Indications for High-Dose Cytotoxic Therapy with Stem Cell Transplantation

1. Indications for High-Dose Cytotoxic Therapy with Stem Cell Transplantation Evidence-Based Reviews

2. Sackett, D.L. et al. Evidence-based medicine: what it is and what it isn't. BMJ 1996;312:71-72. “The practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research.”

3. Goals • Define accepted medical practice • Promote evidence-based decisions • Improve treatment outcomes • Determine areas of needed research

4. Steps • Assemble evidence for selected diseases • Evaluate strength and quality of the evidence • Identify discrepancies in study design or methodology • Make treatment recommendations • Recommend areas of needed research • Advocate best treatment for all patients • Improve access/reimbursement • Inform patients, providers, and payers

5. Benefits of Evidence-Based Medicine • Aid treatment decisions of referral physicians and their patients • Assist in reimbursement policies and decisions • Enhance technology assessment • Identify areas of needed research • Foster quality of study design/methodology • Document best practices/standards of care Improved Patient Care

6. The Review Process ASBMT Steering Committee • Establishes criteria for grading evidence and inclusion/exclusion criteria for evidence • Maintains standards of evidence-based medicine • Identifies diseases for review • Nominates expert panelists for each review

7. The Review Process Expert Panel for Each Disease • Transplant specialists • Disease-specific experts for non-transplant therapies • Third-party payer • Patient advocate

8. The Review Process Expert Panel for Each Disease • Identifies areas of inquiry/parameters of review • Guides and advises literature search, writing • Evaluates strength/quality of evidence • Reaches consensus on treatment recommendations • Recommends areas for further study

9. Completed Evidence-Based Reviews • Diffuse Large B-Cell Non-Hodgkin Lymphoma (2001; Updated January, 2011) • Follicular Lymphoma (2010) • Myelodysplastic Syndromes (2009) • Acute Myeloid Leukemia in Adults (2008) • Acute Myeloid Leukemia in Children (2007) • Acute Lymphoblastic Leukemia in Adults (2006) • Acute Lymphoblastic Leukemia in Children (2005) • Multiple Myeloma (2003)

10. Current and Future Directions • Periodic updating of completed reviews based on evolving standards and new scientific evidence. • Diffuse Large B Cell Lymphoma EBR update in 2011 • Acute Lymphoblastic Leukemia in adults and children EBR updates in 2011 • Acute Myeloid Leukemia in adults and children EBR updates in 2011

11. EBR Update Process • Updates occur in the same order as the publication of original EBRs, unless there is a substantial reason to change the order of a specific review • The original expert panel is invited to participate in the update • New evidence is presented in summary tables along with high level evidence from the original EBR • Updated Treatment Recommendations indicate whether new evidence strengthens, weakens, or does not change the original recommendations ASBMT Policy Statement on updating published EBRs: Biology of Blood and Marrow Transplantation (Vol. 15:761-762) June 2009

12. First Update in the EBR Series! “The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Treatment of Diffuse Large B Cell Lymphoma: Update of the 2001 Evidence-Based Review” Biology of Blood and Marrow Transplantation 2011, in press.

13. Diffuse Large B Cell Lymphoma RECOMMENDATIONS AUTOLOGOUS SCT VS. NON-TRANSPLANT THERAPY • Autologous SCT provides a significant survival benefit and is recommended as part of salvage therapy for patients with chemosensitive relapsed DLBCL. This original recommendation is unchanged with no new data published since the original EBR. • Autologous SCT is not recommended for patients who achieve only a partial response to an abbreviated (3 cycles) induction regimen. This original recommendation is unchanged with no new data published since the original EBR.

14. Diffuse Large B Cell Lymphoma AUTOLOGOUS SCT VS. NON-TRANSPLANT THERAPY • Autologous SCT provides a significant survival benefit and is recommended as part of salvage therapy for patients with chemosensitive relapsed DLBCL. This original recommendation is unchanged with no new data published since the original EBR.

15. Diffuse Large B Cell Lymphoma AUTOLOGOUS SCT TIMING AND PROTOCOL • Based on new data published since the original EBR, older age (> 60 years is not a contraindication for autologous SCT as long as other SCT eligibility criteria are met. However, SCT outcomes (transplant-related mortality, relapse, survival) in older adults are not as good as in younger adults. • Based on new data published since the original EBR, autologous SCT using peripheral blood, compared to bone marrow, provides no survival benefit or improved tumor control. However, autologous SCT using peripheral blood is safer and easier to use with faster engraftment and lower rate of death due to infection, hence peripheral blood is the standard autologous stem cell source.

16. Diffuse Large B Cell Lymphoma AUTOLOGOUS SCT TIMING AND PROTOCOL • Based on new data published since the original EBR, planned tandem or multiple sequential autologous SCTs are not recommended. • The new data published since the original EBR are insufficient to recommend routine post-autologous SCT maintenance with rituximab outside of a clinical trial. • The new data published since the original EBR are insufficient to make a treatment recommendation regarding fewer versus more cycles of induction therapy prior to first-line autologous SCT.

17. Diffuse Large B Cell Lymphoma AUTOLOGOUS VERSUS ALLOGENEIC SCT • Based on new data published since the original EBR, there are equivalent survival outcomes after autologous and allogeneic SCT. Neither donor option is recommended over the other since they have competing risks with regard to relapse and transplant-related mortality. Comparison of these two techniques is biased by different patient selection criteria.

18. Diffuse Large B Cell Lymphoma ALLOGENEIC SCT CONDITIONING • The new data published since the original EBR are insufficient to recommend reduced intensity versus myeloablative conditioning for allogeneic SCT. Based on one study and expert opinion, reduced intensity conditioning appears to be an acceptable alternative approach for selected patients who cannot tolerate a myeloablative allogeneic SCT. Longer follow-up is needed to clarify the competing risks of relapse and chronic GVHD and their impact on overall survival and quality-of-life. Comparison of these regimen intensities is biased by patient selection criteria which have changed over time.

19. Diffuse Large B Cell Lymphoma AREAS OF NEEDED RESEARCH • Identify more effective induction regimens to optimize disease response and reduce the need for autologous SCT. • Identify and examine the efficacy of predictive tests (i.e., Positron Emission Tomography scans) to classify patients who are at high risk for early treatment failure (those who are primary refractory to initial therapies and those who respond but quickly relapse) and candidates for autologous SCT. • Update the International Prognostic Index to include molecular markers and/or gene expression profiling to better discriminate prognostic groups that would benefit from SCT. • Determine the potential benefit of first-line autologous SCT for patients with central nervous system involvement.

20. Diffuse Large B Cell Lymphoma AREAS OF NEEDED RESEARCH • Identify effective salvage regimens to optimize disease response prior to autologous SCT. • Identify effective high dose therapy regimens to optimize complete response, improve hematopoietic recovery, and reduce transplant-related mortality and incidence of secondary malignancies. • Identify effective maintenance regimens to optimize disease control post-autologous SCT. • Examine the efficacy of reduced intensity allogeneic SCT as rescue after a failed autologous SCT.

21. Diffuse Large B Cell Lymphoma THE EXPERT PANEL • Denise M. Oliansky, Roswell Park Cancer Institute (RPCI), Buffalo, NY • Myron Czuczman, RPCI, Buffalo, NY • Richard I. Fisher, University of Rochester, James P. Wilmot Cancer Center, Rochester, NY • Frank D. Irwin, Optum Health Care Solutions, Minneapolis, MN • Hillard M. Lazarus, Case Comprehensive Cancer Center, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH • James Omel, Independent Patient Advocate, Grand Island, NE • Julie Vose, University of Nebraska Medical Center, Omaha, NE • Steven N. Wolff, Meharry Medical College and Vanderbilt University, Nashville, TN • Roy B. Jones, MD Anderson Cancer Center, Houston, TX • Philip L. McCarthy Jr., RPCI, Buffalo NY • Theresa Hahn, RPCI, Buffalo, NY

22. Newest Evidence-Based Review! “The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Therapy of Follicular Lymphoma:An Evidence-Based Review” Biology of Blood and Marrow Transplantation (Vol. 16:443-468) April 2010

23. Follicular Lymphoma RECOMMENDATIONS AUTOLOGOUS SCT VS. NON-TRANSPLANT THERAPY • Based on pre-rituximab data, there is a statistically significant improvement in overall survival (OS) and progression-free survival (PFS) using autologous stem cell transplantation (SCT) as salvage therapy. • With only one retrospective study, there are insufficient data to make a recommendation on the use of autologous SCT versus non-transplantation therapy as salvage treatment for patients who have had rituximab as part of their salvage therapy.

24. Follicular Lymphoma AUTOLOGOUS SCT VS. NON-TRANSPLANT THERAPY • Autologous SCT is recommended for transformed follicular lymphoma patients, based on expert opinion and accepted clinical practice. • Although there is consistent improvement in PFS and event-free survival (EFS) with autologous SCT, it is not recommended as first-line treatment for most patients because of no significant improvement in OS, a higher incidence of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and a lack of comparative data with rituximab-containing regimens. Longer follow-up may be needed to identify differences in OS.

25. Follicular Lymphoma AUTOLOGOUS SCT TIMING AND PROTOCOL • There are insufficient data to make a recommendation on the efficacy of autologous SCT as first-line versus salvage therapy. • Due to conflicting data, a recommendation cannot be made on the use of rituximab as part of first-line or salvage regimens prior to autologous SCT.

26. Follicular Lymphoma AUTOLOGOUS SCT TIMING AND PROTOCOL • There are insufficient data to make a recommendation regarding purging in autologous SCT. • There are insufficient data to recommend one high dose regimen over another. Total body irradiation (TBI)-containing regimens are usually avoided because of a concern for the risk of secondary MDS or AML.

27. Follicular Lymphoma AUTOLOGOUS VERSUS ALLOGENEIC SCT • There are insufficient data comparing autologous SCT and myeloablative allogeneic SCT to recommend one option over the other; both appear to have a survival benefit, but have competing risks. Comparison of these two techniques is biased by different patient selection criteria. • There are currently no data available to make a recommendation regarding the use of reduced intensity/nonmyeloalative allogeneic SCT versus autologous SCT. Comparison of these two techniques is biased by different patient selection criteria.

28. Follicular Lymphoma ALLOGENEIC SCT CONDITIONING AND DONOR SOURCE • Reduced intensity conditioning appears to be an acceptable alternative approach in allogeneic SCT, based on one study and expert opinion. • There are insufficient data to recommend one conditioning regimen over another for allogeneic SCT. • In allogeneic SCT, an HLA-matched unrelated donor appears to be as effective as an HLA-matched related donor using reduced intensity conditioning, based on expert opinion.

29. Follicular Lymphoma AREAS OF NEEDED RESEARCH • Rituximab-based therapy followed by autologous SCT versus rituximab-based therapy without SCT. • Post-autologous SCT rituximab maintenance therapy versus no post-autologous SCT maintenance rituximab. • Ex vivo purged autologous SCT. • T cell-depleted allogeneic SCT.

30. Follicular Lymphoma AREAS OF NEEDED RESEARCH • Comparison of matched-related versus matched-unrelated or other alternative donor for allogeneic SCT. • The efficacy and toxicity of reduced intensity regimens before autologous and allogeneic SCT. • Reduced intensity allogeneic SCT as salvage therapy after failed autologous SCT. • Radioimmunotherapy as part of the preparatory regimen for autologous SCT or reduced intensity allogeneic SCT.

31. Follicular Lymphoma AREAS OF NEEDED RESEARCH • The impact of radioimmunotherapy and newer agents (i.e., bendamustine, rituximab, alemtuzumab, fludarabine, etc.) on stem cell quality. • Identification of surrogate molecular markers pre-SCT that are predictive of long-term survival in follicular lymphoma patients. • The association of FLIPI score at diagnosis and at SCT with prognosis in follicular lymphoma patients.

32. Follicular Lymphoma THE EXPERT PANEL: • Denise M. Oliansky, Roswell Park Cancer Institute (RPCI), Buffalo, NY. • Leo I. Gordon, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Chicago, IL. • Jerry King,Blue Cross and Blue Shield of Illinois, Chicago, IL. • Ginna Laport, Stanford University Medical Center, Stanford, CA. • John P. Leonard, Cornell University, Weill Medical College, New York, NY. • Peter McLaughlin,MD Anderson Cancer Center, Houston, TX. • Robert J. Soiffer,Dana Farber Cancer Institute, Boston, MA. • Koen W. van Besien, University of Chicago, Department of Medicine, Chicago, IL. • Michael Werner, Lymphoma Research Foundation, Chicago, IL. • Roy B. Jones, MD Anderson Cancer Center, Houston, TX. • Philip L. McCarthy, Jr., RPCI, Buffalo, NY. • Theresa Hahn, RPCI, Buffalo, NY.

33. “The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Therapy of Myelodysplastic Syndromes:An Evidence-Based Review” Biology of Blood and Marrow Transplantation (Vol. 15:137-172) January 2009

34. Myelodysplastic Syndromes RECOMMENDATIONS TIMING OF TRANSPLANTATION Early SCT is recommended for patients who: have an IPSS score of INT-2 or high risk are considered high risk based on other factors besides IPSS (i.e., older age, refractory cytopenias) have a suitable donor meet the transplant center’s eligibility requirements

35. Myelodysplastic Syndromes PRE-SCT INDUCTION CHEMOTHERAPY Insufficient data are available to make a treatment recommendation for or against induction chemotherapy Decision to use pre-SCT induction therapy should be made on an individual basis

36. Myelodysplastic Syndromes DONOR SELECTION Data demonstrate a long-term curative outcome for related & unrelated allogeneic SCT No evidence of a survival advantage based on donor relation in allogeneic SCT An allogeneic HLA-matched donor is recommended Autologous SCT can be considered in the context of a clinical trial, if an allogeneic donor is not available

37. Myelodysplastic Syndromes TRANSPLANTATION TECHNIQUES For low-risk disease, allogeneic BMT and PBSCT from related donors have equivalent outcomes For high-risk disease, there may be a survival advantage with related donor allogeneic PBSCT There is insufficient evidence to recommend BMT versus PBSCT for unrelated donor allogeneic SCT No evidence of a survival advantage for BMT versus PBSCT for autologous SCT

38. Myelodysplastic Syndromes TRANSPLANTATION TECHNIQUES There are insufficient data to: • Make a recommendation for an optimal conditioning regimen intensity • Make a recommendation for any one high-dose conditioning regimen over another

39. Myelodysplastic Syndromes AREAS OF NEEDED RESEARCH Important areas of needed research are: Benefit of alternative donor sources for patients without HLA-matched related or unrelated allogeneic donors Role and timing of allogeneic SCT in combination with hypomethylating and immunomodulatory regimens Randomized trials comparing various novel agents Influence of treatment modalities on quality of life

40. Myelodysplastic Syndromes EXPERT PANEL MEMBERS: Denise M. Oliansky, Roswell Park Cancer Institute (RPCI), Buffalo, NY Joseph H. Antin, Dana Farber Cancer Institute, Boston, MA John M. Bennett, University of Rochester, James P. Wilmot Cancer Center, Rochester, NY H. Joachim Deeg, Fred Hutchinson Cancer Research Center, Seattle, WA Christin Engelhardt, Aplastic Anemia and MDS International Foundation, Churchton, MD Kathleen V. Heptinstall, The MDS Foundation, Crosswick, NJ Marcos de Lima, MD Anderson Cancer Center, Houston, TX Steven D. Gore, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD Ronald G. Potts, INTERLINK Health Services, Hillsboro, OR Lewis R. Silverman, Mt. Sinai School of Medicine, New York, NY Roy B. Jones, MD Anderson Cancer Center, Houston, TX Philip L. McCarthy, Jr., RPCI, Buffalo, NY Theresa Hahn, RPCI, Buffalo, NY

41. “The Role of Cytotoxic Therapy withHematopoietic Stem Cell Transplantation in the Therapy of Acute Myeloid Leukemia (AML) in Adults: An Evidence-Based Review” Biology of Blood and Marrow Transplantation (Vol. 14:137-180) January 2008

42. AML in Adults RECOMMENDATIONS  Transplantation versus Chemotherapy • A survival advantage for allogeneic SCT for patients under age 55 with high risk cytogenetics • No survival advantage in patients over age 55 with low risk cytogenetics • In 2nd complete remission, allogeneic SCT is recommended • In 2nd complete remission autologous SCT is recommended if no available allogeneic donor • No significant advantage of autologous SCT over chemotherapy (studies using modern technologies may affect this recommendation)

43. AML in Adults INCONCLUSIVE EVIDENCE There is insufficient evidence to: • Routinely recommend allogeneic SCT for patients with intermediate risk cytogenetics (although it is a reasonable strategy) • Recommend reduced intensity conditioning allogeneic SCT vs. chemotherapy • Recommend the use of myeloablative regimens for patients over age 55

44. AML in Adults RECOMMENDED TECHNIQUES • Allogeneic SCT with a matched related donor is recommended if available • Matched unrelated donor allogeneic SCT using reduced intensity conditioning may provide equivalent outcomes to related donor allogeneic SCT • For high risk disease, allogeneic PBSCT is recommended over BMT; For low risk disease, allogeneic PBSCT and BMT have equivalent outcomes • An HLA-matched related donor SCT is recommended over autologous SCT • Autologous PBSCT is recommended over autologous BMT

45. AML in Adults INCONCLUSIVE EVIDENCE There is insufficient evidence to: • Recommend matched unrelated donor allogeneic SCT over autologous SCT (ongoing studies reflecting modern techniques may provide this evidence) • Recommend purged BMT or PBSCT • Recommend tandem versus single autologous SCT • Recommend T cell-depleted grafts from allogeneic donors • Recommend PBSCT versus BMT in matched unrelated donor allogeneic SCT

46. AML in Adults THERAPY REGIMEN • Fractionated rather than single dose total body irradiation is recommended in allogeneic SCT

47. AML in Adults TECHNIQUES WITH INCONCLUSIVE EVIDENCE • No difference or preference for any one high dose therapy conditioning regimen in autologous SCT • No difference or preference for any one myeloablative conditioning regimen in allogeneic SCT; Studies of late effects may change this recommendation • No data on the benefit of reduced intensity conditioning for allogeneic SCT; regimen intensity is dependent on patient characteristics

48. AML in Adults AREAS OF NEEDED RESEARCH • The role of SCT in treating patients with specific molecular markers (e.g., FLT3, NPM1, CEBPA, BAALC, MLL, NRAS,etc.) especially in patients with normal cytogenetics • The benefit of using SCT to treat different cytogenetic subgroups • The impact on survival outcomes of reduced intensity or nonmyeloablative versus conventional conditioning in older (> 60 years) and intermediate (40-60 years) aged adults • The impact on survival outcomes of unrelated donor SCT versus chemotherapy in younger (< 40 years) adults with high-risk disease

49. AML in Adults THE EXPERT PANEL MEMBERS • Denise M. Oliansky, Roswell Park Cancer Institute (RPCI), Buffalo, NY • Frederick Appelbaum, Fred Hutchinson Cancer Institute, Seattle, WA • Peter A. Cassileth, University of Miami Sylvester Cancer Center, Miami, FL • Armand Keating, University of Toronto, Toronto, Ontario, Canada • Jamie Kerr, Excellus Blue Cross/Blue Shield, Rochester, NY • Yago Nieto, MD Anderson Cancer Center, Houston, TX • Susan Stewart, BMT Infonet, Chicago, IL • Richard M. Stone, Dana Farber Cancer Institute, Boston, MA • Martin Tallman, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL • Philip L. McCarthy, Jr., RPCI, Buffalo, NY • Theresa Hahn, RPCI, Buffalo, NY

50. “The Role of Cytotoxic Therapy withHematopoietic Stem Cell Transplantation in the Therapy of Acute Myeloid Leukemia (AML) in Children: An Evidence-Based Review” Biology of Blood and Marrow Transplantation (Vol. 13:1-25) January 2007