Trapianto allogenico

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1 POST ASH 2013: 3 Workshop Regionale Marchigiano 28 Febbraio - 1 Marzo 2014 Hotel Domus Stella Maris, ANCONA REPORT OF THE BEST ASH NEWS Trapianto allogenico Dr. Claudio Giardini U.O. Ematologia e Centro Trapianto Ospedali Riuniti Marche Nord - Pesaro

2 Selezione e discussione dei 6 abstracts più innovativi sul Trapianto Allogenico presentati all ASH Meeting trapianto da donatore aplo pediatrico F. Locatelli 159 influenza del Killer Immunoglobulin-Like Receptor (KIR) e genotipi HLA dopo condizionamento RIC studio multic. 550 PBSC-BM dopo condizionamento RIC con FLU IBMDR 921 TMO nelle LAM cariotipo normale I RC: influenza prognostica dell età e delle mutazioni del gene FLT3 EBMT 923 Ciclofosfamide per la profilassi della GvHD post-tmo allo match Atlanta 2091 aplo-bmt nei Linfomi HR condizionati con RIC Baltimora

3 Abstract 157 Removal of Alpha/Beta+ T Cells and of CD19+ B cells from the graft translates into rapid engraftment, absence of visceral Graft-Versus -Host Disease and low transplant-related mortality in children with Acute Leukemia given HLA-Haploidentical Hematopoietic Stem Cell Transplantation A. Bertaina, D. Pagliara, D. Pende, and F. Locatelli We recently developed a new method of graft manipulation based on the physical removal of αβ+ T cells and CD19+ B cells, which permits to leave mature NK cells and γδ+ T cells in the graft. 45 patients, aged 10.1 years ( ) 35 ALL, 10 AML 15 transplanted in 1 CR, 27 in 2 CR, 3 in more adv. CR Donors: mother (n=25) or father (n=20) Conditioning: myeloablative regimen, containing TBI in 34 cases No pharmacological graft-versus-host disease (GVHD) prophylaxis was employed after transplant Engraftment: 44/45 pts Ac. GvHD grade I-II: 13 pts Skin limited Chronic GvHD: 2 pts Two pts died for causes other than disease relapse. Seven pts relapsed : 16% LFS: 75% with a median follow-up of 11 months (2-30) The probability of LFS of the 39 pts with either negative or low (<1x10-4) MRD at time of HSCT was 81% as compared to 25% of the 6 pts with positive MRD (p<0.01). The CI of cytomegalovirus (CMV) reactivation was 53% (CO. IN ). These data indicate that a selective graft manipulation results into effective prevention of both acute and chronic GVHD, rapid recovery of neutrophil and platelet counts and low TRM.

4 Abstract 157 In the first 45 days after HSCT, circulating T cells mainly consisted of the γδ+ subset, whileαβ+ T lymphocytes predominated thereafter. CMV reactivation promoted the expansion of Vδ1+ T cells. Mature NK cells expressing inhibitory KIRs and negative for NKG2A, including also the alloreactive cells, were detectable at 1 month in peripheral blood after HSCT, showing the persistence of transplanted cells with potential anti-leukemia activity. These percentages increased at later time points, reaching values comparable to those found in the HSCT donor. Although the median observation time is still limited, also the CI of disease recurrence is encouraging.

5 Abstract 159 Influence of Killer Immunoglobulin-Like Receptor (KIR) and HLA Genotypes on outcomes after Reduced-Intensity Conditioning Allo HSCT for patients with AML and MDS: a report from the Center For International Blood and Marrow Transplant Research Immunobiology Working Committee R. M. Sobecks, M. Gallagher, M. Askar, et al: Cleveland, NY, Minneapolis, Milwaukee, Seattle, Stanford, Ulm (Germany), Westmead (Australia). Disease relapse is a significant cause of treatment failure after allogeneic HSCT. In the setting of reduced-intensity conditioning (RIC), a graft-versus-leukemia (GVL) effect is critical for successful outcomes in patients with advanced myeloid malignancies. A GVL effect has been attributed in part to donor-derived alloreactive natural killer (NK) cells, which are regulated by interaction of KIRs with their HLA-class I ligands. Several models of NK reactivity have been associated with improved outcomes following HLA-matched, HLAmismatched, related, and unrelated donor HCT, particularly for AML patients given myeloablative conditioning. The effect of KIR-HLA combinations on outcomes after RIC HCT, however, is not known.

6 Abstract 159 We retrospectively analyzed donor-recipient KIR/HLA genotypes from 929 URD HCTs facilitated by the National Marrow Donor Program for patients with AML (n=624) or MDS (n=305) treated with RIC between 1990 and donor-recipient pairs were 10/10 HLA-matched and 265 were 9/10 HLA-matched. We hypothesized that donor-recipient KIR-HLA interactions may be associated with improved post-transplant outcomes following RIC HCT for AML and MDS. Patients lacking the HLA-Bw4 ligand for donor inhibitory KIR3DL1 experienced lower relapse following HCT at 1 year (27 vs 36%) and 5 years (31 vs 42%) compared to patients with the Bw4 ligand (Figure). Risk for acute GVHD was higher among patients lacking KIR ligands. The analysis was then restricted to AML patients, the patient population with greatest reported KIR-HLA effects. Patients whose donors were KIR2DS1+ and HLA-C2C2 (n=33) had higher transplant-related mortality (TRM) compared to all other patients. In a multivariate analysis, lack of HLA-C2 in AML patients was associated with higher grade 2-4 acute GVHD, and risk for grade 3-4 acute GVHD was higher in patients lacking multiple KIR ligands. Overall, these results suggest that in the RIC HCT setting, lack of Bw4 ligand for KIR3DL1 is associated with a lower risk of relapse for AML/MDS. This observation corroborates previous findings in myeloablative HCT transplants. Furthermore, tolerance of donor KIR2DS1 by HLA- C2C2 was associated with worse outcome, as manifested by higher TRM, in AML patients. Further elucidation of the biology of NK cell alloreactivity in the RIC setting may provide guidance for future approaches to help optimize conditions for generating GVL reactions without GVHD and less TRM in this transplant population.

7 Abstract 550 Transplantation Of Peripheral Blood Progenitor Cells (PBPC) As Compared To Bone Marrow (BM) From Unrelated Related Donors For Hematologic Cancers Using Fludarabine-Alkylating Agent Based Reduced Intensity Conditioning Regimens M. Eapen, B. Logan, M. Horowitz, R.Champlin CIBMTR, Milwaukee, NY, Seattle, Oxford, Boston, Minneapolis, Houston We explored whether there are differences in GVHD or mortality risks after transplantation of PBPC and BM from unrelated donors in the setting of reduced intensity conditioning. Included are 219 BM and 887 PBPC recipients with AML, MDS or NHL. Patients received an alkylating agent and fludarabine as their conditioning regimen and for GVHD prophylaxis, calcineurin inhibitor (CNI) with methotrexate (MTX) or mycophenolate (MMF). Transplantations occurred in the U.S. between 2000 and The median ages of BM and PBPC recipients were 57 years. Mortality risks were higher after transplantation of PBPC or BM when GVHD prophylaxis included MMF compared to MTX. There were no significant differences in mortality risks after transplantation of PBPC relative to BM with CNI + MTX GVHD prophylaxis, but mortality risks were higher after transplantation of BM compared to PBPC with CNI + MMF. Risks of grade 2-4 acute and chronic GVHD were higher after transplantation of PBPC or BM when GVHD prophylaxis included MMF compared to MTX. Relapse risks were higher after transplantation of BM compared to PBPC with CNI + MMF but not with CNI + MTX GVHD prophylaxis. Independent of graft type and GVHD prophylaxis regimens, in vivo T cell depletion was associated with lower risks of acute and chronic GVHD but relapse risks were higher. The data support BM and PBPC are suitable for unrelated donor transplantation when using fludarabine-alkylating agent based reduced intensity conditioning regimens and CNI + MTX GVHD prophylaxis. The data support avoiding CNI + MMF GVHD prophylaxis in this setting.

8 Abstract 921 Allogeneic Stem Cell Transplantation For Acute Myeloid Leukemia With Normal Cytogenetics (CN-AML): Outcome, Risk Factors and Role Of Molecular Subgroups In 752 Patients A Report From The Acute Leukemia Working Party Of EBMT C. Schmid, M. Labopin, G. Socié, M. Mohty Allogeneic stem cell transplantation (allosct) is the only curative treatment for most patients with CN AML. It is now well established that some relevant molecular markers can allow for the definition of risk groups after conventional chemotherapy. However, the role of these markers among other factors influencing outcome after allosct remains to be defined. Hence, we conductedan EBMT registry-based analysis aiming to define the exact prognostic role of molecular subgroups in conjunction with other classical risk factors after allosct for CN-AML. Inclusion criteria: allosctfor CN-AML between 2000 and 2011, matched sibling (MSD) or unrelated (MUD) donor, and known mutational status of FLT3-ITD and NPM1, the two most frequently observed molecular markers in CN-AML. 752 pts, median age 51y (18-71), disease status at time of allosct CR1 (n=554), CR2/3 (n=90), primary induction failure (PIF, n=39), relapsed disease (n=62).myeloablative and reduced-intensity conditioning regimens were used in 371 and 378 patients, respectively. 597 received allogeneic PBSCs. With a median follow-up of 27 months, The 2-year estimates of overall survival (OS) and leukemia-free survival (LFS) were respectively 68±2% and 61±6% after allosct in CR1, 63±2% and 53±6% in CR2/3, 36±7% and 33±8% in PIF, and 28±7% and 25±6% in relapsed disease. In 554 patients transplanted in CR1, OS, LFS, cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated according to molecular subgroups.

9 Abstract 921 Whereas NPM1mut had no influence on outcome, FLT3-ITD was associated with increased CIR (p<0.0001), decreased LFS (p=0.0002) and OS (p=0.0006) A multivariate Cox model of predefined risk factors was performed. Age >=50 years was the only risk factor for NRM, while the presence of FLT3-ITD was the only risk factor for CIR. Both age >=50 years and FLT3-ITD were associated with inferior LFS and, most importantly, OS. The latter data allowed to identify 3 prognostic groups with 2-years OS of 83±4% (younger age and FLT3-ITDneg), 70±4% (older age OR FLT3-ITD) and 48±5% (older age and FLT3-ITD), (Figure 1). On the contrary, donor type (sibling vs. MUD) or intensity of the conditioning regimen (standard vs. reduced) did not play any significant role in any molecular subgroup. Conclusion: In the largest study on CN-AML performed thus far, we identified age >=50 years andflt3-itd as the major risk factors for OS after allosct in CR1, independently from other risk factors such as type of donor or conditioning. In patients harboring FLT3- ITD, a limited protective role fornpm1 mutation could be observed. These results underscore the importance of post-transplant strategies to prevent relapse in AML with FLT3-ITD. Encouraging results were observed after SCT in PIF, relapse or advanced CR.

10 Abstract 921 Two years probability of OS: 83% age <50 FLT3-ITDneg 70% older age or FLT3-ITD 48% age >50 FLT3-ITD Figure 1: Overall survival from allo SCT for CN-AML in CR1, based on patient age and presence of anflt3-itd

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12 Abstract Calcineurin Inhibitor-Free GVHD Prophylaxis with Post- Transplant Cyclophosphamide and Brief-Course Sirolimus Results in Low Rates of Non-Relapse Mortality and Chronic GVHD Following Matched Related and Unrelated Donor Peripheral Blood Stem Cell Transplantation (PBSCT) M. Sanacore, A. Bashey, S.R. Solomon, Atlanta Calcineurin inhibitors (CNIs) form the foundation of current GVHD prophylaxis regimens. We hypothesized that a CNI-free regimen consisting of post-transplant cyclophosphamide (Cy) and brief-course sirolimus would decrease the risk of chronic GVHD and non-relapse mortality and improve outcomes following reduced intensity allogeneic PBSCT. 27pts with high risk hematologic malignancies: age 61 years (25-73). All patients had a 10/10 locus matched donor; MRD=18, MUD=9. Conditioning consisted of fludarabine 30mg/m2 on days -9 to -6, IV busulfan 130 mg/m2 on days -5 to -4, and Cy 14.5 mg/kg on days -3 and -2 followed by unmanipulated PBSCT. Post-grafting immunosuppression consisted of Cy 50 mg/kg/day on days 3 and 4 and sirolimus starting day +5 and completing day+90 in the absence of GVHD.

13 Abstract 923 Donor engraftment occurred in all patients with a median time to neutrophil and platelet recovery of 15 and 30 days, respectively. The median day +90 donor T cell and myeloid chimerism was 94% (40-100%) and 100% (11-100%) respectively. Three patients received donor lymphocyte infusions for incomplete donor T cell chimerism. The cumulative incidence of grade II-IV acute GVHD, grade III-IV acute GVHD, all chronic GVHD, and severe chronic GVHD was 41%, 15%, and 32%, and 12% respectively. Non-relapse mortality (NRM) and relapse incidence at 2 years was 4% and 17% respectively. With a median follow-up of 18 months, the estimated 2 year overall and disease-free survival was 71% and 80% respectively for the whole cohort, while it was 87% and 89%, respectively in the subgroup of 18 patients receiving MRD transplants. Good immune reconstitution was evidenced by low cytomegalovirus reactivation rates, occurring in only 4 of 19 at-risk patients (21%). CNI-free GVHD prophylaxis with post-transplant Cy and brief-course sirolimus achieves consistent donor engraftment, low rates of GVHD and NRM, and excellent outcomes in recipients of HLA-identical donor allogeneic PBSCT.

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15 Abstract 2091 Outcomes Of Nonmyeloablative (NMA) Haploidentical Blood Or Marrow Transplantation (haplobmt) With High-Dose Posttransplantation Cyclophosphamide (PT/Cy) For Lymphoma Y. L. Kasamon, J. Bolaños-Meade, D. Gladstone,. Johns Hopkins University, Baltimore With recent advances in GVHD prophylaxis, NMA haplobmt has become a viable option for pts who lack a fully matched donor. However, relatively few data are available on disease-specific outcomes following NMA haplobmt. This study evaluated the outcomes of NMA related haplobmt with PT/Cy in pts with lymphoma. 151 consecutive pts, median age 55 (14-73 y), with poor-risk or advanced lymphoma who received NMA related haplobmt with PT/Cy. Pts had a first-degree related haplo donor, and in general PR for aggressive NHL, SD for Hodgkin lymphoma (HL). Conditioning consisted of Cy (14.5 mg/kg IV, days -6 and -5), fludarabine (30 mg/m2 IV, days -6 to -2), and TBI (200 cgy, day -1) in 98% of cases. Grafts were T-cell replete (bone marrow in 99%). GVHD prophylaxis consisted of high-dose PT/Cy (50 mg/kg IV) twice (days 3 and 4; 150 pts), mycophenolate mofetil, and tacrolimus.

16 Abstract 2091 With a median follow-up of 3.8 y (0.5-8), the 3-y probabilities of both progression-free survival (PFS) and disease-free survival were 40%, with a 3-y overall survival (OS) probability of 46 (39-55)% (figure A). Nonengraftment attributed to primary graft failure or to residual bone marrow malignancy occurred in 17/147 evaluable pts (12%), 1-y probabilities of nonrelapse mortality (NRM) and relapse were 16% and 31%, respectively. The probability of grade 2-4 acute GVHD was 32%, grade 3-4 acute GVHD was 5%, and chronic GVHD was 13%. Disease-specific cumulative incidences of relapse, are shown in figure B. PFS for low risk, intermediate and high risk pts are shown in figure C NMA related haplobmt with PT/Cy carries acceptable toxicities that parallel those of NMA matched transplants, while producing durable disease control in a clear subset of lymphoma pts. This approach facilitates the integration of new posttransplantation strategies that could reduce the risk of relapse.

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