HSCT 2023.pptx

HEMATOPOIETIC STEM CELL TRANSPLANTATIO N Laura Cannon, PharmD, MPH, BCOP October 6th, 2023 OBJECTIVES ● Understand rationale for autologous and allogeneic HSCT and selection of donor type ● Compare and contrast HSCT types and choice of conditioning regimen in terms of risk/benefit ● Identify HSCT...

HEMATOPOIETIC STEM CELL TRANSPLANTATIO N Laura Cannon, PharmD, MPH, BCOP October 6th, 2023 OBJECTIVES ● Understand rationale for autologous and allogeneic HSCT and selection of donor type ● Compare and contrast HSCT types and choice of conditioning regimen in terms of risk/benefit ● Identify HSCT supportive care needs and prevention/treatment strategies for GVHD HSCT = hematopoietic stem cell HSCT DEFINITION “A collection of multipotent hematopoietic stem cells from the bone marrow, peripheral blood, or umbilical cord blood from one individual when are then re-infused into the same (autologous) or another (allogeneic) individual”* *definition adapted from ASBMT HSCT OVERVIEW ● Dose-response relationship of cancer treatment limited by myelosuppression ○ HSCT allows for administration of high chemo doses (10-fold higher) ○ Hematopoiesis re-established through stem cell infusion ○ Overcomes chemotherapy resistance at standard doses ○ Must balance with risk of other nonhematological toxicities (cardiac, neuro, renal, etc.) DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach. 11th ed; 2020, Chapter GOALS OF HSCT ● Restore normal functioning of bone marrow ● Replace diseased bone marrow with healthy bone marrow ● Rescue a patient following complete eradication of marrow with ablative pre-transplant chemotherapy ● Create a graft-versus-tumor effect (allogeneic transplant) HSCT TYPES Phelan, R., Arora, M., Chen, M. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR US summary slides, 2020. Phelan, R., Arora, M., Chen, M. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR US summary slides, 2020. Phelan, R., Arora, M., Chen, M. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR US summary slides, 2020. INDICATIONS FOR HSCT ● Most common indications overall are myeloma & lymphomas (NHL + HL) ● Myeloma, NHL, & HL → Autologous HSCT ○ Defect occurs in cells undergoing differentiation in lymph nodes, not in bone marrow ■ Rationale for replacing bone marrow cells autologously ○ HSCT used for dose-response relationship to rescue & reset the bone marrow ○ Utilized in relapsed/refractory setting for HL and NHL, upfront for consolidation with MM ● AML & ALL → Allogeneic HSCT ○ Blast cells in the bone marrow are rapidly proliferating ○ HSCT goal is to rescue and REPLACE the bone marrow ○ Used in upfront setting for consolidation in intermediate or high-risk disease Phelan, R., Arora, M., Chen, M. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR US summary slides, 2020. HSCT DEFINITIONS ● Conditioning Regimen: chemotherapy given prior to stem cells to wipe out bone marrow ● Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body ● Graft-versus-host disease: A condition that occurs when donated stem cells or bone marrow (the graft) see the healthy tissues in the patient’s body (the host) as foreign and attacks them ● Graft-versus-tumor effect: An immune response to a person's tumor cells by immune cells present in a donor's transplanted tissue, such as bone marrow or peripheral blood ● Engraftment: is when the blood-forming cells you received on transplant day start to grow and make healthy blood cells https://www.cancer.gov/publications/dictionaries/cancer-terms HSCT PROCESS OVERVIEW HSCT PROCESS OVERVIEW HEMATOPOIETIC STEM CELLS ● The ‘mother’ cell for all blood cells ○ Erythrocytes, leukocytes, platelets ● Rare cells: 0.01% of all bone marrow cells ● Express CD34 antigen ○ Can identify these cells as CD34+ through flow cytometry ● Found in bone marrow, peripheral blood, and umbilical cord blood (UCB) ● Bone marrow stem cells harvested through anterior & posterior iliac crests ● Peripheral blood stem cells harvested through apheresis ○ Requires use of mobilization to move stem cells from bone marrow to peripheral blood ■ G-CSF, Plerixafor PERIPHERAL BLOOD VS. BONE MARROW PERIPHERAL BLOOD STEM CELL COLLECTION BONE MARROW STEM CELL COLLECTION Phelan, R., Arora, M., Chen, M. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR US summary slides, 2020. PERIPHERAL BLOOD VS. BONE PERIPHERAL BLOOD BONE MARROW STEM MARROW STEM CELL COLLECTION CELL COLLECTION ● 1% of the stem cells located in bone marrow ● May require several collections to get adequate cell amounts ● Minimal risk ● Faster engraftment ● Similar to a dialysis session ● Low risk of tumor cell contamination ● Requires bone marrow harvest under general anesthesia ● Equivalent to 50-100 bone marrow biopsies ● Gets directly to stem cell source! ● One time collection with adequate cell amounts ● Source not readily available AUTOLOGOUS VS. ALLOGENEIC AUTOLOGOUS ● Does not require matching to donor because cells come from the patient ● No risk of graft-versus-host disease ● Faster engraftment ● Overall less intense ● Requires no evidence of disease in blood or bone marrow ● No graft-versus-tumor-effect ALLOGENEIC ● Must find donor who is an adequate match ● Risk of graft-versus-host disease ● May experience graft-versustumor-effect ● Overall more intense ● Disease can still be present in blood or bone marrow AUTOLOGOUS VS. ALLOGENEIC ALLOGENEIC HSCT MATCHING ● Human Leukocyte Antigen (HLA) Matching ● Inherited as haplotypes from each parent ● Involves testing loci from both donor and recipient ● Class I: HLA-A, HLA-B, HLA-C ● Class II: HLA-DRB1, HLA-DQ, HLA-DP ● 10/10 match is preferred! ○ 8/10 or 9/10 match is considered if no fully matched donor is available ● Matched Related Donor (MRD) vs. Matched Unrelated Donor (MUD) ALLOGENEIC HSCT MATCHING ● HLA matching important for: ○ Engraftment of donor cells ○ Tolerance to donor cells ■ Less graft-versus-host disease ● Siblings have 1 in 4 chance of being fully matched Join the Bone Marrow Registry at https://bethematch.org/ CONDITIONING REGIMENS ● Given in both auto and allo transplants ○ ○ Auto → overcome chemo-resistance Allo → overcome chemo-resistance, balance of graft-versustumor and graft-versus-host effect ● Myeloablative ○ ○ ○ ○ High doses of chemotherapy and/or radiation Requires stem cell support! Goals: eliminate disease, host immunosuppression, less graftversus-host effect Associated with lower risk of relapse ● Non-myeloablative/Reduced Intensity ○ ○ ○ Lower doses of chemotherapy Requires more graft vs. tumor effect because chemotherapy alone isn’t wiping out tumor cells Can be used in older of heavily pre-treated patients DOSE LIMITING TOXICITY ● Chemotherapy doses in HSCT are much higher than typical chemotherapy doses ● Shift in dose limiting toxicities ○ Myelosuppression is the goal, not a dose limiting toxicity ● Patients need routine monitoring for end-organ damage ○ Liver, lungs, heart GRAFT-VERSUS-HOST DISEASE ● A condition that occurs when donated stem cells or bone marrow (the graft) see the healthy tissues in the patient’s body (the host) as foreign and attacks them ● Allogeneic transplants only ● Acute GVHD (25-70%) ○ Typically <100 days from transplant ○ Skin, GI tract, liver ● Chronic GVHD (15-80%) ○ Can occur at any time point ○ Skin, GI tract, liver, mouth, lungs, eyes ● Mortality correlated with severity! ACUTE GVHD ● Skin - Most common site (75% of patients) ○ Maculopapular, erythematous rash ■ Palm of hands, soles of feet, cheeks, face, neck, upper trunk, back ● Gastrointestinal (GI) - Second most common ○ Lower GI: secretory diarrhea, anorexia ○ Upper GI: nausea, anorexia, dyspepsia ● Liver - Least common site of involvement ○ Hyperbilirubinemia, increases in AST/ALT N Engl J Med 2017; 377:2167-2179 ACUTE GVHD MANAGEMENT ● PREVENTION → Immunosuppression ● Treatment: Corticosteroids at 1 to 2 mg/kg/day ○ Prednisone or methylprednisolone ● Localized management ○ Skin: topical creams/moisturizer ○ GI: anti-nausea/anti-diarrheal medications, beclomethasone, budesonide CHRONIC GVHD ● Usually preceded by acute GVHD (7080% of patients) ● Can occur at any time point ● Less understood compared to GVHD ● Diagnosis requires distinction from acute GVHD and exclusion of other diagnoses ● Sites of involvement: ○ Skin, mouth, liver, GI tract, eye, lung, esophagus, joint ● PREVENTION → Immunosuppression ● Treatment → Corticosteroids N Engl J Med 2017; 377:2565-2579 HOW DO WE PREVENT GVHD? IMMUNOSUPPRESSION IMMUNOSUPPRESSION ● Goals: ○ Prevent rejection of graft by eliminating host immune system ■ Achieved with chemotherapy conditioning regimen- wipes out WBCs fighers ○ Prevent graft-versus-host-disease ■ Suppress donor immune system and prevent recognition of donor cells as foreign ■ Achieved by immunosuppression received prior to stem cell infusion and continued for ~6 months after transplant (if GVHD not present) ● Agents commonly used for immunosuppression prophylaxis: ○ ○ ○ ○ ○ ○ Tacrolimus Cyclosporin Sirolimus Mychophenolate Mofetil Post-transplant cyclophosphamide Methotrexate SELECTION OF PROPHYLACTIC REGIMEN DEPENDS ON TYPE OF TRANSPLANT AND TRANSPLANT PROTOCOL COMMON IMMUNOSUPPRESSIVE ● Tacrolimus AGENTS ○ ○ ○ ○ MOA: Calcineurin inhibitor Target goal: 5-20 ng/mL Nephrotoxicity - especially at levels >20 ng/mL Interactions: CYP3A4 Substrate ● Cyclosporine ○ ○ ○ ○ MOA: Calcineurin inhibitor Target goal: 150-450 ng/mL Less correlation of levels to nephrotoxicity Interactions: CYP3A4 Substrate Taper doses around day 50-100 depending on risk of relapse if not acute GVHD ● Sirolimus HUGE OPPORTUNITY FOR PHARMACIST ○ MOA: mTOR Inhibitor INVOLVEMENT! ○ Target goal: 3-12 ng/mL ○ Interactions: CYP3A4 Substrate SUPPORTIVE CARE ● Immunosuppression & PK monitoring for allogeneic HSCT ● Nausea/vomiting prevention control ● Growth factor (G-CSF) supplementation ● Blood transfusions ● Infection prophylaxis ○ Antibacterial, antifungal, antiviral ○ Based on transplant type, infectious disease evaluation in pre-transplant work-up ● Mouth and skin care → mucositis ● Nutritional support ● Pain management POST-TRANSPLANT ● Immunosuppression tapering ● Lifelong monitoring and follow-up ○ ○ ○ ○ Relapse Infection Organ damage GVHD ● Post-transplant vaccinations