Hematopoietic Stem Cell Transplantation from HLA Identical Sibling Forsickle Cell Disease an International Survey on Behalf of Eurocord-Monacord, EBMT Paediatric Disease Working Party and CIBMTR

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 541-541 ◽  
Author(s):  
Barbara Cappelli ◽  
Francoise Bernaudin ◽  
Annalisa Ruggeri ◽  
Myriam Labopin ◽  
Fernanda Volt ◽  
...  
Keyword(s):  
Stem Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Acute Gvhd ◽  
Event Free Survival ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Stem Cell Source ◽  
Conditioning Regimens

Abstract Introduction: Hematopoietic stem cell transplantation (HSCT) is, to date, the only curative therapy for sickle cell disease (SCD). However, HSCT is offered to relatively few patients with SCD for a number of reasons including lack of a suitable HLA-matched donor, lack of consensus on indications for HSCT, the potential for trading one chronic condition (i.e., SCD) for another, such as chronic graft-versus-host disease (GVHD), and the mortality associated with the procedure. To-date, most HSCTs for SCD have utilized matched siblings as donors and are performed in children and adolescents. We report outcomes after HLA-matched sibling HSCT of patients reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation (EBMT) and Center for International Blood and Marrow Transplant Research (CIBMTR). Material and methods: One thousandpatients with SCD received HLA identical sibling HSCT between 1991 and 2013; n=439 from CIBMTR and n=561 from EBMT centers. HSCTs were performed in 90 centers in 23 countries. Results: Median age at HSCT was 9 years (range 1-54y); 85% of patients were aged <16 years. Approximately half of patients were female and 53% of HSCTs were performed after 2007. Most patients (94%) were homozygotes for hemoglobin S (HBS). The most common indication for HSCT was stroke. Other indications included: central nervous system event lasting longer than 24 hours, elevated cerebral arterial velocity, acute chest syndrome or vaso-occlusive crisis requiring hospitalization. Red blood cell transfusions were given before HSCT to 93% and hydroxyurea to 56% of the evaluable patients (N=510). Most HSCTs (n=872; 87%) used myeloablative-conditioning regimens, mainly based on the combination of busulfan with cyclophosphamide (n=719; 82%) or fludarabine (n=82; 9%). One hundred and twenty six patients (13%) received reduced intensity conditioning regimens; fludarabine with cyclophosphamide was the predominant regimen (n=48; 38%). Most regimens included in vivo T-cell depletion (71%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The predominant GVHD prophylaxis regimens were cyclosporine alone (19%), or combined with methotrexate (56%). The predominant stem cell source was bone marrow (84%); peripheral blood and cord blood were employed in 7% and 9% of patients, respectively. The median follow-up was 45 (1.1-324.6) months. The cumulative incidence (CI) of neutrophil engraftment at day+60 was 98% (96.6% for CB, 98.3% for BM and 95.2% for PB) with a median time to recovery of 19 days, while that for platelet engraftment was 98 % (96±2% for CB, 99±1% for BM and 98±9% for PBSC) with a median time to recovery of 25 days. Twenty-six patients experienced primary and 47 patients secondary graft failure; 67 patients died mainly due to GVH or infection. The 3-year probabilities of overall (OS) and event-free survival (EFS, alive with engraftment) were 94% (95% CI 92-95) and 90% (95% CI 68-82), respectively. According to stem cell source, 3-year OS was 99% after CB, 94% after BM and 80% after PBS (p<0.0001). In multivariate analysis, every year in age increment (HR 1.1, 95% CI 1.07-1.14, p<0.001) and use of peripheral blood (HR 3.43, 95% CI 1.49-7.88, p=0.004) were associated with higher mortality. In univariate analysis, EFS was better in patients receiving myeloablative compared to reduced intensity conditioning (91±1% vs 82 ±1%, respectively; p<0.001). In multivariate analysis, EFS was lower with every year in age increment (HR 1.05, 95% CI 1.02-1.07, p<0.001), peripheral blood grafts (HR 1.83, 95% CI 1.07-3.15, p=0.03) and HSCTs prior to 2000 (HR 0.77, 95% CI 0.64-0.92, p=0.005). CI of acute GVHD grade 2-4 was 14.4% (12.2-16.7) of chronic GVH 13.3 (11-15.8). Risks of acute GVHD were higher with increasing age (HR1.04 95% CI 1.01-1.07, p=0.008). None of the variables tested were associated with chronic GVHD. Conclusion: This large registry based international study shows that HLA identical sibling transplant is successful more than 90% of the patients with severe SCD with limited transplant related complications (rejection, GVHD). Strategies aimed at lowering graft failure and GVHD are desirable to further optimize the observed 3-year event-free survival. Importantly, these data should increase awareness to early referral to HSCT of patients with severe SCD. Disclosures Walters: ViaCord and AllCells, Inc: Other: Medical director. Bertrand:ERYTECH Pharma: Consultancy. Peters:Medac: Research Funding; Fresenius: Research Funding; Amgen: Research Funding; Jazz: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanovi: Research Funding; Pierre-Fabre: Research Funding.

Allogeneic Hematopoietic Stem Cell Transplantation for Myelofibrosis: PK Guided IV Busulfan Dose Intensity Results in Improved Event Free Survival

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2006-2006
Author(s):  
Uday Popat ◽  
Borje S Andersson ◽  
Roland Bassett ◽  
Stefan Ciurea ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Peripheral Blood ◽  
Cumulative Incidence ◽  
Research Funding ◽  
High Dose ◽  
Unrelated Donor ◽  
Event Free Survival ◽  
High Group ◽  
Hematopoietic Stem ◽  
Free Survival

Abstract Abstract 2006 Background: Allogeneic hematopoietic stem cell transplantation (HCT) is an effective treatment for patients with advanced myelofibrosis. Myeloablative regimens have produced a high rate of morbidity and mortality. Reduced intensity conditioning (RIC) with allogeneic transplantation is being investigated with the goal of reducing non-relapse mortality. There is concern that this benefit might occur at expense of a higher relapse rate. In 2006 we initiated a study of RIC regimen of fludarabine 40mg/m2 (days −5, −4, −3 −2) and IV busulfan 130mg/m2 (day −3,−2). In the first 14 patients (the Bu-low group), 9 patients relapsed. We hypothesized that high dose PK guided IV busulfan would decrease relapse rate without substantially increasing non relapse mortality, thereby improving event free survival (EFS). The next 19 patients received an increased intensity of busulfan (Bu-high group), using pharmacokinetic dose adjustment. Methods: Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Patients received IV busulfan dose to a target daily AUC of 4000 μmol/L × 4days (days −5, −4, −3 −2) Fludarabine 40mg/m2 (days −5, −4, −3 −2). Average busulfan dose in Bu-high group was 473 mg/m2 (range 304–886 mg/m2) or 10.8 mg/kg, and it was 260mg/m2 or 6.5mg/kg in Bu-low group. Both cohorts of patients received tacrolimus and mini methotrexate as graft versus host disease prophylaxis and similar supportive care. Thymoglobulin 2.5 mg/kg × 3 (day −3,−2 and 1) was given to all patients receiving an unrelated donor graft. Results: Between 1/2006 and 12/2010, 33 consecutive patients with myelofibrosis were treated including 14 in the Bu-low and 19 in the Bu-high groups. Patients and disease characteristics were similar for the two treatment groups. There were 16 males and 17 females with a median age of 59 (range 27–70). Eighteen patients had primary MF, 8 post PV MF and 7 Post ET MF. Based on Lille criteria, 17 patients had intermediate risk disease and 16 had high risk disease. Eleven patients had splenectomy prior to transplant; remaining 22 patients had enlarged spleen at the time of transplant. Twenty patients had mutated Jak 2. Median peripheral blood CD 34 count was 54/μl (range 1–16426/μl). Karyotype was abnormal in 12 patients and diploid in 21. Donors were matched siblings for 12 patients, matched unrelated for 17, and one antigen or allele mismatched unrelated for 4 patients. Stem cell source was marrow in 4 and peripheral blood in 29. Circulating blasts were present in 17 patients. All patients engrafted with a median time to neutrophil engraftment of 13 days (0–27) days and a median time to platelet engraftment of 18 (0–105) days. Cumulative incidence of acute GVHD was 28% and chronic GVHD 35% (limited 7%, extensive 28%). Cumulative incidence of non relapse mortality was 10% with overall 3 treatment related deaths: 1 in Bu-high group and 2 in Bu-low group (p=0.44). With a median follow up of 1.6 (0.2–5) years, current EFS (p=0.02) and the cumulative incidence of relapse (p=0.04) were significantly different between Bu-high and Bu-low groups, while overall survival (OS) was not (0.28). Two year estimates for the Bu-high and Bu-low groups are as follows: EFS: 69% and 29%; OS: 87% and 71%; cumulative incidence of relapse: 26% and 57%. Multivariate analysis showed that Bu-high dose (HR 0.25; p=0.01) and peripheral blood CD 34 count >100 μl (HR 3.56; p=0.02) were significant predictors of EFS. Conclusion: Higher dose busulfan, delivered with pharmacokinetic dose adjustment, reduces relapse without increasing non relapse mortality, resulting in better EFS in patients with MF. Disclosures: Popat: Otsuka: Research Funding. Andersson:Otsuka American Pharmaceuticals, Inc.: Consultant for Clinical Protocol Development. Nieto:Otsuka: Research Funding. Qazilbash:Otsuka: Research Funding. Champlin:Otsuka: Research Funding.

scholarly journals Fludarabine Melphalan Versus Fludarabine Treosulfan As Reduced Intensity Conditioning Regimens in Allogeneic Hematopoietic Stem Cell Transplant - a Retrospective Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4493-4493
Author(s):  
Akanksha Chichra ◽  
Lingaraj Nayak ◽  
Rushabh Kothari ◽  
Siddhesh Arun Kalantri ◽  
Avinash Bonda ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Patient Characteristics ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Entire Cohort ◽  
Conditioning Regimens ◽  
Grade 3 ◽  
Haplo Group ◽  
Very High

Introduction Allogeneic hematopoietic stem cell transplantation (AHSCT) has evolved as a curative therapy for various hematological malignancies. Regimen-related toxicity and transplant-related mortality (TRM) preclude the use of myeloablative conditioning (MAC) regimens in older and unfit patients. Reduced intensity conditioning (RIC) regimens have enabled AHSCT in such patients. There is a recent rise in use of RIC regimens even in younger patients in view of decreased toxicity and equal efficacy as reported in some studies. Fludarabine + Melphalan (FM) and Fludarabine + Treosulfan (FT) are 2 such regimens. There are no prospective randomised comparisons between these regimens. We retrospectively analysed these 2 regimens for toxicities and outcomes. Methods This is a retrospective single centre analysis of all consecutive patients with haematological cancers who received either FM or FT from April 2008 to December 2018. The entire cohort was divided into two groups - Matched Sibling Donor (MSD)/Matched Unrelated Donor (MUD) and Haploidentical (Haplo) transplants for analysis. We compared patient characteristics, toxicities and outcomes in both the groups based on conditioning regimen. The FT regimen consisted of fludarabine (30 mg/m2 on days − 6 to − 2) combined with treosulfan (12-14 gm/m2 on days − 6 to − 4) with or without 2 Gy TBI on day-1. The FM regimen consisted of fludarabine (30 mg/m2 on days − 7 to − 3) combined with melphalan (140 mg/m2 on day -1).Prophylaxis for GVHD consisted of calcineurin inhibitor (CNI) plus methotrexate (MTX)or mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide with CNI and MMF. Comorbidities were scored according to the HCT-CI. Disease Risk Index(DRI) and EBMT score were recorded for all patients. Neutrophil (NE) and platelet engraftment (PE) were defined as per standard criteria. Early toxicity after AHCT was graded according to CTCAE version 4. Total parenteral nutrition (TPN) was used in patients as per the physician's discretion. Acute GVHD and chronic GVHD were recorded according to standard criteria. All patients underwent chimerism studies at day 15, 30 and then monthly for 1 year. Mixed chimerism was defined as > 5% to < 95% donor chimerism. The toxicities in various arms were compared by Chi-square test or Fisher exact test, while OS was calculated by Kaplan Meier method and the survival probabilities were compared using log-rank test. Competing risk analysis was used to calculate cumulative incidence of relapse and TRM. Results The study included 138 patients, 98 males and 40 females. The diagnoses were AML- 53, ALL- 30, MDS/MPN- 49 and lymphoma -6. Patient characteristics are outlined in Table 1. MSD/MUD transplants were 105 (FM- 94; FT-11); 33 were Haplo (FM-17; FT-16) transplants. PBSC was the stem cell graft in 136 (99%) patients. In both MSD/MUD and Haplo groups, there were no significant differences in median age, gender, pre transplant CMV status, HCT-CI and EBMT score between the two conditioning regimens. In MSD/MUD group, significantly more patients had high/very high DRI in FT arm (45% vs 17%; P=0.056) Comparison of engraftment and toxicity variables of both FM and FT arms are outlined in Table 2. In MSD/MUD group, 44 (47%) patients in FM arm had grade 3/4 oral mucositis compared to 1 (9%) in FT arm (P=0.02). Corresponding numbers were 7 (41%) and 1 (6%) in Haplo group (P=0.039). Grade 3/4 diarrhoea was higher in the FM vs FT arm of Haplo group (41% vs 6%; P=0.039) but not in the MSD/MUD cohort. More patients received TPN in the FM arms of both MSD/MUD and Haplo groups (Table 2). Incidence of grade III-IV acute GVHD was higher in FT vs FM in MSD/MUD group (27% vs 17%; P=0.04). The median follow up of entire cohort was 4.8 years. The OS (figure 1) at 5 years was 62% in FM arm of MSD/MUD group vs 53% in FT arm (P=NS). Similarly OS (figure 2) at 5 years was 41% and 28 %( P=NS) in FM and FT arms respectively of Haplo group. The cumulative incidence of TRM and relapse at 2 years were not different in FM and FT arms of both MSD/MUD and Haplo groups (Table 2). Conclusion Grade 3 and 4 oral mucositis and diarrhoea were significantly less with FT than FM in both MSD/MUD and Haplo groups. FT provided comparable outcomes to FM in the MSD / MUD group in spite of having higher proportions of patients with high / very high DRI. Prospective randomised studies are required to compare various RIC regimens. Disclosures No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation as a Promising Treatment for Natural Killer-Cell Neoplasms.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3331-3331
Author(s):  
Naoko Murashige ◽  
Masahiro Kami ◽  
Yukiko Kishi ◽  
Sung-Won Kim ◽  
Masami Takeuchi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Stem Cell Source ◽  
Promising Treatment

Abstract The efficacy of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for NK-cell neoplasms is unknown. We investigated the results of allo-HSCT for NK-cell neoplasms between 1990 and 2003 through questionnaires. A hematopathologist reclassified the pathological diagnoses according to the WHO classification. Of 345 patients from 76 hospitals who underwent allo-HSCT for malignant lymphoma, 32 had NK-cell neoplasms: extranodal NK/T-cell lymphoma (n=27), blastic NK-cell lymphoma (n=3), and aggressive NK-cell leukemia (n=2). Fifteen were chemosensitive and 17 chemorefractory. Nine were in CR at the time of allo-HSCT. Twenty-five had matched related donors, 3 mismatched related, 2 matched unrelated, and 1 mismatched unrelated donors. Stem-cell source was bone marrow in 11 and mobilized peripheral blood in 21. Conditioning regimens were myeloablative (n=26) and non-myeloablative (n=6). Total body irradiation was given to 23 patients. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin and short-term methotrexate in 27 patients. Grade 2–4 acute GVHD and chronic GVHD developed in 13 and 9, respectively. Nine died of disease progression, 4 of infection, 2 of veno-occlusive disease, 2 of acute GVHD, 1 of interstitial pneumonitis, and 1 of thrombotic microangiopathy. Two-year progression-free and overall survivals were 33% and 38%, respectively (median follow-up, 32 months). All patients who did not relapse/progress within 10 months achieved progression-free survival during the follow-up. In multivariate analysis, stem cell source (BM vs. PB; relative risk 3.33) and acute GVHD (grade 2–4 vs. grade 0–1; relative risk 2.56) significantly affected progression-free survival. Allo-HSCT is a promising treatment for NK-cell neoplasms. Figure Figure

Evaluation of Graft Versus Host Disease and Relapse Free Survival As Novel Endpoint in Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Joint Naples-Paris Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2285-2285
Author(s):  
Simona Pagliuca ◽  
Antonio M Risitano ◽  
Sylvie Chevret ◽  
Flore Sicre de Fontbrune ◽  
Alienor Xhaard ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Graft Versus Host

Abstract The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including acute and chronic graft-versus-host disease (GVHD), relapse and death. Classical endpoints such as overall survival (OS), desease free survival (DFS) and non relapse-mortality (NRM) had become more and more unsuitable for transplant research because of their inability to a dynamic mesure of transplant-associated comorbidity. For this reason several composite endpoints taking into account also GVHD-associated comorbidity were proposed in the last years. GVHD free/relapse free survival (GRFS), proposed by Holtan et al (Blood 2015), includes grades 3-4 acute GVHD, systemic therapy requiring chronic GVHD, primary disease relapse , or death for any cause considered as events. This endpoint seems to completely characterize the survival without mortality or ongoing morbidity. With the intent to analyse the outcomes of our transplanted cohort, we retrospectively analysed GRFS of 959 consecutive patients receiving HSCT at Federico II University in Naples (n=119) and Saint-Louis Hospital (n=840) in Paris between 2007 and 2014, identifying prognostic factors associated with a better outcome and estimating the incidences of all components of this endpoint: rates of acute and chronic GVHD, disease relapse and death. Patient, disease and transplant characteristics are listed in table 1. Median duration of follow-up after HSCT was 22.1 months (IQR: 5.6-51 months). Cumulative incidence at day 100 of grade II-IV acute GVHD and grade III-IV were 42% and 16%, respectively. Cumulative incidence of chronic GVHD requiring systemic treatment at 1 and 5 years was 23% and 33%, respectively, diagnosed according to NIH criteria [14% of patients had score 1 (mild), 58% score 2 (moderate) and 27% score 3 (severe)cGVHD]. Cumulative incidence of relapse (considering all malignant and non-malignant diseases) was 26.7% (N=219) at 5 years. Overall survival for the whole population was 57% (95%CI, 53.3-60.8) at 5 years and Disease free survival (DFS) and non-relapse mortality (NRM) were respectively 50% (95%CI, 46.6-53.8) and 23% at 5 years. GRFS was 25% (95%CI, 21.8-28.5) at 5 years. Factors identified as influencing GRFS based on univariate analyses were age higher than 45 years (HR=1.64, 95%CI, 1.40-1.92), bone marrow (BM) as stem cell source (HR=0.40, 95%CI, 0.32-0.50); reduced intensity conditioning (RIC) (HR=0.63, 95%CI, 0.53-0.74); disease type [non-malignant disorders: HR=0.24, 95%CI, 0.17-0.33; myelodysplastic and myeloproliferative syndromes (MPN/CML/MDS): HR=1.34, 95%CI, 1.10-1.63; whereas other diagnosis did not influence GRFS] and than unrelated donor (matched: HR=1.71, 95%CI, 1.41-2.07;mismatch:HR=1.81, 95%CI, 1.48-2.23). Based on a multivariable Cox model, only diagnoses (non-malignancies, HR=0.27, 95%CI, 0.19-0.38 and MPN/CML/MDS, HR= 1.35, 95%CI, 1.11-1.65), and HLA unrelated graft (matched, HR=1.42, 95%CI, 1.17-1.73 and mismatched, HR=1.55, 95%CI, 1.26-1.92) remained associated with the outcome (Figure 1 and 2). GRFS could represent the ideal endpoint following HSCT. It differs significantly based upon type of disease and donor type, essentially. This composite indicator yields more information regarding complications of HSCT than the simpler measurement of OS or DFS. Its use willbetter compare these clinically important outcomes that accompany disparate HSCT techniques. All examined prognostic factors could enhance our ability to optimally judge the risk and the probability of true recovery after allogeneic HSCT. Our data support the use of this composite endpoint to describe HSCT outcome, and also pave the way for the investigation of novel endpoints, which may also track the dynamic changes of post-transplant events in the long-term. These retrospective data represent the background to investigate the impact of novel strategies of HSCT aiming to improve the outcome of HSCT, as detectable, by using more sensitive endpoints, tracking clinical events associated with detrimental long-term outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Risitano: Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Novartis: Research Funding; Alnylam: Research Funding; Rapharma: Research Funding. Peffault de Latour:Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

Hematopoietic Stem Cell Transplantation after Reduced Intensity Conditioning in Acute Myeloid Leukemia Patients Older Than 40 Years.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5074-5074
Author(s):  
Cynthia Huisman ◽  
Ellen Meijer ◽  
Eefke J. Petersen ◽  
Henk M. Lokhorst ◽  
Leo F. Verdonck
Keyword(s):  
Stem Cell ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Disease Free

Abstract Reduced intensity conditioning (RIC) protocols are increasingly used for allogeneic hematopoietic stem cell transplantation (HSCT) in elderly patients. We retrospectively analyzed the outcome of RIC HSCT in a homogeneous group of acute myeloid leukemia (AML) patients over the age of 40. Forty-three AML or high-risk myelodysplastic syndrome patients were treated with a fludarabine and low dose total body irradiation (TBI) based regimen, followed by a full peripheral stem cell graft. Antithymocyte globulin was given to matched unrelated recipients (34%) before infusion of fludarabine. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin and mycophenolate mofetil. All but 2 AML patients were in complete remission at the time of transplantation. Seventy-six percent of patients had a poor risk profile. Hematologic recovery was fast and primary graft failure occurred in one patient. Two patients with active disease at the time of HSCT experienced ongoing relapse. Infections were diagnosed in 9 patients (21%) and 6 patients (14%) were treated for CMV reactivation. Sixty percent of patients developed acute GVHD, which was grade 2 in 40% and grade 3 in 12%. Chronic GVHD occurred in 33% of patients. The incidence and severity of both acute and chronic GVHD was similar in patients with related and unrelated donors (P = 0.84 and 0.74, respectively). Treatment-related mortality (TRM) was low (9%), total nonrelapse mortality was 19%. After a median follow-up of 571 days, 16 patients (37%) experienced relapse. One-year progression-free and overall survival were 61% and 67%, respectively. Median disease-free survival has not been reached yet (> 58 months) and median overall survival was 31 months (Fig 1 and 2, respectively). Poor risk AML was significantly associated with disease-free survival in multivariate analysis (P = 0.02). Age > 60 years, gender, donor type, timing of RIC HSCT (upfront or after relapse) and acute GVHD were not identified as prognostic factors. In conclusion, fludarabine plus low-dose TBI-based RIC HSCT is effective in AML patients over the age of 40 without active disease at the time of transplant and is associated with low TRM. Figure Figure Figure Figure

Tacrolimus/Sirolimus Vs. Tacrolimus/Methotrexate for Graft-Vs.-Host Disease Prophylaxis After HLA-Matched, Related Donor Hematopoietic Stem Cell Transplantation: Results of Blood and Marrow Transplant Clinical Trials Network Trial 0402

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 739-739 ◽  
Author(s):  
Corey Cutler ◽  
Brent R. Logan ◽  
Ryotaro Nakamura ◽  
Laura Johnston ◽  
Sung W. Choi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Graft Vs Host Disease ◽  
Grade Ii ◽  
Related Donor

Abstract Abstract 739 The combination of a calcineurin inhibitor and methotrexate has been the standard of care in graft-vs.-host disease (GVHD) prophylaxis for over 25 years, with resultant rates of grade II-IV acute GVHD between 30–50%. The mTOR inhibitor, sirolimus, has demonstrated promise in a number of Phase II trials as an immunosuppressant used for GVHD prophylaxis. The BMT CTN, sponsored by the NHLBI and NCI, conducted a multicenter, randomized controlled trial comparing the combination of tacrolimus and sirolimus (Tac/Sir) with tacrolimus and methotrexate (Tac/Mtx) as GVHD prophylaxis after matched, related donor (MRD) hematopoietic stem cell transplantation (HSCT). Methods: Eligible patients were between ages 2 – 60 years, and had acute leukemia in remission, myelodysplasia or chronic myeloid leukemia in chronic or accelerated phase. All had adequate organ function, and a 6/6 HLA-A, B, DRB1 matched sibling donor. 304 patients were randomly assigned to either Tac/Sir (n = 151) or Tac/Mtx (n = 153) as GVHD prophylaxis after TBI-based conditioning and MRD HSCT. An intent-to-treat analysis was performed on the primary endpoint of Grade II-IV GVHD-free survival 114 days from randomization. Ten subjects who received busulfan-based conditioning and were previously reported were excluded from analysis. Three subjects who did not undergo HSCT are included in the primary analysis, but not secondary analyses. Results: Treatment groups were well balanced. The median age of participants was 44 years (range 13 – 59) and 83% had acute leukemia. Neutrophil and platelet engraftment were both faster in the Tac/Sir group (14 vs. 16 days, p < 0.001; 16 vs. 19 days, p = 0.03, respectively), but this did not affect the time to first hospital discharge (20 vs. 21 days, p = 0.37). The incidence of grade II-IV and grade III-IV acute GVHD at 100 days were lower in the Tac/Sir group (26 vs. 34%, p = 0.17; 8 vs. 15%, p = 0.05). Day 100 treatment-related mortality was no different between groups (7 vs. 7%, p = 0.43). The primary endpoint of 114-day acute GVHD-free survival was not statistically different between groups (67 vs. 62%, p = 0.38, Figure). The cumulative incidence of relapse at 2 years from transplantation was not different between groups (27 vs. 30%, p = 0.81). The competing-risk cumulative incidence of chronic GVHD was higher in the Tac/Sir arm (54 vs. 43%, p =0.044). Overall toxicities were not different between groups, with two notable exceptions. The peak and average OMAS oral mucositis scores were lower in the Tac/Sir arm (peak 0.70 vs. 0.96, p < 0.001; average 0.31 vs. 0.47, p < 0.001), however, there was an increased rate of the endothelial injury syndromes, veno-occlusive disease (11 vs. 4%, p = 0.03), and thrombotic microangiopathy (5 vs. 1%, p = 0.05) in the Tac/Sir arm. Causes of death were not different between groups. At 2 years from transplantation, disease-free (DFS) and overall survival (OS) were not different between study arms (DFS 53 vs. 53%, p = 0.76; OS 60 vs. 61%, p = 0.44). Conclusions: No difference in 114-day acute GVHD-free survival was noted between treatment arms. Compared with Tac/Mtx in MRD HSCT, Tac/Sir is associated with more rapid engraftment, less severe acute GVHD and oral mucositis, excess chronic GVHD and endothelial injury syndromes, and similar long-term outcomes. Understanding the trade-offs between regimens, Tac/Sir can be used as an alternative to Tac/Mtx in MRD HSCT. Disclosures: Cutler: Pfizer, inc: Research Funding; Astellas, Inc: Consultancy, Research Funding. Off Label Use: Sirolimus - Prevention of GVHD Tacrolimus - Prevention of GVHD. Waller:Outsuka: Research Funding.

scholarly journals Targeted busulfan-based reduced-intensity conditioning and HLA-matched HSCT cure hemophagocytic lymphohistiocytosis

2020 ◽  
Vol 4 (9) ◽  
pp. 1998-2010 ◽  
Author(s):  
Matthias Felber ◽  
Colin G. Steward ◽  
Karim Kentouche ◽  
Anders Fasth ◽  
Robert F. Wynn ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
T Cell ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Sinusoidal Obstruction Syndrome ◽  
Event Free Survival ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Reduced Intensity

Abstract Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation–approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti–T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L × h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15+ neutrophils, CD3+ T cells, and CD16+56+ natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.

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