Intensity Allogeneic Hematopoietic Stem Cell Research Articles

Should patients receive consolidation chemotherapy before reduced intensity allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia in first complete remission?

Background:For acute myeloid leukemia (AML) patients, the role of bridging consolidation chemotherapy after achieving first complete remission (CR1) in the transplant setting is a frequently debated issue. The lack of data from Asian patients led us to conduct this study.Methods:We retrospectively studied outcomes of 106 patients in CR1 undergoing allogeneic stem cell transplantation (alloSCT) with reduced intensity conditioning (RIC) based on their exposure to pre-transplant consolidation chemotherapy. There were 35 in the no consolidation group versus 71 in the consolidation group.Results:The median relapse free survival (RFS) was 9 months for the no consolidation group and 51 months for consolidation group (p = 0.023). The median overall survival was 32 months for the no consolidation group and not reached for the consolidation group (p = 0.034). Multivariate analysis recognized consolidation and poor cytogenetics as adverse prognostic factors for RFS. Moreover, RFS was better in patients with a shorter time lapse between last chemotherapy and alloSCT in both the no consolidation group and the consolidation group. Consolidation chemotherapy did not negatively affect neutrophil and platelet engraftment, infection rates, or acute graft-versus-host disease (GVHD) incidence. On the other hand, patients undergoing consolidation chemotherapy showed trends towards a more severe degree of chronic GVHD.Conclusion:The exposure to consolidation chemotherapy in CR1 prior to alloSCT with RIC conditioning did not negatively impact the outcomes in Korean AML patients, for whom a suitable donor is rarely immediately available. Therefore, post-remission consolidation chemotherapy is a reasonable option if required.

Interview with Dr Philip McCarthy.

Philip McCarthy speaks to Roshaine Wijayatunga, Senior Editor: Oncology Philip McCarthy completed his MD at Tufts University School of Medicine, Boston, MA, USA and his Internal Medicine Residency at Yale, New Haven Hospital, New Haven, CT, USA. His Fellowship was completed at Brigham and Women’s Hospital and the Dana Farber Cancer Insitute, Harvard University, Boston, MA, USA. His research interests are devoted to developing novel intensive and reduced intensity allogeneic (allo) and autologous (auto) hematopoietic stem cell transplant (HSCT) approaches for the treatment of hematologic disorders, leading to improved patient outcomes and decreased toxicity. He has over 20 years of experience treating HSCT patients and directing clinical and translational HSCT research studies. He has served as chair or co-chair of several clinical trials including CALGB 100104, a Phase III clinical trial evaluating lenalidomide maintenance after auto-HSCT for multiple myeloma (MM). This study demonstrated an improved progression-free and overall survival for MM patients receiving lenalidomide maintenance therapy after auto-HSCT. The Roswell Park Comprehensive Cancer Center Blood and Marrow Transplant team has developed a systematic approach to the evaluation and treatment of HSCT patients with a specific focus on predicting and minimizing treatment-related mortality. The team participates with a core group of basic science and clinical researchers who are committed to the investigation of the complications of auto- and allo-HSCT and to the developing novel approaches to improve outcomes.

269 - Prognostic Factors of CLL Patients Undergoing Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation in the Immunochemotherapy Era

269 - Prognostic Factors of CLL Patients Undergoing Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation in the Immunochemotherapy Era

Prognostic Factors of CLL Patients Undergoing Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation in the Immunochemotherapy Era

Background: Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative therapy for chronic lymphocytic leukemia (CLL). With this analysis we intended to identify prognostic factors in patients undergoing reduced-intensity conditioning (RIC) or non-myeloablative (NMA) HCT at our center in the immunochemotherapy era.Methods: This retrospective chart review included all CLL patients who underwent RIC or NMA conditioned HCT at Memorial Sloan Kettering Cancer Center (MSKCC) in the immunochemotherapy era between 09/2006 and 10/2014. We then analyzed whether pre-HCT factors including age, disease response status at the time of HCT, presence of Richter's transformation, 17p deletion or TP53 mutation, use of anti-thymocyte globulin (ATG), number of prior lines of treatment, and time from diagnosis to HCT, were associated with overall survival (OS), progression-free survival (PFS), non-progression mortality, and grade 2-4 acute graft versus host disease (aGVHD). Univariate factors were evaluated via log-rank or Gray's test as appropriate, while Cox regression models were used to explore the adjusted effect of multiple factors.Results: Thirty-five patients undergoing RIC or NMA HCT with a median age of 53 years (range 36.3-69.0) were analyzed. The patients had a median of 4 prior lines of therapy (range 1-10) and a median time from diagnosis to HCT of 65.8 months (range 7.5-159.0). With a median follow-up for survivors of 58.8 months (95% CI 17.0-NA), the 5-year PFS and OS were 32.4% (95% CI 17.4-48.4) and 49.4% (95% CI 31.2-65.2), respectively (Figure 1). Treatment-related mortality was 20.0% (95% CI 8.7-34.7) and 31.8% (95% CI 17.0-47.6) at 1 and 2 years, respectively. Chemosensitive disease, defined by complete or partial remission per contemporary International Workshop CLL (iwCLL) response criteria at the time of HCT, was associated with improved 3-year OS of 68.0% (95% CI 46.1-82.5) compared to patients with chemorefractory disease to last line of therapy (stable or progressive disease) with a 3-year OS of 15.0% (95% CI: 1.0-45.7, p = 0.002, Figure 2). Additionally, patients with ≤4 lines of therapy prior to HCT experienced superior 5-year OS of 61.2% (95% CI 37.5-78.2) contrasted to 20.0% (95% CI: 3.1-47.5) in patients with >4 prior lines of therapy (p = 0.008, Figure 3). This difference approached statistical significance in multivariate analysis (HR 2.43, 95% CI 0.91-6.50; p = 0.076) adjusted for chemosensitivity. Furthermore, when adjusted for the number of prior lines of therapy, chemorefractory patients remained at greater risk of death in multivariate analysis (HR 3.29, 95% CI: 1.14-9.48, p = 0.027). Other factors including: age, history of transformed disease, the presence of 17p or TP53 deletion/mutation, time from diagnosis to HCT, or use of ATG with NMA/RIC did not impact PFS or OS.Conclusion: This is the first study to report independent prognostic impact of the number of lines of therapy prior to NMA/RIC HCT on OS for CLL patients in the post-immunochemotherapy era. We confer findings from other groups including: the prognostic significance of chemosensitivity at the time of HCT as well as HCT overcoming poor-risk cytogenetics associated with 17p chromosomal aberrations. Our data is limited by lack of patients previously exposed to recently FDA approved novel kinase or BCL2 inhibitors. Nevertheless, given our reported data, HCT should still be considered as the only therapy with curative potential for poor-risk patients earlier in their disease course, while chemosensitivity is maintained and prior to the accumulation of multiple lines of therapies. [Display omitted] [Display omitted] [Display omitted] DisclosuresPerales:Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Graft-Versus-Host Disease-Free, Relapse-Free Survival (GRFS) after Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplant (HCT) in Older Patients with Myeloid Malignancies

Graft-Versus-Host Disease-Free, Relapse-Free Survival (GRFS) after Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplant (HCT) in Older Patients with Myeloid Malignancies

Severe fludarabine neurotoxicity after reduced intensity conditioning regimen to allogeneic hematopoietic stem cell transplantation: a case report

Key Clinical MessageWe present a case of severe, irreversible neurotoxicity in a 55-year-old-patient with myelofibrosis undergoing hematopoietic stem cell transplantation following a reduced intensity conditioning including fludarabine. The patient developed progressive sensory-motor, visual and consciousness disturbances, eventually leading to death. MRI imaging pattern was unique and attributable to fludarabine neurotoxicity.

Clinical research of reduced intensity allogeneic hematopoietic stem cell transplantation for relapsed or refractory lymphoma

Objective To explore the efficacy and safety of reduced intensity allogeneic stem cell transplantation(allo-HSCT)in the treatment of relapsed or refractory lymphoma. Methods 5 patients with relapsed or refractory lymphoma received reduced intensity allo-HSCT from January 2012 to December 2013 of Beijing Military General Hospital, including 4 males and 1 female, aged from 20 to 39 years old, with the mean age 28.7 years old. 3 cases were HLA-identical matching and the other two cases were HLA-haploidentical. Donors received granulocyte colony-stimulating factor mobilization, and stem cells were collected from both peripheral blood and bone marrow. Pretreatment scheme reduced the strength of pretreatment for fludarabine combined with busulfex and ATG. Combined immunosuppressive agents were used for graft-versus-host disease(GVHD)prophylaxis, including cyclosporine A, methotrexate, mycophenolate mofetil and soon. The toxicity, GVHD and disease-free survival in patients were observed after transplantation. Results All of the patients acquired hematopoietic reconstitution. The average time of the neutrophils count ≥ 0.5 × 109/L and platelets ≥ 20×109/L were 18.8 d and 24.5 d, respectively. Implantation was confirmed by the evidence of 100 % of donor hematopoiesis. As of follow-up to December 2014 with the median 19.2 months(6-35 months), 2 cases died of recurrence, the other 3 patients remained disease-free survival, and the longest disease-free survival time was up to 35 months. Conclusions Reduced intensity allogeneic hematopoietic stem cell transplantation is an effective and safe method for relapsed or refractory lymphoma, which could be chosen as a salvage treatment method for relapsed or refractory lymphoma. Key words: Allogeneic hematopoietic stem cell transplantation; Rducing strength; Rlapsed; Refractory; Lymphoma

Etiology and Spectrum of Non-Relapse Mortality after Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation in Adults with Myeloid Neoplasms

Etiology and Spectrum of Non-Relapse Mortality after Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation in Adults with Myeloid Neoplasms

Allogeneic Transplantation in Elderly Patients with AML and MDS Comparing Reduced-Intensity Conditioning with Flamsa-Busulfan Versus Fludarabine/BCNU/Melphalan

▪By reducing treatment intensity allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become feasible for elderly patients. Different reduced-intensity conditioning (RIC) regimens are available, but there is little consensus about the optimal preparative regimen to use, in particular with regard to the outcomes counterbalancing the aim of feasibility and tolerability with higher rates of relapse. Here, we retrospectively evaluate the outcome of sequential therapy employing RIC with fludarabine 30 mg/m2, cytarabine 2g/m2 and amsacrine 100 mg/m2 for 4 days (FLAMSA; Schmid C et al. JCO 2005) followed by busulfan 10 x 0.8 mg/kg (FLAMSA-Bu) compared to RIC utilizing fludarabine 5 x 30 mg/m2, carmustine (BCNU) 2 x 150 mg/m2 and melphalan 110 mg/m2 (FBM; Marks R et al. Blood 2008) in elderly patients treated consecutively at our institution between July 2005 and October 2012.We analyzed the course of 114 patients (pts) with acute myeloid leukemia (AML; n=99) or myelodysplasia (MDS; n=15) aged ≥ 59 years with 59 pts aged ≥ 66 years who were treated with either FLAMSA-Bu (n=66; n=24 ≥ 66 years) or FBM (n=48; n=35 ≥ 66 years). All patients received sero-therapy with anti-thymocyteglobuline (ATG). Median patient age was 66 years for the entire cohort (68 years FBM; 64 years FLAMSA-Bu). 36 patients (75%) of the FBM and 42 patients (63 %) of the FLAMSA-Bu group suffered from high risk disease defined as relapsed or refractory AML or refractory anemia with excess of blasts in transformation (RAEB-T). The hematopoietic cell transplantation comorbidity index (HCT-CI) was higher for the patients of the FBM group than for the FLAMSA-Bu group with 26 (54 %) versus (vs) 24 patients (36 %) scoring ≥ 2 (p 0.085). Graft source after conditioning with FBM/FLAMSA-Bu was bone marrow (1/2), G-CSF mobilized peripheral blood stem cells (40/62) and double-umbilical cord-blood (7/1). In 23 pts (20 %) HLA-matched related and in 91 pts (80 %) HLA-matched unrelated donor transplantation was performed. Engraftment failure was observed in 1 patient after FLAMSA-Bu, while engraftment was achieved in all evaluable patients of the FBM group in a median of 23 days vs 18 days after FLAMSA-Bu (p 0.003), while 7 pts with double-umbilical cord-blood transplantation where included in the FBM group vs 1 pt in the FLAMSA-Bu group. Non-hematological treatment-related acute toxicity ≥ CTC III (gastrointestinal, hepatic, cardiovascular, renal, centralnervous system) occurred in 12/48 pts (25 %) after FBM and in 18/66 pts (27 %) after FLAMSA-Bu. Incidence of severe acute (III-IV) and chronic GvHD was 22.9 %/16.6 % for FBM vs 18.2 %/19.7 % for FLAMSA-Bu, respectively. After conditioning with FBM 2/48 pts vs 9/66 pts after FLAMSA-Bu were diagnosed with a secondary malignancy (p 0.08). Non-relapse mortality (NRM) after 12 months was 26.8 % for FBM versus 25.2 % for the FLAMSA-Bu group. Incidence of relapse after FBM vs FLAMSA-Bu conditioning was 22.9 % vs 15.2 % after 1 year and 31.3 % vs 16.7 % after 2 years. Occurrence of relapse was significantly related to an incomplete or mixed chimerism (donor cells ≤ 95 % in peripheral blood and/or bone marrow) at day +30 (p 0.001).After a median follow up of 31.4 months (range 4.4-97.5) estimated overall survival (OS) and relapse-free survival (RFS) after 2 years was 55.4 % and 51.4 % for the FBM vs 58 % and 56.7 % for the FLAMSA-Bu group, respectively. Analyzing different subgroups, FBM conditioning might be favorable for pts aged ≥ 66 years when suffering from high risk AML (n=26): Within this group 1-year OS after FBM vs FLAMSA-Bu was 71.4 % vs 66.7 % (p 0.58) and 1-year RFS was 71.4 % vs 58.3 % (p 0.59), respectively. Notably, for pts at highest risk (aged ≥ 66 years and suffering from secondary or therapy-related AML; n=24) the benefit of FBM conditioning becomes more pronounced: 1-year OS after FBM vs FLAMSA-Bu was 62.5 % vs 37.5 % (p 0.26) and 1-year RFS 54.2 % vs 37.5 % (p 0.17).Both conditioning regimens are feasible, and provide similar rates of acute toxicity, NRM and GvHD. There might be evidence for a benefit of conditioning with FBM for the subgroup of “the oldest patients at highest risk”. Taking into account that there is an increasing group of ‘medically fit’ elderly patients in the field of allogeneic transplantation, prospective clinical trials are needed to investigate different conditioning regimens considering their special requirements. DisclosuresNo relevant conflicts of interest to declare.

Impact of Low-Dose TBI on Outcome of Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation from HLA Identical Sibling for Acute Myeloid Leukemia

▪IntroductionIn recent year, reduced-intensity conditioning (RIC) is increasingly used in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML) patients considered unfit for myeloablative conditioning. Several RIC regimens include low-dose total body irradiation (TBI). However, it is unknown whether addition of low-dose TBI to RIC is beneficial. Therefore, we conducted retrospective analysis to elucidate the clinical impact of low-dose TBI in RIC on outcome of allo-HSCT from HLA identical sibling for AML patients.Patients and methodsClinical data of patients with AML aged over 15 years, who received RIC and underwent allo-HSCT from HLA identical sibling for the first time between January 2000 and December 2012, were extracted from the database the Japan Society for Hematopoietic Cell Transplantation. Low-dose TBI was defined as 2-4Gy of TBI. Overall survival (OS), relapse, Non relapse mortality (NRM) and engraftment were compared between patients who received low-dose TBI (TBI group) and patients who did not receive TBI (Non-TBI group) using log-rank test and Gray’s test respectively. To evaluate the association of patient characteristics with low-dose TBI, Cox proportional hazards model and Fine and Gray proportional hazards model were used for multivariate analyses.ResultsThere were 409 patients with AML who received RIC and underwent allo-HSCT from HLA identical sibling. Of those, 108 patients were TBI group and 301 patients were Non-TBI group. In term of graft source, a higher proportion of TBI group received bone marrow (BM) than non-TBI group (54.6% vs. 31.2% [P<0.001]). Age, gender, disease status, performance status (PS), cytogenetic risk category were comparable between both groups. The probability of 5-years OS (36.0% vs. 32.8% [P=0.656]), relapse (37.3% vs. 38.8% [P=0.933]), and NRM (23.9% vs. 25.2% P=[0.686]) were comparable between both groups. Although, the median time to engraftment of neutrophil and platelet were shorter in non-TBI group in whole patients (17d vs. 15d [P=0.031], 22.5d vs. 19d [P=0.024]), subgroup analysis according to donor source showed the median time to engraftment of neutrophil and platelet were similar between both groups in BM recipients (17d vs. 16.5d [P=0.395], 25.0d vs. 23.5d [P=0.392]) and peripheral blood recipients (14d vs. 15d [P=0.213], 20d vs. 17d [P=0.174]). In multivariate analysis, low-dose TBI was not associated with OS, relapse, NRM, and engraftment after adjusting graft source, age, gender, disease status, PS, and cytogenetic risk category.ConclusionThis study showed that adding low-dose TBI to RIC did not affect clinical outcome of allo-HSCT from HLA identical sibling for AML patients. These results suggested RIC regimen without low-dose TBI is valid option for older or medically infirm AML patients who receive allo-HSCT from HLA identical sibling. DisclosuresNo relevant conflicts of interest to declare.

Clinical analysis of reduced conditioning intensity allo-HSCT treatment for relapsed ETO-positive AML

This study was aimed to explore the effect and feasibility of reduced conditioning intensity allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of relapsed ETO positive acute myeloid leukemia (AML) patients. Fifteen cases of relapsed AML received the reducing conditioning intensity allo-HSCT from January 2011 to January 2013 in Beijing Military Command General Hospital. All patients were high-risk type of relapsed or refractory AML, including 10 males and 5 females, aged from 16 to 48 years old with mean age of 32.5 years. Ten cases are HLA-identical matching and other 5 cases are HLA-haploidentical.donors received granulocyte colony-stimulating factor (G-CSF) to mobilize the peripheral blood stem cell for transplantation. Conditioning regimen was fludarabine combined with busulfex, cytarabine and cyclophosphamide. The preventive donor's peripheral blood stem cell infusion were performed after 3 months of transplantation, and the toxicity, GVHD and disease-free survival were observed in patients after transplantation. The results showed that all patients achieved hematopoietic reconstitution, the average time of neutrophils ≥ 0.5 × 10⁹/L and platelets ≥ 20 × 10⁹/L were 15.5 d and 16.8 d respectively. Implantation was confirmed by the evidence of 100% donor hematopoiesis. Follow-up to June 2014, with a median follow-up duration of 27.5 months (18-54 months), GVHD occurred in 8 cases of all patients, one died of complication, the other 4 cases died of relapse and the other three patients remained in disease-free survival. The disease-free survival rate of 2-year was 66.7%,the longest disease-free survival time was up to 54 months. It is concluded that the reduced conditioning intensity allo-HSCT is the effective and safe method for relapsed AML with ETO-positive, and it may be chosen as a treatment method for relapsed ETO positive AML patients.

Equivalent Outcome Between Older Siblings and Unrelated Donors After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Patients Older Than 50 Years with Acute Myeloid Leukemia in First Complete Remission: A Report From the ALWP of EBMT

AbstractAbstract ▪961▪This icon denotes a clinically relevant abstract Background:Current data indicates that allogeneic hematopoietic stem cell transplantation (HSCT) provides identical long-term survival for patients (pts) with acute myeloid leukemia (AML) receiving grafts from matched 8/8 unrelated donor (MUD) or matched sibling donor (MSD) after reduced intensity conditioning (RIC) regimen. Given those results, one may question the requirement for an “older” MSD when a healthy younger MUD is available. This study assessed the impact of older age of MSD on outcomes post-HSCT for pts older than 50 years with AML in first complete remission (CR1) transplanted after a RIC regimen. Patients and methods:From January 2000 to December 2010, this retrospective multi-center study included 1102 pts with AML in CR1 who received PBSC after a RIC regimen, either from MSD (n=854) or from 8/8 HLA MUD (n=248). Conditioning regimen was fludarabine-based in 95% of the pts and Graft versus Host Disease (GvHD) prophylaxis consisted of cyclosporine plus MMF in 42% of cases. To address the role of donor age in our population, 3 groups of pts were defined: pts who were transplanted from a MUD (“MUD group”), pts who received their graft from a sibling aged less than 60 years old (“MSD<60 group”) and pts who were transplanted from a sibling aged of 60 years old or more (“MSD360 group”). Results:Patient characteristics were similar between the 3 groups for gender, disease distribution (FAB classification) and cytogenetic risks (MRC classification). Recipients were younger in the MSD<60 group (57 years versus 60 and 61 years for MUD and MSD360, respectively, p<0.001). Donors were younger for MUD (median age 35 years versus 53 years and 64 years for MSD<60 and MSD360 respectively, p<0.001). In the MUD group, pts were transplanted more recently (2009 versus 2006 and 2007 for MSD<60 and MSD360 respectively, p<0.001), with a longer time interval between diagnosis and HSCT (184 days versus 154 days and 151 days for MSD<60 and MSD360 respectively, p<0.001) and the conditioning regimen included more ATG (p< 0.0001). The median follow-up was 24 months (range, 2–122) for MUD, 42 months (range, 1.5–140) for MSD<60 and 33 months (range, 1–129) for MSD360. During evolution, the cumulative incidence (CI) of acute GvHD was 28% in MUD versus 20% and 17% in MSD<60 and MSD360, respectively (p=0.006) while the CI of chronic GvHD at 2 years was about 50% in each group (p=0.93). CI of treatment related mortality (TRM) and relapse as well as leukemia free survival (LFS) and overall survival (OS) were not different at 2 years between the 3 groups (Table 1). In multivariate analysis, TRM was decreased in pts who received ATG in the conditioning regimen (HR: 0.62; 95%CI 0.41–0.95; p=0.03). A longer interval between AML diagnosis and CR1 (>median) was the only factor associated with relapse (Hazard ratio - HR: 1.35; 95%CI 1.05–1.74; p=0.02). Two independent factors were associated with worse LFS: a longer delay between AML diagnosis and CR1 (HR: 1.34; 95%CI 1.09–1.64; p=0.01) and CMV donor seropositivity (HR: 1.28; 95%CI 1.02–1.6; p=0.04). For pts alive after 2 years post HSCT (n=454), a significant higher rate of TRM was found in pts transplanted from MUD compared with the 2 other groups (Landmark analysis, Table 2). Conclusion:These data suggest equivalence of outcome using MUD, MSD<60 or MSD360 in pts older than 50 years with AML in CR1 transplanted after a RIC regimen. Until prospective studies are completed, this study supports the recommendation to consider HLA-identical donors for HSCT even after 60 years of age (if eligible for donation) prior to younger 8/8 MUD for pts with AML older than 50 years in CR1 after a RIC regimen.Table 1:2-years Cumulative Incidences of TRM, relapse, LFS and OSTRMRelapseLFSOSMUD15±229±355±356±3Sib and donor age <60 years14±130±252±263±2Sib and donor age 36015±233±352±357±3Pvalue0.460.560.740.06Table 2:Landmark analysis after 2 yearsMUD (n=84)TRMRelapseLFSOS21±85±372±974±9Sib and donor age <60 (n=252)5±211±283±390±2Sib and donor age 360 (n=96)7±316±477580±5Pvalue0.0090.370.740.06 Disclosures:No relevant conflicts of interest to declare.

Elevated Preconditioning Serum Levels of C-Reactive Protein Are Associated with Increased Nonrelapse Mortality and Inferior Survival After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation

Abstract 1945 Introduction:Identification of prognostic indicators which predict outcome of allogeneic stem cell transplantation (allo-SCT) is important for selection of patients who may benefit from the procedure. The European Group for Blood and Marrow Transplantation (EBMT) proposed a scoring system for CML which, after modification, also predicted outcomes for patients transplanted for other hematologic malignancies. We have recently shown that the level of C-reactive protein (CRP) measured shortly before transplantation is another important prognostic factor in patients undergoing myeloablative allo-SCT.Patients and Methods: In this study we tested the value of CRP together with other known prognostic factors in 187 consecutive patients who underwent reduced intensity HCT in a single institution from 1995 through 2010. Disease stage was assessed in accordance with EBMT criteria. Preconditioning serum CRP levels were measured at a median of 15 days before stem cell infusion using a standard latex immunoassay. The median age at HCT of the 116 (62%) males and 71 (38%) females was 49 (range 15–67) years. Fifty seven patients (31%) were transplanted in early stage, 34 (18%) in intermediate stage and 96 (51%) in late stage of their disease. The diagnoses included: AML (n = 36; 19%), Hodgkin and non-Hodgkin lymphoma (n = 42; 23%), CML in first chronic phase (n = 29; 16 %), advanced phase CML (n = 21; 11%), MDS (n = 15; 8%), myeloma (n = 16; 9%), ALL (n = 7; 4 %), myelofibrosis (n = 5; 3%), and other (n = 16; 9 %). Patients were transplanted after conditioning containing fludarabine in combination with busulfan (n = 81, 43 %), cyclophosphamide (n = 37, 20 %), and melphalan (n = 47, 25 %); and lomustine, cytarabine, cyclophosphamide and etoposide (LACE) conditioning (n = 21; 11 %). Donors were HLA matched (n = 116; 62 %) and 1 – 2 antigen mismatched (n = 8; 4 %) siblings, matched (n = 46; 25 %) and 1–2 antigen mismatched unrelated (n = 11; 6%), and HLA haploidentical family members (n = 6; 3 %). Results:In univariate analysis, factors associated with day 100 non-relapse mortality (NRM) were disease stage, preconditioning CRP level and donor and recipient HLA match; whereas disease stage, CRP level, HLA match and number of previous allogeneic stem cell transplantations were associated with overall survival. In multivariate analysis only two factors showed independent prognostic value: disease stage (early / intermediate versus late) and CRP level (above versus below 10 mg/L). A CRP level > 10 and late disease stage predicted for higher NRM (RR: 1.83, CI 1.1 – 3.1, P =.021) and (RR: 1.78, CI 1.0 – 3.0, P =.037), and inferior survival (RR: 1.61, CI 1.1 – 2.4, P =.016) and (RR: 1.58, CI 1.1 – 2.3, P =.023) respectively. The day 100 NRM was 31% (95% CI 22 – 44) for patients with elevated CRP, and 13 % (95% CI 8–21) for those with normal CRP (P =.002; figure) and 20 % (95% CI 15–27) for the whole cohort. The 5-year survival was 41 % (95% CI 27 – 56) for patients with normal CRP, 21% (95% CI 12 – 35) for those with elevated CRP (P =.004) and 34 % (95% CI 25 – 44) for the whole cohort. Conclusion:There is no obvious explanation for increased NRM and reduced survival in patients with elevated CRP before initiation of conditioning. Nevertheless our findings provide evidence that preconditioning level of CRP constitutes a key prognostic factor in allo-SCT and should be integrated into existing risk assessment tools when considering allo-SCT. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

HLA Alloantibody Persistence and De Novo Production of HLA Alloantibodies of Donor Origin Following Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation.

AbstractAbstract 1109▪ Background:Platelet refractoriness as a consequence of HLA alloimmunization complicates allogeneic hematopoietic stem cell transplantation (HSCT). Little is known regarding the affects of reduced intensity HSCT on the incidence and duration of HLA alloimmune-mediated platelet refractoriness following reduced intensity HSCT. Methods:We retrospectively studied HLA alloimmunization in 16 patients with malignant and non-malignant hematological disorders, who underwent an allogeneic HSCT from an HLA matched relative using reduced intensity, non-myeloablative conditioning. All patients received a G-CSF mobilized, lymphocyte replete, peripheral blood stem cell (PBSC) allograft following cyclophosphamide (120 mg/kg) and fludarabine (125 mg/m2) based conditioning (+/− equine ATG 40 mg/kg × 4 days) with cyclosporine (CSA; beginning on day −4) and IV methotrexate (5 mg/m2 × 3 days) given as GVHD prophylaxis. Eight patients known to be HLA alloimmunized pre-transplant were compared to 8 control patients who were HLA alloantibody negative pre-transplant. Stored patients' serum samples from pre-transplant (day -30) and post-transplant intervals (days +30, +60, +100, +180, and ≥ 365) were analyzed for the presence of IgG antibodies to HLA class I antigens using a membrane-independent solid phase assay involving color-coded microbeads coated with HLA antigens and analysis with a flow analyzer (LABScan 100; One Lambda, Canoga Park, CA). Panel reactive antibody (PRA) and mean fluorescent intensity (MFI) were analyzed for all samples to measure HLA antibody strength and specificity, respectively. HLA alloantibodies were analyzed and compared with the degree of donor myeloid and T-cell engraftment measured on post-transplant blood samples by PCR of short tandem repeats (STRs). Results:Among the 8 alloimmunized patients who required HLA matched platelets pre-transplant, the median time until HLA antibodies disappeared was 100 days post HSCT. Remarkably, among these patients, 3/8 (37%) had HLA class I antibodies detectable for more than 100 days post-transplant including one patient who continued to show high level alloreactivity greater than 1 year after HSCT. Among the 8 control patients who tested negative for HLA alloantibodies pre-transplant, 3 acquired HLA alloantibodies after HSCT which were first detected at day +30 in all 3 cases. In 2 of the 3 cases, the donors for these patients were found to have pre-existing HLA antibodies of equivalent specificity to those found in the patient post-transplant suggesting patient acquisition of HLA antibodies was mediated by passenger donor lymphocytes that were transplanted in the allograft. Overall, HLA antibodies were detectable for more than 100 days after transplantation in 6/16 (37%) patients analyzed with 3/16 (18%) having alloantibodies detectable for more than 1 year post-transplant despite chimerism being 100% donor in myeloid and T cell lineages. Conclusions:Prolonged production of HLA alloantibodies leading to platelet refractoriness can occur following reduced intensity allogeneic HSCT and may persist even after full donor myeloid and T-cell chimerism have been achieved. Remarkably, we observed that transplantation of passenger donor lymphocytes can result in de novo HLA alloimmunization, complicating post-transplant transfusion management. Screening patients and their donors for HLA antibodies before HSCT would identify the majority of subjects at risk for alloimmune-mediated platelet refractoriness after transplantation. This new screening strategy would not only assist in transfusion support after allogeneic HSCT but could also play a role in the decision analysis for selecting optimal stem cell donors. Disclosures:No relevant conflicts of interest to declare.

Long-Term Follow-up of Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Severe Paroxysmal Nocturnal Hemoglobinuria

AbstractAbstract 3505Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant clonal disorder of hematopoietic stem cells characterized by erythrocyte susceptibility to complement-mediated lysis. Untreated, patients with PNH have a reduced life expectancy compared with age-matched controls. The development of cytopenias with infections related to neutropenia, bleeding associated with thrombocytopenia, and vascular thrombosis all contribute to morbidity and mortality. We previously reported that engrafting donor T-cells mediating graft-vs-host hematopoietic effects can eradicate PNH following reduced intensity (RIC) allogeneic hematopoietic cell transplantation (HCT). Here we present long term follow up data on 16 patients with severe PNH who received a RIC peripheral blood HCT at the NHLBI from May 1999 through January 2007. Eligibility for transplantation included a diagnosis of PNH associated with one or more of the following: 1) Transfusion dependence 2) Prior thrombotic episodes 3) Recurrent debilitating hemolytic crisis. Marrow failure, personal preference or unavailability of the drug precluded the use of eculizumab in all patients. Patients received a T-cell replete G-CSF mobilized blood stem cell transplant from an HLA-matched related donor following conditioning with cyclophosphamide (120mg/kg) and fludarabine (125mg/m2). Patients with a significant transfusion history had equine ATG (40mg/kg/day × 4) added to the conditioning regimen (n= 14). The median CD34+ cell dose was 6.9 × 106cells/kg (range 3.1 to 21.1 × 106) and the median CD3+ cell dose was 2.5 × 108cells/kg (range 1.4 to 4.3 × 108). CSA given alone (n=1) or in combination with either MMF (n=4) or mini-dose methotrexate (n=11) was used as GVHD prophylaxis. FACS analysis on blood samples was performed on all patients at baseline and at multiples time-points post-transplant to measure the percentage of GPI negative PNH-type neutrophils (CD15+/CD66b-/CD16-); the median % of GPI-anchored-protein negative neutrophils pre-transplant was 80.1% (range 5.5%-99%). Half of the patients (n=8) were HLA alloimmunized prior to transplantation with a median 76.5% PRA (range 45%-100%). Neutrophil and platelet recovery occurred at a median 14 days (range 9 to 18) and 12 days (range 5 to 15), respectively. Chimerism assessed in T-cell (CD3) and myeloid (CD14,15) lineages by PCR of short tandem repeats (STR) revealed sustained donor engraftment occurred in both myeloid and T-cell lineages in all patients; the median time to achievement of full donor (>= 95%) myeloid and T-cell chimerism was 15 and 30 days respectively. FACS analysis on blood samples collected sequentially after transplant revealed evidence for donor immune-mediated eradication of PNH; although GPI-anchored-protein negative neutrophils were detectable early after transplant, over time these populations declined in size and eventually disappeared in all patients at a median 100 days (range 30 to 150) post transplant. Two patients died, one from complications related to acute GVHD (day 169) and one from complications related to a peptic ulcer disease (2.8 years). The cumulative incidence of grade 2–4 acute GVHD was 50% (n=8) and the cumulative incidence of chronic GVHD was 68.8% (n=10). With a median follow-up of nearly 6 years (range 2.6–11 years), 14 patients (87.1%) survive without any evidence of PNH, transfusion independent and off all anticoagulation. Conclusion:Graft-vs-PNH effects that occur after RIC allogeneic HCT result in durable remission and can achieve excellent long-term survival in patients with debilitating PNH. Allogeneic HCT using RIC should be considered a viable treatment option for PNH patients who have failed or are not candidates for eculizumab treatment. Disclosures:No relevant conflicts of interest to declare.

EPOCH-FR: A novel salvage regimen for patients with lymphoid malignancies being considered for reduced-intensity allogeneic hematopoietic stem cell transplantation.

6536 Background: There is no standard chemotherapy regimen for patients (pts) with lymphoid malignancies being considered for reduced intensity allogeneic hematopoietic stem cell transplantation (RI-alloHSCT). The ideal regimen would result in disease control and recipient lymphocyte depletion and have limited toxicity. We developed a novel regimen consisting of continuous infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus fludarabine ± rituximab, depending on CD20+ expression (EPOCH-FR). Methods: 147 pts, median age 50 yrs (range 21-71), with high-risk lymphoid malignancies (47% with chemo-resistant disease to last regimen, median 3 prior regimens [range 1-13]) were given EPOCH-FR (74% dose-adjusted) prior to RI-alloHSCT. Pts received 1 (48%), 2 (21%), or 3 (31%) cycles of EPOCH- FR until they were lymphodepleted (CD4+ count < 100/μl) or had progressive disease. Results: Overall response rate (RR) was 41% (16% CR, 25% PR); 39% had SD. RR of FCC/CLL>DLBCL/HL>TCL (p = 0.047). More EPOCH-FR cycles were associated with higher RR (17% vs. 33% vs. 84%) (p < 0.0001). 17% of pts with chemo-resistant disease had CR/PR. EPOCH- FR resulted in significant lymphodepletion (pretreatment median CD3+ = 574/μl, CD4+ = 244/μl, and CD8+ = 249/μl vs. posttreatment CD3+ = 184/μl, CD4+ = 97/μl and CD8+ = 68/μl (p < 0.0001). Pts with greater lymphodepletion of CD3+ (p=0.038) and CD4+ (p=0.017) were more likely to achieve CR/PR. Toxicity in 263 cycles included Grade 4 thrombocytopenia in 25%, neutropenia in 65%, and non-heme toxicity in 6%. Of 147 pts, 143 proceeded to RI-alloHSCT. Pts with greater lymphodepletion of CD3+ (p = 0.0007), CD4+ (p = 0.0004), and CD8+ (p = 0.0019) were more likely to achieve full donor lymphoid chimerism by Day +14 post-transplant. Following transplant, pts with CR/PR vs SD/PD to EPOCH-FR had median EFS = 77.4 vs. 4.8 mos (p < 0.0001) and OS = 98.5 vs. 16.2 mos (p = 0.0006) respectively. Conclusions: EPOCH-FR safely provides disease response and lymphodepletion in pts with lymphoid malignancies being considered for RI-alloHSCT. No significant financial relationships to disclose.

The Graft-Versus-Myeloma Effect Using Non-Myeloablative Or Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Following myeloablative conditioning due to high treatment-related mortality (TRM), some studies have shown an inferior outcome using allogeneic HSCT compared to autologous transplant. More recently, non-myeloablative (NMA) and reduced intensity conditioning (RIC) for allogeneic HSCT was introduced. A prerequisite for this approach is a significant graft-versus-myeloma effect, which has not clearly been demonstrated. Between 1997 and 2005, 177 patients were reported to the CIBMTR following NMA (n=120) or RIC (n=57) and an allogeneic HSCT from an HLA-identical sibling donor.

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplant (RI-HCT) For MDS Using Tacrolimus/Sirolimus As GVHD Prophylaxis

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplant (RI-HCT) For MDS Using Tacrolimus/Sirolimus As GVHD Prophylaxis

Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplant (HSCT) for Myeloma (MM) - Chronic Graft Versus Host Disease (GVHD) is Associated with Lower Risk of Relapse and Superior Progression Free Survival (PFS) - A CIBMTR Analysis.

Abstract 53Prior studies have demonstrated a graft-versus-malignancy effect following allogeneic HSCT that is variably linked to acute or chronic GVHD. Although a graft vs. Myeloma (MM) effect has been shown after myeloablative allogeneic HSCT, a higher treatment related mortality (TRM) risk leads to inferior survival compared with autologous HSCT. Non-myeloablative (NMA) and reduced intensity conditioning (RIC) approaches are used to reduce the risk of TRM while preserving the graft vs. MM effect. The clinical benefit of lower intensity conditioning regimens is thus especially dependent on the impact of acute or chronic GVHD on graft vs. MM effect and TRM. We analyzed the outcomes of 177 matched sibling allogeneic HSCT recipients reported to the CIBMTR between 1997 and 2005 following NMA (n=120) or RIC (n=57) performed within 18 months of diagnosis. Median age was 50 (range 24-69) years and 62% were Durie-Salmon Stage III. Tandem autologous followed by allogeneic HSCT (autologous+ allogeneic) recipients (n=105) were more likely to receive NMA conditioning vs. recipients of an upfront allogeneic HSCT (n=72). Majority (98%) received peripheral blood stem cell grafts. Outcomes at a median follow-up of 36 (3 - 98) months are summarized in table 1.Table 1Outcomes:Probability (95 % CI)Acute GVHD (aGVHD) @ 100 days, grades (I-IV)42 (35 – 49)%Chronic GVHD (cGVHD) @ 3 years55 (47 – 64)%TRM @ 3 years21 (15 – 28)%Relapse @ 3 years44 (35 – 53)%Progression-free survival (PFS) @ 3 years, %35 (27 – 44)%Overall Survival (OS) @ 3 years56 (48 – 65)%In order to assess the impact of GVHD on outcomes, Cox proportional hazards regression models were built with GVHD as the main effect treating it as a time dependent covariate (Table 2). Other covariates in the multivariate models included age, sex, performance status, IgG vs. non IgG myeloma, disease status and chemosensitivity, prior lines of chemotherapy, donor-recipient sex match, NMA vs. RIC and year of transplant. AGVHD was associated with an increased risk of TRM. Tandem autologous + allogeneic HSCT was associated with reduced relapse risk (RR= 0.49, p=0.008). AGVHD had no impact on relapse/progression of MM while cGVHD was associated with a reduced risk of relapse (Figure. 1). The protective effect of cGVHD on relapse was significant in the non IgG MM subgroup. AGVHD had no impact on PFS whereas cGVHD was associated with superior PFS and lower risk of treatment failure. Later year of HSCT was also associated with superior PFS. Overall survival was not affected by cGVHD while recipients of tandem autologous + allogeneic HSCT had a higher mortality in the presence of aGVHD (RR=3.60, p= 0.01). After matched sibling allogeneic HSCT for MM, aGVHD is associated with a higher risk of TRM whereas cGVHD decreases the risk of relapse and improves PFS. The effect of cGVHD may vary with the type of MM with greater impact in non IgG MM. Further study to identify subtypes of MM susceptible to an immune mediated graft vs. MM effect is suggested.Table 2:OutcomesRelative risk (95% CI)TRMRelapseTreatment Failure (Inverse of PFS)MortalityAGVHD2.38 (1.16 – 4.88) P=0.011.04 (0.61 – 1.77) P=NS1.25 (0.83 – 1.88) P= NS1.60 (0.98 – 2.62) P=NSCGVHD1.17 (0.50 – 2.78) P=NS0.43 (0.22 – 0.83) P=0.010.60 (0.36 – 1.00) P=0.040.90 (0.52 – 1.57) P= NSCI=confidence interval; P=pvalue: NS=not significant [Display omitted] Disclosures:Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding.

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RI-HCT) for Myelodysplastic Syndrome (MDS) Using Tacrolimus/Sirolimus-Based Gvhd Prophylaxis.

Abstract 2771Poster Board II-747We previously reported an encouraging result with RI-HCT for MDS (Bone Marrow Transplant 2007; 40:843-50) using flugarabine/melphalan conditioning and cyclosporine (CSA)/mycophenolate (MMF) as GVHD prophylaxis. In order to further improve upon the outcome in the RI-HCT setting, we initiated a series of clinical trials at City of Hope National Medical Center designed to evaluate the impact of tacrolimus (FK)/sirolimus (SIRO)-based GVHD prophylaxis. Here we report the combined, updated results from a consecutive case-series of 89 patients with MDS (including AML progressed from MDS) who underwent RI-HCT from 2000 to 2008 and received either CSA/MMF (n =44) or FK/SIRO (n=45)-based GVHD prophylaxis. All patients received fludarabine 125 mg/m2 plus melphalan 140 mg/m2 followed by an allogeneic HCT (peripheral blood: n=83, bone marrow: n=6) from an HLA-identical sibling (SIB: n=35) or unrelated donor (MUD: n=54). Additional ATG was given to 12 patients. For MUD transplants a short course of methotrexate was added to CSA/MMF or FK/SIRO. The median age was 59 years (range: 20-71) and 31 (35%) patients were female, 58 (65%) were male. Diagnoses at transplant were RA (n=21), RARS (n=1), RAEB/RAEBT (n=36), and AML from prior MDS (n=31). Cytogenetic risk was low in 15 (17%), intermediate in 37 (41.5%), high in 37 (41.5%) patients. By IPSS criteria (for MDS only), 2 patients had low, 24 had int-1, 20 had int-2, and 12 had high-risk MDS. Twenty-seven patients had therapy-related MDS including 14 with prior autologous HCT. The median follow-up time for surviving patients was 39 months (range: 24-68) for the CSA/MMF group and 17 months (range: 4-39) for the FK/SIRO group. All but two patients (1 in CSA/MMF, 1 in FK/SIRO) engrafted with the median neutrophil recovery at 15 days (range: 11-55). The baseline patient, disease and transplant characteristics were similar between CSA/MMF and FK/SIRO, except for an increased percentage of therap-related MDS in the CSA/MMF group (43% vs. 18%, p<0.01). The median donor chimerism by STR at day 30 post-transplant was 100% in both groups (p=0.6). FK/SIRO was associated with a significantly reduced one-year non-relapse mortality (NRM) (11.4%) compared with CSA/MMF (36.2%, p=0.01). This improvement in NRM translated into a trend for improved overall survival (81.4% vs. 52.3%, p=0.1) and disease-free survival (72.2% vs. 52.3%, p=0.08) at one year. While we observed no significant difference in acute GVHD grade II-IV between CSA/MMF and FK/SIRO, FK/SIRO was associated with a significant reduction in grade IV GVHD (0% versus 26%, p<0.01) and a trend for III-IV GVHD (31% vs. 55%, p=0.1). There was no significant difference in chronic GVHD between FK/SIRO (60%) and CSA/MMF (56%, p=0.8). In multivariate analysis, the use of FK/SIRO was independently associated with improved NRM after adjusted for donor type, therapy-related MDS, %bone marrow blasts, and HLA match status (Table). In conclusion, FK/SIRO-based GVHD prophylaxis was associated with an improved outcome after RI-HCT for MDS attributable to the reduced risk for severe acute GVHD.Variables for NRMHazard Ratio (95% CI)p-valueDe novo (n=62) Therapy-related (n=27)baseline 0.75 (0.31–1.89)0.55Sibling donor (n=35) Unrelated donor (n=54)baseline 2.17 (0.70–6.74)0.18Bone marrow blasts < or =10% (n=67) Bone marrow blasts >10% (n=22)baseline 2.13 (0.92–4.96)0.08HLA match (sibling donor or 10/10 MUD, n=72)HLA < mismatch MUD (<10/10 match, n=17)baseline 6.26 (2.11–18.55)0.001FK/SIRO (n=45) CSA/MMF (n=44)baseline 6.58 (2.15–20.14)0.001 Disclosures:Off Label Use: cyclosporine, cellcept, tacrolimus, sirolimus, and methotrexate for GVHD prophylaxis.