Fludarabine-based Reduced-intensity Conditioning Research Articles

Favorable outcomes with durable chimerism after hematopoietic cell transplantation using busulfan and fludarabine-based reduced-intensity conditioning for pediatric patients with hemophagocytic lymphohistiocytosis

BackgroundThe incorporation of a reduced-intensity conditioning (RIC) regimen in hematopoietic cell transplantation (HCT) for patients with hemophagocytic lymphohistiocytosis (HLH) has decreased early mortality but is associated with a high rate of mixed chimerism and graft failure. Here, we present a successful single-center experience using busulfan and a fludarabine-based RIC regimen for the treatment of HLH.MethodsThe medical records of pediatric patients with HLH who underwent HCT using a busulfan/fludarabine-based RIC regimen between January 2008 and December 2017 were reviewed retrospectively.ResultsNine patients received HCT with a busulfan/fludarabine-based RIC regimen. Three patients had primary HLH, and the other six patients had secondary HLH with multiple reactivations. All three patients with primary HLH had UNC13D mutations. All patients achieved neutrophil and platelet engraftment at a median of 11 days (range, 10‒21) and 19 days (range, 13‒32), and all eight evaluable patients had sustained complete donor chimerism at the last follow-up. Two patients (22%) experienced grade 2 acute graft-versus-host disease (GVHD). Two patients (22%) developed chronic GVHD, and one died from chronic GVHD. One patient (11%) experienced reactivation 4 months after HCT from a syngeneic donor and died of the disease. The 8-year overall survival and event-free survival rates were 78%. No early treatment-related mortality within 100 days after HCT was observed.ConclusionOur experience suggests that a busulfan/fludarabine-based RIC regimen is a viable option for pediatric patients with HLH who require HCT.

Risk factors and prognosis of non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation.

Non-infectious pulmonary complications (NIPCs) following allogeneic hematopoietic stem cell transplantation (HSCT) are relatively rare, but frequently fatal. This study investigated the pre-transplant risk factors for developing NIPCs using Japanese transplant registry database entries from 2001 to 2009. Among 13,573 eligible patients, 535 experienced NIPCs (3.9%). Multivariate analysis identified high recipient age (60 + years: HR 1.85, P = 0.003), HLA mismatch (HR 1.61, P < 0.001), female to male HSCT (HR 1.54, P < 0.001), and unrelated bone marrow transplantation (UR-BMT) (HR 3.88, P < 0.001) as significantly associated with an increased risk of NIPCs. In contrast, a non-total body irradiation (TBI) regimen with reduced intensity conditioning (RIC) were associated with a decreased risk of NIPCs compared with a cyclophosphamide (CY) + TBI regimen (busulfan + CY: HR 0.67, P = 0.009, other non-TBI: HR 0.46, P < 0.001), fludarabine-based RIC (HR 0.52, P < 0.001), and other RIC (HR 0.42, P = 0.003). The mortality rate was significantly worse for patients with NIPCs than those without (HR 1.54, 71 P < 0.001). This large-scale retrospective study suggests that both allo-reactions to donor cells and conditioning regimen toxicity contributed to NIPCs following HSCT.

Fludarabine-based Reduced Intensity Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in a Pediatric Patient With Bone Marrow Failure Syndrome Type 3.

Bone marrow failure syndrome (BMFS) type 3 is a rare genetic heterogeneous disorder, considered to be one of Inherited BMFSs related to ribosomopathies. It caused by a novel Homozygous variant in DNAJC21 gene, which affects cytoplasmic maturation of 60S ribosomal, leading to increase cell death, and inhibits cellular proliferation causing shwachman-diamond Syndrome-like syndrome. Only 15 cases of BMFS type 3 have been published in the literature. Therefore, the full phenotypic spectrum and the experience of hematopoietic stem cell transplantation (HSCT) are limited. Herein, we report an uncomplicated HSCT from human leukocyte antigen-identical sibling for a BMFS-3 patient at 22 months of age, who suffered from chronic diarrhea, severe failure to thrive and cytopenia required transfusions. We used a reduced intensity conditioning regimen including fludarabine, low-dose cyclophosphamide, and antithymocyte globulin with cyclosporine for prevent graft versus host disease. This regimen was safe and sufficient to achieve rapid engraftment without significant toxicity. Although, Mixed chimerism between 80% and 90% was observed since day +30, she gained 2 kg during 12 months post-transplant and no need for transfusions has been reported any more. Thus, we recommend HSCT with fludarabine-based reduced intensity conditioning regimen in this syndrome as progressive cytopenia occurs and an human leukocyte antigen-matched family donor is available.

Safety and Efficacy of Co-transplantation of Hematopoietic Stem Cells Combined With Human Umbilical Cord-Derived Mesenchymal Stem Cells in Children With Severe Aplastic Anemia: A Single-Center Experience.

The mostimportant problems thatlimitthe effectiveness of allogeneic hematopoietic stem cell transplantation in patients with severe aplastic anemia are graft failure and graft-versus-host disease. Mesenchymal stem cells can support normal hematopoiesis and prevent graft-versus-host disease. We aimed to analyze the effects of combined transplant of human umbilical cord-derived mesenchymal stem cells and matched donor allogeneic hematopoietic stem cells in children with severe aplastic anemia. We retrospectively examined 15 pediatric patients with severe aplastic anemia who received fludarabine-based reduced intensity conditioning regimen and intravenously infused human umbilical cord-derived mesenchymal stem cells at a dose of 1 × 106/kg recipient body weight within 12 to 18 hours before hematopoietic stem cells infusion. We evaluated the engraftment rate, the frequency and severity of graft-versus-host disease, and the overall survival rate. No patients had adverse events related to intravenously human umbilical cord-derived mesenchymal stem cells infusion. All patients achieved successful engraftment and sustained donor chimerism. The median time for neutrophil and platelet engraftment was 14 and 25 days,respectively. The frequency was 20% for grade III/IV acute graftversus- host disease and 15.3% for chronic graftversus-host disease. Patients were followed-up for a median of 33 months (range, 2-89 months). The 5-year overall survival rate was 80%. Combined transplant of matched donor hematopoietic stem cells with human umbilical cord-derived mesenchymal stem cells is safe in pediatric patients with severe aplastic anemia. The achievement of engraftment in all of our patients and the acceptable frequency of acute and chronic graft-versus-host disease and survival rate are encouraging.

Reduced-intensity conditioning-based hematopoietic cell transplantation for dyskeratosis congenita: Single-center experience and literature review.

Bone marrow failure in dyskeratosis congenita (DKC) is progressive, and allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. However, outcomes after HCT are suboptimal because of mucosal, vascular, pulmonary, and hepatic fragility, which can be exacerbated by chemotherapy conditioning and graft-versus-host disease (GVHD). These toxicities can be mitigated by reducing the intensity of the conditioning regimen. We performed a retrospective analysis on pediatric patients with DKC who underwent HCT at our institution between 2008 and 2019. We identified nine patients (median age, 5.7years) who underwent HCT with a fludarabine-based reduced-intensity conditioning (RIC) regimen. GVHD prophylaxis consisted of tacrolimus plus mycophenolate mofetil (MMF) (n = 8), tacrolimus/pentostatin (n = 1), or cyclosporine/MMF (n = 1). The median time to neutrophil engraftment was 19 days (range, 13-26 days), and the median time to platelet engraftment was 18 days (range, 17-43 days). Lung function, as measured by spirometry in six patients, remained stable during post-HCT observation. Six patients (67%) remain alive, with a median follow-up of 73.5 months. Because of toxicity after myeloablative conditioning, RIC is becoming standard for HCT in DKC. These results suggest that RIC regimen is feasible and safe for patients with DKC and does not accelerate pulmonary damage in the short-to-medium term after HCT.

Augmented Reduced-Intensity Regimen Does Not Improve Postallogeneic Transplant Outcomes in Acute Myeloid Leukemia

PURPOSEReduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials.PATIENTS AND METHODSTwo hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome.RESULTSThere was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival.CONCLUSIONThe intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.

Allogeneic Hematopoietic Stem Cell Transplant Offer Good Outcomes in Pediatric Aplastic Anemia: Experience From Developing World.

Between 2014 and 2020, 31 patients with severe aplastic anemia (SAA) underwent full match allogeneic hematopoietic stem cell transplantation at our center. Of the 31 patients with SAA, 19 had acquired aplastic anemia, 2 had Diamond Blackfan anemia and 10 had Fanconi anemia. Donors were either matched sibling (n=29), related donors (n=2), or unrelated donors (n=3). Peripheral blood stem cells were the graft source in all the cases except 1. Fludarabine-based reduced intensity conditioning was used in all except for patients with a diagnosis of Diamond Blackfan anemia. All patients except 1 achieved hematologic recovery in the form of neutrophil engraftment at 13 days (range, 9 to 17), whereas platelet engraftment occurred at 14 days (range, 10 to 18). Graft versus host disease (GvHD) prophylaxis consisted of cyclosporine and methotrexate ±antithymocyte globulin (horse/rabbit). Acute GvHD developed in 12.9% patients, whereas no patients developed chronic GvHD till the time of last follow-up. The 2-year overall survival for the entire cohort was 93.21±4.6%. In patients with SAA, allogeneic stem cell transplant using fludarabine-based conditioning regimens are very well tolerated and have excellent outcomes in a full match setting.

Favorable Outcome with Durable Chimerism after Allogeneic Hematopoietic Cell Transplantation Using Busulfan and Fludarabine-Based Reduced-Intensity Conditioning for Children with Hemophagocytic Lymphohistiocytosis

Purpose Hematopoietic Stem Cell Transplantation (HSCT) is the only curative treatment for patients with familial, relapsing, or persistent hemophagocytic lymphohistiocytosis (HLH). Here, we present a single center experience of using busulfan (Bu) and fludarabine (Flu) based reduced intensity conditioning regimen (RIC) for treatment of HLH. Methods Medical records of pediatric patients with HLH, who received HSCT using Bu/Flu based RIC regimen.from January 2008 to December 2017, were reviewed retrospectively. HSCT outcomes including engraftment, survival, and GVHD were analyzed. Results Nine patients were received HSCT using Bu/Flu based RIC regimen. Three patients received HSCT after diagnosis of familial HLH and the other 6 received after reactivation. All 3 patients with familial HLH had UNC13D mutations. Median 8.35 × 106 /kg (range, 2.84-10.05 × 106) CD34 positive cells were infused. All patients achieved WBC and PLT engraftment at median 11 days (range, 10-21) and 19 days (range, 13-32) from HSCT with full donor chimerism which sustained until last visit. Cyclosporine and mycophenolate mofetil were applied as GVHD prophylaxis except one patient who received HSCT from syngeneic sibling. Three patients (33%) experienced acute graft-versus-host disease (GVHD) of grade 2 which was well controlled after conventional steroid treatment. Two patients (22%) underwent chronic GVHD, and one of them died. One patient (11%) had reactivation 4 months after HSCT from syngeneic sibling donor, and died. The 5-year overall survival was 78%. Two patients died; one died of disease and the other died of treatment related mortality (TRM). No TRM other than chronic GVHD was existed. Conclusion Our experience suggests that Bu/Flu based RIC regimen can be effective option for pediatric patients with HLH who need HSCT showing durable chimerism and long-term survival with decreased toxicity.

Hematopoietic Stem Cell Transplantation for Progressive Combined Immunodeficiency and Lymphoproliferation in Patients With Activated Phosphatidylinositol–3–OH Kinase δ Syndrome Type 1

To examine clinical features, laboratory findings, treatment, and outcomes of patients with activated phosphatidylinositol-OH-3 kinase δ syndrome type 1 (APDS1) and evaluate hematopoietic stem cell transplant (HSCT) as a potential treatment option.This study included 23 patients with confirmed PIK3CD mutations. Nine of these patients underwent HSCT.This was a retrospective study to characterize clinical characteristics, laboratory findings, treatment, and outcomes of patients with APDS1. Patients were identified by patient registry, physician referral, or having been previously reported in literature. Data were obtained by review of medical records and physician questionnaires.Common clinical features of patients with APDS1 included recurrent infections, lymphoproliferation, and enteropathy, with a median age at symptoms onset of 11 years old. The majority (65%) of patients received immunoglobulin replacement, and some additionally had prophylactic antimicrobial agents. Eleven transplantations were performed for recurrent infections or treatment refractory disease among 9 total patients. Fludarabine-based reduced-intensity conditioning regimens were used in all transplants (90–180 mg/m2), and 55% used human leukocyte antigen–mismatched donors. All but 1 patient ultimately achieved engraftment, but 36.4% had initial graft failure and required retransplantation, boosts of peripheral blood stem cells, or growth hormone administration for delayed T lymphocyte recovery. More than 90% of transplanted patients had an adverse complication, most commonly mild graft-versus-host disease. Despite this, most symptoms were improved post-HSCT, and no patients required ongoing immunoglobulin replacement by day 100 post-HSCT. The 30-year overall survival was 86.1%, and event-free survival was 39.6%.HSCT should be considered in patients with APDS1 and recurrent infections and/or treatment refractory lymphoproliferation. Clinical symptoms improved posttransplantation, although adverse complications and graft failure were frequent.Patients with APDS1 are at increased risk for recurrent infections, bronchiectasis, lymphoproliferation, chronic viral infections, and lymphoma. This article highlights the role that HSCT may play in the future management of patients with APDS1. Although not without its own risks, early HSCT can improve clinical symptoms and reduce the lifetime risk for potentially fatal complications in this disease. Investigators in this study closely examine HSCT regimens for APDS1 patients among various international medical centers, which serves as the first critical step toward improving event-free and overall survival for these patients.

Impact of low-dose irradiation and in vivo T-cell depletion on hematopoietic stem cell transplantation for non-malignant diseases using fludarabine-based reduced-intensity conditioning.

Reduced-intensity conditioning is widely used with hematopoietic stem cell transplantation for non-malignant diseases: however, the optimal conditioning to ensure stable engraftment has not been established. In this study, we retrospectively compared the impact of low-dose (1-6 Gy) irradiation and in vivo T-cell depletion on the clinical outcome of 523 patients with non-malignant disease who underwent a first allogeneic hematopoietic stem cell transplantation using fludarabine-based reduced-intensity conditioning. Use of low-dose irradiation, but not of anti-thymocyte globulin/anti-lymphocyte globulin, showed a beneficial effect on overall survival (adjusted hazard ratio: 0.56; 95% confidence interval: 0.35-0.91, P = 0.018). Furthermore, use of low-dose irradiation was strongly associated with lower transplant-related mortality (adjusted hazard ratio: 0.55; 95% confidence interval: 0.32-0.96, P = 0.034). The addition of low-dose irradiation to the conditioning regimen was beneficial, at least to the short-term clinical outcome. A large prospective study with long-term follow-up is now required to extend these findings and establish the optimal hematopoietic stem cell transplant conditioning for patients with at least some subgroups of non-malignant diseases.

Outcomes of Salvage Haploidentical Transplant with Post-Transplant Cyclophosphamide for Rescuing Primary Graft Failure Patients : A Report By the SFGM-TC

Abstract Prognosis of graft failure patients is dismal, and another transplant is the sole option for long-term survival. Currently, there is no consensus concerning the best option for treating patients undergoing primary graft failure and finding a new donor within an acceptable delay is challenging. In the last years, haploidentical transplants with post-transplant cyclophosphamide (PT-Cy) have shown acceptable results in the treatment of many hematological diseases, including some cases of graft failure. To address the interest of haploidentical transplants as a salvage option in this context, we retrospectively collected and analyzed data from 26 primary graft failure (PGF) patients transplanted between 2011 and 2017 in 15 centers belonging to the Francophone Society for Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). Inclusion criteria were the occurrence of PGF defined as non-achievement of a minimum absolute neutrophil count of 500/μL without evidence of disease relapse at D+28 after transplantation and the use of a haploidentical transplantation with PT-Cy as graft-versus-host-disease (GvHD) prophylaxis. Continuous variables are presented as medians and inter-quartile range. They were compared between groups using the Wilcoxon rank sum. Categorical variables are presented with counts and percentages and were compared using the Fisher exact test. All tests were 2-sided, and a p-value below 0.05 was considered to be significant. Analyses were performed using the R statistical platform (version 3.4.1). This study was performed according to the Declaration of Helsinki and was approved by the SFGM-TC scientific council. Nineteen patients had a diagnosis of myeloid malignancy (8 acute myeloid leukemias, 4 myelodysplastic syndromes, 4 myeloproliferative neoplasms, 1 unclassified myeloid disorder), 3 had a lymphoid neoplasm, and 4 had a bone marrow failure syndrome (2 acquired and 2 congenital). Twenty-four patients had previously received an allogeneic transplantation, and 2 had already failed two previous allogeneic transplants. Male/female ratio was 2.25. Median age at haploidentical transplant was 42 years (2-58). Fifteen patients received peripheral blood as stem cell source, and 11 received bone marrow. Eleven transplants were female to male. Twelve patients received an ABO-matched graft, 6 had a major ABO-incompatibility, 7 a minor incompatibility and one missing data. The median number of infused CD34+ cells was 5.2 x106/kg (1.2 - 12.5). There was no ex-vivomanipulation of cells. CMV matching was available for 22 transplantations, of which 6 were high-risk (seropositive recipient with a seronegative donor). Fludarabine-based reduced intensity conditioning was used in all but one patient who received clofarabine + 4Gy TBI. Twenty patients received TBI 2Gy. Three patients received ATG. Fourteen patients received the Baltimore regimen (53%). The median delay between the previous and the salvage transplantation was 77 days (39-1161). All patients received PT-Cy associated with cyclosporine, and 24 patients also received MMF for GvHD prophylaxis. Median follow up was 487 (16-2010) days. The cumulative incidence (CI) of neutrophil recovery at day 30 was 81%, and the median time to neutrophil engraftment was 19 (13-34) days. Four patients (15%) presented primary graft failure and died within a median time of 5 (3-8) weeks after transplantation of infectious complications. Cumulative incidence of grade II-IV aGvHD at day-100 was 13%, and 1-year CI of cGvHD was 32%. One-year CI of relapse was 16%. Overall survival was 58% at 1 year (Figure 1; confidence interval: 39-85). Among the 22 patients who engrafted, 6 patients died. HSCT complications accounted for 80% of the causes of deaths (4 multiorgan failure, 1 GvHD, 1 interstitial pneumonitis, 1 bacterial infection, 1 post-transplant lymphoproliferative disorder). To the best of our knowledge, this is the first cohort describing the outcomes of haploidentical transplants with PT-Cy rescuing patients with primary graft failure. Our cohort presents promising outcomes in a particularly challenging situation, suggesting that haploidentical transplants with PT-Cy might appear as a valid salvage strategy for patients with PGF. Prospective well-designed trials are urgently needed before the inclusion of Haplo-PT-Cy in the treatment strategy of patients with PGF. Figure 1. Figure 1. Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria. Peffault De Latour:Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1

Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined. Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT. We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities. Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT. Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.

Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan.

BackgroundX-linked inhibitor of apoptosis protein (XIAP) deficiency is a rare immunodeficiency that is characterized by recurrent hemophagocytic lymphohistiocytosis (HLH) and splenomegaly and sometimes associated with refractory inflammatory bowel disease (IBD). Although hematopoietic stem cell transplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory compared with those for SLAM-associated protein deficiency and familial HLH.AimTo investigate the outcomes and adverse events of HSCT for patients with XIAP deficiency, a national survey was conducted.MethodsA spreadsheet questionnaire was sent to physicians who had provided HSCT treatment for patients with XIAP deficiency in Japan.ResultsUp to the end of September 2016, 10 patients with XIAP deficiency had undergone HSCT in Japan, 9 of whom (90%) had survived. All surviving patients had received a fludarabine-based reduced intensity conditioning (RIC) regimen. Although 5 patients developed post-HSCT HLH, 4 of them survived after etoposide administration. In addition, the IBD associated with XIAP deficiency improved remarkably after HSCT in all affected cases.ConclusionThe RIC regimen and HLH control might be important factors for successful HSCT outcomes, with improved IBD, in patients with XIAP deficiency.Electronic supplementary materialThe online version of this article (doi:10.1007/s10875-016-0348-4) contains supplementary material, which is available to authorized users.

Clofarabine versus fludarabine-based reduced-intensity conditioning regimen prior to allogeneic transplantation in adults with AML/MDS.

We have retrospectively compared survivals between acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients who received either a clofarabine/busulfan (CloB2A2) or a fludarabine/busulfan (FB2A2) RIC regimen for allogeneic stem cell transplantation. Between 2009 and 2014, 355 allotransplanted cases were identified from the SFGM‐TC registry as having received either the FB2A2 (n = 316, 56% males, median age: 59.2 years, AML 78.5%, first complete remission [CR1] 72%, median follow‐up: 20 months) or the CloB2A2 (n = 39, 62% males, median age: 60.8 years, AML 62%, CR1 69%, median follow‐up: 22.4 months) RIC regimen. In multivariate analysis, FB2A2 was associated with significant lower overall survival (OS, HR: 2.14; 95%CI: 1.05–4.35, P = 0.04) and higher relapse incidence (RI, HR: 2.17; 95%CI: 1.02–4.61, P = 0.04) and a trend for lower leukemia‐free survival (LFS, HR: 1.75; 95%CI: 0.94–3.26, P = 0.08). These results were confirmed using a propensity score‐matching strategy. However, when considering AML and MDS patients separately, the benefit of the CLOB2A2 regimen was restricted to AML patients (2‐year OS FB2A2: 38% [14.5–61.6] vs. CloB2A2: 79.2% [62.9–95.4], P = 0.01; 2‐year LFS FB2A2: 38% [16–59.9] vs. CloB2A2: 70.8% [52.6–89], P = 0.03). The better survivals were due to the lower risk of relapse in this CloB2A2 AML subgroup (2‐year RI FB2A2: 41.2% [19–62.4] vs. CloB2A2: 16.7% [5–34.2], P = 0.05). This retrospective comparison suggests that the CloB2A2 RIC regimen can likely provide longer survival than that awarded by a FB2A2 RIC regimen and may become a new standard of care RIC regimen for allotransplanted AML patients. A prospective phase 3 randomized study is warranted.

Association Between Uric Acid Levels and Severe Acute Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

Introduction and objectives: There is increasing knowledge on the relevance of danger signals activating the innate immune system in the pathogenesis of graft-versus-host disease (GvHD). Uric acid (UA) is a known danger signal that is released from injured cells during conditioning for allogeneic stem cell transplantation (alloSCT). UA has been identified to enhance dendritic cells maturation and to amplify T-cell responses. Previous reports analyzing the relationship between UA and acute GvHD (aGvHD) have shown controversial results (Ann Hematol 2015; 94: 139; Biol Blood Marrow Transplant 2014; 20: 730).The objective of this study is to investigate the association between UA levels pre-alloSCT and aGvHD.Patients and methods: We retrospectively analyzed data from 548consecutive patients who received an alloSCT from January 2007 to December 2014 on four institutions. The cumulative incidence of aGvHD over the first 100 days post-alloSCT was estimated in the framework of competing risks by taking relapse or death without relapse as competing events. The association between pre-alloSCT UA levels (measured between day -7 and day 0), dichotomized at the median value, and the incidence of aGvHD was investigated by calculating the subhazard rate (SHR) according to Fine & Gray (J Am Stat Assoc 1999; 94: 496).Results: Patients (median age 46y, range 16-67; 66% male) were transplanted for acute leukemia (51%), lymphoproliferative syndrome (22%), myelodysplastic syndrome (12%), multiple myeloma (8%), and other causes (7%). Disease status at the time of alloSCT was 49% complete remission, 17% partial response and 31% active disease. Fifty-one percent patients received alloSCT from related donors, 41% from unrelated donors, and 8% from alternative donors (cord blood units or haploidentical donors). The source of stem cells was peripheral blood in 84% patients. Fludarabine-based reduced intensity conditioning (RIC) regimens were used in 54% of transplants and myeloablative (MAC) in 46%. Most patients received immunosuppression with calcineurin inhibitors in combination with methotrexate (MAC) or mycophenolate mofetil (RIC). Sixteen percent also received ATG. Most patients (82%) received allopurinol 300 mg/day through conditioning regimen until day 0 of transplant. The median serum UA level prior to stem cells infusion was 3.7 mg/dL (range 0.7-8.8). Serum levels of UA (mg/dl) were higher in males than in females (4 vs. 3, p=0.0001), in patients submitted to RIC as compared with MAC alloSCT (4 vs 3.3, p=0.0001), in those not receiving ATG for GvHD prophylaxis (3.8 vs. 2.9, p=0.0002) and in the minority of patients not treated with allopurinol (4.7 vs. 3.3, p=0.0001). By day +100 post-alloSCT, 222 patients had been diagnosed of aGvHD II-IV, 79 had relapsed and 72 had died from causes unrelated to relapse or GvHD. The cumulative incidence of aGvHD II-IV was 40% (95% CI: 35%-44%) whereas the incidence of competing events (death or relapse) amounted to 11% (95% CI: 8%-13%). Patients with levels of UA above the median had an increased incidence of aGvHD II-IV (SHR: 1.4, 95% CI: 1.1-1.8; p=0.015) at the univariate analysis. However, such relationship vanished after multivariate adjustment for other factors associated with the peri-alloSCT UA levels and/or the risk of aGvHD (e.g. age, sex, type of donor, type of alloSCT, GvHD prophylaxis). Additional exploratory and subgroup analyses did not find any relationship between UA levels neither severe aGvHD (grades III/IV), early aGvHD (before day +60) nor type of conditioning regimen (RIC vs. MAC).Conclusions: There is a weak association between higher peri-alloSCT levels of uric acid and increased incidence of aGvHD. Nevertheless, our results suggest that such associations reflect confounding effects rather than causal factors and, therefore, they do not support interventions aimed at preventing aGvHD by reducing uric acid levels. DisclosuresNo relevant conflicts of interest to declare.

Comparison of two fludarabine-based reduced-intensity conditioning regimens in elderly or infirm patients with myeloid malignancies treated with allogeneic haematopoietic stem cell transplantation

Comparison of two fludarabine-based reduced-intensity conditioning regimens in elderly or infirm patients with myeloid malignancies treated with allogeneic haematopoietic stem cell transplantation

90Y-ibritumomab tiuxetan, fludarabine, busulfan and antithymocyte globulin reduced-intensity allogeneic transplant conditioning for patients with advanced and high-risk B-cell lymphomas

BackgroundPatients with advanced B-cell non-Hodgkin's lymphoma (NHL) refractory to initial chemotherapy or relapsing after autologous stem-cell transplantation have a poor prognosis. Allogeneic stem-cell transplantation after reduced-intensity conditioning (RIC) regimen can be a therapeutic option. However, the high incidence of relapse remains a challenging issue. We speculated that the incorporation of 90Y-Ibritumomab tiuxetan into a fludarabine-based RIC regimen would improve the lymphoma control without overwhelming toxicity. Our aim was to evaluate the safety of 90Y-Ibritumomab tiuxetan in association with such a regimen in a prospective multicenter phase II trial. Patients and methodsThirty-one patients with advanced lymphoma from five distinct institutions were included between February 2008 and October 2010. Thirty patients in complete or partial response after failure of a median of 3 (range, 2–4) previous chemotherapy regimens including autologous transplant in 29 were evaluable for nonrelapse mortality (NRM) at day 100 post-transplant that was the primary end point. ResultsWith a median follow-up of 32 months (range, 29–60 months), the 2-year event-free and overall survivals of the whole study group were both 80% [95 confidence interval (CI) 60.8% to 90.5%). The 100-day and 2-year post-transplant cumulative incidences of NRM were 3.3% (95% CI 0.2% to 14.9%) and 13.3% (95% CI 5.4% to 33.2%), respectively. The 2-year cumulative incidence of relapse was 6.7% (95% CI 1.7% to 25.4%). The cumulative incidences of grade II–IV and extensive chronic graft-versus-host disease were 27% and 14%, respectively. ConclusionsFor chemosensitive advanced high-risk B-cell lymphoma, the addition of 90Y-Ibritumomab tiuxetan to a RIC regimen based on fludarabine, busulfan and antithymocyte globulin followed by allogeneic transplant is safe and highly effective.clinicaltrials.gov: NCT00607854.

Allogeneic HCT in Patients with 17p-CLL: Results of a Non-Interventional Study of the EBMT & Eric

Introduction17p-/TP53-mutated CLL (17p- CLL) represents approximately 5 to 10% of newly diagnosed CLL cases. Patients with this abnormality have a poor prognosis after chemo-immunotherapy. According to current guidelines, allogeneic hematopoietic cell transplantation (HCT) is recommended in 17p- CLL cases as part of the first- or second-line treatment. In 2010, the European Society for Blood and Marrow Transplantation (EBMT) and the European Research Initiative on CLL (ERIC) started a non-interventional study, to evaluate the outcome of allogeneic HCT in 17p-CLL. Here we report first results from this study.Patients & MethodsMajor eligibility criteria were 17p- CLL in complete or partial remission after first-line therapy or treatment of relapse, age below 70 years, availability of an HLA-compatible related or unrelated donor with up to one HLA-mismatch at HLA-A, -B, -C or DRB1. The primary objective was to determine relapse-free survival.ResultsForty-one patients (30 males, 11 females) from eleven transplant centres were registered for this study between June 2010 and September 2012. The median age was 59 years (range, 28 to 70 years). Twelve patients (29%) were transplanted in first remission. The median number of pre-treatments was 2 (range, 1 to 7) and included alemtuzumab in 31 patients (76%). The remission status at HCT was reported as partial remission in 31 patients (76%) and as complete remission in 10 patients (24%). The median time between diagnosis and HCT was 35 months (range, 4 to 229 months) and the median time between first treatment of CLL and HCT was 12 months (range, 2 to 227 months). Myeloablative conditioning was administered in 3 patients (7%), fludarabine-based reduced-intensity conditioning in 25 patients (61%) and non-myeloablative conditioning, based on 2 Gray TBI, in 13 patients (32%). Donors were HLA-identical siblings for 11 patients (27%), well-matched HLA-compatible unrelated donors for 25 patients (61%) and partially matched unrelated donors for 5 patients (12%). Thirteen patients received ATG. Fifteen patients experienced grade II to IV graft-versus host disease. By July 2014, 27 patients were alive and 14 patients had died. From the deceased patients, 4 patients died subsequent to relapse and 10 patients died without relapse. Causes of death were GVHD in 7 patients, infection in one patient and other causes in 2 patients. The median observation time for living patients was 16 months (range, 3 to 36 months). The probability of relapse-free survival (see also Figure 1) and overall survival at 2 years was 56% (95% CI, 42% to 74%) and 67% (95% CI, 51% to 83%). At two years the cumulative incidences of relapse and non-relapse mortality were 20% (95% CI, 6% to 34%) and 24% (95% CI, 10% to 39%).ConclusionsWhen considering the high disease-specific risk and the median age of 59 years at transplantation of this cohort of patients, we present favourable early results after allogeneic HCT for patients with 17p- CLL. Non-relapse mortality, mainly caused by GVHD, compromised relapse-free survival. The data suggests that allogeneic HCT remains an attractive treatment option, especially for patients with a low transplant risk and a high disease-specific risk of mortality. These results may serve as benchmark for new drugs which are currently under clinical development or have recently received approval for this indication. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ruxolitinib As Pretreatment Before Allogeneic Stem Cell Transplantation For Myelofibrosis

▪ IntroductionWe investigate early outcome after allogeneic SCT in 22 patients – male (n = 13) and female (n = 9) – with myelofibrosis who received ruxolitinib prior to transplantation in order to reduce spleen size and constitutional symptoms. Patients and methodsThe median age of the patients was 59 years (r: 42 – 74 y) and ruxolitinib was given at doses between 2 x 5 mg (n = 5), 2 x 15 mg (n = 5), and 2 x 20 mg (n = 12) before first (n = 19) or second (n = 3) fludarabine-based reduced intensity conditioning from related (n = 2), and matched (n = 14), or mismatched (n = 6) unrelated donor. Thirteen patients had primary myelofibrosis and 9 post ET/PV myelofibrosis. Before ruxolitinib the patients were classified according to DIPSS as intermediate-1 (n = 3), intermediate-2 (n = 14), or high risk (n = 5). Stem cell source was PBSC (n = 21) or bone marrow (n = 1) with a median CD34+ cell count of 7.1 x 106/kg. Before ruxolitinib 21 patients (96%) had constitutional symptoms and all patients had splenomegaly. The median time from start of ruxolitinib to allogeneic SCT was 133 days (r: 27 – 324) and the median treatment duration was 97 days (r: 20 – 316). Most patients (n = 82%) received ruxolitinib until start of conditioning therapy. Four patients (18%) discontinued ruxolitinib between 28 and 167 days before transplantation due to progressive disease or no response (n = 3) or cytopenia (n = 1). ResultsAt time of transplantation 86% had improvement of constitutional symptoms and 45% had major response (>50% palpable) of spleen size, 28% had response of spleen size which was less than 50%, and 27% had no response or progressive spleen size after ruxolitinib treatment. After discontinuation of ruxolitinib at first day of conditioning regimen no “rebound” phenomenon was seen. One patient transformed to sAML before transplantation despite response of spleen size and constitutional symptoms.After busulfan (n = 16), treosulfan (n = 3), or melphalan (n = 3) dose reduced conditioning no graft failure was observed and the median time for leukocyte and platelet engraftment was 15 days (r: 10 – 66) and 17 days (r: 8 – 122) respectively. Acute GvHD I-IV was seen in 50% of the patients which was severe (III/IV) in 18%.During follow-up 4 patients died, 1 patient with sAML at time of transplant due to relapse on day 102 and 3 patients due to therapy-related mortality. One female patient who received a second unrelated HLA-matched transplantation after treosulfan-based regimen died of CMV pneumonitis on day 75. She did not response to ruxolitinib regarding spleen size and constitutional symptoms. A second patient with iron overload and liver fibrosis died of liver toxicity on day 47. This patient initially responded to ruxolitinib but progressed regarding spleen size prior to transplantation. One patient who responded to ruxolitinib regarding constitutional symptoms and spleen size (< 50%) died of GvHD on day 77. The estimated 1-year OS and PFS was 76% (95% CI: 54 – 98%). ConclusionRuxolitinib reduces spleen size and constitutional symptoms in the majority of patients before allogeneic stem cell transplantation. Discontinuation of ruxolitinib at start of conditioning did not induce rebound phenomenon and did not negatively impact engraftment after transplantation. Longer follow-up is needed to determine late outcome. Disclosures:Wolf:Novartis: Research Funding.

Rapid donor T‐cell engraftment increases the risk of chronic graft‐versus‐host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes

The risk of graft-rejection after allogeneic hematopoietic cell transplantation using conventional cyclophosphamide-based conditioning is increased in patients with bone marrow failure syndromes (BMFS) who are heavily transfused and often HLA-alloimmunized. Fifty-six patients with BMFS underwent fludarabine-based reduced-intensity conditioning and allogeneic peripheral blood progenitor cell (PBPC) transplantation at a single institution. The conditioning regimen consisted of intravenous cyclophosphamide, fludarabine, and equine antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A alone or in combination with either mycophenolate mofetil or methotrexate. To reduce the risk of graft-rejection/failure, unmanipulated G-CSF mobilized PBPCs obtained from an HLA-identical or single HLA-antigen mismatched relative were transplanted rather than donor bone marrow. Despite a high prevalence of pretransplant HLA-alloimmunization (41%) and a heavy prior transfusion burden, graft-failure did not occur with all patients having sustained donor lympho-hematopoietic engraftment. The cumulative incidence of grade II-IV acute-GVHD and chronic-GVHD was 51.8% and 72%, respectively; with 87.1% surviving at a median follow-up of 4.5 years. A multivariate analysis showed pretransplant alloimmunization and rapid donor T-cell engraftment (≥95% donor by day 30) were both significantly (P < 0.05) associated with the development of chronic-GVHD (adjusted HR 2.13 and 2.99, respectively). These data show fludarabine-based PBPC transplantation overcomes the risk of graft-failure in patients with BMFS, although rapid donor T-cell engraftment associated with this approach appears to increase the risk of chronic-GVHD. (Clinicaltrials.gov identifier: NCT00003838).