Replete Bone Marrow Research Articles

Diagnostic performance of automated red cell parameters in predicting bone marrow iron stores.

The aim of the study was to determine the diagnostic performance of novel automated red cell parameters for estimating bone marrow iron stores. The study was a retrospective single-centre study based on data from an automated haematology analyser and results of bone marrow iron staining. Red cell parameters were measured on a Sysmex XN-series haematology analyser. Bone marrow iron stores were assessed semiquantitatively bycytochemical reaction according to Perls. The analysis included 429 bone marrow aspirate smears from 393 patients. Median age of patients was 67 years, 52 % of them were female. The most common indication for bone marrow examination was a plasma cell dyscrasia (n=104; 24 %). Median values of percentage of hypochromic and hyperchromic red blood cells (%HYPO-He, %HYPER-He), reticulocyte haemoglobin equivalent (RET-He) and microcytic red blood cells (MicroR) were statistically significantly different between cases with iron deplete and iron replete bone marrow. In a logistic regression model, ferritin was the best predictor of bone marrow iron stores (AUC=0.891), outperforming RET-He and %HYPER-He (AUC=0.736 and AUC=0.722, respectively). In a combined model, ferritin/MicroR index achieved the highest diagnostic accuracy (AUC=0.915), outperforming sTfR/log ferritin index (AUC=0.855). While single automated red cell parameters did not show improved diagnostic accuracy when compared to traditional iron biomarkers, a novel index ferritin/MicroR has the potential to outperform ferritin and sTfR/log ferritin index for predicting bone marrow iron stores. Further research is needed for interpretation and implementation of novel parameters and indices, especially in the context of unexplained anaemia and myelodysplastic syndromes.

Siremadlin Monotherapy and in Combination with Donor Lymphocyte Infusion for Patients with Acute Myeloid Leukemia Post Allogeneic Stem Cell Transplantation Who Are in Complete Remission but at High Risk for Relapse

Background: Relapse post allogeneic stem cell transplantation (SCT) remains the main cause of treatment failure (~40%) for patients (pts) with acute myeloid leukemia (AML). Many pts who ultimately relapse post SCT do so within the first year post transplant, and earlier relapse is associated with poorer survival. Therapeutics that prevent early relapse for these pts are urgently needed. Early cellular or pharmacologic intervention or maintenance strategies that enhance the graft-versus-leukemia (GvL) effect after SCT are of renewed interest as they have the potential to reduce relapse risk post SCT. Siremadlin (HDM201) is a novel investigational MDM2 inhibitor with single-agent, anti-AML activity. MDM2 inhibitors, including siremadlin, possess potent immunomodulatory effects in murine solid tumor and AML models. MDM2 inhibition has been shown to synergize with the allogeneic immune response, increase the vulnerability of AML cells to allogeneic donor T cells, and promote the cytotoxicity and longevity of allogeneic donor T cells in murine models. As such, the post-SCT setting is ideal for investigating the immunomodulatory effects of MDM2 inhibition on enhancing the GvL effect (Ho et al. Blood. 2022). Here we describe the design of a Phase Ib/II, open-label study of siremadlin as monotherapy and in combination with donor lymphocyte infusion (DLI) in pts with AML post SCT who are in complete remission (CR) but at high risk for relapse based on the presence of pre-SCT risk factors (NCT05447663). Study Design: The trial is not yet recruiting but aims to enroll ~38 adult pts with AML who underwent first SCT and are currently between Day 60-120 post SCT. Prior to a patient's SCT, they must have a risk factor that puts them at high risk for relapse, including AML in first CR with adverse risk genetics per 2017 European LeukemiaNet risk stratification, therapy-related AML, or secondary AML; or AML in second or greater CR. The SCT must be from an 8/8 human leukocyte antigen (HLA) matched related or unrelated donor at HLA-A, -B, -C, -DRB1 loci using unmanipulated/T-cell replete bone marrow or peripheral blood stem cells as a stem cell source. Post SCT, pts must have achieved CR or CR with incomplete hematologic recovery (CRi) with no evidence of hematologic relapse. Exclusion criteria include prior exposure to an MDM inhibitor, active graft-vs-host disease (GvHD), past history of grade ≥III acute GvHD (aGvHD) or moderate/severe chronic GvHD (cGVHD), recipient of SCT from a haploidentical family donor or cord blood transplant, and prior systemic AML-directed treatments given at any time after SCT (including DLI). This study contains 2 parts, Part 1 is a dose confirmation of siremadlin monotherapy and will enroll ~12 pts. Siremadlin will be tested at a maximum of 3 dose levels with a starting dose of 30 mg/d on Days 1-5 of a 28-day cycle, dose level +1 at 40 mg/d and dose level -1 at 20 mg/d. The safety and tolerability of these dose levels will be assessed to determine the siremadlin recommended dose (RD) for Part 2. Pts in Part 1 of the study will receive siremadlin monotherapy for the entire duration of the treatment and will not receive DLI. Subsequently, ~26 pts will be enrolled in Part 2 and proceed through a priming phase with siremadlin monotherapy at the RD, followed by a combination phase of siremadlin + DLI, and subsequently a maintenance phase with siremadlin monotherapy (Figure). Primary safety endpoints of the study are incidence of dose-limiting toxicities (DLTs) in Part 1 and time to DLT in Part 2. The primary efficacy endpoint is the proportion of pts in Part 2 who are alive and maintained CR/CRi without hematologic relapse ≥6 months after the start of study treatment. Secondary endpoints include number of pts in Part 1 who are alive and maintained CR/CRi without hematologic relapse ≥6 months after the start of study treatment at the RD for Part 2, time to first documented hematologic relapse or death, incidence of relapse at 1 year and 2 years post study treatment, safety, GvHD-free/relapse-free survival, incidence of and time to treatment-emergent grade ≥III aGvHD or moderate/severe cGvHD, and pharmacokinetics. Conclusions: This Phase Ib/II study investigates siremadlin monotherapy and siremadlin in combination with DLI in pts with AML in remission but at high risk of relapse post SCT. The study will evaluate the unique immunomodulatory potential of siremadlin to reduce risk of relapse in this population with high unmet need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of Mobilized Peripheral Blood Stem Cells Versus Unmanipulated Bone Marrow Haploidentical Transplantation Using Post-Transplant Cyclophosphamide: A Retrospective Study of SFGM-TC in 176 Patients

IntroductionThe administration of high dose cyclophosphamide post-transplant (HD-Cy) has improved the outcome of patients who receive an unmanipulated haploidentical graft. The modalities described by the group of Baltimore originally associated a non myeloablative conditioning regimen and the use of a T cell replete bone marrow (BM) graft. Nevertheless, mobilized peripheral blood (PB) is increasingly used as it is more convenient. A very recent report from the United States showed a lower rate of graft versus host disease (GVHD) with BM but an increased risk of relapse in leukemic patients, as compared to PB, leading to a similar overall survival (OS). We report the French experience of haploidentical transplantation using HD-Cy and unmanipulated BM or PB, with a particular interest on the contents of the grafts.Patients and methodsOne hundred seventy-six patients with hematologic malignancy received a haploidentical transplant in 21 French centers from May 2012 to December 2015. We compared the outcome of patients who received a BM graft (n=89) with those receiving a PB graft (N=87). Median age at transplant was 44 year-old (2.5-72). One hundred thirteen (64%) patients had myeloid disease, 19 (11%) had acute lymphoblastic leukemia and 44 (25%) had lymphoid neoplasm. Prophylaxis of GVHD consisted in anticalcineurin and mycophenolate in 94% of the cases. All patients received HD-CY post-transplant (100 mg per kg total dose).ResultsThe 2 groups were comparable for age, disease status at transplant, type of conditioning regimen (RIC 71% and 80% for BM and PB respectively; p=0.16), recipient cytomegalovirus (CMV) seropositive status, ABO mismatch. PB recipients were more likely to receive antithymocyte globulin (ATG) (N=19 vs 0) and to have a higher disease risk index (DRI). The number of CD34+ and CD3+ infused cells was higher in PB grafts (median 2.64x106 CD34/Kg and 26 x106 CD3/Kg for BM and 6.03x106 CD34/Kg and 191 x106 CD3/Kg for PB. Median follow up was 281 days (6-1851).In univariate analysis, the rate of patients who recovered neutrophils and platelet (>50G/L) were similar in both groups (91% and 75% vs 96% and 75% for BM vs PB respectively). However, median time to neutrophil engraftment was significantly longer in BM than in PB group (20 days (13-59) vs 18 days (13-45) respectively, p=0.004). Median time to platelet recovery was not significantly different (30 days (17-250) vs 24 days (13-52) in BM and PB, p=0.14). Patients who recovered neutrophils received a graft which contained more CD3+ cells than patients who did not (p=0.007).At one year, OS, progression free survival (PFS) and relapse were similar in the 2 groups (OS = 64% vs 53% (p=0.1), PFS= 53% vs 46 % (p=0.17) and relapse rate 28% vs 34% (p=0.19) in BM and PB respectively). Acute GVHD II-IV or III-IV and chronic GVHD were similar in both groups (aGVHD II-IV= 18% vs 28% (p=0.09) and aGVHD III-IV = 7% vs 9% (p=0.48), cGVHD=13% vs 15% (p=0.6) in BM and PB respectively), resulting in a similar GVHD-free relapse-free survival (GRFS) at 1 year (48% vs 37% (p=0.09)). Interestingly, the number of infused CD3+ cells/Kg impacted the incidence of acute GVHD II-IV (p=0.049).High DRI and the lack of complete remission at transplant had a significant pejorative effect on OS, PFS, relapse, GRFS and platelet recovery. CMV seropositive recipients had a worse GRFS (p=0.045).ConclusionIn this retrospective study the use of PB instead of BM does not significantly impact the outcome of patients who received a haploidentical unmanipulated graft for a malignant disease with HD-CY. PB graft contained more CD3+ and CD34+ cells than BM and were associated with a faster neutrophils recovery. A higher number of CD3+ cells increased the risk of acute GVHD II-IV in univariate analysis, without significant effect on GRFS. Prospective randomized studies are needed to evaluate the effect of PB vs BM in haploidentical settings. DisclosuresPeffault De Latour:Pfizer: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders

Graft failure requires urgent salvage HSCT, but there is no universally accepted approach for this situation. We investigated T-cell replete haploidentical HSCT with post-transplantation cyclophosphamide following serotherapy-based, radiation-free, reduced intensity conditioning in children with non-malignant disorders who had rejected their primary graft. Twelve patients with primary or secondary graft failure received T-cell replete bone marrow grafts from haploidentical donors and post-transplantation cyclophosphamide. The recommended conditioning regimen comprised rituximab 375 mg/m2, alemtuzumab 0.4 mg/kg, fludarabine 150 mg/m2, treosulfan 20–24 g/m2 and cyclophosphamide 29 mg/kg. After a median follow-up of 26 months (7–95), eleven of twelve patients (92%) are alive and well with complete donor chimerism in ten. Neutrophil and platelet engraftment were observed in all patients after a median of 18 days (15–61) and 39 days (15–191), respectively. Acute GVHD grade I was observed in 1/12 patients (8%) and mild chronic GVHD in 1/12 patients (8%). Viral reactivations and disease were frequent complications at 75% and 42%, respectively, but no death from infectious causes occurred. In summary, this retrospective analysis demonstrates that a post-transplantation cyclophosphamide-based HLA-haploidentical salvage HSCT after irradiation-free conditioning results in excellent engraftment and overall survival in children with non-malignant diseases.

Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis

BackgroundSome patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.Case reportA girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.ConclusionAllogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.

Haploidentical BMT Using Fully Myeloablative Conditioning, T Cell Replete Bone Marrow Grafts, and Post-Transplant Cyclophosphamide (PT/Cy) Has Limited Toxicity and Promising Efficacy in the First Prospective Multicenter Trial for Pediatric, Adolescent, and Young Adult Patients with High Risk Acute Leukemias and Myelodysplastic Syndrome

Promising results have been reported for patients with high-risk hematologic malignancies undergoing T-cell-replete myeloablative bone marrow transplant (BMT) from HLA-haploidentical donors with post-transplantation cyclophosphamide (PT/Cy). Here, we report results from the first prospective multicenter pilot trial in the Pediatric Blood and Marrow Transplant Consortium (PBMTC) for pediatric, adolescent, and young adult patients with high risk acute leukemias and myelodysplastic syndrome (MDS) in the US and Canada. Nine centers transplanted 32 patients with acute leukemias or MDS in complete remission (CR) who received myeloablative conditioning consisting of IV Busulfan (pharmacokinetically adjusted) and Cyclophosphamide (Cy, 50 mg/kg/day) days –2 and –1 except for patients with acute lymphocytic leukemia who received Cy (50 mg/kg/day x 2) and total body irradiation (1200cGy). T-cell-replete bone marrow from haploidentical related donors was used for all patients. Postgrafting immunosuppression consisted of Cy (50 mg/kg/day) days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 90-180 days. Median age of patients was 12y (range, 1-23) and donors was 35y (range, 4-53). Diagnoses included AML (CR1 = 7, CR2 = 6), ALL (CR1 = 8, CR2 = 5), mixed lineage leukemia (1), and MDS (5). One patient had received a prior BMT. Donor engraftment occurred in 27/32 (84%). Primary graft failures included 3 patients with MDS and 2 with AML (CR1 = 1, CR2 = 1); three of these patients had received suboptimal bone marrow grafts (TNC/kg ≤2e8) and all successfully engrafted after second transplants. Median time to neutrophils >500/μL was 22 days and platelets >20,000/μL was 21 days. Transplant related mortality (TRM) at 180 days, our primary objective, was 0%. Cumulative incidence of acute GVHD grades II-IV at Day 100 was 13%. No patients developed severe acute GVHD grades III-IV. The cumulative incidence of mod-severe chronic GVHD at 1 year was 4%. The cumulative incidence of relapse at 1y was 32%. With a median follow-up of surviving patients of 477 days (range, 180-1127), actuarial overall survival is 77% at 1y. With a median follow-up of event-free patients of 451 days (180-1127), actuarial event-free survival is 68% at 1y. For this first reported multicenter pediatric myeloablative HLA-haploidentical HSCT for high-risk leukemias and MDS with T-cell replete bone marrow and PT/Cy, we have demonstrated a 0% TRM, low cumulative incidences of acute and chronic GVHD, and favorable rates of relapse and survival. Further investigation as to potential reasons for graft failure and consideration of any changes needed to ensure engraftment for certain disease groups are underway. A larger trial comparing haploidentical BMT with other alternative donor sources is in development.

Successful Allogeneic Hematopoietic Cell Transplantation (HCT) with Low Toxicity and Gvhd in a Heterogeneous Cohort of Primary Immunodeficiency (PID) Patients

HCT has been used for decades as a definitive therapy for patients with PIDs. These patients often enter HCT with significant comorbidities and disease sequelae and may have limited donor options if family members are also affected, so the ability to offer HCT to all who require it remains suboptimal. Twenty-nine children and adults with various underlying PIDs received a serotherapy-free, radiation-free reduced intensity conditioning platform designed with the goals of optimizing immune reconstitution, minimizing complications such as graft-versus-host disease (GVHD), and permitting use of alternative donors. Conditioning consisted of pentostatin, low-dose cyclophosphamide and 2 days of busulfan, and GVHD prophylaxis included post-transplantation cyclophosphamide, mycophenolate mofetil, and sirolimus. All received T cell replete bone marrow or peripheral blood stem cell allografts. Patient and donor characteristics are shown in Fig 1a. Neutrophil recovery occurred at median day +17 (range 14-42). With median follow-up of 14 months (range 3-33), graft-failure-free, steroid-refractory grade 3-4 GVHD-free survival was estimated at 82% at 1 year (Fig 2). Two deaths occurred in patients with HCT-CI scores of 6 (bacterial sepsis and invasive Aspergillosis, day +44) and 8 (presumed viral encephalitis, day +110). There were 3 graft failures (1 primary, with autologous recovery on day +14 and 2 secondary on day +34 and +159). Two patients were successfully retransplanted with eventual full donor chimerism, while the third's infection was sufficiently temporized by the first transplant to make an immediate retransplant not necessary. The kinetics of donor chimerism differed between myeloid and lymphoid compartments. Most patients had complete donor myeloid chimerism by day +28 but a slower rise in donor CD3 chimerism (median 77% at day +28 to 94% at day +60) (Fig 3). GVHD rates have been low, with cumulative incidence of steroid-responsive grade 2-4 acute GVHD at 1 year of 14% (death and graft failure as competing risks) and no chronic GVHD to date. HCT-related outcomes and complications are listed in Fig 1b. Of note, BK-associated hemorrhagic cystitis occurred at high rates, but serious viral complications were infrequent. Some degree of phenotype reversal is evident in all evaluable patients. All 10 patients with lymphoma or lymphoproliferative disorder are in remission, and, of 24 engrafted survivors, only two continue to require immunoglobulin replacement beyond 6 months post-HCT. Future directions include reducing the duration of post-HCT immunosuppression to hasten improved viral control and increasing pre-HCT lymphodepletion for selected patients at high risk for graft failure. Continued long term follow up is needed to better characterize phenotype reversal, graft durability, immune reconstitution and late toxicities of the platform.

Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide

AbstractThe intensive and prolonged immunosuppressive therapy required to prevent or treat graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT) puts patients at substantial risk for life-threatening infections, organ toxicity, and disease relapse. Posttransplantation cyclophosphamide (PTCy) can function as single-agent GVHD prophylaxis after myeloablative, HLA-matched related (MRD), or HLA-matched unrelated (MUD) donor T-cell–replete bone marrow allografting, obviating the need for additional prophylactic immunosuppression. However, patients who develop GVHD require supplemental treatment. We assessed the longitudinal requirement for immunosuppressive therapy in 339 patients treated with this transplantation platform: 247 receiving busulfan/cyclophosphamide (BuCy) conditioning (data collected retrospectively) and 92 receiving busulfan/fludarabine (BuFlu) conditioning (data collected prospectively). Approximately 50% of MRD patients and 30% of MUD patients never required immunosuppression beyond PTCy. In patients requiring further immunosuppression, typically only 1 to 2 agents were required, and the median durations of systemic pharmacologic immunosuppression for the BuCy MRD, BuFlu MRD, BuCy MUD, and BuFlu MUD groups all were 4.5 to 5 months. For these 4 groups, 1-year probabilities of being alive and off all systemic immunosuppression were 61%, 53%, 53%, and 51% and 3-year probabilities were 53%, 48%, 49%, and 56%, respectively. These data suggest that PTCy minimizes the global immunosuppressive burden experienced by patients undergoing HLA-matched alloBMT.

Prospective study of nonmyeloablative, HLA-mismatched unrelated BMT with high-dose posttransplantation cyclophosphamide

AbstractAllogeneic blood or marrow transplantation (BMT) candidates may lack HLA-matched, related haploidentical, and unrelated umbilical cord options. Barriers to partially HLA-mismatched, unrelated donor (mMUD) BMT include excess graft-versus-host disease (GVHD), graft failure, and death. We prospectively studied nonmyeloablative (NMA) mMUD BMT with high-dose posttransplantation cyclophosphamide (PTCy) for patients with hematologic malignancies. Three transplants were performed with busulfan/fludarabine conditioning, with subsequent change to fludarabine/Cy/total body irradiation (flu/Cy/TBI). Twenty mMUD transplants are reported using flu/Cy/TBI, T-cell replete bone marrow grafts, and PTCy, mycophenolate mofetil, and sirolimus or tacrolimus (1 patient) for GVHD prophylaxis. The median patient age was 56. Of these unrelated grafts, 45% had ≥2 mismatched HLA loci, 25% had ≥3 mismatched loci, and 50% had HLA-C mismatches. No graft failure or grades 3-4 acute GVHD occurred. The median times to neutrophil recovery (≥500/µL) and platelet recovery (≥20 000/µL) were 19 days and 31 days, respectively. Full-donor chimerism was achieved in 95% of evaluable patients by day 60. The 180-day probability of grades 2-4 acute GVHD (all grade 2) was 25%, and the 1-year probability of any chronic GVHD was 16% (none severe). The 2-year nonrelapse mortality probability was 6%. With 4-year median follow-up, the 1-year progression-free and overall survival probabilities were 65% and 75%, respectively. NMA, T-cell replete mMUD BMT is thus a potentially viable option for patients without other suitable donors. This trial was registered at www.clinicaltrials.gov as #NCT01203722.

Shortened-Duration Tacrolimus after Nonmyeloablative HLA-Haploidentical (NMA haplo) BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Facilitates Strategies for Relapse Reduction

▪Background: With PTCy as GVHD prophylaxis, outcomes of NMA haplo and matched BMT are similar, and relapse rather than toxicity is the leading cause of treatment failure. Early discontinuation of IS may augment a graft-versus-tumor effect and permit early implementation of strategies to reduce relapse, but may increase GVHD. We present a completed, prospective single-center trial of stopping tacrolimus (tacro) 3 or 4 months earlier than our Day (D) 180 standard after NMA haplo BMT (ClinicalTrials.gov: NCT01342289). Methods: From 8/2011-11/2015,105 evaluable patients (pts) with hematologic malignancies received NMA haplo BMT on this trial. The primary objective was to evaluate the feasibility and safety of reduced-duration tacro, stopping tacro without taper before D 180.Transplant criteria included age ≤ 75, ECOG PS ≤ 2, LVEF ≥ 35%, FEV1 and FVC ≥ 40% predicted, transaminases < 5 x ULN and no prior allogeneic BMT. All received Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete bone marrow. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and tacro from D 5. Pretransplantation, pts were assigned to stop tacro early if eligible, contingent on having ≥ 5% donor T cells at ~D 56 onward, no relapse and no grade 2-4 acute or significant chronic GVHD. Tacro was first planned through D 90 (n=47), then through D 60 (n=55). A D 120 cohort (n=3) enrolled while D 90 safety data were maturing. For pts ineligible for planned early tacro cessation, IS was individualized and continued to at least D 180. Monitoring rules declared reduced IS feasible if ≥ 33% of pts stopped tacro early as planned. Safety stopping rules for early tacro cessation were based on ≥ 65% probability of a ≥ 20% incidence of grade 3-4 acute plus severe chronic GVHD, ≥ 10% nonrelapse mortality (NRM) or ≥ 5% graft failure, measured from the tacro stop date to ~D 180. Historical data from 212 haplo transplants at our center using the same regimen but tacro until D 180 informed safety risk calculations. Results: Of the 105 pts (median age 61, range 13-74), the most common diagnoses were acute leukemia (50%), MDS (17%), NHL (16%) and HL (8%). By refined Disease Risk Index, 11% were low risk, 70% intermediate and 19% high. Shortened IS was feasible in 63 pts (60%) overall. Ineligibility for shortened IS was due most commonly to GVHD, followed by low donor chimerism or graft failure and early relapse. Of the 47 pts in the D 90 cohort (median follow-up 44 months), 23 (49%) stopped tacro early as planned. Safety stopping criteria were not met. Of these 23 pts, 16 (70%) had no safety events before D 180, 5 (22%) developed grade 2 acute GVHD (1 complicated by severe chronic GVHD) and 2 (9%) developed grade 3-4 acute GVHD. Of the 55 pts in the D 60 cohort (median follow-up 14 months), 38 (69%) stopped tacro early as planned, and safety stopping criteria were likewise not met. Of these 38 pts, 25 (66%) had no safety events before D 180, 1 developed graft failure, 9 (24%) developed grade 2 acute GVHD and 3 (8%) developed grade 3-4 acute GVHD. GVHD outcomes by cohort relative to historical outcomes are shown in Figures A and B. In both cohorts, the D 180 CuI of grade 2-4 acute GVHD was < 40% and was < 10% for grade 3-4 acute GVHD and NRM. The 1-year CuI of any chronic GVHD was 11% for the D 90 arm and 13% for the D 60 arm (12% historically). The 1-year probabilities of PFS, OS and GVHD-free relapse-free survival (GRFS, Figure C) were 40%, 59% and 27% respectively for the D 90 arm and 63%, 77% and 53% respectively for the D 60 arm. Conclusion: These data suggest that reduced-duration tacro is feasible and carries an acceptable safety profile in pts receiving NMA haplo BMT with PTCy. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with tacro until D 180. A larger prospective study is needed to define the optimal duration of IS that balances GVHD risk and relapse risk. However, these data show that many pts (60% in this trial) can discontinue tacro without taper well before D 180. There is even a suggestion of improved PFS and GRFS in the D 60 arm compared to the D 90 arm, although the trial was not powered for these endpoints. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early tacro cessation, provides an ideal setting to incorporate novel posttransplantation approaches for relapse reduction. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Nonmyeloablative (NMA), HLA-Mismatched Unrelated Donor (mMUD) BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Has Outcomes Similar to Matched BMT

Background: The results of NMA, related HLA-haploidentical (haplo) BMT with PTCy are comparable to matched BMT (Blood 2015;125;3024). However, patients (pts) may lack related donors, often because of familial disease susceptibility or cytotoxic antibodies against donor HLA molecules. Although partially HLA-mMUD BMT could be considered if a MUD is unavailable, mismatches > 1 HLA antigen have historically been associated with unacceptable rates of GVHD, graft failure, and nonrelapse mortality (NRM). We hypothesized that PTCy may overcome this HLA barrier.Methods: We developed a prospective, regimen-finding study of NMA BMT for hematologic malignancies pts without an acceptable matched or first-degree related haplo donor. The objective was to identify a regimen with ≤ 25% severe acute GVHD and ≤ 20% NRM by day 100, using mMUD's or non-first-degree relatives. Results of mMUD BMT with our standard conditioning are presented. Pt eligibility included age 0.5-75 years, no suitable family donor, ECOG PS ≤ 2, LVEF ≥ 35%, FEV1 and FVC ≥ 40% predicted, and adequate hepatic function. The mismatched donor shared ≥ 5/10 HLA alleles (based on molecular typing of HLA-A, -B, -Cw, -DRB1, and -DQB1) with ≥ 1 allele matched for a HLA class I gene and ≥ 1 allele matched for a class II gene. Donors matched at ≥ 1 allele at each locus were prioritized, followed by donors having the fewest number of mismatched loci. All pts received fludarabine (30 mg/m2 IV days -6 to -2), Cy (14.5 mg/kg IV days -6 and -5), TBI (200 cGy day -1) and T-cell replete bone marrow. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV days 3 and 4), mycophenolate mofetil on days 5-35, and either sirolimus (15 pts) or tacrolimus (1 pt) on days 5-180. GCSF was given from day 5 until neutrophil recovery. Safety was continuously monitored.Results: Sixteen pts (median age 57, range 37-66) received mMUD BMT on this study from 7/2011-6/2014 (9 AML cases, 4 MDS or MPN, 1 CML, 2 PTCL). Major reasons for utilizing a mMUD included the absence of an adult haplo first-degree relative and the presence of prohibitive donor-specific anti-HLA antibodies (DSA's). The unrelated grafts had a median of 2 HLA mismatches and included three 7/10 matches, one 6/10 match, and one 5/10 match. HLA-C mismatch was present in 10 grafts (63%) and complete DP mismatch in 6 (38%).By revised Disease Risk Index, 25% of pts were high risk, 69% intermediate risk, and 6% low risk; 69% were in CR at BMT. The median graft doses were 3.36 x 108 total nucleated cells/kg and 3.87 x 107 CD3+ cells/kg. All pts engrafted, and there were no non-relapse deaths or prohibitive toxicities. By competing-risk analysis, the estimated cumulative incidence (CuI) of neutrophil recovery was 100% by day 29, with a median of 20 (range 14-29) days. The CuI of platelet recovery ≥ 20,000/µL was 100% by day 46, with a median of 32 (range 12-46) days. By day 60, 14/15 (93%) evaluable pts achieved full donor chimerism in either CD3+ or unsorted cells. Notably, there were no cases of acute grade 3-4 GVHD. Acute grade ≥ 2 GVHD was limited to 2 cases of skin-only grade 2 GVHD and 1 case of grade 2 skin and ungradable visceral GVHD. By competing-risk analysis, the estimated CuI of acute grade 2 GVHD was 12% at day 100 (90% CI, 0-27%) and 19% at day 180 (90% CI, 2-37%)(Fig A). The CuI of any chronic GVHD at 1 and 2 years was 7% (90% CI, 0-18%)(Fig A). Critical illness prior to relapse was limited to 1 case of sepsis which resolved. With a 3-year median follow-up, the probability of PFS was 56% at 1 year and 50% at 3 years (Fig B). The estimated CuI of relapse was 44% at 1 year. Median OS has not been reached, with an estimated 1 year and 3 year OS of 68% (Fig B).Conclusion: These results suggest that virtually no pt should be denied allogeneic BMT because of lack of an HLA-matched or haplo donor. mMUD searches were successful in pts with DSA's that were too high for desensitization. [Display omitted] DisclosuresOff Label Use: posttransplantation cyclophosphamide for GVHD prophylaxis.

Haploidentical BMT Using Fully Myeloablative Conditioning, T Cell Replete Bone Marrow Grafts, and Post-Transplant Cyclophosphamide (PT/Cy) Has Limited Toxicity and Promising Efficacy in Largest Reported Experience with High Risk Hematologic Malignancies

Haploidentical BMT Using Fully Myeloablative Conditioning, T Cell Replete Bone Marrow Grafts, and Post-Transplant Cyclophosphamide (PT/Cy) Has Limited Toxicity and Promising Efficacy in Largest Reported Experience with High Risk Hematologic Malignancies

Transplant Outcomes of 9/10 HLA Matched Unrelated Donors (MUD) Treated with Post-Transplant Cyclophosphamide for Prevention of Graft Versus Host Disease

Background:Graft-versus-host disease (GVHD) is a major complication of allogeneic stem cell transplantation (ASCT). The incidence of GVHD with conventional GVHD prevention is higher with HLA mismatched compared to matched donors, with 69% of patients (pts) developing grade 2-4 and 16% grade 3-4 acute (aGVHD) and more than half the pts developing chronic (cGVHD), as previously reported by us(Ciurea SO abstract ASH 2010). Here we report preliminary results of 9/10 MUD transplant pts receiving GVHD prophylaxis with post-transplantation cyclophosphamide (PTCY), in addition to tacrolimus and mycophanolate mofetil (MMF).Methods:Patients were treated prospectively using a 9/10 MUD on a separate arm of a phase II clinical trial (2009-0266). Conditioning regimen consisted of Melphalan 140 mg/m2 on day −8 (100mg/m2 for pts ≥55 years or with comorbidities), Thiotepa 5-10 mg/kg on day −7 and Fludarabine 40 mg/m2/day on days −6, −5, −4, and −3. All patients received T-cell replete bone marrow graft. GVHD prophylaxis included PTCY 50mg/kg on days +3 and +4, MMF was given until day 100 and Tacrolimus until day 180 if no GVHD. Primary objectives were to determine the incidence of acute and chronic GVHD and non-relapse mortality (NRM), while secondary objectives included progression free survival (PFS) and overall survival (OS).Results:39 patients with median age of 50 years (range 20-64) received a 9/10 MUD with PTCY GVHD prophylaxis. 20 patients (51%) were women and AML/MDS was the most common indication for transplantation in 13(33%), NHL 8(21%), ALL 7(18%), AA in 4(10%) and CLL, CML/MPD, HL and MM constituted rest of the patients. Poor, intermediate and low risk cytogenetics were seen in 6, 8 and 4 patients with leukemia, respectively. 22 patients (56%) were not in complete remission at the time of transplantation. Median follow-up time for survivors was 35.9 months (range: 2.6–123.5). All patients engrafted the donor cells. Day 100 NRM for all pts was 18%.The cumulative incidence (CI) of grade II-IV aGVHD and gr III-IV aGVHD was 42% and 17%, respectively. CI of all cGVHD was only 20% and extensive only cGVHD was 13%. NRM for all pts was 36% at 1 year and 40% at 3 years. OS for all pts at 1 and 3 yr was 57% and 44%, while PFS at 1 and 3 yr was 43% and 39%, respectively.Conclusions:Post-transplant cyclophosphamide for prevention of GVHD which has been successfully used in haploidentical transplantation, resulted in a modest improvement in the rates of grade 2-3 and 3-4 acute GVHD compared to reports of standard GVHD prophylaxis for 9/10 MUD transplants. However, a promising low rate of chronic GVHD was observed. This approach can produce durable remissions for patients with hematologic malignancies who lack an HLA matched donor. [Display omitted] DisclosuresAndersson:Otsuka Pharmeceuticals: Research Funding, Research funding from Otsuka Pharmeceuticals Other.

Nonmyeloablative HLA-Haploidentical (NMA Haplo) BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Is Associated with Similar Outcomes to Matched BMT When Stratified By Disease Risk Index (DRI)

Background: Recent advances in NMA haplo BMT, including high-dose PTCy for GVHD prophylaxis, have expanded potentially curative treatment options for patients (pts) without a matched donor. The DRI (Blood 2012;120:905), based on disease type and status, was developed to stratify pt risk across histologies and conditioning regimens. The current study evaluated the newly refined DRI (Blood 2014;123:3664) in the largest series of NMA haplo BMT to date.Methods: We retrospectively analyzed the outcomes of 374 consecutive adult hematologic malignancy pts who received NMA related haplo BMT with PTCy at Johns Hopkins. Eligibility included ECOG PS ≤ 2, LVEF ≥ 35%, adequate pulmonary and renal function and absence of uncontrolled infection. All pts received fludarabine (30 mg/m2IV D -6 to -2), Cy (14.5 mg/kg IV D -6 and -5), TBI (200 cGy D -1) and T-cell replete bone marrow. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil and tacrolimus. Maintenance therapy (e.g., imatinib) after engraftment was permitted. The median age was 55 (range 18-75) at BMT, 132 (35%) pts were aged ≥ 60 and 71 (19%) had prior autologous BMT. Diagnoses were acute leukemia or lymphoblastic lymphoma (115 pts; 31%), MDS or MPN (36 pts; 10%), aggressive NHL (95 pts; 25%), Hodgkin lymphoma (36 pts; 10%), mantle cell lymphoma (29 pts; 8%) and indolent lymphoid cancers (63 pts; 17%). By the new DRI, disease risk was low in 72 pts (19%), intermediate (int) in 242 (65%), high in 50 (13%) and very (v) high in 10 (3%).Overall results: With a median follow-up of 3.4 (range 0.5-11.4) years (y) in surviving pts, 3-y probabilities of PFS and OS were 40 (95% CI 35-45)% and 50 (45-56)%, respectively. The probability of neutrophil recovery was 89% by D30 (median 17 d). By competing-risk analyses, the D180 probability of nonrelapse mortality (NRM) was 8 (95% CI 5-10)%, grade 2-4 acute GVHD was 32 (27-37)%, and grade 3-4 acute GVHD was 4 (2-6)%. The 2-y probability of chronic GVHD was 13 (10-17)%.Results by DRI: Among the 3 DRI risk groups (low, int, high/v high), there were no statistically significant differences in histology (lymphoid vs myeloid), HCT-CI risk category, median CD34+ graft dose or pt CMV serostatus. Median pt age was greater in the higher risk groups (P = 0.01). On unadjusted analyses of the new DRI, the probability of relapse by competing-risk differed clearly between the groups (P < 0.0001; Fig. A), with no statistically significant difference in NRM (P = 0.53). This was coupled with statistically significant differences in both PFS and OS. In low, int and high/v high risk groups, 3-y PFS estimates were 64%, 37% and 22%, respectively (P < 0.0001; Fig. B), and 3-y OS estimates were 69%, 49% and 34% (P = 0.0001). Furthermore, on multivariate analyses adjusted for age and year of BMT, the new DRI was independently associated with overall outcomes. Compared to low-risk pts, the HR for relapse was 3.0 (95% CI 1.8-5.2) for int risk pts (P = 0.0001) and 4.7 (2.6-8.5) for high/ v high risk pts (P < 0.0001). HRs for both PFS and OS were ≥ 2-fold greater for int and high/v high risk pts compared to low risk pts (each P ≤ 0.0002). On multivariate analyses, the original DRI (13% low risk, 68% int, 19% high/v high) was also independently associated with relapse, PFS and OS (each P ≤ 0.003). When stratified by DRI, survival outcomes with reduced-intensity, matched related or unrelated BMT (based on 614 pts from the original DRI study cohort; personal communication, P. Armand) and haplo BMT with PTCy appeared similar (Table).Conclusion: The DRI appears to effectively stratify and prognosticate pts undergoing NMA haplo BMT. When stratified by DRI, the efficacy and survival outcomes with NMA haplo BMT with PTCy appear comparable to those reported with matched BMT. Within this transplant platform, the results support the use of the DRI in outcome analyses and randomized clinical trials involving heterogeneous groups of pts. [Display omitted] TableSurvival Estimates by DRI3-y PFS (%)3-y OS (%)Original DRIMatchedHaploMatchedHaploLow66637071Intermediate31394749High / very high15252538 [Display omitted] DisclosuresOff Label Use: High-dose posttransplantation cyclophosphamide.

Graft-Versus-Host Disease (GVHD) and Survival Outcomes after HLA-Haploidentical (Haplo) Bone Marrow Transplant (BMT) Compare Favorably with Matched Related Donor (MRD), and Matched Unrelated Donor (MUD) BMT Utilizing High-Dose Posttransplantation Cyclophosphamide (PTCy)

Background: High-dose PTCy has been shown to effectively reduce acute (a) and chronic (c) GVHD after MRD and MUD BMT and to enable the safe implementation of haplo BMT. However, GVHD-related risk factors and survival outcomes, the impact of donor type, and novel composite endpoints, such as cGVHD-free relapse-free survival (cGFRFS), have not been fully characterized in BMT with PTCy.Methods: We retrospectively analyzed 582 consecutive adult pts with advanced or poor-risk hematologic malignancies who received allogeneic BMT with PTCy at Johns Hopkins from 2002-2012. All pts received a T-cell replete bone marrow graft and PTCy (50 mg/kg/d IV) on D+3 and +4. Platforms consisted of: 1) myeloablative conditioning (MAC) with Busulfan/Fludarabine or Busulfan/Cy followed by MRD (n = 193; 33%) or MUD (n=119; 20%) allografting and PTCy as sole GVHD prophylaxis; or 2) nonmyeloablative (NMA) conditioning with Fludarabine/Cy/TBI followed by related haplo (n = 270; 46%) allografting and PTCy, mycophenolate mofetil D5-35, and tacrolimus D5-180.Results: The median follow up was 4 (range 0.3-11.4) years (y). The median pt age at time of BMT was 49 (range 18-66) in the MAC cohort and 54 (range 18-73) in the NMA cohort. On competing risk analysis, the D200 probability of grade II-IV aGVHD was 27% after haplo, 37% after MRD, and 50% after MUD BMT, and grade III-IV aGVHD was 4%, 11%, and 14% respectively. The 3-y probability of cGVHD was 12% after haplo, 8% after MRD, and 19% after MUD BMT. On multivariate analysis adjusted for age and original disease risk index (DRI), MRD and MUD BMT were associated with a statistically significantly higher risk of grade II-IV and grade III-IV aGVHD compared to haplo BMT (each p ≤ 0.001). Compared to haplo BMT, MUD, but not MRD, BMT was also associated with a significantly higher risk of cGVHD (p = 0.009). On multivariate analysis, female into male allografting was independently associated with a higher risk of cGVHD (p = 0.007), whereas age and CMV serostatus of the pt and donor were not statistically significantly associated with risks of acute or chronic GVHD. Pts with grade II-IV aGVHD or cGVHD had a lower probability of relapse, but a higher probability of nonrelapse mortality (NRM) at 3 y compared to pts without GVHD. Among pts with GVHD, an HCT-CI score ≥ 5 was associated with significantly inferior overall survival compared to lower HCT-CI scores. Although MAC matched BMT was associated with less relapse risk than NMA haplo BMT, the 3-y probabilities of NRM, DFS, and overall survival were comparable between the transplant platforms (Table). On multivariate analysis adjusted for pt age and DRI, there were no statistically significant differences in DFS, OS, or cGFRFS in MAC related or unrelated BMT compared to NMA haplo BMT.Conclusions: High-dose PTCy safely modulates acute and chronic GVHD across multiple BMT platforms. The apparently lower risk of aGVHD after NMA haplo BMT with PTCy likely reflects the reduced conditioning intensity and longer duration of immunosuppression utilized. Despite the limitations inherent to a retrospective analysis, these data suggest that key outcomes after BMT with PTCy are comparable across donor types and conditioning intensities. Notably, in all these settings, 3-y estimates of cGFRFS appeared to approach those of DFS. Thus, PTCy may minimize the late morbidity and mortality of cGVHD and allow earlier implementation of novel posttransplantation strategies for relapse prevention. TableOutcomes of BMT with PTCy3-y probabilitiesNMA HaploMAC MRD*MAC MUD*NRM141717DFS384144OS495856cGFRFS313533* p = NS for all comparisons to haplo BMT on multivariate analysis DisclosuresOff Label Use: High-dose posttransplantation cyclophosphamide.

HLA-Haploidentical Donor Lymphocyte Infusions for Patients with Relapsed Hematologic Malignancies after Related HLA-Haploidentical Bone Marrow Transplantation

Treatment of relapse after related HLA-haploidentical T cell–replete bone marrow transplantation (haploBMT) with post-transplantation cyclophosphamide (PTCy) using haploidentical donor lymphocyte infusion (haploDLI) is not documented. All patients who received haploDLI after haploBMT with PTCy between June 2003 and October 2012 were identified and assessed for graft-versus-host disease (GVHD) and outcomes. Forty patients received 52 haploDLI doses. Sixteen patients had acute myeloid leukemia, 11 had lymphomas, and 34 had nonmyeloablative conditioning before haploBMT. The median time from haploBMT to relapse was 183 (range, 0 to 1399) days. The median age at haploDLI was 48 (range, 3 to 70) years. The first haploDLI doses were 1 × 105 CD3+ cells/kg with subsequent escalation. The most commonly used first haploDLI dose was 1 × 106 CD3+ cells/kg. The median follow-up after haploDLI was 7 (mean, 15.4; range, .5 to 96) months for the entire cohort, and 17.5 (mean, 28; range, 2.4 to 96) months for the responders. Acute GVHD developed in 10 patients (25%), 6 patients had grade 3 to 4, and 3 developed chronic GVHD. Twelve (30%) patients achieved a complete response (CR) with a median duration of 11.8 (mean, 22.5; range, .4 to 94) months. At last follow-up, 8 responders were alive in CR; 6 for over a year. HaploDLI for relapse after haploBMT is associated with acceptable toxicities and can result in durable responses.

HLA Haplo-Identical Peripheral Blood Stem Cell Transplantation Using High-Dose Cyclophosphamide Post-Transplantation For Poor Prognosis Or Refractory Acute Leukemia and Myelodysplastic Syndrome: A Prospective Pilot Study At a Single Center

Recently nonmyeloablative, haplo-identical T-cell replete bone marrow transplantation using high-dose cyclophosphamide (CY) post-BMT to control GVHD and prevent graft rejection by inducing bi-directional tolerance was reported. This strategy resulted in promising outcomes with low transplantation-related mortality (TRM) due to a low incidence of GVHD and infectious disease. However, the high relapse rate remained a major problem in high-risk hematological disease. We therefore planned a prospective pilot study of myeloablative or reduced intensity HLA haplo-identical allogeneic hematopoietic cell transplantation (HCT) using reduced doses of CY post-transplantation, followed by administration of peripheral blood stem cells (PBSC) instead of bone marrow, for those with a poor-prognosis or refractory leukemia and MDS.As of 30 June 2013, 17 patients had been enrolled in this prospective pilot study. Patients with a poor prognosis or refractory leukemia and MDS requiring prompt HCT were eligible for this study if they lacked a donor who was serologically HLA-identical or had a single antigen mismatch.The conditioning regimen consisted of fludarabine 15 mg/m2 and cytarabine 2.0 g/ m2 twice a day on days -11 and -10, thymoglobulin 2.0 mg/kg on days -8 and -7, and fludarabine 30 mg/ m2/day with intravenous busulfan 3.2 mg/kg/day on days -6 to -3 (n=11) or melphalan 100 mg (n=6) on day -2. Nine patients received a single dose of 25 mg/kg CY on day 3 and eight patients, double doses of 25 mg/kg CY on days 3 and 4 post-peripheral blood stem cell transplantation (PBSCT). Tacrolimus and oral mycophenolate mofetil was started after the completion of high-dose CY post-HCT.The median age of patients was 42 years (range 18–65). Disease diagnoses included AML (n=14), ALL (n=2) and MDS (n=1). In 12 (71%) of 17 patients, disease status was non-remission, with active disease at the time of PBSCT. Eight (47%) of 17 patients had a history of prior HCT. Donors were partially HLA-mismatched (haplo-identical) first degree relatives of the patients and differed from the patients at a median of 3/8 HLA loci in both the HVG and GVH directions. All patients received G-CSF-mobilized, unmanipulated PBSC containing a median of 3.0 x 106 CD34+cells/kg and 1.4 x 108CD3+T-cells/kg.Non-infectious fever due to PBSC infusion occurred in 14 (82%) patients and persisted until day 2 in most patients. Except for one patient who died soon after PBSCT due to disease progression, full donor T-cell chimerism was achieved at day 30 following PBSCT in all patients. Nine of 17 developed grade II-III acute GVHD. None developed grade IV acute GVHD. Three of nine patients receiving a single dose of CY, but only one of eight patients receiving double doses of CY developed grade III acute GVHD. In 12 of 16 evaluable patients, CMV reactivation was observed by day 100. Three patients developed CMV disease. BK virus cystitis occurred in four of eight patients receiving double doses of CY, however, none receiving a single dose of CY post-PBSCT developed BK virus cystitis. The cumulative incidence of TRM at one year was 13%. At one year, the overall survival of all patients, and the percentages of patients in remission and those with active disease were 43%, 75% and 31%, respectively.The results of our study demonstrated that our HLA haplo-identical transplantation using high-dose CY post-PBSCT resulted in a low incidence of TRM and was feasible even in patients with high-risk acute leukemia and MDS as an alternative stem cell source. Of note, the dose of CY post-PBSCT affected the incidence of both BKV cystitis and severe GVHD. The optimal dose of CY following HLA haplo-identical PBSCT and preparative regimen should be further explored to establish a standard regimen. Disclosures:Nakamae:Otsuka Pharmaceutical Co., Ltd.: Honoraria, Travel/accommodations/meeting expenses, Travel/accommodations/meeting expenses Other; Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses Other. Off Label Use: Mycophenolate mofetil was used as one of drugs for acute GVHD prophylaxis. Koh:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nishimoto:Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nakashima:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nagasaki:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nakane:Otsuka Pharmaceutical Co., Ltd.: Honoraria, Speakers Bureau; Kyowa Hakko Kirin Pharma, Inc.: Speakers Bureau, Travel/accommodations/meeting expenses Other. Nakamae:Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Travel/accommodations/meeting expenses Other. Hino:Sanofi K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku Co.,Ltd.: Honoraria, Research Funding; Kyowa Hakko Kirin Pharma, Inc.: Honoraria, Research Funding, Travel/accommodations/meeting expenses Other.

Encouraging Outcomes In Older Patients (Pts) Following Nonmyeloablative (NMA) Haploidentical Blood or Marrow Transplantation (haploBMT) With High-Dose Posttransplantation Cyclophosphamide (PT/Cy)

▪ BackgroundRecent advances in NMA haploBMT have expanded potentially curative treatment options for pts lacking a matched donor. However, there is a paucity of data on the safety and efficacy of haploBMT in pts aged ≥ 60 y. This study evaluated the impact of older age on outcomes of NMA haploBMT with PT/Cy. Patients and methodsWe retrospectively analyzed the outcomes of 273 consecutive pts with poor-risk or advanced hematologic malignancies, aged 50-75 y, who received NMA related haploBMT with PT/Cy at Johns Hopkins. Eligibility included ECOG PS ≤ 1 or 2, LVEF ≥ 35%, adequate pulmonary and renal function and no uncontrolled infection. Morphologic CR was required for acute leukemia, ≥ PR for aggressive lymphoma. All pts received Cy (14.5 mg/kg IV days -6 and -5), fludarabine (30 mg/m2 IV days -6 to -2), TBI (200 cGy day -1) and T-cell replete bone marrow (272 pts) or peripheral stem cells (1 pt). GVHD prophylaxis consisted of high-dose PT/Cy (50 mg/kg IV) either once (day 3; 10 pts) or twice (days 3 and 4; 263 pts), mycophenolate mofetil and tacrolimus. Maintenance therapy was permitted and included rituximab in 55/126 B-NHL or CLL cases (44%). ResultsOf the 273 pts (median age 61 y, range 50-75), 154 were aged ≥ 60, including 27 pts aged 70-75. Diagnoses were aggressive lymphoma (79 pts), mantle cell lymphoma (25), indolent lymphoma or CLL (41), acute leukemia or lymphoblastic lymphoma (76), MDS (20), MPD (17), Hodgkin lymphoma (8) or multiple myeloma (7). Forty-one pts (15%) had prior autoBMT, and 138 (51%) had a high-risk comorbidity index score (HCT-CI ≥ 3). There were no statistically significant differences in HCT-CI risk category, histology (lymphoid vs myeloid), graft dose or CMV mismatch according to age by decade. By Disease Risk Index (DRI) category (Blood 2012; 120: 905), 32 pts (12%) were low-risk, 197 (72%) intermediate-risk, 44 (16%) high-risk and none very high-risk. No pts aged ≥ 70 were in the low-risk group. a) Overall results: With a median follow-up of 2.1 (range < 1 - 7.9) y in event-free pts, 2-y probabilities of PFS and OS were 39 (95% CI, 32-44)% and 53 (47-60)%, respectively. The probability of neutrophil recovery was 89% at day 30 (median 16 days). The probability of platelet recovery ≥ 20,000/µL was 85% at day 60 (median 26 days). Graft failure occurred in 12% of evaluable pts, with autologous count recovery in most cases. By competing-risk analysis, the 180-day probability of nonrelapse mortality (NRM) was 11 (95% CI, 7-14)%, grade 2-4 acute GVHD was 32 (27-38)%, and grade 3-4 acute GVHD was 3 (1-6)%. The 1-y probabilities of NRM and chronic GVHD were 14 (95% CI, 10-19)% and 12 (8-16)%. b) Age-specific results: Notably, as compared to age 50-59, we found no statistically significant association between advanced pt age and either NRM (fig A) or PFS. On univariate analysis, older age relative to ages 50-59 was associated with a tendency toward more grade 2-4 acute GVHD, without an evident increase in severe acute GVHD. The 2-y PFS probabilities for pts in their 50's, 60's and 70's were 39%, 36% and 39%, respectively (p = 0.9; fig B), with corresponding 2-year OS probabilities of 51%, 56% and 44 % (p = 0.9). In univariate analyses, no statistically significant association was seen between PFS and older age as a continuous variable (HR 1.01, 95% CI 0.99-1.03, p = 0.44) or categorical variable (ages 60-69 and ≥ 70, relative to 50-59). In contrast, the DRI category was significantly associated with both PFS (p < 0.003; fig C) and OS (p = 0.01). Likewise, in a multivariate analysis adjusted for year of BMT, the DRI was independently associated with PFS (p = 0.047). However, in multivariate analyses of PFS and NRM, no statistically significant association was seen with older age. ConclusionThese data suggest that in NMA related haploBMT with PT/Cy, advanced pt age is not associated with prohibitive toxicities. In fact, there was no apparent decrement in overall outcome in pts aged ≥ 70 when compared to those in their 50's. Additionally, the DRI is useful for risk stratification. Advanced age is thus no longer a barrier to successful outcomes with partially HLA-mismatched BMT. [Display omitted] Disclosures:Off Label Use: Posttransplantation cyclophosphamide for GVHD prophylaxis.

Low-Dose Total Marrow/Total Lymphoid Irradiation (TMI/TLI) Instead of TBI Induce Full Donor Chimerism Before T-Replete Haploidentical Transplantation

Nonmyeloablative (NMA) T replete haploidentical transplantation (TR-H) has been increasingly applied in high-risk hematologic patients when a HLA-matched donor was absent. Some data suggested that the outcome was similar to those obtained with matched related bone marrow transplantation, mainly in lymphoproliferative diseases. Recently, the Baltimora group reported a low dose TBI-based NMA regimen followed by T cell replete bone marrow, with post-infusion cyclophosphamide (Cy) to control GVHD and graft rejection.

Haploidentical bone marrow transplants for haematological malignancies using non‐myeloablative conditioning therapy and post‐transplant immunosuppression with cyclophosphamide: results from a single Australian centre

To demonstrate safety and efficacy of haploidentical bone marrow transplantation with non-myeloablative conditioning and high-dose post-transplant cyclophosphamide in adult patients with leukaemia or lymphoma. Human leukocyte antigen haploidentical bone marrow transplantation is a treatment option in patients with haematological malignancies who have no available human leukocyte antigen-matched donor but is limited by conditioning regimen toxicity, graft failure, relapse and graft-versus-host disease (GvHD). Twelve patients, median age of 51 years, underwent transplantation with T cell replete bone marrow from a haplotype-matched relative. The conditioning regimen consisted of cyclophosphamide, fludarabine and low-dose total body irradiation. Post-transplant immunosuppression consisted of a single dose of cyclophosphamide 50 mg/kg on day 3, followed by oral tacrolimus and mycophenolate mofetil. Outcomes reported are overall survival, engraftment and chimerism, toxicity, and clinical outcome. All patients had neutrophil recovery (median 14.5 days), and 11 of 12 had platelet engraftment (median 17 days). Two patients had autologous reconstitution. Seven of nine assessable patients had complete donor chimerism. Four patients had grades II-III GvHD, and none had grade IV GvHD. Four patients developed limited stage chronic GvHD. Five patients with acute myeloid leukaemia relapsed. Two patients died of nonrelapse causes, both from other malignancies, and five patients remain alive and relapse free. Median overall survival was 324 days (range 88-1163). This regimen is feasible and well tolerated in older patients with high-risk leukaemia or lymphoma, with minimal short-term toxicity and low rates of GvHD. The proportion of disease-free survivors indicates a graft-versus-malignancy effect is present in survivors.