Back to the Future: The Resurgence of Bone Marrow??

Back to the Future: The Resurgence of Bone Marrow?? Thomas Spitzer, MD Director. Bone Marrow Transplant Program Massachusetts General Hospital Professor of Medicine, Harvard Medical School

Bone Marrow Harvesting vs HPC-A Collection via Apheresis

Bone Marrow (HPC-M) vs PBPC (HPC-A): An An Historical Perspective Marrow - Rich source of progenitor cells - Rich source of accessory cells - Straightforward procedure with known risks - Donor recovery time not insubstantial PBPC - Rich source of progenitor cells (? more lineage committed) - > 1 log more T-cells (? increased GVHD risk) -? Donor safety concerns (both short and long term)

Bone Marrow Transplantation: A Brief History Auto PBPC Allo PBPC Appelbaum F. N Engl J Med 2007;357:1472-1475

Transplantation of Bone Marrow as Compared With Peripheral-Blood Cells from HLA-Identical Relatives in Patients with Hematologic Cancers Bensinger WI, Martin PJ, Sorer B, et al. N Engl J Med 2001;344:175-181.

Characteristics of the Patients, According to Treatment Assignment. 1) PBSC (n=81) 2) BM (n=91) 3) Hematologic malignancies 4) Approximately ½ with less advanced and ½ with more advanced hematologic malignancies 5) Well matched for disease, gender, age, CMV serostatus Bensinger WI et al. N Engl J Med 2001;344:175-181.

Characteristics of the Transplanted Cells, According to Patients' Treatment Assignment. Bensinger WI et al. N Engl J Med 2001;344:175-181.

Time to Engraftment and Transfusion Requirements, According to Treatment Assignment. Bensinger WI et al. N Engl J Med 2001;344:175-181.

Cumulative Incidence of Chronic Graft-versus-Host Disease (GVHD) in the Two Study Groups. 46% vs 35%; p=0.54 Bensinger WI et al. N Engl J Med 2001;344:175-181.

Probability of Survival in the Two Study Groups. 66% vs. 54%; p=0.06 Bensinger WI et al. N Engl J Med 2001;344:175-181.

Peripheral Blood vs. Bone Marrow Transplantation for Hematologic Malignancies CENTER/GROUP EBMT 2005 Stem Cell Trialists Collaborative Group 2005 SFGM-TC 2002 CBMTG 2002 Patient No./Trial Design 350 Prospective, Randomized 1111 Meta-Analysis 101 Prospective, Randomized 228 Prospective, Randomized Donors MRD MRD 1 Ag mismatched related donors Outcomes cgvhd 73% vs 55% (p=0.003) Extensive cgvhd 36% vs 19% (p=0.002) LFS, OS (p=ns) Increased grades 3-4 agvhd, cgvhd, extensive cgvhd Decreased relapse in early and late disease. Improved DFS,OS in late disease MRD cgvhd 65% vs 36% (p=0.004) Extensive cgvhd 44% vs 17% (p=0.004) OS (p=ns) MRD Grades 2-4 agvhd 44% vs 44%. Extensive cgvhd 40% vs 30% (p=0.37) OS : 68% vs 60% (p=0.04)

Long-term outcomes after transplantation of HLA-identical related G-CSF-mobilized peripheral blood mononuclear cells versus bone marrow. 10 year follow up of HPC=A vs HPC-M transplants: - Sustained DFS benefit and lower relapse probability with HPC-A - No significant difference in cgvhd, duration of systemic immunosuppression or OS cgvhd Mielcarek M, et al. Blood 2012; 15: 2675-2678

MRD Hematopoietic Cell Transplantation: HPC-A or HPC-M? Faster hematologic recovery with HPC-A Probably no difference in acute GVHD Possibly more chronic GVHD with HPC-A Probably no difference in NRM Probably no difference in DFS Probably no difference in OS

Based on existing data regarding HPC-M vs HPC-A for MRD HCT it is difficult to make a compelling case for a major change in practice.

Peripheral-Blood Stem Cells versus Bone Marrow from Unrelated Donors Anasetti C, Logan BR, Lee SJ, et al. N Engl J Med. 2012 18;367:1487-96.

Characteristics of the Patients, Donors, and Transplantation Regimens, According to Study Group. 1) PBSC (n=273) 2) BM (n=278) 3) AML, ALL, CML, MDS CMML, MF 4) High risk disease 28% in both groups 5) Mostly myeloablative conditioning 80% with HLA 10/10 matched donors 6) 2.75 (BM) vs 7.70 (PBSC) X 10e6/kg CD34+ cells Anasetti C et al. N Engl J Med 2012;367:1487-1496.

Outcomes after Transplantation, According to Study Group. OS DFS NRM Rel ANC Plts agvhd cgvhd Anasetti C et al. N Engl J Med 2012;367:1487-1496.

Survival after Randomization in the Intention-to-Treat Analysis. Anasetti C et al. N Engl J Med 2012;367:1487-1496.

Primary Causes of Death among Patients Who Underwent Transplantation. Anasetti C et al. N Engl J Med 2012;367:1487-1496.

URD Hematopoietic Cell Transplantation: HPC-A or HPC-M? Faster hematologic recovery with HPC-A Probably no difference in acute GVHD More chronic GVHD with HPC-A Probably no difference in NRM Probably no difference in DFS Probably no difference in OS

Therefore, compelling evidence exists for an increased incidence of chronic GVHD after URD HPC-A HCT which will likely lead to changes in practice

HPC-A vs HPC-M HCT: A Decision Analysis Pidala J, et al. Biol Blood Marrow Transplant 2009; 15: 1415-1421 - Externally validated Markov model - MAC and MRD HCT - 7 month overall and qualityadjusted life expectancy with HPC-A - HPC-M superior when relapse probability @ 1 year is < 5%

Recommendations for HPC-A vs HPC-M for HCT HPC-A 1) HCT for hematologic malignancies at high(er) risk of relapse 2) HCT for conditions where rapid resolution of neutropenia and/or thrombocytopenia is critical HPC-M 1) HCT for non-malignant conditions 2) HCT for hematologic malignancies at low risk of relapse

Bone Marrow Harvests 2003 2014: MGH 60 50 40 30 20 MRD MUD Total 10 0 03 04 05 06 07 08 09 10 11 12 13 14

Not every dark cloud has a silver lining

Challenges of Going Back to the OR 1) Expense 2) Physician and other practitioner availability 3) Variability of product quality 4) Higher rate of bacterial contamination 5) More donor complications Pulsipher MA, et al. Blood 2013; 121: 197-206

Future Directions Reduction of Chronic GVHD 1) In vivo anti-t cell antibody therapy (e.g. ATG) 2) Post-transplant pharmacoprophylaxis ( e.g. high dose cyclophosphamide) Improvement of Harvest Progenitor Cell Yields 1) Novel devices 2) Small volume aspirations 3) Growth factor (e.g. G-CSF) mobilized harvests 3) Graft engineering

Novel Devices for Bone Marrow Aspiration OnControl Aspiration System (Vidacare)

Conclusions 1) Outcomes of HCT using HPC-A vs HPC-M vary according to study and donor source. 2) Chronic GVHD risk is increased after URD and possibly MRD HCT. 3) HPC-A HCT likely confers a superior GVL effect at least for higher risk hematologic malignancies. 4) Based on the available data, sweeping changes in practice are not warranted. 5) Future efforts should focus on improved methods of HPC-M procurement and on optimizing the balance between GVHD and GVL.

Transplantation of Bone Marrow as Compared With Peripheral-Blood Cells from HLA-Identical Relatives in Patients with Hematologic Cancers Bensinger WI, Martin PJ, Sorer B, et al. N Engl J Med 2001;344:175-181. - DFS: 65% vs. 45% (p=0.03) - Overall survival 66% vs. 54% (p=0.06) - OS (Less advanced disease): 75% vs 72% (p=0.63) - OS (more advance disease): 57% vs. 33% (p=0.04)