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 • Acute Lymphoblastic Leukemia in Children (2005, updated 2012) • Acute Lymphoblastic Leukemia in Adults (2006, updated 2012) • Diffuse Large B-Cell Non-Hodgkin Lymphoma (2001, updated 2011) • Follicular Lymphoma (2010) • Myelodysplastic Syndromes (2009) • Acute Myeloid Leukemia in Adults (2008) • Acute Myeloid Leukemia in Children (2007) • Multiple Myeloma (2003)

10. Future Directions • Periodic updating of completed reviews based on evolving standards and new scientific evidence. • Acute Myeloid Leukemia in adults - update in 2012 • Acute Myeloid Leukemia in children - update in 2012

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. “The Role of Cytotoxic Therapy withHematopoietic Stem Cell Transplantationin the Therapy of Pediatric Acute Lymphoblastic Leukemia (ALL): Update of the 2005 Evidence-Based Review” Biology of Blood and Marrow Transplantation 2012, in press.

13. ALL in Children RECOMMENDATIONS  Allogeneic SCT is recommended for pediatric ALL patients who experience primary induction failure, but subsequently achieve a first complete remission (CR1); new evidence has changed the original recommendation Allogeneic SCT is recommended for pediatric patients with precursor-B ALL in CR2 after an early marrow relapse; new evidence has changed the original recommendation

14. ALL in Children RECOMMENDATIONS  Allogeneic SCT is recommended for pediatric T-lienage ALL patients in CR2 after a marrow relapse; this is a new recommendation based on evidence in the original review and expert opinion Allogeneic SCT is recommended for pediatric patients with ALL in CR3 or greater; this is a new recommendation based on new evidence

15. ALL in Children RECOMMENDATIONS  Allogeneic SCT may be considered for some patients with T-lineage ALL in CR1; this is a new recommendation based on new limited evidence and expert opinion. Allogeneic SCT may be considered for children with hypodiploid ALL (<44 chromosomes) in CR1; this is a new recommendation based on expert opinion

16. ALL in Children RECOMMENDATIONS  Allogeneic SCT may be considered for patients with ALL in CR1 or CR2 who have minimal residual disease detected by a validated assay; this is a new recommendation based on expert opinion Allogeneic SCT may be considered for patients with ALL who are not in morphologic CR; this is a new recommendation based on expert opinion

17. ALL in Children RECOMMENDATIONS  Allogeneic SCT and chemotherapy provide equivalent outcomes for pediatric precursor-B ALL patients in CR2 after experiencing a later marrow relapse; new data have changed the original recommendation Allogeneic SCT and intensive chemotherapy with imatinib have equivalent early outcomes for Ph+ ALL in CR1; new evidence changed the original recommendation. Further study is needed in this area

18. ALL in Children RECOMMENDATIONS  Allogeneic SCT is not recommended for an isolated CNS relapse in precursor-B pediatric ALL patients; this is a new recommendation based on new evidence Autologous SCT is not recommended in CR1; this is a new recommendation based on new evidence

19. ALL in Children RECOMMENDATIONS  Allogeneic SCT is not recommended when MLL+ ALL is the sole adverse risk factor; this is a new recommendation based on new evidence. The presence of MLL+ along with other adverse risk factors (older age, high WBC, prednisone response, other cytogenetic abnormalities) has been used to define very high risk subgroups for which allogeneic SCT may be recommended

20. ALL in Children Allogeneic SCT TECHNIQUES Myeloablative Total Body Irradiation (TBI) containing conditioning regimens are recommended; new data have strengthened the original recommendation HLA-matched related and unrelated donors provide equivalent outcomes. In the absence of an HLA-matched related donor, an HLA-matched unrelated donor (using marrow, peripheral blood or cord blood ) is acceptable for allogeneic SCT; this is a new recommendation based on new evidence

21. ALL in Children Allogeneic SCT TECHNIQUES Allogeneic SCT using the best possible HLA-matched unrelated donor is recommended. HLA-mismatched unrelated donor allogeneic SCT may result in higher morbidity and mortality than an HLA-matched unrelated donor, but this does not preclude use of HLA-mismatched unrelated donors; this is a new recommendation based on new evidence

22. ALL in Children INCONCLUSIVE EVIDENCE There is insufficient evidence to support a recommendation regarding:  Allogeneic SCT for treatment of an isolated CNS relapse in pediatric patients with T-lineage ALL Allogeneic SCT for treatment of an isolated testicular relapse in pediatric ALL patients Use of a maternal vs a paternal donor for allogeneic SCT in pediatric ALL patients Use of imatinib therapy along with allogeneic SCT in pediatric Ph+ ALL patients

23. ALL in Children AREAS OF NEEDED RESEARCH Re-evaluate allogeneic SCT versus intensive chemotherapy regimens in the current era, as both approaches have changed Investigate the role and potential benefit of maternal antigen microchimerism to reduce the risk of graft-versus-host disease and enhance the graft- versus-leukemia effect after allogeneic BMT Identify and address the treatment of high risk T-lineage ALL subsets

24. ALL in Children AREAS OF NEEDED RESEARCH Re-evaluate the promising early studies of imatinib in combination with chemotherapy or SCT for Ph+ ALL in larger studies Investigate the optimal treatment for patients who are persistently positive for minimal residual disease Improve the detection and monitoring of MRD during initial treatment to guide individual patient eligibility and timing of allogeneic SCT Monitoring MRD after SCT to detect early post-SCT relapse in need of pre-emptive therapy

25. ALL in Children AREAS OF NEEDED RESEARCH Investigate the indications for using reduced intensity versus myeloablative conditioning regimens for allogeneic SCT Determine conditioning regimens which reduce or eliminate the need for TBI while maintaining effectiveness for ALL Investigate the prognostic role of initial risk classification (NCI SR/HR assignment) on outcomes after relapse

26. ALL in Children AREAS OF NEEDED RESEARCH Investigate whether allogeneic SCT performed in CR1 patients identified as very high risk for relapse by molecular methods (i.e., specific gene mutations, gene expression profiles, etc.) improves outcome compared to chemotherapy Investigate the impact of psychosocial support and shared decision-making models to assist families in weighing the risks versus benefits of SCT for their children with ALL

27. ALL in Children THE EXPERT PANEL MEMBERS Denise Oliansky, Roswell Park Cancer Institute (RPCI), Buffalo, NY Bruce Camitta, Midwest Center for Cancer and Blood Disorders, Medical College of Wisconsin and Children’s Hospital of Wisconsin, Milwaukee, WI Paul Gaynon, Children’s Hospital of Los Angeles, Los Angeles, CA Michael L. Nieder, All Children’s Hospital, St Petersburg, FL Susan K Parsons, Tufts Medical Center, Boston, MA Michael A Pulsipher, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT Hildy Dillon, The Leukemia and Lymphoma Society, White Plains, NY Thomas A Ratko, Blue Cross and Blue Shield Technology Evaluation Center, Chicago, IL Donna Wall, University of Manitoba, Cancer-Care Manitoba, Winnipeg, Manitoba, Canada Philip L. McCarthy, Jr., RPCI, Buffalo, NY Theresa Hahn, RPCI, Buffalo, NY

28. “The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Treatment of Adult Acute Lymphoblastic Leukemia: Update of the 2006 Evidence-Based Review” Biology of Blood and Marrow Transplantation(Vol. 18:18-36) 2012

29. ALL in Adults RECOMMENDATIONS Myeloablative allogeneic SCT is recommended for adult ALL in CR1 for all disease risk subgroups; this is a new recommendation based on new evidence Allogeneic SCT is recommended for adult ALL in CR2; new evidence strengthens the original recommendation Imatinib therapy before and/or after allogeneic SCT is recommended for adult Ph+ ALL; this is a new recommendation based on new evidence

30. ALL in Adults SCT TECHNIQUES Allogeneic SCT is recommended over autologous SCT for adult ALL; new evidence strengthens the original recommendation In the absence of a suitable allogeneic SCT donor, autologous SCT may be considered for adult ALL in CR1; this is a new recommendation based on new evidence

31. ALL in Adults ALLOGENEIC SCT TECHNIQUES HLA-matched related and unrelated donor allogeneic SCT produces equivalent survival outcomes, but post-SCT complications may differ; new evidence strengthens the original recommendation In the absence of an HLA-matched donor, a cord blood transplant may be considered; this is a new recommendation based on new evidence

32. ALL in Adults ALLOGENEIC SCT TECHNIQUES Myeloablative TBI-containing regimens in preparation of allogeneic SCT are recommended; new evidence strengthens the original recommendation Reduced intensity conditioning regimens produce similar outcomes to myeloablative regimens, but are recommended only for patients with adult ALL in remission who are unsuited for myeloablative conditioning regimens

33. ALL in Adults INCONCLUSIVE EVIDENCE There is insufficient evidence to make a recommendation regarding: The superiority of one conditioning regimen over another The benefit of any one induction regimen before allogeneic SCT

34. ALL in Adults AREAS OF NEEDED RESEARCH Re-evaluate allogeneic SCT versus more intensive chemotherapy regimens, especially in younger (<35 yrs) adults, and in the context of biologic therapies and TKIs (for Ph+ ALL) Assess the ability of TKIs to reduce the leukemia burden pre- or post-SCT in Ph+ ALL patients and evaluate whether this can improve survival outcomes after autologous and allogeneic SCT. Studies of different TKIs, dose and schedule will be important

35. ALL in Adults AREAS OF NEEDED RESEARCH Improvement in the detection and monitoring of minimal residual disease (MRD) during initial treatment to guide individual patient eligibility and timing of allogeneic SCT Monitoring of MRD after SCT to detect early post-SCT relapse in need of pre-emptive therapy. This may indicate patients at higher risk of early recurrence, but effective therapy will also need to be developed Indications for using reduced intensity versus myeloablative conditioning regimens for allogeneic SCT

36. ALL in Adults AREAS OF NEEDED RESEARCH Evaluation of cord blood transplantation techniques, such as single unit, double unit, and ex vivo expansion, to improve survival outcomes and reduce TRM Assessment of patient quality of life and functional status after successful SCT Assess the impact of management plans and follow-up care to facilitate better quality of life for ALL patients, regardless of treatment

37. ALL in Adults THE EXPERT PANEL MEMBERS Denise M. Oliansky, Roswell Park Cancer Institute (RPCI), Buffalo, NY Richard A. Larson, University of Chicago, Chicago, IL Daniel Weisdorf, University of Minnesota, Minneapolis, MN Hildy Dillon, The Leukemia & Lymphoma Society, White Plains, NY Thomas A. Ratko, Blue Cross Blue Shield Association Technology Evaluation Center, Chicago, IL Donna Wall, University of Manitoba/CancerCare Manitoba, Winnipeg, Manitoba, Canada Philip L. McCarthy Jr., RPCI, Buffalo NY Theresa Hahn, RPCI, Buffalo, NY

38. “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, 17:20-47.

39. 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.

40. 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.

41. 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.

42. 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.

43. 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.

44. 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.

45. 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.

46. 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.

47. 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

48. “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

49. 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.

50. 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.