. R-ISS Stage III: β2M > 5.5 mg/L AND either high-risk cytogenetics or high LDH.
Primary Treatment — Transplant-Eligible: Induction with VRd (bortezomib + lenalidomide + dexamethasone) is standard of care (Category 1). Daratumumab quadruplets (Dara-VRd, Dara-VTd) are increasingly preferred, especially in high-risk disease. After induction, autologous stem cell transplant (ASCT) is performed followed by maintenance. Lenalidomide maintenance post-ASCT is Category 1 (improves OS). Doublet maintenance (bortezomib + lenalidomide) is considered for high-risk patients.
Primary Treatment — Transplant-Ineligible: Dara-Rd (daratumumab + lenalidomide + dexamethasone — MAIA trial) is preferred. VRd-lite or Rd are alternatives.
Key Supportive Care Rules: Bone disease: zoledronic acid 4 mg IV over ≥ 15 minutes (dose-adjust for CrCl < 60 mL/min); pamidronate 90 mg IV over ≥ 2 hours (≥ 4 hours per ASCO); denosumab 120 mg SubQ every 4 weeks (preferred in severe renal dysfunction; do NOT use IV or at 60 mg dose — 60 mg is the Prolia osteoporosis dose). For hypercalcemia of malignancy: full-dose zoledronic acid 4 mg IV is appropriate up to SCr 4.5 mg/dL; add calcitonin 4 IU/kg SubQ or IM for rapid symptom relief (calcitonin intranasal route is NOT appropriate for this indication). TLS: associated with venetoclax — NOT bortezomib or IMiDs. Antiviral prophylaxis (acyclovir/valacyclovir): required for ALL patients receiving proteasome inhibitors (bortezomib, carfilzomib, ixazomib), daratumumab, or elotuzumab. VTE prophylaxis with IMiDs: aspirin for low-risk (SAVED score < 2); prophylactic-dose apixaban 2.5 mg BID or LMWH for high risk. Bortezomib SubQ has significantly less peripheral neuropathy than IV bortezomib — preferred route.
Relapsed/Refractory MM: Early relapse (1–3 prior lines): daratumumab-based or isatuximab-based triplets, KRd (carfilzomib + lenalidomide + dexamethasone). Late relapse (> 3 prior lines): BCMA-targeted therapies — CAR-T cells (idecabtagene vicleucel, ciltacabtagene autoleucel), bispecific T-cell engagers (teclistamab, elranatamab). Teclistamab premedication: dexamethasone + acetaminophen + diphenhydramine (NOT tocilizumab). Teclistamab prophylaxis: acyclovir for herpes zoster prevention. Daratumumab/isatuximab: infusion reactions, interference with blood typing (Coombs test). Patients relapsing within 12 months of ASCT: best treated with clinical trials or novel agents — second ASCT is NOT recommended for early relapse (< 12 months).
PRACTICE QUESTIONS — MULTIPLE MYELOMA
Which of the following is considered a diagnosis for multiple myeloma?
A. Serum monoclonal protein = 2 g/dL and BMPC = 8%
B. Serum monoclonal protein = 4 g/dL, BMPC = 30%, Ca = 8 mg/dL, Hgb = 14 g/dL, and SCr = 0.8 mg/dL
C. FLCR = 1.8, Ca = 10 mg/dL, Hgb = 12 g/dL, and SCr = 1.2 mg/dL
D. BMPC = 70%
Explanation: The diagnosis of active multiple myeloma requires ≥ 10% clonal plasma cells in the bone marrow plus at least one CRAB criterion or one SLiM biomarker. BMPC ≥ 60% is one of the SLiM biomarkers that independently establishes the diagnosis of active MM even without CRAB features. Option D with BMPC = 70% meets this criterion. Option A has low protein (< 3 g/dL) and low BMPC (< 10%) — consistent with MGUS. Option B has high protein and BMPC but no CRAB features or biomarkers — could represent SMM. Option C has abnormal values but none severe enough to meet CRAB criteria or the SLiM biomarker thresholds (FLC ratio of 1.8 is far below the ≥ 100 threshold; Ca = 10 mg/dL is not > 11 mg/dL; Hgb = 12 g/dL is not < 10 g/dL).
[/expand]NK is a 55-year-old patient diagnosed with MM. Albumin = 4 g/dL, β2M = 2.5 mg/L, LDH = 220 U/L, and cytogenetics reveals trisomy 3. According to R-ISS, what stage of disease does this patient have?
A. Stage I
B. Stage II
C. Stage III
D. Stage IV
Explanation: The R-ISS staging criteria for Stage I require ALL of the following: β2M < 3.5 mg/L, albumin ≥ 3.5 g/dL, normal LDH, and absence of high-risk cytogenetics [del(17p), t(4;14), t(14;16)]. This patient has: β2M = 2.5 (< 3.5 ✓), albumin = 4.0 (≥ 3.5 ✓), LDH = 220 (normal ✓), and trisomy 3 (NOT a standard high-risk cytogenetic abnormality ✓). All criteria for Stage I are met. Stage III requires β2M > 5.5 mg/L AND either high-risk cytogenetics or high LDH. Stage II is all cases not classified as Stage I or III. There is no Stage IV in the R-ISS system.
[/expand]JM is a 54-year-old male with newly diagnosed MGUS. His baseline labs include SCr 0.80 mg/dL, calcium 8.6 mg/dL, Hgb 12.5 g/dL. According to NCCN Guidelines, which of the following would be the most appropriate therapy for JM?
A. Lenalidomide, dexamethasone
B. Bortezomib, melphalan, prednisone (VMP)
C. Bortezomib, lenalidomide, dexamethasone (VRd)
D. Observation
Explanation: MGUS requires observation only. It is a plasma cell proliferative disorder with a risk of progressing into smoldering and active MM at approximately 1% per year; however, chemotherapy is reserved for patients with active MM. JM's labs show no CRAB features (calcium 8.6 mg/dL is normal, SCr 0.80 mg/dL is normal, Hgb 12.5 g/dL is above the < 10 g/dL threshold, no bone lesions described). Options A, B, and C are treatment regimens reserved for active MM and are not appropriate for a patient with MGUS.
[/expand]JM has progressed to active MM and presents with lethargy and constipation. His labs are: calcium 10.9 mg/dL, SCr 2.6 mg/dL, and albumin 2.5 g/dL. In addition to aggressive hydration, which of the following interventions would be most appropriate for JM?
A. Calcitonin 4 IU/kg intranasal
B. Furosemide 20 mg IV
C. Zoledronic acid 3 mg IV + calcitonin 4 IU/kg SubQ
D. Zoledronic acid 4 mg IV + calcitonin 4 IU/kg SubQ
Explanation: Bisphosphonate therapy reduces hypercalcemia of malignancy. The prescribing information for zoledronic acid recommends full dose (4 mg IV) when used for hypercalcemia of malignancy in patients with SCr up to 4.5 mg/dL — JM's SCr of 2.6 mg/dL is below this threshold. Because the patient is symptomatic (lethargy and constipation), calcitonin SubQ or IM should be added to provide more rapid reduction in calcium — the bisphosphonate effect takes 48–96 hours. Calcitonin intranasal route is ineffective and not recommended for this indication. Loop diuretics alone (furosemide) should not be the only therapy for symptomatic hypercalcemia and may be given to maintain aggressive hydration in addition to bisphosphonate ± calcitonin. Zoledronic acid 3 mg is a dose-reduced regimen used when CrCl is 30–60 mL/min — but for hypercalcemia of malignancy, the full 4 mg dose is given up to SCr 4.5 mg/dL regardless of renal function.
[/expand]Following JM's initial presentation, he is incidentally found to have a lower extremity DVT. Pertinent labs: 78 kg, SCr 0.92 mg/dL, platelets 38,000/mcL. According to NCCN Guidelines, which of the following is the most appropriate treatment of DVT in anticipation of JM's discharge?
A. Aspirin 325 mg
B. Enoxaparin 40 mg SubQ q12h
C. Enoxaparin 80 mg SubQ q12h
D. Apixaban 15 mg BID × 21 days, then 20 mg/day thereafter
Explanation: The enoxaparin dose must be adjusted in the setting of mild thrombocytopenia. With platelets between 25,000 and 50,000/mcL (JM has 38,000/mcL), the enoxaparin dose should be adjusted to 0.5 mg/kg every 12 hours. For JM at 78 kg: 0.5 × 78 = 39 mg, rounded to 40 mg SubQ q12h. Aspirin 325 mg is not appropriate treatment for an acute DVT. Enoxaparin 80 mg q12h is full 1 mg/kg dosing — this would put him at significant bleeding risk with his thrombocytopenia. Apixaban dosing of 15 mg BID × 21 days is not correct — the loading dose for apixaban for DVT treatment is 10 mg BID × 7 days; however, dose adjustment data for oral anticoagulants in thrombocytopenia is limited, making LMWH the preferred option here.
[/expand]AS is a 62-year-old female with newly diagnosed MM. Corrected calcium is 11.4 mg/dL, 40% plasma cells, R-ISS stage III with del(17p) and t(4;14), SCr 0.85, ECOG 0. She is eligible for ASCT and is interested in receiving induction therapy with a monoclonal antibody. Which of the following is the most appropriate first-line treatment option for AS?
A. Daratumumab, lenalidomide, dexamethasone
B. Elotuzumab, pomalidomide, dexamethasone
C. Daratumumab, bortezomib, thalidomide, dexamethasone
D. Isatuximab, pomalidomide, dexamethasone
Explanation: The only monoclonal antibody-based induction therapies recommended for transplant candidates are daratumumab + VTd (CASSIOPEIA trial) and daratumumab + VRd (GRIFFIN trial). Option C (Dara-VTd) is the appropriate monoclonal antibody-containing induction regimen for transplant-eligible patients. Option A (Dara-Rd) is appropriate for non-transplant candidates per the MAIA trial but not for transplant-eligible patients. Options B and D both contain elotuzumab or isatuximab with pomalidomide — neither is recommended in the frontline setting; these are reserved for relapsed/refractory MM.
[/expand]AS is a 62-year-old female with newly diagnosed MM. Corrected calcium 11.4 mg/dL, 40% plasma cells, R-ISS stage III with del(17p) and t(4;14), SCr 0.85, ECOG 0. She is eligible for ASCT and will be starting primary induction therapy. Which of the following is the most appropriate first-line treatment option?
A. Bortezomib, dexamethasone
B. Daratumumab, lenalidomide, dexamethasone
C. Daratumumab, bortezomib, lenalidomide, dexamethasone
D. Elotuzumab, lenalidomide, dexamethasone
Explanation: For a transplant-eligible patient with newly diagnosed high-risk MM (del(17p) and t(4;14)), a four-drug regimen containing a proteasome inhibitor (bortezomib), an immunomodulatory drug (lenalidomide), a steroid (dexamethasone), and an anti-CD38 monoclonal antibody (daratumumab) is strongly recommended. D-VRd has shown superior efficacy particularly in high-risk patients. Option A (doublet bortezomib + dexamethasone) is an inferior regimen lacking an IMiD. Option B (DRd) is effective but lacks bortezomib, which is key for tackling high-risk disease. Option D (elotuzumab-based) is less potent than daratumumab and not recommended in newly diagnosed patients.
[/expand]AS is a pianist and concerned about peripheral neuropathy (PN). Which of the following bortezomib-based regimens is least likely to cause PN?
A. 1.3 mg/m² IV days 1, 8, 15, and 22
B. 1.3 mg/m² IV days 1, 4, 8, and 11
C. 1.3 mg/m² SubQ days 1, 4, 8, and 11
D. 1.5 mg/m² IV days 1, 8, 15, and 22
Explanation: Subcutaneous (SubQ) administration of bortezomib has demonstrated significantly reduced all-grade peripheral neuropathy compared to intravenous (IV) bortezomib. This is the most important factor in reducing PN risk for AS as a pianist. Options A, B, and D are all administered intravenously, which is associated with increased peripheral neuropathy compared to SubQ administration. Among weekly schedules vs days 1,4,8,11, patients who received weekly bortezomib experienced similar incidence of PN; however, the total bortezomib dose per cycle was higher in the weekly group and they required more dose reductions. The SubQ route at the standard schedule remains the least likely to cause PN.
[/expand]AS has completed 4 cycles of daratumumab + VTd, ASCT, and 2 consolidative cycles achieving a stringent complete response. She chose to forego maintenance therapy. She presents 2 years later with progressive disease. Which of the following is the most appropriate therapy for AS at this time?
A. Bortezomib, melphalan, prednisone (VMP)
B. Elotuzumab, ixazomib, dexamethasone
C. Carfilzomib, lenalidomide, dexamethasone (KRd)
D. Bendamustine, bortezomib, dexamethasone
Explanation: KRd (carfilzomib, lenalidomide, dexamethasone) is a Category 1 recommendation from the NCCN Guidelines for relapsed multiple myeloma. AS has relapsed after daratumumab + VTd — this regimen did not include lenalidomide or carfilzomib, making both agents novel in the relapsed setting. VMP is not a preferred regimen by NCCN Guidelines when superior targeted options are available. Elotuzumab + ixazomib + dexamethasone is not a preferred NCCN regimen in this setting. Bendamustine + bortezomib + dexamethasone is not a preferred NCCN regimen and would offer inferior efficacy.
[/expand]AS has completed 4 cycles of daratumumab + VRd, ASCT, and 2 consolidative cycles achieving a stringent complete response. She then continued lenalidomide maintenance until presenting 2 years later with progressive disease. Which of the following is the most appropriate therapy for AS at this time?
A. Bortezomib, melphalan, prednisone (VMP)
B. Bortezomib, lenalidomide, dexamethasone
C. Daratumumab, carfilzomib, dexamethasone
D. Elotuzumab, lenalidomide, dexamethasone
Explanation: A key principle in treating relapse is to use agents with novel mechanisms of action to which the patient is unlikely to be resistant. AS's initial therapy included daratumumab, bortezomib, and lenalidomide — she is potentially resistant to all three. VRd (option B) and VMP (option A) both include agents from prior therapy (bortezomib and/or lenalidomide) and are suboptimal. Elotuzumab (option D) is less potent and often used in lenalidomide-sensitive patients. DKd (option C) provides carfilzomib — a next-generation proteasome inhibitor she has not received — combined with daratumumab (which may still show some activity despite prior exposure). This provides two novel agents compared to her initial therapy.
[/expand]AS is inquiring about what supportive care medications she should start with the initiation of KRd. She has ECOG 0 with no significant comorbidities or risk factors. In addition to VTE prophylaxis, which of the following do you recommend?
A. Acyclovir
B. Valganciclovir and sulfamethoxazole/trimethoprim
C. Valacyclovir and posaconazole
D. No infectious prophylaxis needed
Explanation: All patients receiving therapy with a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib), daratumumab, or elotuzumab should receive antiviral prophylaxis (acyclovir, valacyclovir, or famciclovir) for prevention of herpes zoster reactivation. KRd contains carfilzomib — a proteasome inhibitor — making antiviral prophylaxis mandatory. Valganciclovir should be reserved for CMV treatment and prophylaxis — not routine for KRd. PJP prophylaxis with SMX-TMP is not required for carfilzomib, lenalidomide, and dexamethasone unless high-dose dexamethasone is used. Posaconazole prophylaxis is not warranted unless the patient develops profound or prolonged neutropenia. No infectious prophylaxis at all (option D) is incorrect because antiviral prophylaxis IS required for carfilzomib.
[/expand]AS is starting KRd. She has ECOG 0 with no significant comorbidities or risk factors. Which of the following do you recommend she start with the initiation of KRd?
A. Aspirin, acyclovir
B. Aspirin, sulfamethoxazole/trimethoprim
C. Aspirin, acyclovir, fluconazole
D. Aspirin
Explanation: KRd contains lenalidomide and dexamethasone — the combination of an IMiD with dexamethasone warrants VTE prophylaxis. In the absence of additional patient-specific risk factors (AS has ECOG 0 with no significant comorbidities), aspirin 81–325 mg daily is appropriate as VTE prophylaxis (low-risk, SAVED score < 2). KRd also contains carfilzomib — a proteasome inhibitor — mandating antiviral prophylaxis with acyclovir (or equivalent) for herpes zoster prevention. SMX-TMP (option B) for PJP prophylaxis is NOT recommended for KRd. Fluconazole (option C) is not warranted unless the patient develops profound or prolonged neutropenia. Aspirin alone (option D) lacks the necessary antiviral prophylaxis.
[/expand]AS is now on cycle 2 of KRd. Her oncologist would like to resume bone-modifying therapy. Her CrCl is 85 mL/min. Which of the following do you recommend initiating at this time?
A. Zoledronic acid 4 mg IV push over 5 minutes
B. Pamidronate 90 mg IV over 4 hours
C. Denosumab 120 mg IV over 30 minutes
D. Denosumab 60 mg SubQ
Explanation: All patients with active multiple myeloma should receive bone-modifying therapy with a bisphosphonate or denosumab regardless of the presence of lytic bone lesions. Pamidronate 90 mg IV over 4 hours (per ASCO, at least 2 hours minimum; at least 4 hours per many guidelines) is a recommended option per both ASCO and NCCN Guidelines. Zoledronic acid 4 mg IV push over 5 minutes is incorrect — zoledronic acid must be administered over at LEAST 15 minutes to reduce the risk of renal toxicity; IV push is never appropriate. Denosumab must be administered as a SubQ injection — NOT intravenously. Denosumab 60 mg is the Prolia dose for osteoporosis — the MM dose is 120 mg SubQ.
[/expand]AS is now on cycle 2 of KRd. Her oncologist would like to resume bone-modifying therapy. Her CrCl is 85 mL/min. Which of the following do you recommend initiating at this time?
A. Pamidronate 30 mg IV push over 5 minutes
B. Zoledronic acid 4 mg IV over 30 minutes
C. Denosumab 120 mg IV over 30 minutes
D. Denosumab 60 mg SubQ
Explanation: All patients with active multiple myeloma should receive bone-modifying therapy. Zoledronic acid 4 mg IV over at least 15 minutes (30 minutes is acceptable) is a recommended option per NCCN and ASCO Guidelines for patients with adequate renal function. AS has a CrCl of 85 mL/min — no dose adjustment is required. Pamidronate 30 mg IV push is incorrect — pamidronate should be administered as 90 mg over at least 2 hours. Denosumab must be administered as a SubQ injection — not intravenously. Denosumab 60 mg is the osteoporosis dose — the MM dose is 120 mg SubQ (preferred in patients with severe renal dysfunction).
[/expand]AS is deemed to be at high risk of VTE due to lenalidomide-based therapy, obesity, and prior history of VTE. She is not interested in injections and requests an oral medication for VTE prophylaxis. According to the SAVED and IMPEDE criteria, which of the following is most appropriate for AS?
A. Apixaban 2.5 mg twice daily
B. Aspirin 81 mg once daily
C. Rivaroxaban 20 mg once daily
D. Warfarin (INR 1.5–2.5)
Explanation: AS is deemed to be at HIGH risk of VTE based on both the SAVED and IMPEDE scoring systems (lenalidomide-based therapy, obesity, prior VTE). For high-risk patients, prophylactic-dose apixaban 2.5 mg twice daily is appropriate. Alternatively, enoxaparin 40 mg SubQ daily, dalteparin 5,000 units SubQ daily, or warfarin (INR 2–3) may be used. Aspirin 81 mg daily is insufficient for high-risk VTE per SAVED and IMPEDE criteria. Rivaroxaban 20 mg once daily is a treatment dose for an existing clot — not a prophylactic dose; 10 mg once daily may be appropriate for prophylaxis in non-myeloma oncology patients. Warfarin is acceptable at a target INR of 2–3, not 1.5–2.5 as stated in option D.
[/expand]AS presents to the ED with a painful, swollen, warm left lower leg concerning for VTE. What are AS's risk factors for deep vein thrombosis (DVT)?
A. Therapy with lenalidomide and dexamethasone
B. Zoledronic acid administration
C. Therapy with carfilzomib
D. BMI < 25 kg/m²
Explanation: Therapy with lenalidomide and dexamethasone (an IMiD combined with a steroid) significantly increases the risk of blood clots in multiple myeloma patients. This is the basis for mandatory VTE prophylaxis with IMiD-based regimens. Zoledronic acid administration is NOT a risk factor for VTE — it is a bone-modifying agent with no known thrombotic risk. Carfilzomib alone does not independently increase the risk of blood clots (carfilzomib is associated with cardiovascular toxicity and hypertension, not VTE). Normal weight (BMI < 25) is NOT a risk factor for VTE — obesity is a risk factor, not normal weight.
[/expand]SB is a 62-year-old female with newly diagnosed LOW RISK smoldering myeloma with serum monoclonal protein of 3.5 g/dL and 15% plasma cells in the bone marrow. Her baseline labs include SCr 0.60 mg/dL, calcium 9.2 mg/dL, Hgb 12.7 g/dL. According to NCCN Guidelines, which of the following would be the most appropriate therapy for SB?
A. Observation
B. Lenalidomide, dexamethasone
C. Daratumumab, lenalidomide, dexamethasone
D. Bortezomib, lenalidomide, dexamethasone
Explanation: Smoldering myeloma requires observation only. It is a plasma cell proliferative disorder with a risk of progressing into active MM; however, induction chemotherapy is reserved for patients with active MM. SB has no CRAB features (calcium 9.2 mg/dL — normal; SCr 0.60 mg/dL — normal; Hgb 12.7 g/dL — above the < 10 g/dL threshold for active MM; no bone lesions described). Options B, C, and D are treatment regimens reserved for patients with active MM and are not appropriate for a patient with smoldering myeloma.
[/expand]TL is a 62-year-old male with newly diagnosed MM. Corrected calcium 11.8 mg/dL, 55% plasma cells, R-ISS stage II with t(11;14), SCr 0.91, ECOG 0. He is eligible for ASCT and will be starting primary induction therapy. Which of the following is the most appropriate first-line treatment option for TL according to NCCN Guidelines?
A. Daratumumab, bortezomib, dexamethasone
B. Daratumumab, lenalidomide, dexamethasone
C. Elotuzumab, lenalidomide, dexamethasone
D. Bortezomib, lenalidomide, dexamethasone
Explanation: VRd (bortezomib, lenalidomide, dexamethasone) is a recommended induction regimen for transplant-eligible newly diagnosed MM patients and is Category 1. TL has intermediate-risk cytogenetics (t(11;14)) — not high-risk — making a standard three-drug induction appropriate. The only monoclonal antibody-based induction therapies currently recommended by NCCN for transplant candidates are Dara-VRd (GRIFFIN trial), Dara-VTd (CASSIOPEIA trial), and Dara-CyBorD (LYRA trial). Daratumumab + bortezomib + dexamethasone (option A, only doublet + daratumumab without an IMiD) is a suitable therapy for relapsed/refractory MM — not newly diagnosed transplant-eligible patients. Dara-Rd (option B) is for non-transplant-eligible patients per the MAIA trial. Elotuzumab + Rd (option C) is for relapsed/refractory MM only.
[/expand]TL was treated with 4 cycles of induction VRd, ASCT, and 2 cycles of VRd consolidation achieving a complete response. He then continued lenalidomide maintenance until presenting 4 years later with progressive disease. Which of the following is the most appropriate therapy for TL at this time according to NCCN Guidelines?
A. Bendamustine, lenalidomide, dexamethasone
B. Selinexor, dexamethasone
C. Isatuximab, carfilzomib, dexamethasone
D. Teclistamab
Explanation: Isatuximab, carfilzomib, dexamethasone (Isa-Kd) is a Category 1 recommendation from NCCN Guidelines for relapsed MM with early relapse (1–3 prior lines). TL has relapsed after VRd and lenalidomide maintenance — carfilzomib and isatuximab are both novel agents he has not previously received. Bendamustine + lenalidomide + dexamethasone (option A), selinexor + dexamethasone (option B), and teclistamab (option D) are all therapies recommended for late relapse (> 3 prior lines of therapy) — TL has only received 1 prior line, making these less appropriate at this time.
[/expand]TL is treated with Isa-Kd for 1 year, then progresses. He is then treated with third-line elotuzumab + pomalidomide + dexamethasone and fourth-line selinexor + bortezomib + dexamethasone. He presents with disease relapse and is to start fifth-line treatment with teclistamab. Which of the following is the most appropriate premedication regimen to recommend upon initiation of teclistamab to reduce the risk of cytokine release syndrome?
A. Dexamethasone, acetaminophen
B. Dexamethasone, acetaminophen, diphenhydramine
C. Acetaminophen, diphenhydramine
D. Tocilizumab, acetaminophen, diphenhydramine
Explanation: Patients receiving teclistamab should receive dexamethasone, an antipyretic (acetaminophen), and a histamine-1 receptor antagonist (diphenhydramine) prior to at least the 0.06 mg/kg, 0.3 mg/kg, and 1.5 mg/kg step-up doses when initiating teclistamab to reduce the risk of cytokine release syndrome. Option A is missing diphenhydramine (an H1 antagonist), which is required. Option C is missing dexamethasone, which is required. Option D is incorrect because tocilizumab is NOT a recommended premedication prior to teclistamab — it is used to TREAT cytokine release syndrome after it occurs, not to prevent it.
[/expand]TL is treated with Isa-Kd for 1 year, then progresses. He is treated with third-line selinexor + bortezomib + dexamethasone and fourth-line elotuzumab + pomalidomide + dexamethasone. He presents with a new osteolytic lesion, rising free light chain ratio, and an increase in M-spike. His CBC is within normal limits. TL is to start fifth-line treatment with teclistamab. Which of the following is the most appropriate antimicrobial prophylaxis to recommend upon initiation of teclistamab?
A. Acyclovir
B. Acyclovir, letermovir
C. Acyclovir, levofloxacin
D. Levofloxacin, fluconazole, letermovir
Explanation: Patients receiving teclistamab should receive herpes zoster reactivation prophylaxis during therapy with an agent such as acyclovir, famciclovir, or valacyclovir. Letermovir (option B) is used for CMV prophylaxis — there are no current recommendations for CMV prophylaxis with teclistamab. Levofloxacin (option C) is antibacterial prophylaxis — not warranted in this setting since the patient is not neutropenic (CBC within normal limits) and is not otherwise empirically recommended with teclistamab. Option D omits acyclovir (the most critical prophylaxis here) and adds agents not warranted in this clinical scenario.
[/expand]TL completes 4 cycles of induction VRd, ASCT, and 2 cycles of VRd consolidation achieving a complete response. He is now to be considered for maintenance therapy. According to NCCN Guidelines, which of the following would be the most appropriate maintenance therapy for TL?
A. Bortezomib
B. Lenalidomide
C. Bortezomib plus lenalidomide
D. Observation only — maintenance not required since a complete response was achieved
Explanation: Lenalidomide is a Category 1 recommended maintenance therapy for patients after undergoing ASCT. It has demonstrated an improvement in overall survival and is preferred over bortezomib as single-agent maintenance. Bortezomib (option A) has not demonstrated an improvement in overall survival in the maintenance setting and is not preferred over lenalidomide as monotherapy, though it can be an alternative. Doublet maintenance with bortezomib + lenalidomide (option C) would be considered for patients with HIGH-RISK cytogenetics — TL has intermediate-risk t(11;14), not high-risk disease. Observation only (option D) is incorrect — maintenance therapy is recommended regardless of the depth of response achieved following ASCT in MM.
[/expand]With his most recent relapse, TL has an osteolytic lesion. His oncologist would like to resume bone-modifying therapy. His CrCl is 70 mL/min. Which of the following is the most appropriate to recommend for TL at this time?
A. Zoledronic acid 5 mg IV push over 15 min every 12 months
B. Pamidronate 90 mg IV over 15 min every 4 weeks
C. Denosumab 120 mg SubQ every 4 weeks
D. Denosumab 60 mg SubQ every 6 months
Explanation: All patients with active MM should receive bone-modifying therapy regardless of lytic bone lesions. Denosumab 120 mg SubQ every 4 weeks is a recommended option per both ASCO and NCCN Guidelines. Zoledronic acid 5 mg IV every 12 months is the Reclast dose for osteoporosis — the MM dose is 4 mg IV over ≥ 15 minutes every 4 weeks. Pamidronate 90 mg over only 15 minutes is incorrect — pamidronate must be administered over at least 2 hours (ASCO recommends at least 4 hours) to reduce nephrotoxicity risk. Denosumab 60 mg is the Prolia dose for osteoporosis — NOT the MM dose; the MM dose is 120 mg SubQ.
[/expand]With his most recent relapse, TL also has a new osteolytic lesion of the right femur. His oncologist would like to resume a bone-modifying agent. His CrCl is 35 mL/min. Which of the following is the most appropriate to recommend for TL at this time?
A. Denosumab 120 mg IV over 60 min every 4 weeks
B. Denosumab 60 mg SubQ every 4 weeks
C. Zoledronic acid 4 mg IV over 15 min every 4 weeks
D. Zoledronic acid 3 mg IV over 15 min every 4 weeks
Answer: D. Zoledronic acid 3 mg IV over 15 min every 4 weeks
Explanation: With CrCl = 35 mL/min, zoledronic acid requires a dose adjustment. Per prescribing information, the dose is reduced to 3 mg IV over 15 minutes for patients with CrCl 30–60 mL/min. The route (IV) and frequency (every 4 weeks) are correct in option D — only the dose has been adjusted for renal function, making it the correct answer. Denosumab must be administered as a SubQ injection — NEVER intravenously (option A is incorrect route). Denosumab 60 mg is the Prolia osteoporosis dose — NOT the MM dose (option B is incorrect dose). Zoledronic acid 4 mg without dose adjustment (option C) would be inappropriate given his CrCl of 35 mL/min — full dosing is associated with nephrotoxicity at this renal function level.
[/expand]NK is a 63-year-old male who presents with confusion, lethargy, and constipation. Labs: calcium 15.6 mg/dL, SCr 3.1 mg/dL, albumin 3.4 g/dL. Along with aggressive intravenous hydration, which of the following initial interventions would be most appropriate for NK?
A. Zoledronic acid 4 mg IV once + calcitonin 4 IU/kg SubQ every 12 hours
B. Zoledronic acid 3 mg IV once + calcitonin 4 IU/kg SubQ every 12 hours
C. Calcitonin 4 IU/kg SubQ every 12 hours only — a bisphosphonate is contraindicated with his renal function
D. Denosumab 120 mg IV once
Explanation: For hypercalcemia of malignancy, full-dose zoledronic acid (4 mg IV) is recommended up to a SCr of 4.5 mg/dL — NK's SCr of 3.1 mg/dL is below this threshold, so full dose is appropriate without dose reduction. Because NK is symptomatic (confusion, lethargy, constipation), calcitonin SubQ or IM should be added to provide more rapid reduction in calcium before the bisphosphonate effect begins in 48–96 hours. Zoledronic acid 3 mg (option B) is the dose-adjusted regimen for regular bone disease treatment in renal impairment — for hypercalcemia of malignancy, the full 4 mg dose is given up to SCr 4.5 mg/dL. Bisphosphonate therapy is NOT contraindicated with this renal function level for hypercalcemia of malignancy (option C is incorrect). Denosumab (option D) should be reserved for bisphosphonate-refractory hypercalcemia, and must be given SubQ — not IV.
[/expand]NK is receiving bortezomib, lenalidomide, and dexamethasone. He is African American, no recent history of surgery, no history of VTE, and will receive 120 mg of dexamethasone per cycle. His SAVED score is 1. According to the SAVED criteria, which of the following is most appropriate for NK?
A. Aspirin 81 mg once daily
B. Apixaban 2.5 mg twice daily
C. Enoxaparin 40 mg once daily
D. No thromboprophylaxis required
Explanation: NK has a SAVED score of 1, which classifies him as LOW risk for VTE. For patients at low risk per the SAVED scoring system (score < 2), aspirin 81 mg once daily is appropriate VTE prophylaxis. Apixaban 2.5 mg BID and enoxaparin 40 mg SubQ daily are options for HIGH-risk patients (SAVED score ≥ 2 or IMPEDE high-risk). Thromboprophylaxis is still REQUIRED in a patient receiving an IMiD (lenalidomide) and dexamethasone — option D (no prophylaxis) is incorrect. The choice between aspirin and anticoagulation depends on risk stratification, and low-risk patients are appropriately managed with aspirin.
[/expand]Upon presenting to the clinic for Cycle 2 Day 1 of VRd, NK reports lower extremity swelling in his right leg. Ultrasound reveals a DVT despite adequate thromboprophylaxis. Pertinent labs: 63 kg, SCr 1.1 mg/dL, platelets 130,000/mm³. According to NCCN Guidelines, which of the following is the most appropriate treatment of NK's DVT?
A. Edoxaban 60 mg once daily
B. Rivaroxaban 20 mg once daily
C. Enoxaparin 30 mg SubQ q12h
D. Enoxaparin 60 mg SubQ q12h
Explanation: Enoxaparin 1 mg/kg every 12 hours is the most appropriate agent for treatment of an acute DVT in a cancer patient. For NK at 63 kg: 1 × 63 = 63 mg — the closest commercially available dose is 60 mg q12h. Edoxaban (option A) when used for acute DVT treatment in cancer must first be preceded by at least 5 days of parenteral anticoagulation — starting edoxaban directly is not appropriate. Rivaroxaban (option B) treatment requires a loading dose of 15 mg BID × 21 days before continuing on 20 mg daily — option B skips the loading phase. Enoxaparin 30 mg q12h (option C) would be appropriate only if platelets were 25,000–50,000/mm³ (dose adjusted to 0.5 mg/kg); NK's platelets are 130,000/mm³ — this would be significant underdosing and is not appropriate.
[/expand]AM is a 76-year-old male with type 2 diabetes, peripheral neuropathy, and hypertension, found to have newly diagnosed HIGH-RISK smoldering myeloma with serum monoclonal protein of 4.2 g/dL and 20% plasma cells in the bone marrow. His baseline labs include Hgb 12.5 g/dL, SCr 0.80 mg/dL, corrected calcium 9.4 mg/dL. According to NCCN Guidelines, which of the following would be the most appropriate therapy for AM?
A. Daratumumab, bortezomib, lenalidomide, dexamethasone
B. Daratumumab, carfilzomib, lenalidomide, dexamethasone
C. Bortezomib, lenalidomide, dexamethasone
D. Observation
Explanation: Smoldering myeloma — even high-risk — requires observation as the standard approach per NCCN Guidelines. Induction therapy is reserved for patients with active MM defined by CRAB criteria or SLiM biomarkers. AM has no CRAB features (calcium 9.4 mg/dL is normal; SCr 0.80 mg/dL is normal; Hgb 12.5 g/dL is above < 10 g/dL; no bone lesions described). While clinical trial enrollment is also a recommended consideration for high-risk SMM patients, standard induction therapy is not indicated outside of a clinical trial. Options A, B, and C are treatment regimens reserved for active MM and are not appropriate for smoldering myeloma.
[/expand]KN is a 50-year-old man with ISS stage III MM and CHF. He completed 4 cycles of VRd but presented with confirmed progressive disease after his 4th cycle. Which of the following is the most appropriate therapy for KN at this time?
A. Panobinostat, bortezomib, dexamethasone
B. Bortezomib, lenalidomide, dexamethasone
C. Daratumumab, carfilzomib, dexamethasone
D. Daratumumab, lenalidomide, dexamethasone
Explanation: KN has progressive disease during initial VRd therapy, meaning his disease is refractory to both bortezomib and lenalidomide. Options B (VRd) and D (Dara-Rd) both contain lenalidomide — re-exposing a lenalidomide-refractory patient to lenalidomide is not appropriate. Option A (panobinostat + bortezomib + dexamethasone) is rarely used today due to significant toxicity and also includes bortezomib to which KN is already refractory. DKd (option C) offers two new effective agents — daratumumab and carfilzomib — neither of which was in his initial regimen. His history of CHF is a critical concern: carfilzomib has known cardiovascular toxicity, and his CHF must be carefully optimized and monitored. However, in the setting of early aggressive relapse refractory to standard agents, DKd remains the best available option among those listed.
[/expand]Treatment for a myeloma patient who relapsed 6 months after autologous SCT is:
A. Second autologous SCT
B. Allogeneic SCT
C. Matched unrelated SCT
D. Clinical trials
Explanation: Patients who relapse within the first 12 months after autologous HSCT have a shorter median overall survival compared to those who relapse after 12 months. A second autologous HSCT is NOT recommended for patients who relapse within 12 months of the first transplant — the PFS following a second HSCT would likely be even shorter than the benefit seen with the first transplant. These patients are best treated with active agents they have not received before or novel agents as part of clinical trials investigating new therapies. Agents with novel mechanisms of action in myeloma include anti-CD38 monoclonal antibodies (daratumumab), cell cycle-specific drugs, HDAC inhibitors, proteasome inhibitors, and CAR-T/bispecific therapies. Allogeneic HSCT may be considered as part of a clinical trial but is not the standard recommendation outside of one.
[/expand]Side effects from thalidomide include:
A. Somnolence
B. Peripheral neuropathy
C. Thrombosis
D. All of the above
Explanation: Thalidomide is an oral agent with antiangiogenic and immunomodulatory properties. Its primary target is cereblon. All three listed adverse effects are documented and clinically significant. Somnolence and fatigue are common — occurring in approximately 25% of patients; the sedation decreases with continued therapy and can be minimized by taking the drug in the evening before bed. Peripheral neuropathy (sensory more than motor, axonal neuropathy) occurs in up to 30–80% of patients with prolonged therapy and may not be reversible — it is dose-dependent. Thrombosis: VTE incidence increases up to 25% of patients when thalidomide is combined with dexamethasone, necessitating mandatory VTE prophylaxis. Constipation is also a common dose-related side effect of thalidomide.
[/expand]True regarding lenalidomide are all EXCEPT:
A. Increases overall response rate and time to disease progression
B. Causes significantly more cytopenias
C. Safe in renal failure
D. Can cause stem cell damage
Explanation: Lenalidomide is NOT safe in renal failure without dose adjustment — it is secreted via the kidneys and must be used with caution in patients with renal impairment. For patients with moderate kidney impairment, the dose should be reduced to 10 mg/day; for severe renal impairment, 15 mg every other day. The other statements are true: lenalidomide increases overall response rates and time to disease progression (true); lenalidomide causes significantly more cytopenias (grade 3/4 neutropenia 30–40%, thrombocytopenia 12–15%) compared to thalidomide (true); prolonged lenalidomide use can reduce stem cell mobilization — after more than 4 cycles, the number of CD34+ cells collected is reduced and failed collections increase, particularly when mobilized with G-CSF alone (true).
[/expand]Side effects of bortezomib are all EXCEPT:
A. Peripheral neuropathy
B. Thrombosis
C. Cutaneous reactions
D. Increased risk of herpes zoster
Explanation: Thrombosis is NOT a side effect of bortezomib. Thrombotic complications are associated with thalidomide, lenalidomide, and pomalidomide (IMiDs) — especially when combined with dexamethasone or chemotherapy. Bortezomib's actual toxicities include: peripheral neuropathy (dose-limiting in ~35% of patients — often painful, sensory more than motor; managed with SubQ administration and dose reductions); thrombocytopenia (43% of patients; nadir typically at day 11; rarely severe enough to postpone cycles); cutaneous reactions (skin rash has been reported); and increased risk of herpes zoster reactivation (antiviral prophylaxis with acyclovir or valacyclovir is mandatory for all patients receiving bortezomib).
[/expand]ZP is a 69-year-old female with a history of congestive heart failure who presents with newly diagnosed symptomatic stage III multiple myeloma. Which of the following chemotherapy regimens would be most appropriate for her?
A. Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide + bortezomib (VTD-PACE)
B. High-dose dexamethasone
C. Carfilzomib/cyclophosphamide/dexamethasone
D. Bortezomib/lenalidomide/dexamethasone
Explanation: ZP is 69 years old with CHF — she is not an ideal candidate for autologous HSCT. Per NCCN Guidelines, VRd is a preferred option for newly diagnosed MM patients regardless of ASCT status. VTD-PACE (option A) is a highly toxic multi-drug regimen also including anthracyclines and platinum — cardiotoxic agents that should be avoided given ZP's CHF. High-dose dexamethasone alone (option B) has significantly lower response rates and would be an inferior regimen. Carfilzomib (option C) carries known cardiovascular toxicity including cardiomyopathy and heart failure — it should be avoided in a patient with pre-existing CHF. VRd provides the best balance of efficacy and safety for this patient.
[/expand]KM is a 73-year-old male with elevated protein on a routine exam. Serum protein electrophoresis revealed elevated monoclonal protein. Which of the following tests would be appropriate for diagnostic and staging work-up for multiple myeloma?
A. Chest X-ray, bone marrow biopsy, skeletal survey
B. Chest X-ray, skeletal survey, β2-microglobulin
C. Bone marrow biopsy, skeletal survey, β2-microglobulin
D. Bone marrow biopsy, β2-microglobulin, chest X-ray
Explanation: Per NCCN Guidelines, the initial diagnostic workup for multiple myeloma includes bone marrow biopsy (required to confirm ≥ 10% plasma cells), skeletal survey or whole-body PET/CT scan (to rule out bone metastasis and osteolytic lesions), and β2-microglobulin (prognostic value and essential for R-ISS staging). A chest X-ray does not help in the diagnostic or staging work-up for multiple myeloma — it is not part of the standard initial workup. Options A, B, and D all include chest X-ray, making them incorrect. Bone marrow biopsy confirms the diagnosis; skeletal survey identifies bone involvement; β2-microglobulin provides prognostic staging.
[/expand]JJ is a 74-year-old female with recently diagnosed multiple myeloma. Multiple myeloma is a disorder of:
A. Plasma cells
B. Macrophages
C. Platelets overproduction
D. T-lymphocytes
Explanation: Multiple myeloma is a malignant disorder characterized by abnormal overproduction of clonal plasma cells in the bone marrow. These malignant plasma cells produce monoclonal immunoglobulin (M-protein) or light chains, leading to organ damage including bone destruction, renal impairment, anemia, and immunodeficiency. Plasma cells are derived from B-lymphocytes — not T-lymphocytes. Macrophages are not involved in the pathophysiology of multiple myeloma. While patients may have low platelet counts due to plasma cells crowding out normal hematopoiesis, myeloma is not a disorder of platelet overproduction — the opposite occurs (thrombocytopenia, not thrombocytosis).
[/expand]Multiple myeloma is a hematologic malignancy primarily affecting the older population. Which of the following clinical manifestations are associated with multiple myeloma?
A. Hypercalcemia, renal failure, hepatic failure, bone metastasis
B. Hypercalcemia, renal failure, anemia, bone metastasis
C. Hypercalcemia, anemia, hepatic failure, bone metastasis
D. Renal failure, anemia, hepatic failure, hypercalcemia
Explanation: The classic clinical manifestations of multiple myeloma are defined by the CRAB criteria: C — hyperCalcemia (> 11 mg/dL), R — Renal impairment (SCr > 2 mg/dL or CrCl < 40 mL/min), A — Anemia (Hgb < 10 g/dL), B — Bone lesions (lytic bone disease, fractures). Multiple myeloma does NOT typically cause liver injury — hepatic failure is not a recognized CRAB criterion or hallmark feature. All options containing hepatic failure (options A, C, and D) are therefore incorrect. While renal impairment, anemia, and bone lesions are more common, hypercalcemia is present in a significant subset of patients and is included in the diagnostic criteria.
[/expand]SECTION 4: HAIRY CELL LEUKEMIA (HCL)
CONCEPTUAL SUMMARY
Definition: Hairy Cell Leukemia (HCL) is a rare, indolent B-cell leukemia characterized by malignant lymphocytes with "hairy" cytoplasmic projections on microscopy. The BRAF V600E mutation is present in approximately 90% of classic HCL cases — a key diagnostic and therapeutic target.
First-Line Therapy: Purine analogues are the standard of care. Cladribine (2-CdA) is the preferred first-line agent and can produce durable long-term remissions. Pentostatin is an alternative purine analogue with similar efficacy.
Relapsed/Refractory Disease: If relapse occurs after several years, retreatment with cladribine or pentostatin ± rituximab is appropriate. For early relapse (< 1–2 years, especially < 1 year after prior purine analogue) — suggesting purine analogue-resistant disease — BRAF inhibitors such as vemurafenib ± rituximab are preferred. This is because approximately 90% of classic HCL cases harbor the BRAF V600E mutation, making BRAF-targeted therapy a rational and effective option. Interferon alfa is now considered obsolete for HCL except in pregnancy or for unfit patients due to low efficacy. Moxetumomab pasudotox-tdfk (anti-CD22 cytotoxin) is used for patients who have failed at least two prior systemic therapies.
PRACTICE QUESTIONS — HAIRY CELL LEUKEMIA
FL is a 60-year-old man who was diagnosed with hairy cell leukemia (HCL). He started cladribine 9 months ago, but unfortunately his disease relapsed. Which one of the following is considered the preferred regimen for FL's treatment?
A. Pentostatin
B. Vemurafenib +/- rituximab
C. Interferon alfa
D. Rituximab
Explanation: FL relapsed within 9 months of starting cladribine — this is considered early relapse (< 1 year), strongly suggesting purine analogue-resistant disease. Approximately 90% of classic HCL cases harbor the BRAF V600E mutation, making BRAF inhibitor therapy with vemurafenib a rational and targeted option in relapsed/refractory settings, especially for early relapse after prior purine analogue use. Adding rituximab to vemurafenib provides synergistic effect and is the preferred approach. Pentostatin (option A) is not preferred in early relapse especially after prior purine analogue therapy — retreatment with another purine analogue would be unlikely to overcome purine analogue resistance. Interferon alfa (option C) is now considered obsolete for HCL except in pregnancy or for unfit patients due to its comparatively low efficacy. Rituximab alone (option D) can be used but is not as effective as vemurafenib ± rituximab in early relapses after purine analogues. The BRAF V600E mutation present in ~90% of classic HCL cases makes vemurafenib the most rational targeted choice in this clinical scenario.
[/expand]Which of the following agents used for CML should be only be taken on an empty stomach?
- A. Imatinib (29%)
- B. Dasatinib (19%)
- C. Nilotinib (39%)
- D. Hydroxyurea (13%)
[expand] Answer (C)
[/expand]27. JK is a 63-year-old female who is getting ready to start second-line therapy with bortezomib, lenalidomide, and dexamethasone for multiple myeloma. As the pharmacist, you are educating the patient regarding the risks of bortezomib treatment. Which of the following are common side effects of bortezomib?
- A. Thrombocytopenia, viral infection, pulmonary fibrosis (15%)
- B. Thrombocytopenia, pulmonary fibrosis, peripheral neuropathy (22%)
- C. Peripheral neuropathy, thrombocytopenia, viral infection (50%)
- D. Peripheral neuropathy, viral infection, pulmonary fibrosis (13%)
- The third answer is correct because bortezomib is a proteasome inhibitor. Thrombolytics and peripheral neuropathy are the dose-limiting toxicities of bortezomib. In addition, an increased incidence of herpes zoster infection was identified in the post-marketing use of bortezomib. Therefore, every patient who is on bortezomib should receive acyclovir prophylaxis.
- Pulmonary fibrosis is not a serious or common adverse effect of bortezomib.
- Bortezomib is associated with the following toxicities: thrombocytopenia, peripheral neuropathy, and herpes virus infections.
- Bortezomib can be given intravenously or subcutaneously. The subcutaneous route is associated with a lower risk for peripheral neuropathy.
40. JK is an 8-year-old male who is starting lenalidomide-based therapy for his multiple myeloma (MM). You are responsible for counseling this patient on lenalidomide. Which of the following common toxicities of lenalidomide should JK be informed about?
- A. Hand-foot syndrome, coagulopathy, secondary malignancies (13%)
- B. Coagulopathy, neutropenia, secondary malignancies (75%)
- C. Neuropathy, ototoxicity, sedation (4%)
- D. Ototoxicity, neuropathy, hand-foot syndrome (8%)
- The second answer is correct as patients on lenalidomide are at an increased risk for thrombosis and should be started on prophylactic aspirin 81–325 mg. Neutropenia and secondary malignancies are also potential risks with lenalidomide.
- Although there is a lower risk of peripheral neuropathy with lenalidomide vs. thalidomide, some patients may still experience this toxicity.
- Hand-foot syndrome is a common toxicity of many anti-VEGFR tyrosine kinase inhibitors, but not of lenalidomide (first and last answers).
- Sedation and ototoxicity are not typically associated with lenalidomide (third and last answers).
- Lenalidomide therapy is associated with an increased risk of coagulopathies, neutropenia, secondary malignancies, and peripheral neuropathy.
- Exposure to myelotoxic drugs (alkylating agents) and prolonged exposure to lenalidomide should be limited to avoid compromising stem cell reserve before stem cell harvest in transplant-edible MM patients.
86. Which of the following BCR-ABL TKIs is NOT matched appropriately with its corresponding toxicity?
- A. Ponatinib arterial thrombosis (20%)
- B. Bosutinib pancreatitis (47%)
- C. Dasatinib pleural effusion (18%)
- D. Nilotinib QTc prolongation (15%)
- Ponatinib, NOT bosutinib, has been associated with pancreatitis.
- Ponatinib has a black box warning for arterial thrombosis and hepatotoxicity, dasatinib is associated with pleural effusions, and nilotinib has a black box warning for QTc prolongation.
- While all of the BCR-ABL TKIs are relatively well tolerated, the differences in their toxicity profiles should be considered when selecting an appropriate drug for each patient.
- Per the NCCN guidelines, nilotinib or bosutinib may be preferred for patients at risk for developing pleural effusions or with a history of lung disease. On the other hand, dasatinib or bosutinib may be preferred in patients with a history of arrhythmias, heart disease, pancreatitis, or hyperglycemia.
98. LC is a 38-year-old female with chronic myeloid leukemia who has failed to achieve a complete response with imatinib. The physician would like to start her on a different TKI. Considering LC has a history of GERD for which she takes pantoprazole daily, which of the following agents is most appropriate for LC?
- A. Dasatinib (21%)
- B. Bosutinib (19%)
- C. Nilotinib (38%)
- D. All of the above agents are appropriate and do not have any significant interactions with proton pump inhibitors (PPI) (23%)
- Studies have not shown a significant reduction in the rate and extent of nilotinib absorption when given with a PPI. Thus, nilotinib would be the most appropriate choice for LC.
- Concomitant administration of H2 receptor antagonists or PPIs with dasatinib and concomitant administration of PPIs with bosutinib is not recommended as this may decrease TKI drug levels and lead to reduced efficacy. The use of short-acting antacids should be considered instead.
- Both dasatinib and bosutinib levels may be significantly decreased when given with proton pump inhibitors. Short-acting antacids should be used instead.
- Nilotinib should be given on an empty stomach, preferably 1 hour before or 2 hours after food. The bioavailability is increased 82% when administered 30 minutes after a high-fat meal.
123. Which of the following statements is FALSE concerning ponatinib (iclusig)?
- A Ponatinib may be taken with or without food. (12%)
- B It has a black box warning for vascular occlusion, heart failure and hepatotoxicity. (8%)
- C Patients with CML with T315I mutations should be started on dasatinib first, then switched to ponatinib if they fail first line treatment. (69%)
- D Ponatinib may cause hypertension, which is likely associated with the pan-VEGF inhibition exhibited with this TKI. (11%)
The T315I mutation is known as the "gatekeeper" mutation and confers resistance to all currently available TKIs except ponatinib. Ponatinib is indicated for the treatment of patients with CML positive for T315I mutation or for patients whom no other TKI therapy is indicated.
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