Fludarabine-based Reduced-intensity 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.

Hematopoietic Cell Transplantation for Congenital Dyserythropoietic Anemia: A Report from the Pediatric Transplant and Cellular Therapy Consortium

Hematopoietic cell transplantation (HCT) is the sole curative option for congenital dyserythropoietic anemia (CDA), a rare type of hemolytic anemia characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. In this retrospective multicenter study, wereport the outcomes of children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium centers. Clinical information on HCT and associated outcomes was collected retrospectively using a common questionnaire. Data were analyzed using descriptive statistics and appropriate analysis. Eighteen patients with CDA who underwent allogeneic HCT between 2002 and 2020 were identified. The majority of patients (n= 13) had CDA type II, and the remainder had either CDA type I (n=2) or CDA of unknown type (n=3). Mutations were identified in 7 patients (39%), includingSEC23Bin 5,GATA1in 1, and abnormality of chromosome 20 in 1. Thirteen patients had evidence of iron overload pre-HCT and received chelation therapy for a median duration of 10 months (range, 2 months to 17 years) pre-HCT. The median age at the time of HCT was 5.5 years (range, 0.7 to 26 years). Donors were HLA-matched (sibling, 4; unrelated, 10) and mismatched (haploidentical, 1; unrelated, 3). Graft sources were bone marrow in 15 patients, umbilical cord blood in 2 patients, or both in 1 patient. Conditioning included busulfan-based myeloablative (67%), fludarabine-based reduced-intensity (27%), or nonmyeloablative (6%) regimens. Five patients developed veno-occlusive disease, and 4 had viral reactivation. The cumulative incidence of acute graft-versus-host disease (GVHD) was 33%, and that of chronic GVHD was 22%. Four patients (22%) experienced graft failure; all engrafted following either a second HCT (n=2) or third HCT (n=2) but sustained considerable morbidities (3 GVHD, 1 death, 2 viral reactivation). With a median follow-up of 3.2 years (range, 0.6 to 14 years)), the 2-year overall survival, event-free survival (EFS), and GVHD-free EFS were 88% (95% confidence interval [CI], 73% to 100%), 65% (95% CI, 45% to 92%), and 60% (95% CI, 40% to 88%), respectively.Univariate analysis did not identify any patient- or transplantation-related variables impacting outcomes. Our study indicates that HCT can be curative for patients with CDA. Strategies such as aggressive chelation, use of preconditioning therapy, and early HCT in the presence of a suitable donor before comorbidities occur are needed to improve engraftment without increasing the risk for toxicity and mortality.

Carfilzomib in Addition to Standard Cyclosporine/Methotrexate Combination Effectively Prevents Acute Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation from Unrelated Donors

Background: Acute graft-versus-host disease (GVHD) remains a major obstacle for successful allogeneic stem cell transplantation (HSCT) from unrelated donors. Novel preventive regimens are thus needed. The proteasom inhibitor bortesomib has immune modulatory effects that were shown to be beneficial in several studies adding a short treatment course to the standard calcineurin/ methotrexate regimen in matched and mismatched unrelated donor transplant. Carfilzomib is a second generation irreversible proteasome inhibitor. It is more selective than bortesomib and was shown to be more effective in relapsed refractory multiple myeloma. However, there is no data on the effect of carfilzomib in GVHD prevention. We explored a novel regimen consisting of 2 doses of carfilzomib at 20 mg/m2, given on days 1 and 2 after HSCT combined with standard anti GVHD prophylaxis regimen of cyclosporine/ methotrexate. The study enrolled patients with acute myeloid leukemia (AML) in remission (CR) or patients with myelodysolastic syndrome (MDS) with less than 10% blasts, given a 10/10 or 9/10 matched unrelated donor transplant with fludarabine-based reduced-intensity or reduced-toxicity conditioning.Patients and Methods: 20 patients, 8 male, 12 female, median age 63 years (range, 30-72) were recruited to the study. Fifteen patients had AML and 5 had MDS. Ten patients were in CR1, 5 in CR2 and 5 were previously untreated at the time of transplantation. The conditioning regimen included fludarabine combined with intravenous busulfan at reduced doses (n=6) or myeloablative doses (n=11) or with treosulfan (n=3). All patients were also given antithymocyte globulin (ATLG ,Grafalon ,Neovii, total dose 15 mg/kg). The donors were all unrelated donors and were 10/10 HLA matched (n=10) or 9/10 matched (n=5). Transplantation outcomes were compared to a historical group of 100 patients with similar patient and transplant characteristics given unrelated donor transplant with a standard anti GVHD cyclosporine/ methotrexate GVHD prevention regimen.Results: Eighteen patients completed the planned two days of carfilzomib on day 1 and 2 post-transplant. One patient had only one dose and one none of the doses due to adverse events that dictated stopping treatment by protocol. The median follow-up is 11 months (range 1-29). All patients engrafted with a median of 15 days (range, 10-31) compared with 14 days (range, 9-23) in the control group (P=0.14). Mucositis grade ≥3 occurred in 60% and 24% of the study patients and historical controls, respectively (P=0.001). There was no difference in the rate of all other grade ≥3 organ toxicities, 20% and 30%, respectively (P=0.36). Acute GVHD grade II-IV occurred in only one patient in the study group, a cumulative incidence of 5% (95%CI, 1-34) compared with 39% (95%CI, 30-50) in the control group (P=0.007). Chronic GVHD occurred in 5 patients in the study group , a cumulative incidence of 58% (95%CI, 30-100) compared with an incidence of 41% in the historical controls (95%CI, 33-52) (P=0.58). Notably, all study pts had mild chronic GVHD while, the incidence of moderate to severe chronic GVHD was 0% and 18% (95%CI, 11-30), respectively (P=0.17). Non-relapse mortality (NRM) occurred in 2 patients on study, one died of acute GVHD and the other of multi-organ failure. The cumulative incidence of NRM was 11% (95%CI, 3-39) and 22% (95%CI, 15-32), in the study and control group, respectively (P=0.68). Finally, only one study patient relapsed, cumulative incidence 8% (95%CI, 1-53), compared to 26% (95%CI, 18-36) in the historical controls (P=0.310). In all, 17/20 study patients are alive with an estimated 2-year survival of 81% (95%CI, 68-100) compared to 56% (95%CI, 46-66) in the control group, respectively (Figure, P=0.31).Conclusions: Carfilzomib in addition to standard cyclosporine/ methotrexate as anti GVHD prophylaxis after unrelated- donor transplant is safe and allows better prevention of acute GVHD without compromising the graft-versus-leukemia effect. The add on of carfilzomib results in favorable outcome. Larger studies with longer follow-up are required to confirm these initial promising results. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

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.

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.

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.

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.

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

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.

Long-Term Outcome of Fludarabine-Based Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation for Debilitating Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis, venous thrombosis, and bone marrow failure. Seventeen patients with debilitating PNH, including 8 who were HLA-alloimmunized, underwent a reduced-intensity allogeneic hematopoietic cell transplantation (HCT). All received cyclophosphamide/fludarabine +/− antithymocyte globulin followed by a granulocyte colony-stimulating factor–mobilized HCT from an HLA-matched relative. Glycosylphosphatidylinositol-negative neutrophils were detectable after engraftment but disappeared completely at a median 100 days after transplantation. With a median follow-up of nearly 6 years, 15 patients (87.8%) survived, all without any evidence of PNH, transfusion independent, and off anticoagulation. Allogeneic reduced-intensity HCT remains a curative therapeutic option for PNH patients who are not candidates for eculizumab treatment.

Clofarabine Salvage Therapy Prior To Allogeneic Hematopoietic Stem Cell Transplantation (HCT) In Patients With Relapsed Or Refractory Acute Leukemia

HCT is the only potentially curative approach that may provide long-term disease control for patients con relapsed and/or refractory acute leukemia (Re/Ref AL). However, active disease burden at HCT is associated with high relapse rates and dismal outcomes. Recently, promising results in this way have been reported using sequential treatment schedules. We performed a retrospective multicentre analysis to investigate the safety and efficacy of clofarabine (CLO) cytoreduction prior to HCT for Re/Ref AL. Spanish Agency Qualification was obtained (AAH-CLO-2013-01/EPA-OD).A total of 50 patients from 14 Spanish centres (AML 33; ALL 17) who received CLO and had an HLA-matched donor were included. Median age was 37 years (18-64); sex: 26 M, 24 F. High risk cytogenetic/molecular profile in 31.4%, Intermediate 54%, and low risk 14.6%. Patients received first-line chemotherapy (ct) regimens based on cooperative national groups (PETHEMA, CETLAM and SHOP) and 2nd lines with fludarabine-based regimens in 85%. Prior to CLO, 56.3% of patients had received 2 CT lines and 35.5% ≥ 3 lines including 6 auto-HCT and 12 allogeneic HCT. Disease status at CLO administration was primary refractoriness (29.2%) secondary refractoriness (33.3%), first relapse (10%) and ≥2nd relapse (27%). CLO was administered at 20-40 mg/m2/day for 5 consecutive days combined with ARA-C in AML cases and Citoxan-Etoposide in ALL cases. Response was assessed by IWG-2006 criteria and toxicity evaluated according to CTCAE v3.Out of 50 included patients, 16 did not underwent allogeneic HCT due to early toxic deaths (N=6) or due to lack of disease control (N=10)1.- Response was valuable in 44 cases, achieving 11 CR and 7 PR. Effective Cytoreduction (defined as <20% of marrow cellularity and/or <10% of marrow blast count) was achieved in 59% of cases.2.- Most frequent toxicity was haematological gr.4 in 100% of cases, mucositis gr.≥ 3 in 15%, liver toxicity with bilirrubin and/or SGOT elevation gr.≥3 in 23%, infections gr.≥3 in 50% and skin toxicity gr.2 in 4%3.- Eventually, HCT was performed in 34 patients (22 AML and 12 ALL); 19 form HLA-matched sibling donor, 7 HLA-matched unrelated donor, 4 HLA-matched umbilical cord and 4 HLA-haploidentical donor. Conditioning regimen was fludarabine-based reduced-intensity in 19 patients and myeloablative in 15 patients. Median elapsed time from CLO administration and HCT was 37 days (range: 6-105).4.-Transplant-related mortality (TRM)at day +100 and +365 was 20.6% and 41% respectively. Acute GVHD was developed in 16 patients (grades III-IV in 6 cases) and chronic GVHD was observed in 6 patients. With a median follow-up of 14.3 months after HCT, Overall Survival was 28.5% for the global series, 39.6% for AML patients and 15% for ALL patients. Patients achieving effective cytoreduction with CLO had a significantly superior Relapse Free Survival (48% vs. 0%, P=.002). Similarly, patients receiving CLO at earlier disease status (first relapse or primary refractoriness) had a significantly better OS than those treated at more advanced disease (48% vs. 5%). Elapsed time from CLO administration and HCT shorter than 50 days was also associated to a better OS (40.2% vs. 12.2%, P =.14) ) although no statistical difference was reached.Salvage CLO-based regimens as bridge to HCT in patients with Re/Ref AL can be administered with an acceptable toxicity profile and are followed by an acceptable TRM. Achievement of effective cytoreduction and no delayed HCT procedure could identify patients with less leukemic burden capable to achieve long-lasting sustained disease control. Disclosures:No relevant conflicts of interest to declare.

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).

Pre-transplant risk factors for cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia after hematopoietic cell transplantation

Cryptogenic organizing pneumonia (COP), previously known as bronchiolitis obliterans organizing pneumonia (BOOP), is a significant complication after allogeneic hematopoietic SCT (HCT). However, the pathogenesis of this complication has not yet been elucidated. Therefore, we identified the pre-transplant risk factors for the development of COP/BOOP using the Japan transplant registry database between 2005 and 2009. Among 9550 eligible recipients, 193 experienced COP/BOOP (2%). HLA disparity (odds ratio (OR) 1.51, P=0.05), female-to-male HCT (OR 1.53, P=0.023), and PBSC transplant (OR 1.84, P=0.0076) were significantly associated with an increased risk of COP/BOOP. On the other hand, BU-based myeloablative conditioning (OR 0.52, P=0.033), or fludarabine-based reduced-intensity conditioning (OR 0.50, P=0.0011) in comparison with a TBI-based regimen and in vivo T-cell depletion (OR 0.46, P=0.055) were associated with a lower risk. Of the 193 patients with COP/BOOP, 77 died, including non-relapse death in 46 (59%). Pulmonary failure and fatal infection accounted for 41% (n=19) and 26% (n=12) of the non-relapse death. Allogeneic immunity and conditioning toxicity could be associated with COP/BOOP. Prospective studies are required to elucidate the true risk factors for COP/BOOP and to develop a prophylactic approach.

Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced

Secondary malignancies are well established complication in long-term survivors after allogeneic stem-cell transplantation (SCT) with myeloablative conditioning (MAC). Fludarabine-based reduced-intensity (RIC) and reduced-toxicity conditioning (RTC) regimens are increasingly used in the last decade; however, due to limited long-term follow-up, there is no data on secondary malignancies in this setting. The records of 931 consecutive patients given allogeneic SCT with MAC (n=257), RIC (n=449) or RTC (n=225), in a single institution over a 13-year period, were reviewed. Twenty-seven patients had secondary malignancy, diagnosed a median of 43 months (7 months-11.5 years) after SCT. The 10-year cumulative incidence was 5.6% (95% confidence interval (CI), 3.6-8.7), twice the expected rate in matched normal population. The incidence was 1.7, 7.4 and 5.7% after MAC, RIC and RTC, respectively (P=0.02). Multivariate analysis identified fludarabine-based conditioning (hazard ratio (HR) 3.5, P=0.05), moderate-severe chronic graft-versus-host disease (HR 2.8, P=0.01) and diagnosis of chronic myeloproliferative or non-malignant disease (HR 0.2, P=0.04) as risk-factors for secondary malignancy. The related 10-year mortality rate was 2.4% (95% CI, 1.0-5.4). In conclusion, the risk of secondary malignancies is not reduced and is even possibly increased in the era of fludarabine-based RIC/RTC. Patients and physicians should be aware of this association and life-long cancer screening is required for all transplant survivors.

Excellent outcome of allogeneic bone marrow transplantation for Fanconi anemia using fludarabine-based reduced-intensity conditioning regimen

Fanconi anemia (FA) is a disorder characterized by developmental anomalies, bone marrow failure and a predisposition to malignancy. It has recently been shown that hematopoietic stem cell transplantation using fludarabine (FLU)-based reduced-intensity conditioning is an efficient and quite safe therapeutic modality. We retrospectively analyzed the outcome of bone marrow transplantation (BMT) in eight patients with FA performed in two institutes between 2001 and 2011. There were seven females and one male with a median age at diagnosis = 4.5 years (range 2-12 years). The constitutional characteristics associated with FA, such as developmental anomalies, short stature and skin pigmentation, were absent in three of the patients. One patient showed myelodysplastic features at the time of BMT. All patients received BMT using FLU, cyclophosphamide (CY) and rabbit anti-thymocyte globulin (ATG) either from a related donor (n = 4) or an unrelated donor (n = 4). Acute graft-versus-host disease (GVHD) of grade I developed in one patient, while chronic GVHD was not observed in any patient. All patients are alive and achieved hematopoietic recovery at a median follow-up of 72 months (range 4-117 months). BMT using FLU/low-dose CY/ATG -based regimens regardless to the donor is a beneficial therapeutic approach for FA patients.

Fludarabine-Based Reduced-Intensity (RIC) or Reduced-Toxicity Conditioning (RTC) May Be Associated with Increased Risk for Secondary Malignancies After Allogeneic Stem-Cell Transplantation (SCT)

Fludarabine-Based Reduced-Intensity (RIC) or Reduced-Toxicity Conditioning (RTC) May Be Associated with Increased Risk for Secondary Malignancies After Allogeneic Stem-Cell Transplantation (SCT)

Splenic Irradiation as a Component of a Reduced-Intensity Conditioning Regimen for Hematopoietic Stem Cell Transplantation in Myelofibrosis with Massive Splenomegaly

Primary myelofibrosis is a hematologic neoplasm characterized by bone marrow fibrosis and extramedullary hematopoiesis. A similar clinical condition can occur at late stage of myeloproliferative neoplasms such as polycythemia vera and essential thrombocythemia. Although allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative strategy for both conditions, massive splenomegaly frequently observed in patients with myelofibrosis is considered to be a risk factor for graft failure or engraftment delay after transplantation. A proportion of patients can benefit from splenectomy before transplantation but such procedures have been associated with substantial surgical morbidity. Here, we report two elderly patients with myelofibrosis who received scheduled splenic irradiation for massive splenomegaly immediately prior to allogeneic HSCT instead of undergoing splenectomy. The first patient was a 60-year-old woman who received peripheral blood stem cell transplantation for post-essential thrombocythemia myelofibrosis from an HLA-identical sibling; the second patient was a 60-year-old man who received unrelated bone marrow transplantation for primary myelofibrosis. After receiving fractionated splenic irradiation and fludarabine-based reduced-intensity conditioning regimens, these patients showed remarkable reduction of their splenomegaly at the time of transplantation. They attained successful donor cell engraftment without severe complications related to splenic irradiation, while improvement in splenomegaly was durable. Our experience suggests that splenic irradiation before allogeneic HSCT might be a safe and effective alternative to splenectomy for myelofibrosis patients with massive splenomegaly in terms of reducing the risk of surgical morbidity.

Feasibility of Reduced-Intensity Cord Blood Transplantation as Salvage Therapy for Graft Failure: Results of a Nationwide Survey of Adult Patients

To evaluate whether rescue with cord blood transplantation (CBT) could improve the poor survival after graft failure (GF), we surveyed the data of 80 adult patients (median age, 51 years) who received CBT within 3 months of GF (primary 64, secondary 16), with fludarabine-based reduced-intensity regimens with or without melphalan, busulfan, cyclophosphamide, and/or 2-4 Gy total-body irradiation (TBI). A median number of 2.4 × 10(7)/kg total nucleated cells (TNC) were infused, and among the 61 evaluable patients who survived for more than 28 days, 45 (74%) engrafted. The median follow-up of surviving patients was 325 days, and the 1-year overall survival rate was 33% despite poor performance status (2-4, 60%), carryover organ toxicities (grade 3/4, 14%), and infections (82%) prior to CBT. Day 100 transplantation-related mortality was 45%, with 60% related to infectious complications. Multivariate analysis showed that the infusion of TNC ≥2.5 × 10(7)/kg and an alkylating agent-containing regimen were associated with a higher probability of engraftment, and that high risk-status at the preceding transplantation and grade 3/4 organ toxicities before CBT were associated with an increased risk of mortality. In conclusion, in an older population of patients, our data support the feasibility of CBT with a reduced-intensity conditioning regimen for GF.

Impact of ABO Imcompatibility On Acute GvHD and Thrombotic Microangiopathy After Reduced-Intensity Cord Blood Transplantation.

Abstract 2298Poster Board II-275 Introduction:Althouth ABO blood type is one of two antigen system for transplantation, the effect of ABO incompatibility on transplantation outcome still remains controversy. Furthermore, there is little data about ABO incompatibility on the outcome of unrelated cord blood transplantation following reduced-intensity conditioning (RI-CBT). Design and Methods:We retrospectively analyzed data of 155 patients who underwent RI-CBT performed at Toranomon Hospital from January 2005 to December 2008. The patients include 45 ABO-identical, 47 minor, 43 major, and 20 bidirectional ABO mismatched. All patients were performed using fludarabine-based reduced-intensity conditioning, and 114 patients (74%) were performed using TBI-containing regimen. Median age were 57 years-old and 94 patients (61%) were over 55 years-old. We evaluated the association between ABO incompatibility and neutrophil engraftment, one-year overall survival (OS) ; one-year non-relapsed mortality (NRM) ; and one-year relapse rate. We also analyzed the incidence of pre-engraftment immune reaction (PIR), acute graft-versus-host disease (GvHD) including severity, and thrombotic microangiopathy (TMA). Results:There were no significant differences in neutrophil-engraftment time, reticulocyte-engraftment time, and the incidence of PIR. The incidence of acute GvHD and grade 2-4 acute GvHD were significantly higher in major/bidirectional ABO-incompatible group than ABO-identical/minor ABO-incompatible group (respectively P=0.0008 and P=0.0116). The incidence of TMA tended to be higher in minor/bidirectional ABO-incompatible group than ABO-identical/major ABO-incompatible group (P=0.0637). There were no significant differences in one-year OS, NRM, and relapse rate. In multivariate analysis, risk factors of acute GvHD were age over 55, TBI-containing regimen, CD34-positive cells>0.7×10e5/kg, and major/bi-directional ABO incompatibility, and those of TMA were grade 3-4 acute GvHD and minor/bi-directional ABO incompatibility. Discussion:This study showed major-directional ABO incompatibility setting increased the incidence of acute GvHD. Sex incompatibility and HLA incompatibility were not significantly influenced the incidence of acute GvHD. The use of steroid for severe GvHD and the expression of ABO antigen on the surface of vascular endothelial cell may influence pathogenesis of TMA. Further studies including larger patients numbers are required to elucidate the impact of ABO incompatibility on the clinical outcome of RI-CBT. Disclosures:No relevant conflicts of interest to declare.