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Hematopoietic Stem Cell Transplantation Yasar Tasnif, PharmD, BCPS, FAST Associate Professor of Practice | UTEP School of Pharmacy Objectives • Compare and contrast the advantages and disadvantages of the various types of hematopoietic stem cell transplants (HSCTs) • Describe the goals of conditi...
Hematopoietic Stem Cell Transplantation Yasar Tasnif, PharmD, BCPS, FAST Associate Professor of Practice | UTEP School of Pharmacy Objectives • Compare and contrast the advantages and disadvantages of the various types of hematopoietic stem cell transplants (HSCTs) • Describe the goals of conditioning regimens used in HSCTs • Recognize common side effects of myeloablative preparations regimens for HSCT • Discuss the use of non-myeloablative or reduced intensity conditioning • Explain the use of purging, mobilization, and infusion of HSCs Hematopoietic Stem Cell Transplantation • Process of intravenous infusion of hematopoietic progenitor stem cells (HPSC) from donor to recipient, after preparative regimen of chemotherapy and/or radiation in order to re-establish normal hematopoietic and immune function • Is used to treat and cure patients with various malignant and non-malignant disorders Hematopoietic Stem Cells • Pluripotent stems cells can differentiate into hematopoiesis stem cells which primarily occurs in the bone marrow of the pelvis, sternum, vertebral column, and skull • Stem cells also express the CXCR4 receptor which anchors stem cells in the bone marrow • Blockage of CXCR4 http://www.cancer.gov Autologous Transplantation • Procedure in which bone marrow or peripheral blood stem cells are removed from the patient • Patient’s own bone marrow (BM) maybe administered after harvesting or peripheral blood stem cells (PBSCs) replaces th e patient’s stem cells after the patient receives radiation or high-dose chemotherapy • Used hematologic cancers • Multiple myeloma • Hodgkin lymphoma “Purging” in Autologous HPSCs • In-vitro purging may be used to remove cancerous cells from contaminated cancer cells after stem cell collection • Types of in vitro purging methods • 4-hydro-peroxy-cyclophosphamide (a congener of cyclophosphamide) • Mafosfamide (cyclophosphamide derivatives) Rationale for Use of BMT/HSCT • Autologous BMT • Allows for delivery of intensive doses of chemotherapy • Lower rate of complications compared to allogeneic transplant • Lower rate of transplant related mortality compared to allogeneic transplant • Does not cause graft versus host disease (GVHD) • Problem: higher rate of relapse Allogeneic Transplantation • Procedure in which a patient receives bone marrow from another healthy matched person other than an identical twin • Donor is genetically not identical to recipient but shares some common tissue HLA antigens HLA (Chromosome 6) – Matching • Human Leukocyte Antigens (HLA) • HLA helps to determine foreign from not foreign • Needed in allogeneic transplant • Finding a suitable matched donor is important to reduce risk of posttransplant complications • Finding a suitable matched donor can take time if patient does not have a matched sibling • Match happens when HLA-A, B, C and HLA-DR from donor and patient have Rationale for Use of BMT/HSCT • Allogeneic BMT • Can rescue recipient from myeloablative therapy • Eradicates an abnormal hematopoietic system and replaces it with normal functioning hematopoietic cells from another person • Highest rates of transplant related mortality • Establishes graft vs tumor effect • However, it has a lower rate of relapse Types of Allogeneic Types • Matched sibling donor (MSD) • Matched related donor (MRD) • Mismatched sibling donor (MMSD) • Mismatched related donor (MMRD) • Matched unrelated donor (MUD) • Mismatched unrelated donor (MMUD) • Syngeneic (identical twin) donor https://emedicine.medscape.com/article/208954- Reduction of T-cell in Haploidentical HSCT • Sometimes, strategies are used ex-vivo or invitro to decrease T-cells in order to reduce the incidence of graft failure and graft versus host disease (GVHD) due to haploidenticalHSCT • Anti-thymocyte globulin (ATG) • Alemtuzumab • Post-transplant cyclophosphamide infusion Umbilical Cord Blood Cells • Pregnant women are recruited as potential cord blood donors prior to delivery • Concentration of stem cells in cord blood depends on remaining stem cells in the placenta • Restricted by amount of stem cells collected and weight of intended recipient HSCT Pre-Transplant Process • Patient evaluation • Appropriateness for transplant • Patient assessment • Medical history and physical assessment • Labs • Diagnostic procedures • Financial counseling and insurance clearance Selection of Donor Source • Factors • Overall health • HLA match • Age • Sex • Race • Number of pregnancies in female donor • Blood type and ABO compatibility • Serologic status for cytomegalovirus Harvesting of Bone Marrow • Traditionally, bone marrow was used as the source of stem cells • Advantages: • Collections can be completed in several hours and is generally well tolerated • Use of bone marrow results in a decreased risk of chronic GVHD • Disadvantages: • Cells obtained from the bone marrow do not engraft as early as peripheral blood stem cells (PBSCs) • Adverse complication rate <0.3% Peripheral Blood Stem Cells (PBSCs) • During the past 20 years, the use of PBSC has increased significantly compared to bone marrow stem cells • Advantages: • Can be performed as an outpatient procedure with no need for general anesthesia • Cells obtained from the peripheral blood engraft earlier than cells obtained from the bone marrow (decreased neutropenia, fewer infections, decreased hospital stay) • Disadvantages: • Requires cells to be mobilized prior to Stem Cell Mobilization • • Goal is to increase number of circulating stem cells to peripheral blood for harvesting Methods of mobilization • Autologous • Single agent granulocyte colony stimulating factor (G- CSF) • Chemotherapy + G-CSF • Plerixafor + G-CSF • Allogeneic • Single agent G-CSF Plerixafor (Mozobil) • Can rapidly increases mobilization of CD34+ hematopoietic stem cells • Plerixafor is a CXCR4 antagonist which mobilizes platelets from bone marrow • FDA approved in combination with G-CSF in autologous transplantation patients to mobilize hematopoietic stem cells to the peripheral blood in non-Hodgkin’s lymphoma and multiple myeloma Plerixafor • Mostly given to patients with high-risk of poor mobilization because it is expensive • High-risk characteristics include: • Extensive exposure to chemotherapy, lenolidomide or radiation • Older age • Hypocellular bone marrow • Low platelet count • Adverse effects • Pain and erythema at injection site • Nausea • Diarrhea Umbilical Cord Blood (UCB) Stem Cells Advantages Disadvantages • Ease of collection; noninvasive (medical waste) • No risk for mother or child • Less costly than bone marrow collection • Less risk for transmission of blood borne infection transmission • Less need for stringent antigen typing • Decrease rate of GVHD • Less rejection • Small number of stem cells are obtained from UCB • Adults may need more than 2 units • Theoretical risk of disease transmission • Additional cell doses are unavailable • Higher incidence of engraftment failure • Slowest engraftment time Differences between Stem Cells Characteristic BM PBSC Availability Limited Limited Donor attrition Yes (can be high) Yes Collection ease Hard Moderate Collection times Once (or twice) Multiple Collection risk Higher risk Moderate risk Procedure cost High High Stem cell content Adequate Adequate Progenitor cell content Adequate High T-cell content Low High (therefore ↑ GVHD) Tumor cell contamination High risk Low risk HLA matching More restrictive More restrictive Engraftment times Between PBSC and UCB Fastest Acute GVHD Same to less than PBSC Same to more than BM Chronic GVHD Between PBSC and UCB Highest Chimerism Presence of donor hematopoietic and/ or lymphoid cells in the recipient after allogeneic transplant • Mixed chimerism • Both recipient and donor cells are present in the recipient • Full chimerism • All hematopoietic and lymphoid cells are from the donor Graft vs Tumor Effect (GVT) • Immune mediated effect of allogeneic stem cell transplant with full chimerism • Much of the benefit of allogeneic stem cell transplant is due to the immune graft versus tumor (GVT) effect • Donor derived T-cells react against both normal hematopoietic cells and cancer cells of the host • However, often seen in conjunction with graft versus host disease (GVHD) Conditioning Regimens • Myeloablative conditioning regimen • Designed to ablate (remove all) of the patient’s bone marrow • Eradicate the cancer cells • Suppress the immune system • Open spaces in bone marrow for engraftment of donor stem cells • Uses high dose chemotherapy (alkylating agents) sometimes combined with total body irradiation (TBI) • Infusion of stem cells is required to restore hematopoiesis Reduced Intensity Conditioning (RIC) Regimen • Uses much reduced conditioning regimen • Non-myeloablative regimen (mini-transplant) • Is preferred in the elderly since causes less toxicity • Causes mixed chimerism upon engraftment • Causes less graft vs. host disease due to less initial inflammation causes by initial release of cytokines (cytokine storm) caused by the stem cell transplant • Allows for development of graft vs. tumor effect (GVT) Non-Myeloablative HSCT Conditioning Regimens • Uses low dose chemotherapy and/or low dose total body irradiation • Tumor eradication depends on graft versus tumor (GVT) effect which occurs due to donors T-cells • Often is followed by donor T-lymphocyte infusion (DLI) • Patient will need immunosuppression to allow engraftment Schema for nonmyeloablative transplantation for hematologic malignancy. Recipients (R) receive a reduced-intensity conditioning regimen and an allogeneic hematopoietic stem cell transplant (HSCT). Initially, mixed chimerism is present with the coexistence of donor (D) cells and recipient-derived normal and leukemia/lymphoma (RL) cells. Donor-derived T cells mediate a graft-versus-host hematopoietic effect that eradicates residual recipient-derived normal and malignant hematopoietic cells. Donor lymphocyte infusions (DLIs) can be administered to enhance graft-versus-malignancy effects. Common Conditioning Regimens Name HSCT/Dx BEAM: carmustine (BCNU), etoposide, cytarabine (Ara-C), melphalan Auto HD BuCy (busulfan, cyclophosphamide) Allo/Auto Hematologic al cancers BuFlu (busulfan, fludarabine) Allo Hematological cancers Cyclophosphamide +ATG Allo AplasticAnemia Melphalan Auto Multiple Myeloma Carboplatin + etoposide Germ cell cancer Cyclophosphamide + fludarabine Allo MDS, HD Fludarabine + melphalan Allo Hematological cancers Myeloablative NonMyeloablative Drug Dose Limiting Toxicities for Chemotherapeutic Agents in Myeloablative Conditioning Dose-limiting Toxicity Regimens Busulfan Hepatic, seizures (requires phenytoin prophylaxis), mucositis, pulmonary fibrosis Carboplatin Hepatotoxicity, renal, mucositis, peripheral neuropathy Carmustine (BCNU) Pulmonary, hepatic Cisplatin Renal, peripheral neuropathy Cyclophosphamide Cardiomyopathy Etoposide Mucositis Ifosfamide Renal Melphalan Mucositis Thiotepa Mucositis, central nervous system RELATED ALLOGENEIC PERIPHERAL STEM CELL TRANSPLANT Patient Name MR# 222222222 Protocol: 99041 Diagnosis: AML, induction failure not in remission HLA: A 2402/6801, B 0702/0801 C 0701/0702, DRB1 0301/1301 DQB1 0201/0603 DPB1 0401/1901 Referring MD: A. Sunshine MD Case Mgr: September Mitchell RN Friday 10/22/04 Day -17 Monday 10/25/04 Day -14 Tuesday Wednesday Thursday 10/26/04 10/27/04 10/28/04 Day -11 Day -12 Day -11 Friday Saturday 10/29/04 10/30/04 Day -10 Day -9 Sunday Monday Tuesday Wednesday Thursday Friday Saturday Sunday 10/31/04 11/1/04 11/2/04 11/3/02 11/4/04 11/5/04 11/6/04 11/7/04 Day -8 Day -7 Day -6 Day -5 Day -4 Day -3 Day -2 Day -1 Monday 11/8/04 Day 0 ABW-actual body weight Donor: Donor Name MR# 44444444 HLA: A 2402/6801, B 0702/0801 C 0701/0702, DRB1 0301/1301 DQB1 0201/0603 DPB1 0401/1901 DOB: 12/04/1961 Age/gender: 60yr/F Ht/W t: 173cm/78kg CMV: reactive HSV: ABO: A positive Allergies: Penicillin, Aztreonam, Betalactams GVHD prophylaxis: MMF, Cyclosporine A Dilantin 300mg PO TID x 1 day, then QD until completion of TBI Busulfan 22mg/m² ABW IV at 0800, blood levels to follow Radiation planning and simulation @ 1300 Simulation check @ 1300 Busulfan 22mg/ m² IV or at adjusted dosage at 0800 Busulfan at adjusted dosage IV every 6 hours and continue for a total 16 dose. Busulfan IV every 6 hours for total 16 doses Busulfan IV every 6 hours for total 16 doses Busulfan IV every 6 hours for total 16 doses TBI 120cGy x2 TBI 120cGy x3 TBI 120cGy x3 Begin Donor GCSF injections TBI 120cGy x2 VP-16 30mg/kg AIBW IV Red cell exchange Begin Cyclosporine A 3mg/kg/day AIBW Donor apheresis Infusion of donor stem cells. MMF 30 mg/kg/day AIBW in 2 divided doses to begin at least 2 hours after stem cell infusion. Donor apheresis if necessary AIBW-adjusted ideal body weight DOB: 12/25/1972 Age/gender: 48yr/M ABO: O positive CMV: nonreactive HSV: negative Ht/W t: 183cm/77kg Allergies: Penicillin, MD Transplan t • Calendar Day -17 to -3 – Insertion of central venous catheter – Informed consent – Preparative regimen • Day -1 to -2 – Rest • Day 0 – Transplant/Infusion •Day 1++++ Amoxicillin – Close observation – Symptom management Total Body Irradiation (TBI) • May be used in combination with chemotherapy in hematologic cancer in autologous or allogeneic stem cell transplantation due to its immunosuppressive effects and its ability to penetrate into sanctuary sites • Typically uses fractionated radiation administration of the total dose over several days • Is associated with immediate and delayed toxicities • Acute - nausea, vomiting, transient acute parotiditis, xerostomia, mucositis, and diarrhea • Stem Cell Rescue Infusion • Intravenous reinfusion of hematopoietic cell graft into the patient following myeloablative or non-myeloablative therapy • Infusion of hematopoietic stem cells occurs on Day 0 • May be referred to as “transplantation” or “re-infusion” • Patient may be given pre-medications to minimize infusion reaction • Diphendramine 25-50 mg IV • Hydrocortisone 250 mg IV Complication of Stem Cell Rescue • Facial flushing • Tickling sensation in throat • Rare • Bradycardia • Abdominal pain • Seizure • Renal failure • Encephalopathy • Encephalopathy prevention • Divide large volume infusion over 2 days • Infuse product slowly Engraftment • Stem cells first travel to the lungs, then travel through the bloodstream to the bone marrow, where they begin to engraft and produce new WBC's, RBC's, and platelets • Engraftment usually occurs within 2 to 4 weeks (day 14+ to day 28+) following transplantation • Complete recovery of immune function takes much longer • Up to several months for autologous transplant recipients • 1 to 2 years for patients receiving allogeneic transplants Engraftment • Neutrophils • Sustained ANC >500/mm3 for 3 consecutive days • Time frame • BM = ~19 days • PBSC = ~14 days • UCB = 22-27 days • Platelets • Sustained platelet count 20,000/mm3 for 7 consecutive days • Time frame • BM = ~25 days • PBSC = ~18 days Engraftment Failure • Types • Primary – failure to establish engraftment • Secondary – loss of established graft • Incidence • Matched sibling donor transplant <5% • Matched unrelated donor 10-15% • Risk factors • Aplastic disease • Occurrence of GVHD • Use of non-myeloblative therapies Use of Immunosuppression • Prevention of graft rejection vs. graft versus tumor effect • Component of conditioning regimen • Eradicates host immune system (T-cells) to allow acceptance of donor cells (prevent rejection of host versus graft) • Prevention of graft versus host disease (GVHD) • Suppress donor immune system (T lymphocytes) and minimize recognition of host cells as foreign Commonly Used Immunosuppressants Class Calcineurin Inhibitors Immunosuppress ant Folate inhibitor Corticosteroids mTOR inhibitor Drug • Tacrolimus • Cyclosporine • Mycophenolate mofetil • • • • Methotrexate Methylprednisolone Prednisone Sirolimus Recovery • First 100 days post stem cell infusion are the most critical • Patients may experience multiple toxicities from the preparative regimen • Mucositis/ stomatitis • Venoocclusive occlusion • Interstitial pneumonitis Immune Recovery • B-cell counts usually return to normal within 3-12 months post-transplant • Recovery may not occur until at least 2 years in patients with chronic GVHD Stem Cell Transplantation Side Effects Short Term Side Effects Long Term Side Effects • Nausea, vomiting, diarrhea • Stomatitis > mouth sores, esophagitis • Hair loss (alopecia) • Skin changes • Loss of appetite • Fatigue • Electrolyte wasting • Secondary malignancies • Reproductive & sexual issues • Body image changes • Skin changes • Memory loss • Electrolyte wasting References • Elizabeth D, Janelle P. Hematopoietic Cell Transplantation. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill; 2023. Accessed May 02, 2023. • Dr. Chavez, HSCT Lecture, 2022 • Be the Match. Transplant Indications and Outcomes. https://bethematchc linical.org/resources-and-education/materials-catalog/ Questions • Please contact me at: [email protected]
