ESTADO ACTUAL DEL TRASPLANTE DE MEDULA OSEA CON CICLOFOSFAMIDA POSTTRASPLANTE COMO PROFILAXIS PARA LA ENFERMEDAD DEL INJERTO CONTRA EL HUESPED
Hugo Castro Malaspina Attending and Member Memorial Sloan Kettering Cancer Center Professor of Clinical Medicine Weill Medical College of Cornell University
Beatty P, et al.
ALLOGENEIC HSCT GVHD PROPHYLAXIS ¢ CSA
or tacrolimus + MTX is the gold standard ¢ T cell depletion In vivo ¢ Non-selective: anti-T cell antibodies: ATG, Campath ¢ Selective: posttransplant cyclophosphamide Ex vivo ¢ Complete: Miltenyi device: CD34+ selection ¢ Selective: depletion of alpha/beta + T cells and CD19 B cells
SOURCES OF HEMATOPOIETIC STEM CELLS FOR ALLOGENEIC TRANSPLANTATION IN THE
USA ¢ HLA
compatible sibling in ~ 25 of patients ¢ Matched unrelated donor in ~ 50% of patients ¢ Alternative donor needed in~25%
Mismatched donor, related or unrelated Unrelated cord blood units Haploidentical donor with in vivo selective T cell depletion with posttranplant cyclophosphamide
SOURCES OF HEMATOPOIETIC STEM CELLS FOR ALLOGENEIC TRANSPLANTATION IN COUNTRIES WITH LESS RESOURCES ¢ HLA
compatible sibling: in about of 25% patients ¢ Unrelated donor and cord blood units require accreditation to have access of unrelated donor banks and cord blood unit banks and the process of confirmatory tissue typing of unrelated donors and procurement of unrelated BM or PB and cord blood units is very expensive. ¢ Haploidentical donors are probably the best option for the remainder 75% of patients in countries with less resources. Is this justifiable in 2016?
EBMT TRANSPLANT ACTIVITY 2013
Passweg JR, BMT 2015
POST-TX CY AS PROPHYLAXIS FOR GVHD RATIONALE ¢ Cyclophosphamide
is a potent immune suppressing agent and has no toxicity to primitive hematopoietic stem cells. ¢ Cyclophosphamide selectively depletes proliferating alloreactive cells responsible for GvHD and graft rejection while preserving resting memory T cells essential for post-transplant immunologic recovery. ¢ Cyclophosphamide depletes residual host alloreactive cells that can cause graft rejection
CYCLOPHOSPHAMIDE INDUCTION OF TOLERANCE
POST-TX CY AS PROPHYLAXIS FOR GVHD OUTLINE • • •
• • • • •
Historical perspective Early trials Complications associated with • Graft rejection Importance of patient’s HLA antibodies against donor HLA antigens • Cytokine release syndrome Other centers experience Source of HSC: PB vs BM Post-tx CY vs CBT Post-tx Cy vs MRD and MUD Complications commonmly associated with post-CY
POST-TRANSPLANT CYCLOPHOSPHAMIDE AS GVHD PROPHYLAXIS HISTORICAL PERSPECTIVE ¢ 1963,
Berenbaum HC et al: CY prolonged the survival of skin allografts if given 3 days after placement of the skin graft (Nature 1963; 200:84) ¢ 1966, Santos G and Owens AHJ at John Hopkins: CY suppressed the incidence of GvHD in rats given allogeneic splenocytes, especially if CY given 2 days after cell infusion (Nature 1966; 210:139). ¢ 1989, Mayumi H and Good RA: induced tolerance to MHC by giving mice IV splenocytes and 2-3 days later IV CY (J Exp Med 1989; 160:213). ¢ 1990 Kastan MB et al : HSC express high levels of aldehyde dehydrogenase which confers SC cellular resistance to CY (Blood 1990; 75:1947)
POST-TRANSPLANT CYCLOPHOSPHAMIDE AS GVHD PROPHYLAXIS HISTORICAL PERSPECTIVE ¢ 1995:
Colson YL et al: showed in a mouse model of mismatched BMT that the dose of TBI required for stable engraftment was decreased when mice were given CY 2 days post BMT (J Immunol 1995; 155:4179) ¢ 2001: Luznik et al: describes mouse model of haplo transplant using a NMA prep with fludarabine and low dose TBI and post-tx CY as GvHD prophylaxis resulting in durable engraftment and limited GvHD (Blood 2001; 98:3456).
POST-TX CY AS GVHD PROPHYLAXIS AFTER NMA HAPLO HSCT: FIRST PHASE 1, 2 TRIAL O’DONNELL, PV ET: BBMT 2002; 8:377 ¢ N:
13 patients enrolled with advanced disease ¢ Donors: haploidentical ¢ Prep: Fludarabine 30 mg/m2/d/5d and TBI 200 cGy. ¢ GvHD prophy: post-tx CY 50 mg/kg d +3, tacrolimus and MMF ¢ Results: 2 of the first 3 cohort rejected the graft > CY added to prep on d-5 and d-6 -> 6 of next 10 pts engrafted. -> In the phase 2 part: 6/8 pts GvHD, 5 long term, survivors ¢ Based on this findings next trial the dose of posttx CY was increased to 2 days to decrease GvHD
POST-TX CY AS GVHD PROPHYLAXIS AFTER NMA HAPLO HSCT: FIRST PHASE 1, 2 TRIAL: IMMUNE RECONSTITUTION O’DONNELL, PV ET: BBMT 2002; 8:377
POST-TRANSPLANT CYCLOPHOSPHAMIDE AS GVHD PROPHYLAXIS: FIRST PHASE 1, 2 TRIAL O’DONNELL, PV ET: BBMT 2002; 8:377
POST-TRANSPLANT CY AS GVHD PROPHYLAXIS AFTER NMA HAPLO HSCT: PHASE 2 TRIAL LUZNIK, L ET: BBMT 2008; 14: 641 ¢ N:
68 pts with advanced diseases (John Hopkins and Fred Hutchinson) ¢ Prep: Fludarabine 30 mg/m2/d/5d and TBI 200 cGy, CY 14.5 mg/kg/d/2d ¢ GvHD prophy: post-tx CY 50 mg/kg d +3 and +4* tacrolimus and MMF. ¢ Results:
Graf failure: 13% GvHD III/IV: 6% cGvHD: 10% NRM 1 y: 15% OS and RFS at 2 y: 36 and 26%
POST-TRANSPLANT CY AS GVHD PROPHYLAXIS AFTER NMA HAPLO HSCT: PHASE 2 TRIAL LUZNIK, L ET: BBMT 2008; 14: 641
POST-TRANSPLANT CY AS GVHD PROPHYLAXIS AFTER NMA HAPLO HSCT: PHASE 2 TRIAL LUZNIK, L ET: BBMT 2008; 14: 641
POST-TRANSPLANT CY AS GVHD PROPHYLAXIS AFTER NMA HAPLO HSCT: PHASE 2 TRIAL LUZNIK, L ET: BBMT 2008; 14: 641
POST-TRANSPLANT CY AS GVHD PROPHYLAXIS AFTER NMA HAPLO HSCT: PHASE 2 TRIAL LUZNIK, L ET: BBMT 2008; 14: 641
HAPLOIDENTICAL HSCT: EFS AFTER NMA MYELOBLATIVE HSCT WITH POST-TX CY (MUNCHEL AT ET AL, BEST PRACT RES CLIN HEMAT)
- aGvHD III-IV 100 d: 5% - cGvHD 1-year: 13% - NRM 2-years: 16% - Relapse 2-years: 50%
POST-TRANSPLANT CY AS GVHD PROPHYLAXIS AFTER NMA HAPLO HSCT: LEVEL OF HLA MISMATCH
MCCURDY SR, ET AL, BLOOD 2015, 125:3024
PosT-tx CY and NMA Haplo BMT by DRI group
Shannon R. McCurdy et al. Blood 2015;125:3024-3031 ©2015 by American Society of Hematology
Age-specific outcomes of NMA haploidentical PB or BMT with post-tx CY by age
Yvette L. Kasamon et al. JCO 2015;33:3152-3161 ©2015 by American Society of Clinical Oncology
POST-TX CY AS PROPHYLAXIS FOR GVHD SUMMARY OF INITIAL EXPERIENCE ¢ Post-tx
CY is an effective method of GvHD prevention with much less frequent rate of acute and chronic GvHD as compared to standard ISS. ¢ Graft failure in small proportion of patients that decreased after adding a second dose fo CY post-tx ¢ Patients who engraft achieve full donor chimerism in myeloid and T cells ¢ Rapid immune recovery and less opportunistic infections ¢ High rate of relapse related to patient selection in initial trials.
POST-TX CY AS PROPHYLAXIS FOR GVHD CAN IT BE USED AFTER MYELOABLATIVE PREP?
POST-TX CY AS A SINGLE AGENT AFTER MEYLOABLATIVE PREP (BU/CY) FROM MRD AND MUD
Leo Luznik et al. Blood 2010;115:3224-3230 ©2010 by American Society of Hematology
BMT WITH POST-TX CY AS A SINGLE AGENT FOLLOWING A MYELOABLATIVE CONDITIONING
(BU/CY) KANACRY ET AL, BLOOD 2014, 124:3817
POST TX CY AFTER MYELOABLATIVE HSCT FROM MRD AND MUD KANAKRY CG ET AL. JCO 2014; 32:3497
Transplantation outcomes for nonrelapse mortality and graft-versus-host disease (GVHD) by donor type.
Christopher G. Kanakry et al. JCO 2014;32:3497-3505
Š2014 by American Society of Clinical Oncology
Disease-free and overall survival.
Christopher G. Kanakry et al. JCO 2014;32:3497-3505 Š2014 by American Society of Clinical Oncology
OTHER CY ASCENTERS PROPHYLAXIS EXPERIENCE FOR OTHER CENTERS EXPERIENCE
GVHD
MDACC PLATFORM Conditioning: Melphalan 140 mg/m2 on day −8 (100mg/m2 for pts Conditioning: Thiotepa 5-10 mg/kg on day −7 OR TBI 200 ≥55 years or with comorbidities) Thiotepa Melphalan 5-10 140mg/kg mg/m2 onon day day −7−8 OR (100mg/m2 TBI 200 for pts
TNC T-cell replete bone marrow graft; goal >3x108/kg
BW) MMF until day 100 (no taper) Tacrolimus until day 180 (tapered)
RESULTS Myeloid in CR (N=40)
Lymphoid malignancies (N=17)
ALL (N=12)
3-year PFS
56.5
62.3
44.4
1-year TRM
11.8
25.9
33.3
1-year CIR
30.1
24.4
33.3
25
35.3
50
0
11.8
41.7
12.5
11.8
44.4
10
5.9
8.3
Outcomes (%)
aGVHD grade 2-4 aGVHD grade 3-4 cGVHD cGVHD (extensive)
MDACC – FMT RESULTS
24%at 3 years
NRM
38% at 3 years
Relapse
MYELOID PATIENTS BY DISEASE STATUS P=0.008
P=0.014
TX CY AS PROPHYLAXIS FOR CY ASGPROPHYLAXIS VHD FOR CAN PB BE USED INSTEAD OF BM AS SOURCE OF SC GVHD
VS
PB
CASTAGNA L ET AL. BBMT 2014, 20:724
POST-TX CY: BM CASTAGNA L ET AL. BBMT 2014, 20:724 POST-TX CY: BM VS PB CASTAGNA L ET AL. BBMT 2014, 20:724
OS HAPLOIDENTICAL HSCT WITH POST-TX CY: BM VS PB CASTAGNA L ET AL. BBMT 2014, 20:724 The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again.
HAPLO BMT VS
GVHD MRD VS MUD (BM OR PB)
Transplantation outcomes.
Leo Luznik Š2010 by American Society of Hematology
POST-TRANSPLANT CY AFTER HLA MATCHED AND HAPLOIDENTICAL TRANSPLANTS RASHIDI A ET AL. BMT, 2016
SINGLE CENTER COMPARISONS: MDACC
N=227
Di Stasi, BBMT 2014
NON RELAPASE vs MUD IN MORTALITY AML, NMA & MAV (CIBMTR) NON RELAPASE MORTALITY
Stefan O. Ciurea et al. Blood 2015;126:1033-1040
©2015 by American Society of Hematology
vsRELAPSE RELAPSE
Stefan O. Ciurea et al. Blood 2015;126:1033-1040
©2015 by American Society of Hematology
OVERALL MUD IN SURVIVAL AML, NMA & MAC PREP (CIBMTR) OVERALL SURVIVAL
Stefan O. Ciurea et al. Blood 2015;126:1033-1040
©2015 by American Society of Hematology
HAPLO BMT VS. CBT TX CY AS PROPHYLAXIS FOR GVHD HAPLO BMT VS. CBT
BMT CTN PHASE 3 TRIAL COMPARING HAPLOIDENTICAL BMT WITH POST-TX CY TO DOUBLE UMBILICAL CORDS AFTER REDUCED INTENSITY CONDITIONING
Treatment plans.
Claudio G. Brunstein et al. Blood 2011;118:282-288
Š2011 by American Society of Hematology
GVHD.
Claudio G. Brunstein et al. Blood 2011;118:282-288
©2011 by American Society of Hematology
Phase 3 trial DUCBT vs Haplo: Relapse and OS
Claudio G. Brunstein et al. Blood 2011;118:282-288
Š2011 by American Society of Hematology
POST-TRANSPLANT CY AS GVHD PROPHYLAXIS
COMPLICATIONS: GRAFT FAILURE DUE TO PATIENT’S ANTIBODIES AGAINST DONOR
¢ Recipients
HLA ANTIGENS (DSA)
are often multiply transfused before undergoing transplantation and may have antibodies against HLA antigens of haplo donor. ¢ This antibodies have been shown to cause rejection in organ transplantation and CBT. ¢ Choice of donor is determined by the presence of DSA, however if there is no several donors, patient needs to undergo treatments to lower the concentration of antibodies.
Reduc&on of Alloreac&ve DSA Hopkins Regimen
MDACC Regimen
Start 7-14 days prior to condi&oning depending on &ter
Start 14 days prior to condi&oning
Plasmapheresis – 1 volume QOD Tacrolimus 1 mg PO/IV/day IVIg 100 mg/kg QOD MMF 1 gram PO BID Minimum 5-6 treatments for CXR+ PP/IVIg stopped during condi&oning PP repeated day -1 and +1 if DSA rebound
N = 15 haplo transplant recipients Median &ter = Not reported Mean reduc&on in MFI = 64% 14/15 engraYed
Rituximab 375 mg/m2/week x 2 Plasmapheresis – 1 volume QOD x 3 start 11 days prior to condi&oning Some pa&ents received IVIg prior to condi&oning Some pa&ents received buffy coat infusion day -1
22/122 pa&ents had DSA C1q+ pa&ents mean MFI = 15,279 (9) C1q- pa&ents mean MFI = 2,471 (13) Among C1q+ pa&ents 5/9 remained posi&ve at HCT and 4/5 rejected 2/13 remaining pa&ents rejected
POST-TRANSPLANT CY AS GVHD
PROPHYLAXIS COMPLICATIONS: CYTOKINE RELEASE SYNDROME ¢ Febrile
syndrome with negative blood cultures early post infusion of haplo allograft ¢ Hypotension SBP< 90 refractory to intravenous fluid ≥ 15 mL/kg or requiring vasopressors OR ¢ Respiratory distress/hypoxia requiring increasing supplemental oxygen or ventilatory support OR ¢ Acute coronary syndrome with positive troponin and/or ECG changes OR ¢ Encephalopathy or delirium endangering patient safety, or seizure/suspected seizure • Rapidly rising creatinine
IL-6 LEVELS AFTER HAPLO TRANSPLANTS Abboud R et al, BBMT 2016; 22:1851
CYTOKINE RELEASE SYNDROME: GRADING
CRs TREATMENT ALGORITHM
CRS TREATMENT ALGORITHM
SURVIVAL & CRS AFTER HAPLO TRANSPLANTS Abboud R et al, BBMT 2016; 22:1851
POST-TRANSPLANT CY AS GVHD PROPHYLAXIS
IS BETTER THAT STANDARD PROPHYLAXIS AND EX VIVO TCD?
CNI free Trial: 3-arm Phase III <65y Early disease Any HLA matched donor MA eligible
BM Tac/MTX BM PTCy CD34 Selected PBSC
• 345 (115/arm): 85% power to detect a 20% difference over the 22% baseline of the primary endpoint.
POST-TX CY AS PROPHYLAXIS FOR GVHD SUMMARY ¢ Post-tx
Cy as GvHD prophylaxis is very effective in preventing GvHD and T cell mediated rejection ¢ Similar results to CBT as shown by a randomized trial. ¢ Similar results to MRD and MUD HSCT based upon retrospective single center or registry data. ¢ PB gives similar results to BM, but this needs a randomized trial ¢ Two serious complications: graft failure due to donor specific antibodies and cytokine release
POST-TX CY AS PROPHYLAXIS FOR GVHD SUMMARY ¢ The
determination of the best GvHD prophylaxis awaits the results of ongoing randomized trial comparing standard prophylaxis to ex vivo TCD and in vivo TCD with post-tx CY ¢ In the meantime and in view of current results it seems to be perfectly valid to use this method of GvHD prophylaxis because of his low cost and feasibility, it does not needs a complicated infrastructure needed for CB and MUD HSCT
MUCHAS GRACIAS