CONCEPTUAL SUMMARY
TYPES OF HSCT AND INDICATIONS
Patient's own stem cells collected, stored, then reinfused after high-dose/myeloablative conditioning. Indications: relapsed DLBCL (complete response to salvage therapy), multiple myeloma, Hodgkin lymphoma. Standard myeloablative conditioning for DLBCL: BEAM-R (carmustine + etoposide + cytarabine + melphalan + rituximab). NOT appropriate for poor-risk AML where allogeneic graft-versus-leukemia (GVL) effect is needed — allogeneic HCT is superior for poor-risk AML. CAR-T therapy (anti-CD19): FDA-approved for DLBCL after ≥ 2 prior lines of therapy — not before autologous HSCT in first relapse with complete response.
Allogeneic HSCT: Donor stem cells. Provides GVL effect. Preferred for poor-risk AML, ALL, MDS with adverse features. Donor hierarchy: matched sibling donor (MSD) preferred → matched unrelated donor (MUD) → haploidentical (half-matched, e.g., children or parents) → umbilical cord blood. Haploidentical vs. cord blood: randomized trial demonstrated improved OS with haploidentical transplant compared to umbilical cord blood.
Myeloablative Conditioning (MAC): High-dose chemotherapy/radiation that completely destroys the bone marrow. Examples: busulfan + cyclophosphamide (BuCy), fludarabine + busulfan (FluBu), fludarabine + TBI. Reduced Intensity Conditioning (RIC): Lower doses — does not fully ablate marrow; used for older/frailer patients. Non-myeloablative conditioning (NMA): Least intensive; relies primarily on GVL effect.
CONDITIONING REGIMEN TOXICITY PREVENTION:
Veno-occlusive disease (VOD) / Sinusoidal Obstruction Syndrome (SOS):
- Risk factors = myeloablative conditioning, busulfan, high-dose TBI, allogeneic HSCT.
- Prevention: ursodiol (hepatoprotective) — start before conditioning and continue through engraftment.
- Defibrotide: was studied for VOD prevention but NOT shown effective in large randomized trial for prevention (it IS used for TREATMENT of severe VOD).
- Hemorrhagic cystitis from cyclophosphamide/ifosfamide: Prevention: mesna ± saline hyperhydration. Continuous bladder irrigation is NOT recommended per ASCO guidelines (mesna is preferred).
- High-dose cytarabine: chemical conjunctivitis → dexamethasone 0.1% ophthalmic drops every 4–6 hours × 7 days post-therapy.
- Busulfan: seizures → antiepileptic prophylaxis required. Levetiracetam or phenytoin (phenytoin traditionally used, levetiracetam now preferred at many centers).
- Thiotepa: skin toxicity → twice daily skin washing/cleaning.
- Melphalan conditioning: ice chips (cryotherapy) — MASCC/ISOO guideline recommended; shown to minimize mucositis with melphalan.
- High-dose chemo with TBI for autologous HSCT with radiation: palifermin (KGF) — reduces mucositis severity and duration. Palifermin is NOT consistently beneficial in allogeneic HSCT setting — not recommended for allogeneic HCT per MASCC/ISOO. Palifermin is NOT recommended for melphalan conditioning.
- Doxepin mouth rinses: for TREATMENT of mucositis pain — not prevention.
- Sargramostim mouthwashes: NOT recommended by MASCC/ISOO.
GVHD PROPHYLAXIS
- Haploidentical HSCT: Standard of care = tacrolimus + mycophenolate + post-transplant cyclophosphamide (PTCy). PTCy is the cornerstone of haploidentical HSCT GVHD prevention — eliminates alloreactive T cells while preserving regulatory T cells.
- Matched sibling or unrelated donor HSCT: cyclosporine + methotrexate (older standard) OR tacrolimus + methotrexate. Anti-thymocyte globulin (ATG): added for mismatched unrelated donors.
ACUTE GVHD GRADING AND TREATMENT:
- Grade I: skin rash < 25% body surface area only.
- Grade II: skin rash 25–50% BSA + gut diarrhea 500–1,000 mL/day + bilirubin 2–3.
- Grade III: skin rash > 50% BSA + diarrhea 1,000–1,500 mL/day OR bilirubin 3–6.
- Grade IV: skin rash with desquamation + severe diarrhea > 1,500 mL/day + deep jaundice/severe organ dysfunction.
First-line treatment:
- Methylprednisolone 2 mg/kg/day — for grades II–IV acute GVHD involving lower GI tract or multiple organs.
- Upper GI GVHD ONLY (dyspepsia, nausea, anorexia — grade II upper GI): prednisone 0.5 mg/kg/day + beclomethasone 8 mg daily (topical GI steroid). This lower steroid dose + topical agent is appropriate because upper GI GVHD without lower GI or skin involvement is less severe. If GVHD develops during calcineurin inhibitor taper: INCREASE the original immunosuppressive agent (tacrolimus) back to therapeutic levels PLUS add methylprednisolone 2 mg/kg/day.
- Ruxolitinib: approved for STEROID-REFRACTORY acute GVHD — NOT for first-line treatment.
- Infliximab: added to methylprednisolone increases toxicity WITHOUT increasing efficacy — NOT recommended in combination upfront.
CHRONIC GVHD: Prednisone 1 mg/kg/day — first-line for chronic GVHD. Ruxolitinib: approved for steroid-refractory chronic GVHD.
INFECTION PROPHYLAXIS POST-HSCT
Pre-engraftment (neutropenic phase, typically day 0 to day +30):
- Antibacterial: fluoroquinolone (levofloxacin preferred — broad gram-negative coverage).
- Antiviral HSV/VZV: acyclovir (or valacyclovir as acceptable alternative).
- Antifungal: depends on risk — fluconazole (standard risk) or posaconazole (high-risk for mold infections).
- CMV prophylaxis: letermovir — FDA-approved for CMV prevention through day +100 in CMV-seropositive allogeneic HSCT recipients. Not used beyond day +100 per current guidelines. Valganciclovir is NOT recommended as CMV prophylaxis (more toxic than letermovir, not superior; better as preemptive therapy).
Post-engraftment (day +30 to day +100): Continue antiviral (acyclovir/valacyclovir), PJP prophylaxis (TMP-SMX). Letermovir continued for CMV prophylaxis through day +100.
Active GVHD on steroids (any time):
- PJP prophylaxis: TMP-SMX first-line. If sulfa allergy: dapsone, atovaquone, or inhaled pentamidine (pentamidine is less effective and has narrower spectrum).
- Antifungal: posaconazole — PREFERRED over fluconazole AND voriconazole for GVHD patients on steroids (proven superior to fluconazole; voriconazole not shown superior to fluconazole in all post-allogeneic patients; posaconazole also has a better toxicity profile).
- Antiviral: acyclovir (valacyclovir acceptable, lower evidence grade for allogeneic).
- Penicillin: added for patients with CHRONIC GVHD (capsular organism coverage for Streptococcus pneumoniae) — NOT for acute GVHD without chronic GVHD.
- Letermovir: FDA-approved for CMV prevention through day +100 ONLY — NOT recommended beyond day +100 per guidelines.
- Antibacterial prophylaxis (levofloxacin/fluoroquinolone): indicated during NEUTROPENIC phase. Not indicated once patient has ENGRAFTED (non-neutropenic) and does not have chronic GVHD.
POST-TRANSPLANT MAINTENANCE THERAPY:
FLT3-ITD AML after allogeneic HSCT: SORAFENIB is the preferred post-transplant maintenance agent — multiple randomized trials show decreased relapse compared to no maintenance. Midostaurin: conflicting evidence, not preferred. Venetoclax: preliminary data only, not standard. Lenalidomide: CONTRAINDICATED post-allogeneic HSCT — increases GVHD risk.
VACCINATION POST-HSCT:
Vaccines are generally NOT started until engraftment is established and immunosuppression is appropriate. Inactivated vaccines: can begin at 6 months post-transplant. Hepatitis B: recommended for ALL patients at 6 months post-transplant. Live vaccines (MMR, varicella, live attenuated influenza): NOT given until ≥ 2 years post-transplant AND complete cessation of immunosuppression AND no active GVHD. Pneumococcal polysaccharide (PPSV23): NOT given until after completing the pneumococcal CONJUGATE (PCV) vaccine series.
DRUG INTERACTIONS WITH CALCINEURIN INHIBITORS:
Tacrolimus and cyclosporine are primarily metabolized by CYP3A4. Strong CYP3A4 inhibitors INCREASE calcineurin inhibitor levels → REDUCE the dose empirically and monitor closely. Posaconazole: strong CYP3A4 inhibitor → DECREASE tacrolimus dose when starting posaconazole. Voriconazole: also a strong CYP3A4 inhibitor → DECREASE tacrolimus dose. Letermovir: also inhibits CYP3A4 (and P-gp) → increases tacrolimus levels, but posaconazole has a MORE PRONOUNCED effect. When both are started, posaconazole is the primary reason for dose reduction. CYP3A4 INDUCERS (rifampin, phenytoin, carbamazepine): DECREASE calcineurin inhibitor levels → may need DOSE INCREASE.
CMV RISK STRATIFICATION: Highest risk: recipient CMV seropositive, donor CMV seronegative (D−/R+) — donor cannot provide CMV-specific immunity. Also high risk: R+ regardless of donor status. Low risk: R− / D−. Letermovir is approved for CMV seropositive recipients of allogeneic HSCT.
PRACTICE QUESTIONS — HEMATOPOIETIC STEM CELL TRANSPLANTATION
KB is a 72-year-old woman with relapsed DLBCL who achieved a complete response after R-ICE salvage chemotherapy. What is the most appropriate therapy for KB at this time?
A. BEAM-R myeloablative conditioning followed by autologous HSCT
B. Busulfan + fludarabine reduced intensity conditioning followed by autologous HSCT
C. Busulfan + fludarabine myeloablative conditioning followed by allogeneic HSCT
D. Anti-CD19 CAR-T cell therapy
Explanation: The standard of care for DLBCL patients who achieve a complete response to salvage therapy (first relapse) is high-dose/myeloablative chemotherapy followed by autologous HSCT. BEAM-R (carmustine + etoposide + cytarabine + melphalan + rituximab) is the standard myeloablative conditioning regimen for B-cell lymphomas. Reduced intensity autologous HSCT (option B) is not appropriate — myeloablative conditioning is required for this indication. Myeloablative allogeneic HSCT (option C) is not standard for DLBCL before attempting autologous HSCT — allogeneic is reserved for select cases (mobilization failure, residual bone marrow disease) due to higher toxicity. Anti-CD19 CAR-T (option D) is FDA-approved for relapsed/refractory DLBCL after ≥ 2 prior lines of therapy — not for first relapse with complete response, where autologous HSCT remains preferred.
[/expand]KB is planning to receive BEAM-R conditioning followed by autologous HSCT. Which intervention is most appropriate to prevent mucositis from her conditioning regimen?
A. Sargramostim mouth rinses
B. Doxepin mouth rinses
C. Ice chips
D. Palifermin
Explanation: BEAM-R conditioning contains melphalan — for mucositis prevention with MELPHALAN-containing regimens, ice chips (cryotherapy) are recommended by MASCC/ISOO guidelines. The cold reduces blood flow to the oral mucosa during drug administration, decreasing drug exposure to oral tissue. Sargramostim mouthwashes (option A) have been studied but are NOT recommended. Doxepin mouth rinses (option B) are used for TREATMENT of mucositis pain — not prevention. Palifermin (option D) has NOT demonstrated benefit specifically in melphalan conditioning regimens — it is beneficial for autologous HSCT with TBI conditioning (myeloid malignancies), not for melphalan-based lymphoma conditioning.
[/expand]KB is now 1 year post autologous HSCT for DLBCL. She has no laboratory abnormalities and no signs of organ dysfunction. Which screening should KB receive for long-term complications at this time?
A. Echocardiogram
B. Bone mineral density testing
C. Renal ultrasound
D. Pulmonary function tests
Explanation: Per the 2012 guidelines for recommended screening and preventive practices for long-term HSCT survivors, ALL WOMEN should receive bone mineral density testing at 1 YEAR post-transplant. This is indicated because conditioning regimens, prolonged corticosteroids, and hormonal changes (menopause from conditioning) all contribute to significant bone loss. Echocardiogram, renal ultrasound, and pulmonary function tests (options A, C, D) are not routine screening at 1 year post-transplant — they would be ordered only if indicated by specific clinical signs, symptoms, or risk factors.
[/expand]SV is a 65-year-old male with AML in first complete remission planning haploidentical allogeneic HSCT with nonmyeloablative fludarabine + cyclophosphamide + total body irradiation conditioning. Which agent should SV receive to prevent conditioning-related toxicity?
A. Continuous bladder irrigation
B. Phenytoin
C. Ursodiol
D. Twice daily skin cleaning
Explanation: SV is receiving cyclophosphamide-containing conditioning + allogeneic HSCT — both are risk factors for sinusoidal obstruction syndrome (SOS/VOD). Ursodiol (ursodeoxycholic acid) is recommended for prevention of SOS/VOD in patients undergoing allogeneic HSCT with myeloablative or high-risk conditioning. Continuous bladder irrigation (option A) is NOT recommended by ASCO guidelines for hemorrhagic cystitis prevention — mesna is the preferred agent. Phenytoin (option B) is required with BUSULFAN therapy to prevent seizures — SV is NOT receiving busulfan. Twice daily skin cleaning (option D) is recommended for THIOTEPA — SV is not receiving thiotepa.
[/expand]SV is planning haploidentical allogeneic HSCT. What is the most appropriate GVHD prophylaxis regimen for SV?
A. Cyclosporine + methotrexate
B. Post-transplant cyclophosphamide
C. Tacrolimus + mycophenolate + anti-thymocyte globulin
D. Tacrolimus + mycophenolate + post-transplant cyclophosphamide
Explanation: For HAPLOIDENTICAL HSCT, the standard GVHD prophylaxis regimen is the combination of tacrolimus + mycophenolate + post-transplant cyclophosphamide (PTCy). PTCy is the cornerstone of haploidentical HSCT — it selectively eliminates alloreactive T cells that cause GVHD while preserving regulatory T cells. Multiple clinical trials have demonstrated acceptable acute and chronic GVHD rates with this approach. Cyclosporine + methotrexate (option A) — older standard for matched sibling/unrelated donor HSCT, not for haploidentical. Post-transplant cyclophosphamide alone (option B) — PTCy must be combined with tacrolimus and mycophenolate for optimal GVHD prevention. ATG + tacrolimus + mycophenolate (option C) — ATG is used for mismatched unrelated donors, not the standard approach for haploidentical transplants.
[/expand]SV (haploidentical HSCT, received tacrolimus + mycophenolate + PTCy for GVHD prophylaxis) presents on day +35 with maculopapular skin rash on 45% of body AND 1,200 mL of diarrhea in 24 hours. Diagnosed with grade III acute GVHD. Which GVHD treatment is most appropriate for SV?
A. Ruxolitinib 5 mg BID
B. Prednisone 0.5 mg/kg/day + beclomethasone
C. Methylprednisolone 2 mg/kg/day
D. Methylprednisolone 2 mg/kg/day + infliximab
Explanation: SV has grade III acute GVHD involving BOTH skin and lower GI tract. First-line treatment per NCCN and ASTCT guidelines is methylprednisolone 2 mg/kg/day — this is the standard for moderate-severe acute GVHD (grade II–IV) involving lower GI or multiple organs. Ruxolitinib (option A) — approved for STEROID-REFRACTORY acute GVHD only; not appropriate as first-line. Prednisone 0.5 mg/kg/day + beclomethasone (option B) — appropriate for UPPER GI GVHD ALONE (grade II, GI only); NOT recommended for lower GI or multi-organ GVHD. Methylprednisolone + infliximab (option D) — combination adds toxicity without improving efficacy; infliximab is not a recommended upfront addition.
[/expand]SV (haploidentical HSCT, tapered off all immunosuppression by day +190) later develops moderate chronic GVHD involving skin and oral mucosa and starts prednisone 1 mg/kg/day at day +240. Which infection prophylaxis regimen is most appropriate for SV at this time?
A. Acyclovir, pentamidine, posaconazole, and penicillin
B. Valganciclovir, pentamidine, fluconazole, and penicillin
C. Valacyclovir, TMP-SMX, voriconazole, and penicillin
D. Acyclovir, TMP-SMX, posaconazole, and penicillin
Explanation: SV has CHRONIC GVHD requiring systemic immunosuppression (prednisone) — comprehensive infection prophylaxis is essential.
- HSV/VZV prophylaxis: acyclovir (recommended; valacyclovir is acceptable alternative but has a lower evidence grade for allogeneic HCT).
- PJP prophylaxis: TMP-SMX (first-line; pentamidine in option A has narrower spectrum and is less effective).
- Antifungal: posaconazole — guideline-preferred for patients with GVHD on corticosteroids; superior to fluconazole for preventing invasive mold infections; voriconazole NOT shown superior to fluconazole in all post-allogeneic patients; posaconazole also has better toxicity profile vs. voriconazole.
- Penicillin: recommended for CHRONIC GVHD patients to prevent Streptococcus pneumoniae — continued as long as active chronic GVHD treatment is administered.
- Valganciclovir (option B) is not appropriate as CMV prophylaxis — it is more toxic as prophylaxis; preferred as preemptive therapy.
LC is a 56-year-old African American female with AML (complex karyotype, FLT3-ITD positive) in first remission. No siblings found; no matched unrelated donors identified in registry. She has two biological children (haploidentical donors). What is the most appropriate post-remission therapy plan for LC?
A. High-dose cytarabine
B. Myeloablative autologous HCT
C. Non-myeloablative umbilical cord blood allogeneic HCT
D. Myeloablative haploidentical allogeneic HCT
Explanation: LC has POOR-RISK AML (complex karyotype + FLT3-ITD) with good performance status. For poor-risk AML in first remission in physiologically younger patients, allogeneic HCT in first remission is the preferred post-remission strategy per NCCN guidelines — allogeneic HCT provides a graft-versus-leukemia (GVL) effect superior to chemotherapy alone or autologous HCT. Without a matched sibling or unrelated donor, haploidentical donors from her children are an ACCEPTABLE alternative. A randomized trial demonstrated improved OS with haploidentical transplant compared to umbilical cord blood transplant — making option D superior to option C. High-dose cytarabine (option A) alone is insufficient for poor-risk AML. Autologous HCT (option B) lacks GVL effect and is inferior for poor-risk disease.
[/expand]LC (haploidentical allogeneic HCT, tacrolimus taper began at day +100) presents at day +130 with grade III acute GVHD (skin rash 45% BSA + 1,200 mL diarrhea/24 hours) during the calcineurin inhibitor taper. What is the most appropriate GVHD treatment for LC?
A. Ruxolitinib 5 mg BID + therapeutic tacrolimus
B. Methylprednisolone 2 mg/kg/day + therapeutic tacrolimus
C. Prednisone 0.5 mg/kg/day + beclomethasone
D. Methylprednisolone 2 mg/kg/day + discontinue tacrolimus
Explanation: LC's grade III GVHD developed DURING tacrolimus taper — per NCCN guidelines, when GVHD develops during a taper of the original immunosuppressive regimen, the correct approach is to: (1) INCREASE the original calcineurin inhibitor (tacrolimus) back to THERAPEUTIC levels, AND (2) add methylprednisolone 2 mg/kg/day for grade III acute GVHD. This dual approach addresses both the restoration of baseline immunosuppression and treatment of active GVHD. Ruxolitinib (option A) — for steroid-refractory disease only; not first-line. Prednisone + beclomethasone (option C) — for upper GI GVHD only; LC has lower GI involvement and skin GVHD → requires higher steroid doses. Discontinuing tacrolimus (option D) — incorrect; tacrolimus should be RE-ESCALATED, not discontinued.
[/expand]LC (same patient) presents during tacrolimus taper with GRADE II GVHD involving UPPER GI TRACT ONLY (dyspepsia, nausea, anorexia — no lower GI symptoms, no skin involvement). In addition to increasing tacrolimus to a therapeutic level, what is the most appropriate GVHD treatment per NCCN guidelines?
A. Ruxolitinib 5 mg BID
B. Methylprednisolone 2 mg/kg/day
C. Prednisone 0.5 mg/kg/day + beclomethasone 8 mg daily
D. Methylprednisolone 2 mg/kg/day + sirolimus
Explanation: LC has GRADE II GVHD involving UPPER GI TRACT ONLY — no lower GI, no skin, no liver involvement. For upper GI GVHD alone, the NCCN guideline-recommended approach (in addition to restoring calcineurin inhibitor to therapeutic level) is: prednisone 0.5 mg/kg/day (lower steroid dose appropriate for isolated upper GI involvement) + beclomethasone 8 mg daily (topical GI steroid that acts locally in the GI tract to reduce inflammation). Methylprednisolone 2 mg/kg/day (option B) — this higher dose is recommended for grade III–IV or multi-organ GVHD; it is ABOVE the recommended dose for isolated upper GI grade II GVHD. Ruxolitinib (option A) — steroid-refractory only. Sirolimus + methylprednisolone (option D) — sirolimus has not demonstrated benefit in combination for front-line GVHD therapy.
[/expand]LC has grade III acute GVHD at day +130 and is on tacrolimus + methylprednisolone 2 mg/kg/day. No known drug allergies. What is the most appropriate infection prophylaxis for LC at this time?
A. TMP-SMX, acyclovir, posaconazole
B. Levofloxacin, acyclovir, letermovir, fluconazole
C. Penicillin, acyclovir, posaconazole, pentamidine
D. TMP-SMX, letermovir, voriconazole
Explanation: LC has active acute GVHD on high-dose steroids (methylprednisolone 2 mg/kg/day) — comprehensive prophylaxis needed. PJP prophylaxis: TMP-SMX (first-line, no allergies). HSV/VZV prophylaxis: acyclovir (ongoing immunosuppression). Antifungal: posaconazole — guideline preferred for GVHD on steroids; superior to fluconazole and better toxicity profile than voriconazole. Antibacterial (levofloxacin): NOT needed — LC has ENGRAFTED (non-neutropenic) and does not yet have CHRONIC GVHD; antibacterial prophylaxis is for neutropenic phase or chronic GVHD with penicillin. Penicillin: for CHRONIC GVHD only — this is ACUTE GVHD. Letermovir: FDA-approved CMV prophylaxis through day +100 ONLY — LC is past day +100; letermovir is not recommended beyond this per current guidelines.
[/expand]LC is 2 months post-haploidentical allogeneic HCT for FLT3-ITD-positive AML. No GVHD present. She is interested in strategies to prevent relapse. Which maintenance agent is most likely to decrease LC's risk of relapse?
A. Midostaurin
B. Sorafenib
C. Venetoclax
D. Lenalidomide
Explanation: LC has FLT3-ITD-positive AML post-allogeneic HSCT. SORAFENIB is the preferred post-transplant maintenance agent for FLT3-ITD AML — multiple randomized trials have demonstrated decreased incidence of relapse compared to no maintenance therapy. Midostaurin (option A) — a FLT3 inhibitor but NOT preferred for post-transplant maintenance; conflicting clinical trial evidence and inconsistent relapse benefit. Venetoclax (option C) — has only preliminary data for post-transplant maintenance, not yet the standard of care; typically studied in combination with other agents. Lenalidomide (option D) — CONTRAINDICATED post-allogeneic HSCT; known to significantly increase GVHD incidence.
[/expand]LC is now 6 months post-transplant. Her medications include tacrolimus 1 mg BID, prednisone 10 mg daily, acyclovir, posaconazole, and TMP-SMX. The team wants to begin revaccination. Which vaccine should LC receive at this time?
A. Measles, mumps, and rubella (MMR)
B. Pneumococcal polysaccharide vaccine (PPSV23)
C. Hepatitis B
D. Vaccines are not appropriate at this time
Explanation: Vaccination can be started at 6 months post-transplant per IDSA and NCCN guidelines. Hepatitis B revaccination is recommended for ALL post-transplant patients beginning at 6 months. MMR (option A) is a LIVE vaccine — contraindicated because LC has ongoing immunosuppression (tacrolimus, prednisone) and is < 2 years post-transplant. Live vaccines require ≥ 2 years post-transplant AND complete cessation of immunosuppression AND no active GVHD. PPSV23 (option B) — pneumococcal polysaccharide vaccine is NOT given until AFTER completing the pneumococcal conjugate (PCV) vaccine series; the series should precede PPSV23.
[/expand]LC is planning tacrolimus + mycophenolate + post-transplant cyclophosphamide for GVHD prophylaxis. Which supportive care is most appropriate to prevent toxicity from her GVHD prophylaxis regimen?
A. Palifermin
B. Defibrotide
C. Mesna
D. Leucovorin
Explanation: LC's GVHD prophylaxis includes POST-TRANSPLANT CYCLOPHOSPHAMIDE — which carries a risk of HEMORRHAGIC CYSTITIS (from acrolein metabolite). Mesna (with or without saline hydration) is the appropriate preventive agent for cyclophosphamide-induced hemorrhagic cystitis in the transplant setting. Palifermin (option A) — not recommended in allogeneic HSCT per MASCC/ISOO guidelines; not consistently beneficial in the allogeneic setting. Defibrotide (option B) — was studied for VOD/SOS PREVENTION but was NOT shown effective in a large randomized trial for prevention; it IS used for TREATMENT of severe VOD. Leucovorin (option D) — prevents toxicity from METHOTREXATE; LC is not receiving methotrexate as part of her regimen.
[/expand]LC is planning haploidentical HSCT with tacrolimus, mycophenolate, and PTCy for GVHD prophylaxis, and levofloxacin + acyclovir + letermovir + posaconazole for infection prophylaxis.
What empiric dose change to tacrolimus is most appropriate based on anticipated drug-drug interactions?
A. Decrease due to posaconazole
B. Decrease due to letermovir
C. Increase due to posaconazole
D. No change is necessary
Explanation: Tacrolimus is primarily metabolized by CYP3A4. Posaconazole is a STRONG CYP3A4 INHIBITOR — it significantly inhibits tacrolimus metabolism → tacrolimus plasma levels increase substantially → risk of toxicity (nephrotoxicity, neurotoxicity, electrolyte abnormalities). An EMPIRIC DOSE REDUCTION of tacrolimus is required when starting posaconazole, with close therapeutic drug monitoring. Letermovir also inhibits CYP3A4 (and P-gp) and can increase tacrolimus levels — but posaconazole has a MORE PRONOUNCED and clinically significant effect, making posaconazole the primary driver of dose adjustment. Increasing tacrolimus (option C) would cause dangerous over-exposure. No change (option D) is unsafe given the well-established interaction.
[/expand]LC (pre-transplant screening): recipient CMV seropositive, donor CMV seronegative. Both recipient and donor are HSV seropositive. High-risk for mold infections. No known drug allergies. What is the most appropriate infection prophylaxis during the pre-engraftment transplant period?
A. Ciprofloxacin, acyclovir, letermovir, fluconazole
B. Levofloxacin, acyclovir, letermovir, posaconazole
C. Penicillin, acyclovir, posaconazole
D. Cefpodoxime, letermovir, voriconazole
Explanation: Comprehensive pre-engraftment prophylaxis must address all four major risk categories:
- Antibacterial: levofloxacin (fluoroquinolone — preferred for gram-negative bacterial prophylaxis during neutropenic phase; ciprofloxacin is an acceptable alternative but levofloxacin provides broader coverage).
- HSV/VZV: acyclovir (both patient and donor are HSV seropositive).
- CMV: letermovir — the patient is CMV seropositive with a CMV seronegative donor (D−/R+) — this is HIGH-RISK for CMV reactivation; letermovir is FDA-approved for CMV seropositive allogeneic HSCT recipients.
- Antifungal: posaconazole — deemed high-risk for mold infections by transplant team; fluconazole (option A) has NO activity against molds; posaconazole provides broad-spectrum coverage including Aspergillus.
- Option C lacks CMV prophylaxis and uses penicillin (not standard neutropenic prophylaxis).
- Option D lacks acyclovir for HSV prophylaxis and uses cefpodoxime (not preferred for neutropenic bacterial prophylaxis — fluoroquinolones preferred).
10. For transplant preparative regimens, what is the primary non-myeloadaptive dose-limiting toxicity seen with etoposide?
- A. Pulmonary fibrosis (14%)
- B. Hemorrhagic cystitis (9%)
- C. Neurotoxicity (29%)
- D. Mucositis (49%)
- Etoposide’s primary non-myeloadaptive adverse effect is mucositis.
- Cytarabine is well known to produce various neurotoxic events, including cerebellar ataxia and dysarthria.
- Hemorrhagic cystitis and cardiotoxicity are seen with high-dose cyclophosphamide.
- Pulmonary fibrosis may be seen with carmustine or busulfan.
51. For transplant preparative regimens, what is the primary non-myeloadaptive dose-limiting toxicity seen with cyclophosphamide?
- A. Thromboembryopenia 20%)
- B. Neutropenia (21%)
- C. Cardiotoxicity (46%)
- D. Pulmonary fibrosis (13%)
- Cardiotoxicity is the dose-limiting toxicity seen with cyclophosphamide.
- Hematologic toxicities would not be an issue since the patient will be receiving the hematopoietic stem cell transplantation.
- Pulmonary fibrosis is a possible adverse effect from such drugs as carmustine and busulfan.
70. A 50-year-old woman undergoes a matched sibling allogeneic hematopoietic stem cell transplant for a relapsed acute myelogenous leukemia. She received busulfan and cyclophosphamide preparative regimen followed later by methotrexate and tacrolimus for graft versus host disease prophylaxis. Which of the following is the most appropriate monitoring plan while receiving this prophylactic regimen in someone with normal hepatic and renal function?
- A CBC, methotrexate and tacrolimus levels (31%)
- B Creatinine, blood pressure, tacrolimus levels (52%)
- C Lipid panel, blood pressure, lipase, amylase (10%)
- D Creatinine, magnesium, methotrexate level (8%)
- Patients on methotrexate and tacrolimus should have routine creatinine, hepatic tests, and electrolyte (especially potassium) monitoring.
- Since tacrolimus can increase blood pressure, it is important to develop a baseline and serially record these values.
- Tacrolimus levels should be monitored routinely since this agent is subject to many drug interactions via CYP3A4 and p-glycoprotein.
- Methotrexate is typically administered in small doses (≤5mg/m² for up to 4 doses). In combination with tacrolimus to prevent graft versus host disease. Methotrexate’s clearance can be altered by several factors, including renal, hepatic disease, and drug interactions.
- Since this patient has normal renal and hepatic disease, you do not need to check methotrexate levels.
- These agents do not regularly cause lipid abnormalities, and hypercholesterolemia is uncommon.
79. BJ is a 61-year-old male who is about to receive thiopeta and cyclophosphamide for an allogeneic HSCT. He has a history of myocardial infarction, hypertension, blood clots, and diabetes mellitus. Which of the following monitoring parameters is most relevant for cyclophosphamide therapy?
- A Hemoglobin A1c (4%)
- B Plasma calcium (7%)
- C Abdomen CT scan (5%)
- D Electrocardiography (84%)
- High-dose cyclophosphamide (over 100 - 200 mg/kg within 48 hours) is typically given in patients undergoing HSCT.
- Patients receiving high-dose cyclophosphamide are at increased risk of non-hematologic toxicity, including hemorrhagic cystitis, cardiac toxicity, GI toxicity, and SIADH.
- Particularly, cardiac toxicity is a dose-limiting toxicity of cyclophosphamide. BJ already has a history of myocardial infarction. Therefore, it is imperative to have baseline cardiac function assessed (electrocardiography, answer d).
- Hemoglobin A1c is important for a patient’s history of diabetes, but not for cyclophosphamide (answer a).
- Plasma calcium and CT scan are not imperative for cyclophosphamide toxicity monitoring (answers b and c).
[/expand]
94. For transplant preparative regimens, what is the primary non-myeloadaptive dose-limiting toxicity seen with cytarabine?
- A. Hemorrhagic cystitis (13%)
- B. Neurotoxicity (65%)
- C. Cardiotoxicity (12%)
- D. Sinusoidal obstruction syndrome (11%)
[expand] Answer (B)
- Cytarabine is well known to produce various neurotoxic events, including cerebellar ataxia and dysarthria.
- Hemorrhagic cystitis and cardiotoxicity are seen with high-dose cyclophosphamide.
- Sinusoidal obstruction syndrome is seen with agents such as busulfan.
- A. Cardiotoxicity (24%)
- B. Graft versus host disease (10%)
- C. Hemorrhagic cystitis (15%)
- D. Sinusoidal obstruction syndrome (52%)
[expand] Answer (D)
- Busulfan is well known to cause sinusoidal obstruction syndrome (SOS) or venoocclusive disease of the liver.
- Symptoms of SOS include weight gain, elevated bilirubin, painful hepatomegaly, and edema.
- The reason why busulfan causes this adverse effect is unknown, but the result can be deadly.
- Cardiotoxicity and hemorrhagic cystitis are seen with high dose cyclophosphamide.
- Graft versus host disease is a result of the newly transplanted allogeneic hematopoietic cells attacking the host.
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119. UL is a 21-year-old male who received an allogeneic HSCT and conditioning chemotherapy that consists of cyclophosphamide plus busulfan. He is now receiving methotrexate and tacrolimus for GVHD prophylaxis. Which of the following would provide the best monitoring parameters for ULs immunosuppressive drugs?
- A Echocardiogram, urinalysis, albumin (5%)
- B Urinalysis, platelet, pulmonary function test (7%)
- C Pulmonary function test, hepatic panel, potassium (12%)
- D Hepatic panel, serum creatinine, potassium (77%)
- Tacrolimus (Prograf) can increase the risk of renal toxicity, hepatotoxicity, electrolyte/wasting, and hypertension.
- In addition, methotrexate can affect renal and hepatic function, and a further decline in renal or hepatic function should lead to an adjustment in the dosing of methotrexate.
- Therefore, the last answer choice is the correct answer for optimal toxicity monitoring and dosing of immunosuppressants.
- The first three answer choices are incorrect.