Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist

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