Haploidentical Transplantation (HAPLO) with Post-Transplant High-Dose Cyclophosphamide for Graft Vs Host Disease (GVHD) Prevention in the Treatment of High Risk Hematological Neoplasms

Abstract Abstract 4545 Introduction: Allogeneic transplantation is the only curative option in the treatment of multiple high risk hematologic neoplasms. Only 25–30% of patients have an HLA identical sibling donor and searching for a compatible unrelated donor or cord blood renders satisfactory results in around 60–70%. Haploidentical transplantation (HAPLO) offers a therapeutic alternative to more than 95% of such patients with the advantages of quick availability, easy programming and a committed donor. Patients and Methods: We evaluate the results of HAPLO with a reduced intensity conditioning regimen (Fludarabine 30 mg/m2 ×5 days (-6 to -2), Cyclophosphamide 14,5 mg/kg ×2 days (-6 and -5), IV Busulfan 3,2 mg/kg × 1–3 days (BUX, days -4 to -2) employing high doses of Cyclophosphamide post graft infussion (50 mg/kg days +3 and +4) as GVHD prophylaxis together with standard doses of cyclosporine and mycophenolate from day +5. Results: From Dec-2007, we have done 26 HAPLO in 4 spanish centers. Median age was 38 years (16–57), 20 were male and all were in advanced phases of their diseases (12 Hodgkin′s, 6 AML, 3 ALL, 2 MM, 1 MDS, 1 MF y 1 NHL). Previous autologous HSCT has been employed in 13 and allogeneic HSCT in 6 (2 MURD and 4 UCB). Disease status at HAPLO was CR in 8, PR in 14 and refractory in 4. Bone marrow was used in 16 and unmodified peripheral blood in 10. The haploidentical donor was patient′s mother (8), father (3), siblings (11) or other relatives (4). BUX was used in 1 dose (15), 2 doses (8) or 3 doses (2) and TBI 200 cGy in 1 case. Mean neutrophils engraftment was achieved on day +18 (13–26) and platelets >50K on day +27 (17–150) in all but 2 cases of graft failure (7.7%) due to progression (MF) or relapse (M7-AML). Main toxicities were grade 1–2 mucositis in 50%, febrile neutropenia in 75% and CMV reactivations in 58% with a 100 days NRM of 3.8% (1/26, VOD and MOF) and 10% NRM at 6 months (2/20). Grade II-IV acute GVHD appeared in 10/23 patients at risk (43%) and grade III-IV in 4/23 (17%). Chronic GVHD affected to 4/15 (27%), being extensive in 1/15 (6.7%). With a median follow-up of 9 months (1–38), 13/22 (59%) are alive in CR, progression or relapse has ocurred in 6/24 (25%). Immune reconstitution seems fast and complete in those evaluated. Conclusions: HAPLO with high-dose cyclophosphamide as GVHD prophylaxis is a useful alternative in the treatment of high risk hematologic tumours, with low toxicity, acceptable GVHD incidence and severity, long lasting remissions, and fast immunological reconstitution. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

The Addition of ONE-Day Rest Between LAST ATG Infusion and STEM CELL Infusion DID NOT Affect Gvhd Occurrence After Allogeneic TRANSPLANTATION with Fludarabine-Busulfan-ATG Conditioning.

Blood ◽

10.1182/blood.v120.21.3029.3029 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3029-3029

Author(s):

Roberto Crocchiolo ◽

Sabine Fuerst ◽

Jean El-Cheikh ◽

Angela Granata ◽

Claire Oudin ◽

...

Keyword(s):

Stem Cell ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Disease Status ◽

Allogeneic Transplantation ◽

Unrelated Donor ◽

Progression Rate ◽

Gvhd Prophylaxis

Abstract Abstract 3029 Introduction: Antithymocyte globulin (ATG) is part of many conditioning regimens for allogeneic stem cell transplantation (AlloSCT) with the aim of reducing graft-versus-host disease (GvHD), due to in vivo T-cell depletion. ATG administration may be accompanied by fever, chills, headache or other side effects that affect patient's management and can cause a delay in stem cell infusion. In order to improve ATG tolerance, since November 2010 we modified our fludarabine-busulfan-ATG (FBA) conditioning for RIC transplants with the addition of 1-day rest between the last ATG administration and stem cell infusion. No modification of drugs or GvHD prophylaxis occurred: five days of fludarabine, two days of i.v. busulfan and two days of ATG Thymoglobuline (10 mg/kg total dose) were administered during conditioning, and ciclosporine for GvHD prophylaxis together with MMF only in the presence of a mismatched unrelated donor (MMUD). Aim: To analyse whether the addition of 1-day rest between ATG administration and stem cell infusion impacted on outcome of adult patients receiving AlloSCT after FBA conditioning with respect to previous no-rest modality, in particular acute grade 2–4 or grade 3–4 GvHD. Methods: The 1-day rest cohort (ATG-rest) was compared with a previous consecutive cohort of patients (no rest) transplanted at our center. Analysis of acute GvHD among the two groups was performed as well as of chronic GvHD, OS, PFS, NRM, relapse/progression. Results: A total of 64 and 63 patients were included in ATG-rest and no-rest cohorts respectively. First patient in the no-rest cohort received AlloSCT on November 2008. Follow-up was thus longer in this cohort: median 27 months (21–37) vs. 15 (11–20), p<0.0001. No significant differences of patients' age, diagnosis and disease status at AlloSCT between the two groups were observed; matched unrelated donors (MUDs) were higher in the ATG-rest group whereas the number of MMUDs was similar in both groups (see Table 1). Rate of acute and chronic GvHD and NRM, probabilities of OS and PFS did not differ between the two groups (Table 1). Unexpectedly, relapse/progression rate was lower in the ATG-rest groups (p=0.002), although disease status at AlloSCT was not significantly different between the two cohorts. Median day of relapse or progression from AlloSCT in the no-rest group was +165 (35–476) vs. +57 (8–215) in ATG-rest one, p=0.004. No difference in relapse/progression was observed according to donor (HLA-identical sibling vs. MUD vs. MMUD) and a lower relapse risk in 1-day rest group is confirmed after adjustment for type of donor: HR = 0.29 (0.12–0.72), p=0.01. Conclusion: The addition of 1-day rest between last ATG administration and stem cell infusion did not impacted on GvHD occurrence after AlloSCT after FBA conditioning. The finding of a reduced rate of relapse/progression in the ATG-rest group deserves to be investigated and requires longer follow-up. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Haploidentical Stem Cell Transplantation (HAPLO-HSCT) With High Dose Cyclophosphamide Post-Transplant (HD-CY) As Gvhd Prophylaxis In High Risk Hematologic Malignancies: Multicentric Spanish Experience

Blood ◽

10.1182/blood.v122.21.2173.2173 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2173-2173

Author(s):

Jorge Gayoso ◽

Pascual Balsalobre ◽

Mi Kwon ◽

María Jesús Pascual ◽

Cristina Castilla-Llorente ◽

...

Keyword(s):

High Risk ◽

Immune Reconstitution ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Hematologic Malignancies ◽

High Dose ◽

Unrelated Donor ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Grade Ii

Abstract Introduction Allogeneic transplantation is the only curative option for patients with high risk hematologic malignancies. Only one third of them have an HLA identical sibling donor and around 60-70% will find an unrelated donor, that´s why HAPLO-HSCT offers a therapeutic option to most of these patients with the advantages of quick availability, easy programation and logistics, and a committed donor. Patients and methods We retrospectively evaluate the results of HAPLO-HSCT with reduced conditioning or myeloablative regimens and GVHD prophylaxis based on HD-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5 performed in GETH centers. Results From Dec-2007, 80 HAPLO-HSCT have been done in 14 centers. Median age was 37 years (16-66), 67.5% were males and all were in advanced phases of their disease or presented high risk features (29 Hodgkin´s, 22 AML, 9 ALL, 8 MDS, 5 NHL, 4 myeloma and 2 myelofibrosis). Previous HSCT has been employed in 65%, autologous in 38 and allogeneic in 15 (5 siblings, 3 unrelated and 7 cord blood transplants), and in 35% the HAPLO-HSCT was their first transplant. Disease status at HAPLO-HSCT was CR in 45%, with persistent disease in 55%. Bone marrow was the graft source for 51% and peripheral blood for 49%, non T-cell depleted in all cases. The haploidentical donor was the patient´s mother (21), father (7), brother/sister (35) or offspring (17). Non-myeloablative conditioning was employed in 77.5% and myeloblative in 22.5%. Median neutrophils engraftment was reached at day +18 (13-45) and platelets >50K at day +27 (11-150). Main toxic complications were grade II-III muchositis in 36%, febrile neutropenia in 75% and CMV reactivations in 62%, with a transplant related mortality rate of 12.5% at day +100 and 19% at 6 months post-transplant. Acute GVHD grade II-IV affected to 24/73 patients at risk (33%), with grade III-IV in 10/73 (14%). Chronic GVHD was present in 12/51 (24%), being extensive in 6/51 (12%). After a median follow-up of 9 months (0.3-49), 26/80 patiens have died due to relapse in 13, infections in 10 and GVHD in 3 cases. Event-free survival and overall survival at 1 year were 48% and 60% respectively. Immune reconstitution was fast and complete in those evaluated. Conclusions HAPLO-HSCT with HD-CY is a useful tool in the treatment of high risk hematologic malignancies, rendering long-lasting remissions with limited toxicity, low GVHD incidence and early immune reconstitution. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Phase I/I Clinical Trial for the Evaluation of Bortezomib within the Reduced Intensity Conditioning Regimen (RIC) and Post-Allogeneic Transplantation As Gvhd Prophylaxis Among High-Risk Myeloma Patients. EudraCT: 2005–004858-27

Blood ◽

10.1182/blood.v118.21.3025.3025 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3025-3025

Author(s):

Jose Antonio Perez-Simón ◽

Teresa Caballero-Velazquez ◽

Cristina Encinas ◽

Cristina Castilla-Llorente ◽

Rodrigo Martino ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Conditioning Regimen ◽

Disease Status ◽

Allogeneic Transplantation ◽

Reduced Intensity Conditioning ◽

Advisory Committees ◽

Gvhd Prophylaxis ◽

Reduced Intensity Conditioning Regimen ◽

Reduced Intensity

Abstract Abstract 3025 Introduction: Although allogeneic stem cell transplantation (allo-SCT) is the only curative treatment for MM, it is associated to a high morbility and mortality. Moreover, relapses are common after allo-RIC. Accordingly, new strategies are required to reduce both the risk of relapse and the toxicity of the procedure. As we have previously demonstrated, Bz induces a selective depletion of alloreactive T-cells and has immunomodulatory properties which might be of potential benefit for GVHD control. The primary end point of this study was to evaluate the efficacy of allo-RIC in terms of response when Bz was added as part of a reduced intensity conditioning prior to allo-SCT. Secondary end points included incidence of GVHD and analysis of the toxicity of the procedure when Bz is also administered post-infussion as part of the GVHD prophylaxis. Method: Prior to allo-RIC, patients received two cycles of Bz plus dexamethasone. Conditioning consisted of fludarabine (30 mg/m2 intravenously on days -9 to -5) and melphalan (70 mg/m2 intravenously on days -4, -3) plus Bz 1, 3mg/m2 on day - 11 and -2. GVHD prophylaxis included cyclosporine (CsA) and methotrexate for the first 9 patients and CsA plus MTX and Bz on days +3 and +7 for the remaining 7 patients. From day +50 post allo-RIC 7 cycles of Bz (+1, +8, +15) were administered, the first two cycles every 28 days and the rest every 56. Results: 16 patients from the Twenty-one initially enrolled, were evaluable. All 16 patients had received at least 2 lines of therapy including autologous-SCT. Disease status was CR or nCR in 4 patients, 9 had PR and the remaining 3 patients had relapsed / progressive disease. 15 patients maintained or improved status at transplant including all × patients with active disease at transplant. Eight patients (50%) relapsed, four with extramedullary involvement. No patient developed grade 4 aGVHD.Grades 2–3 aGVHD occurred in 6 patients (37%). Interestingly, two out of the nine (29%) patients who received Bz on days +3 and 7 developed grades 2–3 acute GVHD as compared to four of the nine (44%) who did not receive it. In terms of toxicity, one patient did not achieve platelet engraftment and 2 patients developed peripheral neuropathy requiring treatment withdrawal. 8 patients died, four of them due to relapse (MRT: 25%). With a median follow-up of 457 days overall survival was 46%. Conclusions: The current trial is the first evaluating the efficacy and safety of Bz as part of a reduced intensity conditioning regimen among patients with high risk MM undergoing allogeneic transplantation. Regarding the efficacy of the procedure all but one patient improved disease status post-alloRIC although relapse rate was still high in this heavily pretreated population. In addition, Bz post-alloSCT is well tolerated and may decrease the incidence of GVHD. Disclosures: Perez-Simón: Janssen-Cilag: Patents & Royalties. Off Label Use: This study evaluates the efficacy of Bortezomib as part of a reduced intensity conditioning regimen among patients with high risk MM undergoing allogeneic transplantation. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Busulfan, Cyclophosphamide and Melphalan As Conditioning Regimen for Pediatric Patients with AML in 1st or 2nd CR: A Retrospective Analysis from the AIEOP HSCT Registry

Blood ◽

10.1182/blood-2018-99-111805 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2106-2106

Author(s):

Annalisa Ruggeri ◽

Marco Zecca ◽

Franca Fagioli ◽

Adriana Balduzzi ◽

Mattia Algeri ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Pediatric Patients ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Status ◽

Unrelated Donor ◽

Advisory Committees ◽

Donor Type

Abstract Allogeneic stem cell transplantation (HSCT) is largely adopted as post-remissional therapy in children with acute myeloid leukemia (AML) in first complete remission (CR1) but with high-risk characteristics (including high-risk cytogenetics or high levels of minimal residual disease at the end of induction therapy) or to rescue patients reaching CR2 after a previous relapse. Busulfan-based regimens represent the standard of care for these patients in association with alkylating agents. One of the most frequent drugs combination used in Europe in pediatric patients is Busulfan, Cyclophosphamide and Melphan (BuCyMel), which provide a potent anti-leukemic effect, despite remarkable extramedullary toxicities, especially in adolescents. We aimed at analyzing the results of children with AML receiving BuCyMel and reported to the AIEOP registry from 2008 to 2015. A total of 182 patients were reported by 15 transplant centers. Median age at HSCT was 9 years (range 0.3-18); 100 patients (55%) were male. Disease status at HSCT was CR1 in 159 (88%) patients and CR2 in the remaining 23 (12%). All patients received the same myeloablative conditioning regimen with BuCyMel and GVHD prophylaxis was mainly based on calcineurin inhibitors, with the addition of methotrexate in unrelated donors recipients. In vivo T-cell depletion/modulation with ATG was used in 90 cases (49.5%). In almost all cases, pharmacokinetics monitoring of Busulfan was performed, with the drug dosage adjusted according to the systemic exposure evaluated after the first dose. Donor type was an HLA-matched family donor (MFD) in 82 (45%) patients and an unrelated donor (UD) in 100 (55%); 154 (85%) patients received bone marrow (BM) as stem cell source, while the remaining patients (15%) were transplanted with peripheral blood stem cells (PBSCs). Median follow up for surviving patients was 39 months (range 1-111). All patients achieved neutrophil engraftment. The cumulative incidence (CI) of grade II-IV and grade III-IV aGVHD was 35% (95%CI 28-42) and 11% (95% CI 7-16), respectively. The CI of aGVHD was not different according to the type of donor, being 37% (95%CI 28-50) and 32% (95%CI 24-46) in MFD and UD, respectively (p=0.38). The CI of chronic GVHD at 3 years was 17% (95%CI 12-24), while that of extensive cGVHD was 6% (95%CI 3-10). No difference was found in the CI of CGVHD according to the donor employed (MFD 15% and UD 19%, p=0.49). Overall, the CI of relapse and non-relapse mortality (NRM) at 3 years was 18% (95%CI 12-26) and 15% (95%CI 10-22), respectively. The CI of relapse and NRM was significantly different according to age at HSCT (using 12 years as cut-off): (Relapse age<12y: 21% (95%CI 15-32) and age>12y: 11% (95%CI 3-32), (p=0.003); NRM age<12y: 10% (95%CI 5-20) and age>12y: 24% (95%CI 15-37), (p=0.005). According to disease status at HSCT the CI of relapse and NRM were as follows: Relapse: CR1: 18% (95%CI 18-26), CR2 15% (95%CI 5-41) p=0.90) and NRM CR1: 14% (95%CI 9-21), CR2 19% (95%CI 8-46) p=0.38). Also, there was no difference in relapse and NRM by donor type, relapse: MFD 16% (95%CI 9-28), UD 19% (95%CI 11-32) p=0.38) NRM: MFD 19% (95%CI 11-34), UD 11% (95%CI 7-20) p=0.62). Causes of deaths were disease recurrence (39%), infections (27%), and GVHD (12%). Three- years overall survival (OS) and disease-free survival (DFS) were 74% (95%CI 67-81) and 68% (95%CI 60-70). DFS was 70% (95%CI 60-77) and 67% (95%CI 47-87) for patients transplanted in CR1 and CR2 respectively, (p=0.39); and was 70% (95%CI 59-81) and 65% (95%CI 53-78), p=0.77, for UD and MFD HSCT recipients, respectively. In conclusion, our results confirm the efficacy of BuCyMel in preventing relapse in a large series of pediatric patients affected by AML in CR1 and CR2. Adolescents represent a population of more fragile patients at risk of developing transplant-related fatalities. Optimization of toxicity profile and supportive care could further improve outcomes. Prospective randomized clinical trials are warranted to assess the best conditioning regimen for children and adolescents with AML. Disclosures Zecca: Chimerix: Honoraria. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Strategies for Graft Versus Host Disease Prophylaxis after Reduced-Intensity Conditioning Transplantation: Combination of Sirolimus Plus Tacrolimus Allows to Obtain the Best Outcome

Blood ◽

10.1182/blood.v124.21.1165.1165 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1165-1165

Author(s):

Rocío Parody ◽

Dolores Caballero ◽

Martinez Carmen ◽

Rodrigo Martino ◽

Carlos Solano ◽

...

Keyword(s):

Clinical Trials ◽

Chronic Gvhd ◽

Disease Status ◽

Allogeneic Transplantation ◽

The Other ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Gvhd Prophylaxis ◽

Group 2 ◽

Reduced Intensity

Abstract INTRODUCTION AND AIMS: Different strategies for GVHD prophylaxis have been evaluated in the last decade in different clinical trials in the setting of reduced-intensity conditioning allogeneic transplantation (RIC-AlloSCT) within the Grupo Español de Trasplante Hematopoyetico (GETH). Following multicenter clinical trials, some of these strategies have been adopted as standard practice in some centers. With this background, we analyzed in a multicenter retrospective study the outcomes of the different strategies used as GVHD prophylaxis in the setting of RIC-AlloSCT. MATHERIAL AND METHODS: A total of 558 patients from 6 Spanish centers underwent to RIC-AlloSCT from January 2007 to December 2013. Conditioning chemotherapy consisted of fludarabine plus melphalan or busulphan (for lymphoid and myeloid malignancies, respectively). Regarding GHVD prophylaxis, group 1 (n:170) received Sir-TKR, (plus ATG, n: 15); group 2 (n:161) a calcineurin-inhibitor (CNI)+MTX (plus ATG, n:23) and group 3 (n:217) received CNI+Mophetil Micophenolate (MMF), (plus ATG, n:28). Patients who received ATG, regardless the type of associated immunosuppression, were analyzed separately as well as within each subgroup. There were no statistically significant differences regarding transplant characteristics except for a higher frequency of unrelated donor in Sir-TKR subgroup and more frequent non-remission status of basal disease in CNI-MMF subgroup. RESULTS: After a median follow-up of 31 months, (IC-95%: 27-34), the 3-year cumulative incidence of relapse was significantly higher with CNI-MTX (37.6%) as compared to the other two strategies (24,8% for Sir-TKR and 26,1% for CNI-MMF, p=003) whereas transplant-related mortality (TRM) was significantly higher within patients receiving CNI-MMF (27% at 1 year / 37,9% at 3 years) as compared to Sir-TKR (14,4% at 1 year / 20,2% at 3 years) and CNI-MTX (19,7% at 1 year / 25,6% at 3 years, p=0.01). Overall survival (OS)was higher in Sir-TKR subgroup (78% at 1 year/68% at 3 years) as compared to the other 2 groups (64% at 1 year / 47% at 3 years for patients receiving CNI-MTX and 57% at 1 year / 45% at 3 years for those receiving CNI-MMF, p:0.01). The addition of ATG as prophylaxis did not significantly modified the prognosis for any of the subgroups. In multivariate analysis, significant factors for OS were: chronic GVHD [HR=0,68 (95%CI=0,47-0,98), p=0,03], acute GVHD [HR=2,03 (95%CI=1,54-2,67), p< 0.001), age older than 50 years [HR=1,47 (95%CI=1,07-2), p=0,01], disease status at transplant [HR=1,36 (95% CI=1,02-1,82), p=0,03 in case of non-remission disease) and GVHD prophylaxis other than Sir-TKR [HR=1,85 (95%CI=1,19-2-87),p=0,006 for CNI-MTX and HR=1,94 (95%CI=1,32-2,86),p=0,0006 for CNI-MMF]. CONCLUSION: The present study shows a favorable impact of Sir-TKR in outcome as compared with other strategies in the setting of RIC-AlloSCT, with OS up to 68% at 3 years. Disclosures Valcarcel: Celgene: Honoraria, Speakers Bureau.

Download Full-text

Allogeneic Transplantation with a Treosulfan-Fludarabine Conditioning Regimen Is Feasible and Effective in Elderly Patients with Refractory or Relapsed Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndrome (MDS); Preliminary Results From a Single Center Experience.

Blood ◽

10.1182/blood.v114.22.4318.4318 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4318-4318

Author(s):

Massimo Bernardi ◽

Jacopo Peccatori ◽

Michela Tassara ◽

Alessandro Crotta ◽

Carlo Messina ◽

...

Keyword(s):

Performance Status ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Status ◽

Initial Response ◽

The Elderly ◽

Allogeneic Transplantation ◽

Median Number ◽

High Dose ◽

Conditioning Treatment

Abstract Abstract 4318 Background the majority of AML and poor risk MDS cases in the elderly (>60 years) are resistant to induction chemotherapy or relapse after initial response; thereafter, most of these patients (pts) receive only supportive treatments, with an expected survival of few weeks. Allogeneic (allo) stem cell transplantation (SCT) could be the only potentially salvage strategy; actually, for the high probability of letal toxicites due to the conditioning regimen, acute graft-versus-host disease (aGvHD) and infections, these pts are rarely offered this procedure. Since 2005, we have transplanted 12 pts, age>60, with refractory or relapsed AML/MDS, from an allogeneic donor. Data on feasibility and outcome are here reported. Aim to retrospectively evaluate data on alloSCT in elderly pts with refractory or relapsed AML and MDS, transplanted at our Institute. Patients and Methods period 9/2005 to 4/2009, 12 pts, median age 65 (61-72). Performance status (Karnofsky): median 90% (80-100), HCT-CI: median score 1 (0-4). Diagnosis (WHO): AML 3, AMLMD 4, RAEB2 2, MDS/MPD 2, therapy-related AML 1. Median number of chemo cycles before SCT: 2 (1-7), all pts received at least 1 cycle with intermediate or high-dose cytarabine, 2 pts also received an autologous SCT. Donors: matched sibling 2, matched unrelated 2, related haploidentical 7, cord blood 1. Disease status at SCT: primary refractory 7, relapsed 5. Conditioning regimen: treosulfan (TREO) 14 g/sqm for 3 days, fludarabine (FLU) 30 mg/sqm for 5 days, ATG 10 mg/kg for 3 days for SCT from alternative donors. GvHD prophylaxis: T-cell depletion in 2 cases, cyclosporine (CSA)/methotrexate in 7, rapamycin/mycophenolate mofetil (MMF) in 3. Results 11/12 (92%) pts engrafted and were in CR at day +30, with 95-100% donor chimerism (VNTR). Deaths within day 30 and day 100 were 0 and 3 (25%), respectively. Acute GvHD: 6 pts (55%), grade II (3) or III (3), only of skin in 3 cases, skin+liver in 1, only intestinal in 2. Relapses were 4 (36%). Overall TRM was 25% (3 pts), with all deaths due to infections during immunosuppression for aGVHD; 5 more pts died because of disease progression. Median OS from SCT of all 12 pts was 180 (56-1150) days, DFS (11 pts) was 128 (24-1114) days. At last follow-up (FU) 4 pts (33%) are alive, all in CR with a median FU of 406 (128-1150) days. Conclusions alloSCT proved to be feasible in our elderly pts with AML/MDS refractory to induction or relapsed after initial complete remission. Early letal toxicities, due to the conditioning treatment, were absent; aGVHD, infections and relapses were the principal causes of mortality. Up to now, prolonged survival (>1 year) free from disease has been obtained in 25% of pts; of the 4 pts alive in CR, only 1 is receiving immunosuppression (CSA), for chronic GVHD. In conclusion, the TREO-FLU association showed a reduced-toxicity profile in these frail pts and a substantial anti-leukemic effect. Better prevention of aGVHD should be obtained, expecially after SCT from alternative donors, possibly with the rapamycin/MMF combination, which we are currently investigating at our Institute. AlloSCT after TREO-FLU conditioning can be considered an effective option for AML/MDS elderly pts with active disease after failure of previous intensive treatments. Disclosures: bonini: MolMed S.p.A.: Consultancy.

Download Full-text

Favorable Outcome of Sequential HLA-Haploidentical Transplantation Using Ptcy As GvHD Prophylaxis in High Risk AML and MDS of the Elderly

Blood ◽

10.1182/blood-2018-99-119103 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3458-3458

Author(s):

Alessia Fraccaroli ◽

Dusan Prevalsek ◽

Sarah Elena Häbe ◽

Veit Bücklein ◽

Christoph Schulz ◽

...

Keyword(s):

High Risk ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

The Elderly ◽

High Dose ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Therapeutic Concept ◽

Haploidentical Transplantation

Abstract Sequential conditioning regimens, comprising cytoreductive chemotherapy shortly applied prior to reduced intensity conditioning are successfully used for high-risk (HR) AML/MDS in matched related and unrelated donor hematopoietic stem cell transplantation. However, few data are available for sequential conditioning in the context of HLA-haploidentical transplantation (haplo-HSCT), especially in the elderly. To investigate the relative merits of sequential haplo-HSCT in the elderly we retrospectively analyzed the outcome of thirty-five patients (pts) with advanced AML/MDS (>=50 years old). Thirty-three pts suffering from HR AML, defined by refractory, relapsed or secondary leukemia, or complete remission with adverse-risk genetics according to ELN criteria and two pts with HR MDS according to IPSS-R, who underwent T-cell-replete haplo-HSCT at our institution between January 2009 and November 2016 were included. Disease was active in 29 pts while 6 had achieved CR. Pre-transplantation risk factors were scored using the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) which was ≥3 in 13 pts (median HCT-CI:2, range 0-8). A sequential therapeutic concept using either FLAMSA (n=26) or clofarabine (n=9) for cytoreduction was used prior to RIC in all pts. Bone marrow (54%) and peripheral blood stem cells (46%) were both used as graft source. Post-grafting immunosuppression consisted of high-dose cyclophosphamide, tacrolimus and MMF in all pts. Median age was 60 years (50-70). One graft rejection occurred. Three pts died early in aplasia. Neutrophil and platelet engraftment was achieved in 95% and 77% of evaluable pts, respectively at a median of 16,5 (13-89) and 31,5 (11-103) days.Acute GvHD grade I-III occurred in 25/32 of the pts (grade III n=2); no patient developed grade IV aGvHD. Chronic GvHD was observed in 13/29 pts and was most frequently assessed as mild (n=6) or moderate (n=5) while 2 pts developed severe cGvHD. No GvHD related death was observed. CI of NRM at day 100, 1-year and 3-years was 11%, 23% and 23%, respectively. CI of relapse at 1- and 3-years was 15% and 27%, with a median time to relapse of 152 days (20-413). At a median follow up of 27 months (4-74), estimated one- and three-year overall survival (OS) was 62% and 52% respectively. One- and three-year leukemia-free survival (LFS) was 59% and 52%. Our results suggest that using a sequential therapeutic concept in PTCY-based haplo-HSCT is safe and properly tolerated while it provides a favorable disease control when treating elderly HR MDS/AML pts. Thus, sequential haplo-HSCT seems to be a valuable alternative in pts who lack a conventional donor or are in urgent need for prompt transplantation. Disclosures Tischer: Jazz Pharmaceuticals: Other: Jazz Advisory Board.

Download Full-text

HLA-Identical Sibling-Matched, CD34+ Selected, T Cell Depleted Peripheral Blood Stem Cells Following Myeloablative Conditioning for First or Second Remission Acute Myeloid Leukemia (AML): Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303.

Blood ◽

10.1182/blood.v114.22.655.655 ◽

2009 ◽

Vol 114 (22) ◽

pp. 655-655 ◽

Cited By ~ 1

Author(s):

Steven M. Devine ◽

Robert J Soiffer ◽

Marcelo C. Pasquini ◽

Shelly Carter ◽

Parameswaran N Hari ◽

...

Keyword(s):

T Cell ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Post Transplant ◽

Gvhd Prophylaxis

Abstract Abstract 655 Allogeneic hematopoietic cell transplantation (HCT) is the most effective means to prevent relapse in patients (pts) with AML in complete remission (CR). However, quality of life and overall survival (OS) are often affected by both acute and chronic graft versus host disease (GVHD). GVHD is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft, but has been limited in its use by logistical difficulties, lack of an FDA-approved method, and concerns regarding potential risk of graft rejection, post transplant infections, and leukemic relapse. Most reported TCD studies represent single centers, multiple disease types and processing methods with varying degrees of TCD, all of which affect outcome. Therefore we designed a trial using a single processing method providing extensive TCD that did not require post transplant GVHD prophylaxis involving adult pts with AML in first or second CR. We hypothesized that the undesired side effects of TCD HCT would be reduced if combined with a conditioning regimen that was highly immunosuppressive and anti-leukemic. The primary objective was to achieve a disease-free survival (DFS) rate at 6 months (mos) post transplant that exceeded 75%. Secondary objectives included assessments of engraftment, transplant related mortality (TRM), GVHD, relapse, and performance of a single TCD method (CD34+ cell selection using the Miltenyi CliniMACS device) at participating centers. From 10/2005 to 12/2008, 47 pts were enrolled and 44 transplanted at 8 different centers. Median age was 48.5 years (range 21-59) with 28 female and 16 male pts. Of 37 AML CR1 pts, 49% had an unfavorable cytogenetic or molecular risk profile. The conditioning regimen consisted of hyperfractionated total body irradiation (1375cGy in 11 fractions) with partial lung shielding, thiotepa (10mg/kg), cyclophosphamide (120mg/kg), and rabbit antithymocyte globulin (2.5mg/kg). The donors, all HLA-identical siblings, were given G-CSF for mobilization and scheduled to undergo at least 2 leukapheresis procedures to ensure a graft with a high CD34+ cell content. All allografts were CD34-enriched and were targeted to contain ≥ 5×10e6 CD34+ cells/kg and < 1.0×10e5 CD3+ cells/kg. The median CD34+ and CD3+ doses achieved were 8.1 × 10e6/kg (range 2.4-46.2) and 0.07 × 10e5/kg (range 0.01-0.85), respectively. The majority (81%) of pts received the targeted CD34+ cell dose and no pt received > 1.0×10e5 CD3+ cells/kg. No pharmacological GVHD prophylaxis was given post transplant. There were no significant toxicities related to infusion of the CD34 enriched allografts. The most common grade 3-5 regimen-related toxicities included grades 3 or 4 mucositis (39%) and grades 3-5 pulmonary abnormalities (11%). Only 1 pt experienced hepatic veno-occlusive disease. All pts engrafted rapidly with a median time to neutrophil recovery (ANC > 500/ul) of 11 days (range 9-19). There was 1 secondary graft failure. The assessed outcomes are shown below.Estimate (95% Confidence Interval)Outcome100 Days6 Months12 MonthsAcute GVHD II-IV20.5% (8.7 – 23.3%)Acute GVHD III-IV4.5% (0 – 10.6%)Chronic GVHD17.7% (5.8-29.6%)Extensive Chronic GVHD7.6% (0-15.7%)TRM17.8% (5.8-29.8%)Overall Relapse18.2% (5.9-30.5%)Relapse 1st CR9.6% (0- 19.8%%)Relapse 2nd CR64.3% (27.5-100%)DFS81.3% (66.1-90.2%)64.0% (46.5-77.1%)DFS 1st CR89.2% (73.7-95.8%)72.1% (53.0-84.6%)OS74.3% (57.3-85.4%) The absolute peripheral CD4+ cell count remained on average below 200/ul until day +365. Donor cell chimerism increased in the CD3+ cell compartment through day +365. There were 14 deaths. The most common causes of death were relapse (N=5) and pulmonary toxicity (N=4). The median follow-up of survivors is 489 days (range 96-776). There was no difference in OS or DFS for pts above or below the median age of 48.5 years. We conclude that TCD HCT following myeloablative chemoradiotherapy can be performed in a multi-center setting using a single TCD method without additional post transplant prophylaxis with excellent DFS and OS, consistent engraftment, low TRM, and low incidence of relapse even in pts with unfavorable risk AML in CR1. The low incidences of acute and chronic GVHD in the absence of post transplant prophylaxis were particularly encouraging. A follow-up study of TCD HCT in AML recipients of unrelated donor allografts is being planned by the BMT CTN Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Comparative Analysis of Autologous Hematopoietic Cell Transplantation with Radioimmunotherapy (RIT) Based Conditioning Versus Total Body Irradiation (TBI) for High-Risk Diffuse Large Cell Lymphoma (DLCL): Toxicity and Efficacy

Blood ◽

10.1182/blood.v116.21.32.32 ◽

2010 ◽

Vol 116 (21) ◽

pp. 32-32 ◽

Cited By ~ 1

Author(s):

Amrita Krishnan ◽

Joycelynne Palmer ◽

Auayporn Nademanee ◽

Andrew Raubitschek ◽

Dave Yamauchi ◽

...

Keyword(s):

Comparative Analysis ◽

High Risk ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Conditioning Regimen ◽

Disease Status ◽

Large Cell ◽

High Dose ◽

Toxicity Profile ◽

Group 2

Abstract Abstract 32 Background: RIT based conditioning offers the potential of combining the efficacy of radiation with decreased toxicity over traditional TBI. In pilot trials we demonstrated that combining Yttrium 90 (ibritumomab tiuxetan) with high-dose BEAM (ZBEAM) is feasible and has a toxicity profile similar to high-dose BEAM. Herein we report the results of a comparative analysis designed to evaluate transplant outcomes among DLCL patients who were conditioned with either ZBEAM or a TBI-based conditioning regimen. Patients were matched on age (+/− 5 years), disease status, number of prior regimens, year of diagnosis (+/− 5 years), and year of transplant (+/− 5 years). There was a total of 92 DLCL patients treated from 01/1997-01/2009; 46 patients in each treatment group. The median patient age was 56.5 years (range: 19–78) for the ZBEAM group, and 53 years (range: 21–62) for the TBI group. Both groups had a median of two prior regimens, with 13% (ZBEAM) and 15% (TBI) considered high-risk first remission, 65% beyond 1st CR and 22% induction failures in each cohort. The median length of follow-up for surviving patients was 51–83 months. There was a trend toward improved PFS in the RIT group: 2 year PFS for ZBEAM group 66% (95%CI: 56–74) vs. 50% (95%CI: 43–57) for TBI group (p<0.08). Results to date show that a plateau in PFS appears to have been achieved for both groups (at 2.6 years in the ZBEAM group and 3.7 years for the TBI group), which translates into a 20% improvement in PFS for the ZBEAM patients, >4 years post transplant. Similarly the OS estimate was significantly higher for ZBEAM compared to TBI controls: 84% vs. 59 % (p<0.01). The lower OS rate for the TBI cohort was primarily due to toxicity, with a 2 year non relapse mortality of 0% for ZBEAM vs. 13% for TBI. (p<0.01) The causes of death included: relapse progression n=9 (ZBEAM), n=15 (TBI), infection n=2 TBI, cardiac disease n=2 TBI, pneumonia N= 1 TBI, unknown N=3 TBI. Conclusions: RIT based conditioning demonstrated improved survival when compared to traditional radiation based regimens in the treatment of DLCL due to a more favorable toxicity profile, while maintaining potent anti-lymphoma effects. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Increased Incidence of Chronic Graft-Versus-Host Disease (GVHD) and No Survival Advantage with Filgrastim-Mobilized Peripheral Blood Stem Cells (PBSC) Compared to Bone Marrow (BM) Transplants From Unrelated Donors: Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0201, a Phase III, Prospective, Randomized Trial

Blood ◽

10.1182/blood.v118.21.1.1 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1-1 ◽

Cited By ~ 12

Author(s):

Claudio Anasetti ◽

Brent R. Logan ◽

Stephanie J. Lee ◽

Edmund K Waller ◽

Daniel J. Weisdorf ◽

...

Keyword(s):

High Risk ◽

Randomized Trial ◽

Disease Risk ◽

Performance Status ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Phase Iii ◽

Unrelated Donor ◽

Gvhd Prophylaxis ◽

Unrelated Donors

Abstract Abstract 1 Background: Randomized trials demonstrated that filgrastim-mobilized PBSC compared to BM from HLA-identical siblings improved engraftment kinetics, increased risks of acute and chronic GVHD, but also decreased relapse and improved survival in patients with high risk leukemia. Retrospective analyses of unrelated donor transplants did not appreciate the same PBSC protective effect. Patients and Methods: The BMT CTN, sponsored by the NHLBI and NCI, conducted a Phase III, randomized, multicenter, trial of unrelated donor PBSC versus BM. The primary objective was to compare two-year survival probabilities in the two study arms using an intent-to-treat analysis. Both patients and donors provided informed consent. Fifty centers in the U.S. and Canada enrolled patients between January, 2004 and September 2009. Median follow up is 36 months (interquartile range 25 – 37 months). Randomization was performed in a 1:1 ratio to either PBSC or BM and stratified by transplant center and disease risk. Of the 278 subjects randomized to BM, 5% had no transplant, and 4.3% crossed over to PBSC; of the 273 randomized to PBSC, 4% had no transplant, and 0.4% crossed over to BM, so subjects on both arms had greater than 90% compliance with the assigned therapy. Patient primary disease (AML, ALL, CML, MDS, CMML, and MF), disease risk, gender, age, race, ethnicity, CMV serology, performance status, comorbidity, organ function, conditioning regimen, GVHD prophylaxis, use of growth factors, and donor characteristics were all well balanced between the two groups. Overall, 90% were adults over age 20, 47% had AML, 28% had high risk disease, 48% were conditioned with cyclophosphamide plus total body irradiation, and 71% received tacrolimus plus methotrexate for GVHD prophylaxis. Results: There were no observed differences in outcomes between the two groups except for a higher incidence of overall chronic GVHD (see Table) and more common chronic extensive GVHD with PBSC (46% vs. 31%). There were no survival differences according to graft sources in planned subset analyses of low and high risk malignancy or in those received HLA-matched or mismatched grafts. Primary causes of death were relapse in 54% vs. 49%, graft failure in 7% vs. 0%, acute or chronic GVHD in 22% vs. 34%, others in 16% vs. 16% of the BM and PBSC arms, respectively. Conclusion: This large randomized trial shows that PBSC from unrelated donors is associated with higher rates of chronic GVHD compared to BM, although rates of acute GVHD, relapse, non-relapse mortality and overall survival are similar. Disclosures: Off Label Use: Cyclophosphamide, busulfan, melphalan, fludarabine, anti-thymocyte globulin, irradiation were used to eradicate malignancy. Tacrolimus, cyclosporine, methotrexate were used for GVHD prophylaxis. Westervelt:Novartis: Speakers Bureau.

Download Full-text