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Similar to Haplo-cord transplantation offers similar results compared to MUD transplantation in High-Risk Adult Patients with Hematologic Disorders (20)
Haplo-cord transplantation offers similar results compared to MUD transplantation in High-Risk Adult Patients with Hematologic Disorders
- 1. Haplo-cord transplantation offers similar results compared to MUD transplantation in High-Risk Adult Patients with Hematologic Disorders Mi Kwon Gregorio Marañon Institute for Health Research; Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain Gregorio Marañon Institute for Health Research
- 2. No conflicts of interest to declare Disclosures
- 3. Unrelated umbilical cord blood has been increasingly used as an alternative stem cell source for adult patients eligible for allogeneic SCT lacking HLA-matched adult donors Unrelated Donor Stem Cell Sources by Recipient Age 2001-2010 Unrelated Cord Blood Transplants, by Age Registered with the CIBMTR 2001-2010 Source for allogeneic SCT Age ≤ 20 yrs Age > 20 yrs 0 20 40 60 80 100 2001-2005 2006-2010 2001-2005 2006-2010 Bone Marrow (BM) Peripheral Blood (PB) Cord Blood (CB) 0 100 200 300 400 500 600 700 800 900 1,000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 >= 16 years < 16 years
- 4. Outcomes after Transplantation of Cord Blood or Bone Marrow from Unrelated Donors in Adults with Leukemia Mary J. Laughlin, M.D., Mary Eapen, M.B., B.S., Pablo Rubinstein, M.D., et al. 2004; 351:2265-2275, Nov 25, 2004. “The slow rate of hematopoietic recovery remains a major deterrent to the use and success of cord-blood transplantation in adults, and novel strategies to overcome this obstacle are needed”
- 5. Single CB compared to MUD NRM Months Eapen et al., Lancet Oncol 2010 Neutrophil Recovery
- 6. Dual Transplantation: Haplo-Cord Days after SCT Neutrophils CBU TPD* 3x106 /kg CD34+ <1x104 /kg CD3+ Conditioning (*) Third party donor: G-CSF mobilization and CD34+ Immunomagnetic positive selection (Miltenyi’s CliniMACS®)
- 7. Haplo-Cord SCT experience Reference N Age Disease Conditioning ANC>500/uL F-up months NRM DFS OS Fernandez et al Br J Haem 2010 55 34 High-risk MA CY-Flu-TBI/Bu ATG aaaaaaaaa CsA+Pred 10 days 13 15% 51% 54% Liu et al Blood 2011 45 50 High-risk (58% active) RIC__________ Flu-Mel-ATG 11 days 12 28% 42% 55% Lindemans et al BBMT 2012 Tandem Meeting 2011 9 12 Non-malignant (n=7) MA Bu-CY or Flu ATG or Campath CsA + Pred 12 days (N=8) 8 2/9 33% NR Gormley et al ASH 2011 8 18 SAA MA CY-Flu-TBI-ATG 10 days 9 1/8 7/8 7/8
- 8. The objective of this study was to analyze toxicity and survival rates of adults who underwent haplo-cord SCT and to compare these rates with those in a cohort of patients who underwent myeloablative MUD SCT in our center in the same time period (2004-2012).
- 9. Haplo-cord vs MUD: Patients Characteristics of patients Haplo-Cord (N=29) MUD (N=31) p Age, years Median (p25-p75) 40 (31-47) 38 (31-45) 0.6 Sex, no (%) Male 15 (52) 18 (58) 0.6 Female 14 (48) 13 (42) Weight kg, median (range) 70 (42-103) 68 (45-98) 0.6 Disease status at transplant, no. (%) AML/MDS 15 (52) 22 (71) 0.4CR1 9 (60) 10 (45) Other 6 (40) 12 (55) ALL 8 (28) 4 (13) 0.6CR1 5 (63) 3 (75) Other 3 (37) 1 (25) Lymphoproliferative disease 4 (14) 2 (6) 0.77 Other 2 (7) 3 (10) 0.57 Active disease, (%) 33 (9/27) 45 (13/29) 0.42 Previous transplant, no. (%) 3 (10) 4 (13) 0.68 Months to transplantation (patients in 1st CR) Median (p25-p75) 8 (6-9) 9 (6-14) 0.11 HCT-CI 0-2 25 (86) 24 (83) 1>2 4 (14) 5 (17)
- 10. Conditioning: Haplo-cord vs MUD Haplo-Cord Fludarabine 30 mg/m2/day Busulfan 3.2 mg/kg/day (*) Cyclophosphamide 60 mg/kg/day rATG 2 mg/m2/day Metilprednisolone 1 mg/m2/day CsA from day -5 0-1-2-3-4-5-6-7-8 +10 +50… … * TBI (fr) 10 Gy MUD 0-1-2-3-4-5-6 +3 +11+1 +6 Fludarabine 40 mg/m2/day Busulfan 3.2 mg/kg/day (*) rATG 2.5 mg/m2/day CsA from day -7 MTX * CTX or Mel +50
- 11. Transplant and Graft characteristics Characteristics of transplants Haplo-Cord (N=31) MUD (N=31) ABO blood group mismatch, no. (%) Major / Minior 11 (35) / 5 (16) 12 (39) / 2 (6) None 15 (48) 17 (55) Conditioning, no. (%) BU - FDR - 19 (63) TBI containing regimen 2 (6) 6 (19) BU - FDR - CTX 27 (87) - ATG 31 (100) 29 (93) GVHD prophylaxis, no. (%) CsA + MTX - 30 (97) CsA + steroids 29 (94) 0 CsA +/- MMF 2 (6) 0 CB cells, median (range) * TNC (x 10⌃7/kg) 2.9 (1.48-4.74) - CD34+ (x 10⌃5/kg) 1.9 (0.73-3.2) - Third party donor cells, median (range) ** CD34+ (x 10⌃6/kg) 2.9 (1.5-3.46) - CD3+ (x 10⌃4/kg) 0.25 (0.05-1.5) - MUD cells, median (range) ** TNC (x 10⌃8/kg) - 6 (0.8-18) CD34+ (x 10/⌃6/kg) - 4 (0.8-19) HLA match, no. (%) 8/8 - 31 (100) 6/6 0 - 5/6 8 (26) - 4/6 23 (74) - *After procesing, before cryopreservation ** Infused cells
- 12. Engraftment Haplo-cord MUD ANC > 500/uL 15 (9-28) 16 (12-28) Platelets >20,000/uL 29 (9-84) 12 (9-41) ANC >500/μL at 30 days Platelets >20,000/μL at 60 days Days after SCT Days after SCT Haplo-cord 90% Haplo-cord 77.5% MUD 97% MUD 85% p=0.5 p=0.001
- 13. Haplo-cord SCT: Chimerism The CI of PB complete CB chimerism was 75% at 60 days and 87% at 90 days, achieved in a median of 29 days (range 14-71) All showed sustained CC in the last FU Kwon et al, BBMT 2013, under review
- 14. Haplo-cord SCT: Graft failure • In 2/28 patients, failure of both CB and TPD grafts was documented • Poor viability (1): second haplo-cord, alive in CR • HLA antibodies against CB antigens (1): haploidentical SCT, alive in CR • In 3/28 patients, engraftment occurred at the expense of TPD only • Unknown (1): early relapse after Haploidentical rescue • Poor viability (2): relapse / infection after second haplo-cord • Overall, CB graft failure was documented in 5 cases (17%) Kwon et al, BBMT 2013, under review
- 15. Survival Median follow-up 33 months MUD 34 months (IQR 24-75) Haplo-cord 21 months (IQR 11-78) DFS OS 45% p = 0.7 51% p = 0.7 MonthsMonths
- 16. a Relapse MUD 32% p=0.57 1.0 0.8 0.6 0.4 0.2 20 40 60 80 1000 0.0 Cumulativeincidence Months Haplo-cord 26% at 36 months No patient in either group experienced relapse beyond 2 years after transplantation
- 17. GvHD MUD 32% aGVHD II-IV 1.0 0.8 0.6 0.4 0.2 20 40 60 80 1000 0.0 Cumulativeincidence Days Haplo-cord 10% p=0.06 cGVHD mod-severe 1.0 0.8 0.6 0.4 0.2 20 40 60 80 1000 0.0 Months p=0.03 MUD 27% Haplo-cord 5% In addition, 3 patients from the MUD group developed severe GVHD after rapid withdrawal of IS in 2 patients and DLI 1 patient (relapse and increasing MC)
- 18. Non Relapse Mortality p=0.46 1.0 0.8 0.6 0.4 0.2 20 40 60 80 1000 0.0 Cumulativeincidene Months MUD 23% Haplo-cord 29% at 36 months Most of the transplantation-related deaths occurred within the first year after SCT Haplo-cord: • Infection 4 • GvHD 1 • Toxicity/MOF 3 MUD: • Infection 1 • GvHD 5 • Toxicity/MOF 1
- 19. Infections MUD Haplo-cord Bacteria 13 (1*) 19 (2*) CMV (PCR, preemptive) 19 18 Hemorrhagic cystitis Grade 2-4 5 (BK) 8 (2 CMV 5 BK 1 Adenovirus*) VEB 2 (1*) 2 HHV-6 - 1 Other 1 1 TB - 1 IFI possible 5 7 IFI proven 1 2* Other 1* - * Death
- 20. Haplo-cord vs MUD: Conclusions • Haplo-cord SCT in high-risk patients offers time to engraftment and survival rates comparable to those seen with myeloablative 8/8 HLA-matched unrelated donor transplantation, with significantly lower GVHD rates • In contrast to previous comparative studies including single CB transplantations, the Haplo-cord approach offers similar NRM rates as MUD transplantation • Haplo-cord SCT provides a valuable option for high-risk patients who lack a matched adult donor or who require urgent transplantation • Thus, this CB transplantation approach merits broader evaluation
- 21. Haplo-cord SCT Spanish Experience 140 transplants in 132 patients between 1999 and June 2012 Hospital Universitario Puerta de Hierro (Madrid) N=95 Hospital Universitario Gregorio Marañón (Madrid) N=30 Hospital Duran i Reynals (ICO, Barcelona) N=15 Preliminary Analysis of 125 transplants
- 22. Haplo-cord SCT. 1999-2012. AML 47 40% ALL 40 34% MDS 11 10% CML 5 4% NHL 8 7% Other 6 5% Active disease 39% Previous transplant 25 (21%) TNC x 107/kg 2.4 (1.1-6) CD34+ x 105/kg 1.28 (0.35-5.86) HLA matching 6/6 16 14% 5/6 45 38% 4/6 52 44.5% 3/6 4 3.5% TPD 82% related, 18% unrelated 69% haplo, 31% <haplo CD34+ x 106/kg 2.5 (0.8-4.0) CD3+ x 104/kg 0.24 (0.05-1.5) Median follow-up 5 years (1.4 m – 13.5 years) 125 SCT, 117 patients Age 35 (16-60) M/F 45 (39%) / 72 (61%) Weight 70 kg (42-111)
- 23. a Engraftment ANC >500/uL Plt >20.000/uL ANC > 500/uL Platelets > 20.000/uL Median, days 12 (9-36) 31 (9-98) 97% at 40 days 93% at 100 days Days after SCT Days after SCT
- 24. a CB engraftment: full CB chimerism 75% at 180 days Median 60 days (11-180) Early death 11 Graft failure/Rejection 8 Relapse 7 Early course 2
- 25. FULL CB CHIMERISM Influence of CB TNC & CD34+ cells 0,00 0,25 0,50 0,75 1,00 0 20 40 60 80 100 120 Days <=2,54 >2,54 CB-TNC Median 2.5 x 107/Kg 0,00 0,25 0,50 0,75 1,00 0 20 40 60 80 100 120 Days <0,17 >=0,17 0,00 0,25 0,50 0,75 1,00 0 20 40 60 80 100 120 Cumulative Incidence Plot Days <=0,141 >0,141 CD34+ cells < vs ≥ 0.14 x106/Kg CD34+ cells < vs ≥ 0.17 x106/Kg MN Fernandez. CB symposium 2012 62 58 45 75
- 26. a Relapse 21% at 1 year 25% at 5 years
- 27. a aGvHD 23% Days aGvHD II-IV cGvHD Cumulativeincidence Days 24% 63% limited 37% extensive
- 28. a Non Relapse Mortality 42 deaths: • 18 infections (8 virus, 4 fungus, 2 Toxoplasmosis, 1 Chagas, 2 bacteria, 1 other) • 4 VOD, 8 MOF • 9 GVHD • 1 graft rejection • 2 Toxicity/infection 36% at 2 years 17% at 100 days
- 29. a Survival 40% at 5 years 44% at 5 years Months Months DFS OS
- 30. a Survival in AML/ALL N=87 (74%) 43% at 5 years p = 0.01 Active disease 25% MonthsMonths CR 51% OS OS
- 31. Conclusions: Haplo-cord SCT • Provides a prompt myeloid reconstitution even using CB units with relatively low cell content • CB should be considered as a front line option for patients in need of an allogeneic SCT, especially for patients with acute leukemia • May allow the reduction of cell dose requirements, expanding CB availability and facilitating selection on the basis of HLA match (especially relevant for uncommon haplotypes, CCR5 mutation in HIV+ patients) • Efforts to improve immune reconstitution should continue since post-engraftment infections remain an issue
- 32. Haplo-cord Trasplant Project Spain Hospital Duran y Reinals ICO I S. Ortega-Sánchez R. Duarte Hospital Univ. Gregorio Marañón M. Kwon J. Gayoso D. Serrano I. Buño J. Anguita P. Balsalobre J.L. Díez Martín Hospital Univ. Puerta de Hierro G. Bautista A. de Laiglesia R. Forés I. Millán C. Regidor J.R. Cabrera M.N. Fernández