Download
allogeneic hematopoietic stem cell transplant for the medical oncologist n.
Skip this Video
Loading SlideShow in 5 Seconds..
Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist PowerPoint Presentation
Download Presentation
Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist

Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist

571 Views Download Presentation
Download Presentation

Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

  2. Objectives • Understand basic principles of Allogeneic Transplant: • Types of Preparative Regimens • Stem Cell Source • Donor Types

  3. Hematopoietic Stem Cell Transplantation • Premise – a platform to deliver: • Dose intensive therapy (chemotherapy and/or radiation) for myeloablation and immune ablation • Hematopoietic Stem Cells (replacing damaged or abnormal bone marrow) • Immunotherapy (graft-versus tumour effect)

  4. Stem Cells • By nature have capacity of: • Self renewal • Ability to differentiate into all mature peripheral blood cells • Practical surrogate marker is CD34 • Cell surface marker found on immature WBC • Counts have been associated with hematopoietic recovery

  5. Components of an Allogeneic SCT procedure • Pre SCT Therapy • Conditioning Regimen – the chemotherapy / radiation regimen that may have anti-cancer properties and that provides bone marrow / immune modulation for the graft • Donor stem cell source – the person providing stem cells (sibling, MUD, Mismatch MUD, Haploidentical) • Type of stem cells – bone marrow, peripheral blood, umbilical cord blood • GVHD Prophylaxis – agents that may “temper” the donor immune system in the recipient • Post SCT therapy

  6. Transplant Conditioning Regimens • Myeloablative regimens have been typical approach • Limited use of transplant due to high toxicity (upper age limit of 60 and medically fit) • Based on drugs that can be dose escalated (typically alkylators) and radiation • Standard regimens: CY-TBI and BU-CY

  7. Bu-Cy vs Cy-TBI in myeloid diseases – Bu-Cy favoured? • Survival appears similar in 4 RCTs • Easier to give Bu-Cy over Cy-TBI (lack of TBI allows for easier treatment planning • Meta-analyses performed: • Acute leukemia: CY-TBI had lower relapse and TRM with improved DFS • CML: CY-TBI had higher relapse, lower TRM and similar DFS • CY-TBI had higher rates of cataracts [odds ratio (OR) 12.69, p = 0.01], interstitial pneumonitis and later growth or development problems [OR 5.04, p = 0.008]. • BU-Cy associated with higher rates of VOD [OR 0.43, p < 0.00001], hemorrhagic cystitis, and TRM. Shi-Xia Leuk Lymphoma 2010

  8. Trade-offs in Traditional BMT Regimens – is less better? • BMT is a modality that allows the delivery of radiation in disseminated disease (ie. leukemia) • Toxicities with both are substantial and limit the delivery of therapy • Newer chemotherapy and immunosuppressive agents lead to the development of new regimens • Less myeloablation • More “immunosuppressive” transplant which facilitates engraftment of stem cells • Less direct anti tumour effect

  9. Champlin Criteria of a RIC Regimen • Defines as reduced intensity: • any regimen that does not require stem cell support for hematopoietic recovery and • results in low non-hematologic toxicity and • mixed donor recipient chimerism in a substantial proportion of patients in the early post transplant period (around day +30) Champlin in Giralt+Slavin (text)

  10. The ultimate non-myeloablative regimen – the original Seattle protocol • 2 Gy TBI • CsA + MMF • Tested in AML and CML • Problems with graft failure • Add additional agents (fludarabine) to improve outcome Storb Mol Ther (Review) 2006

  11. Transplant Regimens – Non-myeloablative or Reduced Intensity • Non-myeloablative transplant – autologous marrow and immune recover possible • Fludarabine 30 mg/m2 X 3+ 2 Gy TBI • Reduced Intensity Conditioning (RIC) • Concept: less drug = less toxicity • Regimens vary agents and doses of drugs • Fludarabine + Busulfan 3.2 mg/kg X 2 + 2 Gy TBI • Fludarabine + Busulfan 3.2 mg/kg X 4 + 4 Gy TBI

  12. RIC vs Myeloablative Toxicity • Initial studies lead to a variety of possible regimens • Fludarabine-TBI • Fludarabine-Cyclophosphamide • Fludarabine-Melphalan • Fludarabine-Busulfan • All share the RIC concept – transplant more as immunotherapy

  13. Immunosuppressive and Myelosuppressive Properties of Common Preparative Regimens Storb et al. ASH Education book 2011

  14. NMDP Operational Criteria for a RIC Regimen • TBI – up to 500 cGy single fraction or 800 cGy fractionated • Total busulfan up to 9 mg/kg • Total melphalan up to 140 mg/m2 • BEAM regimen (debatable by some) Giralt BBMT 2009

  15. Matched Pair Comparison of Flu-Bu-ATG and Bu-Cy (Calgary and CIBMTR) • 120 cases, 215 controls • TRM ; Flu-Bu 12%, BuCY 34%, p<0.001 • 2-4 A-GVHD: Flu-Bu:15% BuCY:34%, p<0.001 • Relapse: Flu-Bu:42%, BuCY: 20%, p<0.001 • C-GVHD and DFS similar

  16. FluBu-ATG and BuCY matched pair comparison • Interesting and suggests trade-offs • Toxicity vs. efficacy • Should this be tested in a phase III trial? • Can the platform be improved?

  17. Summary – Conditioning Regimens • Wide variety of intensity in regimens • Safety and comorbidity typically drives decision • Age and organ function can limit choice (age 50, 55 or 60 is often an arbitrary cutoff to limit myeloablative procedures) • RIC or non-myeloablative procedures allows greater availability of transplant procedures

  18. Sources of Hematopoietic Stem Cells • Bone Marrow • Peripheral Blood • Cord Blood • Stimulated (G-CSF) or not

  19. Collection of Stem Cells • Bone Marrow – involves marrow harvest • Anaesthesia, OR, procedure time • Peripheral Blood – requires g-csf to increase peripheral concentration of CD34+ cells and subsequent apheresis • Umbilical Cord Blood – collected from umbilicus at time of birth and stored • Trade-off – procedures vary substantially for patient but RCTs are available

  20. Donor Stem Cell Source – Allogeneic • RCTs confirmed benefit of PB (g-csf mobilized) over BM (steady state) with improved survival • Higher rate of chronic GVHD in patients receiving PB grafts • Pilot data of g-csf mobilized BM demonstrates shorter time to engraftment and less C-GVHD • RCTs evaluating g-csf mobilized PB vs. BM are ongoing • Bone marrow still preferred in situation where GVHD is NOT needed (aplastic anemia)

  21. Impact of Donor Stem Cell Source on Allo-SCT: Improved Survival Bensinger NEJM 2001

  22. Meta-analysis of G-PB vs. BM • Compared to PBSCT, BM had: • Lower rates of neutrophil and PLT engraftment • Decrease in the development of grades II-IV A-GVHD (HR, 0.75; 95% CI, 0.63-0.90; p = 0.002) • Decrease in the rates of overall C-GVHD (HR, 0.70; 95% CI, 0.59-0.83; p < 0.0001) • Higher incidence of relapse (HR, 1.91; 95% CI, 1.34-2.74; p = 0.0004) • Comparable TRM (1.08; 95% CI, 0.56-2.10; p = 0.81) • Comparable LFS (HR, 1.04; 95% CI, 0.83-1.30; p = 0.73) • Comparable OS (HR, 1.06; 95% CI, 0.81-1.39; p = 0.65) Chang Ann Hematol 2011

  23. Next Generation of Trials • Can benefits of bone marrow (lower GVHD) be combined with benefits of PBSCs (improved engraftment and relapse rates)? • Pilot data of g-csf mobilized BM showed promising results and lead to the RCTS: • CBMTG 0601 (related donors) and others • NMDP trial in MUD

  24. Allogeneic Stem Cell Collection • G-CSF mobilized PBSC became standard of care • Mobilization failure unlikely as donors are healthy and typically have normal marrow function • Mobilize with G-CSF alone • Concerns: • Effect of G-CSF (case reports of leukemia) • Familial hematologic disorders (ie. finding malignant/pre-malignant disorders during donor workup)

  25. Summary – Stem Cell Source • Outside of a clinical trial, g-csf mobilized PBSC are typically preferred • More rapid engraftment and lower relapse • Donor preference an issue (type of procedure) • BM can be considered in transplants where GVHD/GVT effect is less important (ie. Aplastic anemia or benign disorders)

  26. Types of Donor • Autologous • Syngeneic (identical twin) • Allogeneic • Sibling (matched / mismatch) • Alternative donor • Unrelated Donor (matched / mismatch) • Haploidentical • Umbilical Cord Blood

  27. Donor Selection and Matching • Most successful results initially with identical twins (fully matched) • Siblings more likely to be matched than MUD depending on degree of testing • Transplant strategy would require more intensive immunosuppression as quality of match decreases • Large prospective series limited – no RCT of sibling vs. other stem cell source

  28. Matching – MHC and HLA • Major Histocompatibility Complex (part of immune system) • Class 1 – found on all nucleated cells and involved in antigen presentation • Class 2 – found on immune cells (APCs) • In humans, the MHC subset that presents APCs on immune cells are called HLA genes (Human Leukocyte Antigens) • Class 1 genes: HLA-A, HLA-B, HLA-C • Class 2 genes: HLA-DPA, HLA-DP, HLA-DQ, HLA-DRA, HLA-DRB1 • HLA genes are highly polymorphic

  29. Matching and Donors • Beyond the scope of the current discussion • Brief summary of NMDP Recommendations • All should have high resolution testing (4 digit) for HLA-A, HLA-B, HLA-C and HLA-DRB1 (8/8 testing) • Mismatches at HLA-DP and HLA-DQ did not affect survival • DRB3, DRB4 and DRB5 have unknown significance http://marrow.org/Physicians/Transplant_Advances/HLA_Typing_Advances.aspx#table-1

  30. Alternative Donor Options • Mismatched transplants are also an option • 9 / 10 or 8 / 10 • Haploidentical transplantation allows almost everyone to have a donor but represents a huge immunologic barrier (high risk) • Haploidentical donor can be a parent so most people potentially have a donor • Degree of mismatch increases risk of TRM

  31. Donor Stem Cell Source • Syngeneic stem cells are lowest risk from TRM standpoint • Concern of lack of immunologic effect (ie. No GVT) • Sibling transplants have traditionally had best outcomes (from NRM and GVHD standpoint) • Outcomes for MUD transplants have improved (better regimens and supportive care) • Cord blood is appealing as less matching may be necessary but stem cell dose (given size of recipient) is often an issue (solution of 2 cords)

  32. Alternative Donor Transplantation – Cord vs. Haploidentical • BMT CTN Phase II trial of RIC allo using double UCB (n=50) or Haplo-marrow (n=50) • Flu-Cy-200 cGy TBI • GVHD prophylaxis with CsA+MMF or FK506+MMF • Haplo received CY on Day+3 and +4 • 1 year OS: 54 (dUCB) vs 62 (haplo) • 1 year PFS: 46 (dUCB) vs 48 (haplo) • 1 year NRM: 24 (dUCB) vs 7 (haplo) • 1 year relapse: 31 (dUCB) vs 45 (haplo) • Based on these results, a phase III trial is planned Brunstein et al. Blood 2011

  33. BMT CTN – dUCB vs. Haplo Primary Endpoint was OS at 6 months – if > 60%, arm was deemed positive Brunstein et al. Blood 2011

  34. Summary – Donor Source • Clear Hierarchy • Syngeneic • Matched Sibling • Matched Unrelated • Mismatch / UCB / Haplo ? MUD • Outcomes of MUD, haplo and UCB have improved with newer approaches • RCTs required to determine optimal donor for patients without sibling match

  35. Allogeneic Transplant – GVHD Prophylaxis • Classical conditioning is calcineurin-inhibitor based (cyclosporine A or tacrolimus) in combination with short course methotrexate • Potent T cell depletion can be achieved ex vivo or in vivo with alemtuzumab (anti CD-52), anti-thymocyte globulin (ATG) • Recently agents such as sirolimus (mTOR inhibitor) and MMF are increasingly utilized

  36. Pre-transplant Assessment • Disease assessment for response • Comorbidity is an important predictor of outcome when older patients are transplanted • Indices can be utilized and have been validated • Pulmonary function, cardiac function • Programs have typical criteria for organ function • Dental assessment (source of bacteremia during neutropenic period)

  37. PAM score • 50 point score based on 8 factors: • Age • Donor type • Disease type • Conditioning regimen • FEV1 • DLCO • Creatinine • ALT Parimon et al Ann Intern Med 2006

  38. PAM Predictive of 2 year Overall Survival Parimon et al Ann Intern Med 2006

  39. Key Question with Comorbidity Indices • We can identify patients with high risk of treatment failure (death due to relapse or non-relapse mortality) • Can we alter this endpoint? • Alter transplant strategy (ie use RIC or NMA) • Avoid transplant strategy • Optimize patient and proceed • Little data about prospectively risk-stratified approaches

  40. The Transplant Procedure • Increasingly common with growing indications • As safety increases, older dogma relaxes • Isolation not required (outpatient transplants) • Dietary restrictions apply • With RIC transplants – patients are quite well and may not even require transfusion

  41. The Transplantation Period • Autologous Transplant • TRM 1-3% typically (as high as 5-10% if transplanting heavily pre-treated, older, co-morbid) • Typical hospital stay is approximately 3 weeks, neutropenic period < 14 days • Allogeneic Transplant • Early TRM is 5-10% (to day +100) and may reach 20% • Typical hospital stay 4 weeks, neutropenic period may be 3 weeks

  42. Early Transplant Complications • Typical issues involve mucositis, neutropenic fever, mild renal or liver dysfunction, infection • Less common but worrisome toxicities include other organ toxicity due to therapy, VOD of the liver, pulmonary hemorrhage, opportunistic infection (viruses such as CMV), acute or hyper-acute GVHD, engraftment syndrome

  43. Late Transplant Complications – Allo • Chronic GVHD and chronic immunosuppression • Infection (Viral, fungal, bacterial) • Secondary Malignancies • Endocrine dysfunction (hypogonadism, hypothyroidism, osteoporosis etc) • Cognitive dysfunction

  44. Demonstrating Graft-versus Tumour Effect – impact of GVHD in ALL Weiden et al NEJM 1979

  45. Graft versus tumour Effect • Reducing immunosuppression or giving more donor cells (DLI) has been shown to kill tumour cells and has lead to sustained remission (ie. cure) in some cases • Most potent in indolent diseases (CML, CLL or indolent NHL, AML) • Less effective in more aggressive diseases (despite being proven in ALL – ie. High grade lymphoma etc.) • The Holy Grail = GVT without GVHD

  46. GVT (or GVL) and DLI • Impact of graft-versus-tumour effect varies based on type of disease • Typically this is not a rapid effect and will not deal with highly aggressive disease • Demonstrated in acute and chronic leukemia, indolent and aggressive NHL, HL, MM • Donor lymphocyte infusion (DLI) can be collected and used to improve chimerism or for anti-tumour effect • Most effective in CML • Least consistent in highly aggressive lymphoma or ALL

  47. The Lesson – RCT data in AML CR1 Cassileth NEJM 1998

  48. Interpreting BMT Studies • Patient selection • Clearly an issue in institutional results • Referral (time) and travel biases • The patient denominator issue • If only selecting responders – their outcome is usually better than non-responders but a transplant strategy must take into account all patients you wish to transplant • Philosophy for threshold of outcome

  49. Summary – Allogeneic Transplant • A very large and potentially complicated area • Multiple components in the procedure • Both an elegant and brutal procedure • Some knowledge necessary for all who manage hematologic malignancies