MRD Groups Research Articles

Total body irradiation-free haploidentical peripheral blood stem cell transplantation compared to related and unrelated donor transplantation in pediatrics with acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer under the age of 15years. Despite the recent advances in therapeutic regimens, relapse occurs in 15%-20% of pediatric patients after chemotherapy, and hematopoietic stem cell transplantation (HSCT) is the best treatment option. However, donor availability is one of the major challenges. Over the last decade, haploidentical donor (HID) transplantation has evolved as an alternative option. Herein, we aimed to compare the transplant outcomes in pediatric patients receiving total body irradiation (TBI)-free myeloablative regimens, between non-HID and HID transplant. The study included 60 pediatric ALL patients who had undergone HSCT from October 2016 until September 2020. Forty-three patients received non-HID HSCT, while 17 patients received HID. The sources of stem cells (SC) were peripheral blood stem cells (PBSC) for all the patients. The conditioning regimen was based on busulfan and cyclophosphamide. For graft-versus-host disease (GvHD) prophylaxis, patients received cyclosporine and methotrexate in the setting of non-HID transplantation, where HIDs received post-transplant cyclosporine and cyclophosphamide. The cumulative incidences of 3-year overall survival (OS) were 73.1%, 66.6%, and 69.5%, for matched sibling donor-matched related donor (MSD-MRD), matched unrelated donor-mismatched unrelated donor (MUD-MMUD), and HID groups, respectively (p=.85). The cumulative incidences of grade II-IV acute GvHD for the MRD, MUD-MMUD, and HID groups were 29%, 41%, and 49%, respectively (p=.47). Furthermore, the 3-year cumulative incidence of chronic GvHD was MSD-MRD: 70% versus MUD-MMUD: 42% versus HID: 45% (p=.64). The 3-year cumulative incidence of relapse post transplantation was 45%, 18%, and 45%, respectively, for the MSD-MRD, MUD-MMUD, and HID groups, and the differences were not statistically significant (p=.55). There was a higher risk for cytomegalovirus (CMV) infection in patients receiving HID transplants compared to those of non-HIDs (p<.01). Our results indicate that PBSC-HID transplant outcomes in the setting of non-TBI conditioning are comparable to those of non-HIDs in pediatric ALL patients.

Impact of donor types on reduced-intensity conditioning allogeneic stem cell transplant for mature lymphoid malignancies.

We retrospectively compared the outcomes of reduced-intensity conditioning (RIC) transplantation from matched related donors (MRD; n = 266), matched unrelated donors (MUD; n = 277), and umbilical cord blood (UCB; n = 513) for mature lymphoid malignancies. The 3-year overall survival rates for the MRD, MUD, and UCB groups were 54%, 59%, and 40%, respectively (P < 0.001). Multivariate analysis showed no differences in survival between the MRD group and the MUD or UCB group. However, survival was significantly affected by the conditioning regimen and graft-versus-host disease (GVHD) prophylaxis in the UCB group, but not in the MRD and MUD groups. Notably, multivariate analysis showed that the risk of overall mortality in the UCB recipients who received the optimal conditioning regimen and GVHD prophylaxis (n = 116) was lower than that in the MRD group (relative risk [RR], 0.69; P = 0.03) and tended to be lower than that in the MUD group (RR, 0.75; P = 0.09). Our results suggest that UCB transplantation performed with the optimal conditioning regimen and GVHD prophylaxis is highly effective. Moreover, UCB is readily available. Thus, UCB transplantation with the optimal conditioning regimen and GVHD prophylaxis is preferable to MUD transplantation when MRD are not available in the setting of RIC transplantation for mature lymphoid malignancies.

Improving Depth of Response with Continued Ibrutinib Therapy in CLL Patients

Introduction: Minimal residual disease negativity (MRD-) predicts long-term survival of CLL patients after chemoimmunotherapy. Data on depth of response and its clinical significance in patients receiving ibrutinib is limited. The fact that ibrutinib is a time-indefinite therapy, as opposed to the time-limited approach with classic chemoimmunotherapy, raises the question of temporal MRD changes during continued treatment. We sequentially quantified MRD in peripheral blood (PB) and bone marrow (BM) by flow cytometry in CLL patients on ibrutinib.Methods and Patients: 86 CLL patients received single-agent ibrutinib 420mg once daily under a phase II investigator-initiated trial (NCT01500733). 3-year safety and efficacy results from this trial were previously reported [Farooqui et al, 2015 ASH Abstract 2937]. Briefly, eligible patients had either TP53 aberration or were ≥65 years old. The study included both treatment-naïve and relapsed/refractory patients. The primary endpoint was response at 6 months according to 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria incorporating 2012 clarifications. Response assessments at 6 and 12 months and annually thereafter included PB and BM flow cytometry and BM biopsy. MRD- was defined as <10-4 CLL cells per leukocytes based on 8-color flow cytometry. Spearman's analysis was used to assess the correlation between PB and BM MRD. Linear mixed models for repeated measures were used to estimate annual reduction of disease burden. Statistical analyses were performed using R (version 3.4.0).Result: Of 86 patients enrolled, 51 (59.3%) patients had TP53 aberration and 35 (40.7%) patients were ≥65 years old. More than half of the patients had previously untreated CLL (53 [62.6%]), advanced Rai stage (58 [67.4%]), and unmutated IGHV (U- IGHV) status (57 [66.3%]). At the median follow-up of 48 months, 52 (60.5%) remained on study. CLL disease burden significantly and continuously decreased with therapy in both PB and BM. Comparison of the paired PB and BM MRD levels revealed strong correlation between the two compartments (P <0.0001). Past the first year, residual CLL burden decreased by 36% in PB and 28% in BM with each additional year of treatment. Median MRD at 3 years was 5.3x10-2 in PB and 7.3x10-2 in BM. Although depth of response significantly improved over time, MRD- (<10-4) was rare even with long-term therapy. Three patients achieved MRD- in PB (each at 2, 3 and 4 years) and three patients achieved MRD- in BM (two at 3 years and one at 4 years, respectively). Low MRD (<10-2) was achieved by 16 (25.4%) of 63 patients at 3 years. We correlated MRD levels to iwCLL response. The CR rate of 38% in the low MRD group was not significantly different from 23% in the high MRD group (P=0.33). Likewise, both MRD groups showed comparable levels of residual disease in lymph nodes, spleen, and BM. Next, we performed subgroup analyses using baseline characteristics to identify factors associated with differential levels of MRD. MRD levels were similar between subgroups stratified by TP53 aberration and prior treatment status. Notably, patients with U- IGHV had significantly lower MRD in PB than patients with mutated IGHV (M- IGHV) starting from the first year on ibrutinib (P <0.05; Figure 1). However, BM MRD levels were similar between IGHV subgroups.Conclusion: Depth of response improved with continued ibrutinib, leading to low levels of MRD. PB and BM MRD levels were highly correlated, suggesting non-invasive testing could replace BM assessments on ibrutinib. Patients with M- IGHV had significantly higher levels of PB MRD than those with U- IGHV, consistent with known differences in redistribution lymphocytosis between two subgroups. Studies using MRD as a decision point for treatment duration with ibrutinib need to take into consideration the different levels of PB MRD achieved in the two IGHV subgroups. [Display omitted] DisclosuresWiestner:Pharmacyclics: Research Funding; Acerta Pharma: Research Funding.

Role of pre-transplant MRD level detected by flow cytometry in recipients of allogeneic stem cell transplantation with AML.

We analyzed the impact of pretransplant MRD level in bone marrow measured by flow cytometry using "different from normal" method on outcomes for 189 AML patients (108 males; median age, 58 (21-80)years). All patients were subdivided into negative (n=96), "low" (0.1%-0.5%, n=32), and "high" MRD (>0.5%, n=61) groups. In multivariate analysis, the hazard ratios for "high" and "low" MRD levels related to MRD negativity were 7.9 (95% CI 3.5-18.1, P<.001) and 5.4 (95% CI 2.1-14, P=.0058) for relapse; 2.3 (95% CI 1.3-4.1, P=.006) and 1.6 (95% CI 0.82-3.3, P=.16) for OS; and 2.8 (95% CI 1.7-4.7, P<.001) and 2.2 (95% CI 1.1-4.2, P=.02) for LFS, respectively. We found no significant impact of "low" MRD level on relapses (0.68, 95% CI 0.33-1.4, P=.30), OS (0.72, 95% CI: 0.36-1.5, P=.36) and LFS (0.79, 95% CI: 0.42-1.5, P=.46) related to "high" MRD group. Presence of detectable MRD was indicative for a high relapse risk, low LFS and OS. "Low" MRD level showed no significant impact on relapse, LFS and OS related to "high" MRD group.

Interaction of Remission Status and Cause of Death in Acute Myeloid Leukemia

BACKGROUND: Historically, causes of death for patients dying with active acute myeloid leukemia (AML) and those in remission have differed. However, it is unknown how changes in therapies and advances in supportive care have impacted death patterns and whether these differ for patients with active disease or those in morphologic remission (with or without measurable residual disease [MRD]) at the time of death. Here, we investigated the cause of death (COD) in AML patients and studied whether these differed for patients in morphologic remission with or without evidence of MRD. PATIENTS AND METHODS:We used an institutional database of adults with newly-diagnosed AML treated with intensive induction chemotherapy from 2006-2017 with either "7+3" (N=140) or cladribine, cytarabine, mitoxantrone and G-CSF ("CLAG-M", N=198). Primary COD, time of death (TOD) and clinical variables were abstracted from chart review. Disease status at TOD was determined by the patient's last bone marrow aspirate/biopsy (BMA) prior to death, unless complete blood count or autopsy clearly showed AML. Complete remission (CR), CR with incomplete hematologic recovery (CRi), and relapse were defined per 2017 ELN criteria. MRD was determined by multiparameter flow cytometry (MFC) and cytogenetics on all BMA. All patients treated on clinical studies gave informed consent in accordance with the Declaration of Helsinki and were treated on Institutional Review Board-approved protocols. RESULTS: Characteristics of the 338 patients are shown in Table 1. With a median follow-up of 928 days, 187/338 (55%) patients died, 2 of which were excluded from subsequent analysis due to incomplete data. The remaining 185 patients were categorized into 3 groups based on disease status at TOD: remission (CR/CRi and MRD negative), MRD (CR/CRi and MRD positive), and relapse. There were 59 (32%) patients in remission, 13 of which had treatment following their last BMA; this treatment consisted of consolidation chemotherapy or transplant in 11/13 patients. There were 17 (9%) MRD patients and in 6/17 the response to last cycle of treatment was unknown. 109 (59%) of patients were in relapse at TOD, and 24/109 were without BMA assessment following last treatment. 36/59 (61%) remission patients underwent hematopoietic cell transplantation, compared to 5/17 (29%) and 42/109 (39%) in the MRD and relapse groups, respectively. Overall, the median survival from the start of initial induction treatment to death was 327 days, with 85/185 (45%) of patients dying within 60 days of their last treatment. Median time between last cycle of treatment and death was 136 days for the remission group, compared to 53 days in MRD and 50 days in relapse groups. Finally, we examined how COD varied by disease status at time of death (Table 2). Of patients dying with morphologic AML (N=109), AML was the most common COD (45%) followed by infection (33%), other (9%), and unknown (7%). For remission patients (N=59), infection was the predominant COD (56%) followed by unknown (17%) and transplant-related complications (12%). In MRD positive patients (N=17), AML was the COD in 1 patient (6%), infection occurred in 6 (35%), with unknown (29%) or other causes (18%) accounting for the remaining deaths. Notably, only 9 (5%) of patients underwent autopsy and of the 50 patients dying with AML as primary cause, the majority (32/50, 64%) died while on hospice and thus AML as primary cause was presumptive. CONCLUSIONS: In our cohort, the majority of deaths occurred within one year of starting induction chemotherapy, and most occurred in patients in active relapse. Only a minor subset of patients dying in morphologic remission had MRD, and COD of patients in the MRD group more closely reflected that of patients in remission. A substantial proportion of deaths occurred within 60 days of treatment, demonstrating that active treatment represents a particularly vulnerable period for patients regardless of disease status. Infection accounted for a substantial proportion of deaths for patients in all disease categories, and is likely undercounted in our study given the high proportion of relapse patients dying on hospice. Thus, despite advances in treatment, infection represents the most common cause of death in AML, highlighting the need for advances in diagnosis and treatment of infections to improve overall outcomes. Disclosures Halpern: Novartis: Other; Bayer: Other; Jazz Pharmaceuticals: Other; Imago BioSciences: Other; Tolero Pharmaceuticals: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Godwin:Pfizer Inc.: Research Funding; Immunogen Inc.: Research Funding.

Evaluating ROR1 As a Target in Childhood Leukemia

Disease relapse in childhood acute lymphoblastic leukemia (ALL) patients may occur due to persistence of resistant cells with leukemia propagating ability (LPC). Immunotherapeutic approaches, such as bi-specific T cell engagers (BiTEs) and chimeric antigen receptor (CAR) T cells against CD19, have been shown to successfully treat relapsed ALL. However, such therapies cannot target LPC that lack or have lost expression of CD19. Receptor tyrosine kinase like orphan 1 receptor (ROR1) is a surface antigen, overexpressed in hematological malignancies, including chronic lymphocytic leukemia (CLL) and solid tumors, with limited expression in normal tissues. ROR1 is found in cancer initiating cells and high levels correlated with metastases and poor outcomes in ovarian and breast cancers, making it a promising target for immunotherapy. Preclinical studies using a ROR1-BiTE have shown efficacy against a range of solid cancers and CLL. The aims of this study were to investigate i) ROR1 expression in B cell precursor (BCP)-ALL, T-ALL and respective LPC; ii) the proliferative ability of ROR1+ cells and iii) the effects of induction therapy on ROR1+ cells. Bone marrow (BM) cells from 16 BCP-ALL and 10 T-ALL samples were stained with antibodies against CD19 or CD7, respectively, in addition to ROR1 and CD34. The proportion of ROR1+ cells and the number of antigen binding sites were determined by flow cytometry. These measurements were also assessed in CD34+/CD19+, CD34+/CD19-, CD34-/CD19+, CD34-/CD19- BCP-ALL LPC, CD34+/CD7+, CD34+/CD7-, CD34-/CD7+, CD34-/CD7- T-ALL LPC and compared with normal BM (NBM) cells. ROR1 expression varied amongst the samples studied with higher levels observed in T-ALL cases. The median expression of ROR1 was 8.2% (range 0.4-83%) in T-ALL cases, significantly higher than in BCP-ALL (median 2.4, range 0.01-85%, P=0.03). The number of ROR1 binding sites was also significantly higher in T-ALL cases (median 233, range 93-1238) compared to BCP-ALL (98, range 2-1540) and NBM cells (55, range 30-223, P=0.01). There was no difference in ROR1 expression between low or risk MRD groups in BCP- and T-ALL cases. In LPC subpopulations, ROR1 was only detected in subpopulations expressing the respective lineage markers. Again, higher numbers of binding sites were detected in LPC from T-ALL cases, CD34+/CD7+ (median 130, range 0-948) and CD34-/CD7+ (112, range 0-1148). To investigate proliferative capacity, ALL cells were incubated with cell trace violet (CTV) and monitored in culture for up to 7 days. ROR1- T-ALL cells had lower CTV median fluorescence intensity (MFI), indicating more divisions, decreasing 19 fold by day 7 compared to ROR1+ cells (4 fold decrease). In LPC subpopulations, greatest proliferation was seen in CD34+/CD19-/ROR1- and CD34+/CD19+/ROR1- cells in BCP-ALL with 269 and 177 fold decreases in the CTV MFI, respectively. In T-ALL cases, most cell divisions were observed in CD34+/CD7-/ROR1- cells (100 fold decrease) followed by CD34-/CD7-/ROR1- (49 fold). Proliferative activity was more modest in the ROR1+ subpopulations with a decrease in the CTV MFI ranging from 28 to 4 fold. To determine whether induction therapy had an impact on ROR1+ cells, samples at day 29 and/or week 14 post treatment were investigated in 3 BCP- and 6 T-ALL cases and compared to the immunophenotype at diagnosis. In BCP-ALL, ROR1+ cells were undetectable at day 29 and week 14. In contrast, in 5/6 T-ALL cases ROR1 levels were higher following treatment. In 3 cases, ROR1 expression increased in CD34-/CD7+ LPC at day 29. While in the other 2 cases emergence of ROR1+ populations were observed in CD34+/CD7+ and CD34-/CD7+ cells at week 14, that were not present at diagnosis. In summary, ROR1 was more prevalent in childhood T-ALL and was co-expressed with CD7 in T-ALL and CD19 in BCP-ALL. ROR1- ALL cells had higher short-term proliferative capacity than ROR1+ cells, including known refractory CD34+/CD19-, CD34+/CD7- and CD34-/CD7- LPC. Further long-term functional studies in vitro and in vivo to investigate the role of ROR1 in ALL are ongoing. However, these data together with persistence of ROR1+ T-ALL cells after treatment, indicate that cell cycle specific agents may be ineffective on these cells. Therefore, ROR1 targeted therapy may be beneficial for T-ALL patients. Disclosures Nathwani: Freeline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties.

Comparision of Outcomes According to HLA Disparity in Acute Leukemia Patients: A Single Center Institution Experience

Introduction:Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) still remains the only established curative approach for the treatment of acute leukemia (AL). HLA-matched sibling or relative donor (MRD) is considered the optimal donor source but when this is not available, a matched unrelated donor (MUD) is considered the best alternative. Prior studies reported comparable results of Allo-HSCT from MSD versus MUD. In this retrospective, single center review, we aimed to compare the transplantation outcomes after 10/10 or 9/10 HLA-matched related to unrelated donor transplantation in adults with AL.Patients and Methods: We retrospectively analyzed 363 consecutive patients with a diagnosis of AL who underwent their first Allo-HSCT between January 2005 and April 2018, using matched 10/10 MRD (n= 244) and MUD (n=54) or mismatched-UD (mmUD) (n=65) at Ankara University School of Medicine, Bone Marrow Transplantation Unit. Patients transplanted using cord blood or haploidentical donors were excluded to homogenously compare adult full-matched sibling or unrelated donors in the acute leukemia setting. Parameters evaluated included hematopoietic engraftment, disease relapse, transplant related complications, mortality, overall survival (OS) and disease free survival (DFS) from transplantation, and the incidence and severity of acute and chronic GVHD.Results:Baseline characteristics are summarized in Table 1. The median age was similar in all groups at the time of transplantation (p= 0.9). Median follow-up from the transplantation for all patients was 25 months (range, 1- 152.8) but median follow up was longer in the MRD group (33.6 months [range, 1-152.8]) than in the MUD and (13.3 months [range, 1-121.5]and mmUD groups (22.3 months [range, 2.3-129.4]and p=0.011). In the MRD group, 90.9% received a myeloablative conditioning (MAC) regimen, while in the MUD and mmUD groups, 73.1% and 81.3% received a MAC regimen (p=0,001). Cyclosporine and methotrexate were used as the main graft versus host disease (GVHD) prophylaxis in all groups. The proportion of patients who received in vivo T cell depletion significantly differed among the two groups (6.6% in the MRD group, 92.6% in the MUD group and 50.8% in the mmUD group, p=0.000). Peripheral blood stem cell (PBSC) was the main stem cell source in all groups (92.2% in the MRD group vs. 90.7% in the MUD group vs. 95.4% mmUD, p<0.1). Most of the patients (94.3%) achieved hematopoietic engraftment, graft failure occurred in 4.5%, 7.4% and 9.2% in MRD, MUD and mmUD groups, respectively (p>0.1). The median time for neutrophil and platelet engraftments was seen faster in MRD group compared to MUD and mmUD (p<0.0001).According to the type of donor the incidence of grades II-IV acute GVHD were similar among MRD, MUD and mmUD (22.1%, 24.1% and 18.5%, respectively). But lower incidence of chronic GVHD was observed post-HSCT with a mmUD than a MSD; 22.2% for MUD, 32.3% for mmUD and 55.6% for MRD (p>0.1). No statistical significance was observed for transplant related mortality (TRM) in terms of the type of donor (MUD group. mmUD groupand MRD group; 22.2%, 23.1% and 18.0%, p=0.572). Relapse incidence was similar among the groups (MRD vs. MUD vs. mmUD; 33.6% vs. 29.8% vs. 30.8%, p=0.807). Two-year leukemia free- and overall survival were not affected the donor types (Figure-1)..Conclusion:Our results suggest that, when an HLA-identical sibling donor is not available for an adult with AL who is otherwise a candidate for Allo-HSCT, a 10/10 or 9/10 UD may be used with the expectation of similar rates of TRM, LFS and OS at 2 years. DisclosuresCivriz Bozdag:NOVARTIS: Consultancy; MSD: Research Funding; TAKEDA: Consultancy. Özcan:Jazz: Other: Travel support; BMS: Honoraria; MSD: Research Funding; Celgene: Other: Travel support, Research Funding; Abbvie: Other: Travel payment; Roche: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel payment, Research Funding; Novartis: Research Funding; Janssen: Other: Travel Support, Research Funding; Bayer: Research Funding; Archigen: Research Funding; MSD: Other: travel support, Research Funding; Jazz: Other. Ilhan:BMS: Speakers Bureau; Roche: Speakers Bureau; Celgene: Speakers Bureau; Alexion: Speakers Bureau. Beksac:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen,Janssen-Cilag,Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Allogeneic Transplantation for Lymphoid Malignancies with Fludarabine and Melphalan Conditioning and Different Donor Types

Introduction: Allogeneic hematopoietic stem cell transplantation (ASCT) remains a curative treatment for patients with advanced lymphomas. Haploidentical donors (HID) have recently extended transplantation for patients without HLA matched donors. Fludarabine (F) with melphalan (M) 140mg/m2 is the current standard of care conditioning regimen for ASCT. We hypothesized that progression-free survival (PFS) of patients with HID is comparable to that of HLA matched transplants, and that lower doses of melphalan (100mg/m2) are equally effective for these patients. Here, we analyzed outcomes of all lymphoma patients who received ASCT from different donors with FM conditioning at our institution between 09/2009-01/2018.Methods: A total of 186 pts (63 matched related, MRD, 98 matched unrelated, MUD and 25 HID) were included. 30 patients had chronic lymphocytic leukemia (CLL), 54 Hodgkin lymphoma (HL) and 77 Non-Hodgkin lymphoma (NHL). The median follow-up was 57 (range 3-101) months. Patients received F160mg/m2 with M140mg/m2 (FM140) or 100mg/m2 (FM100). FM100 regimen was used in older patients/significant comorbidities. Thiotepa 5mg/kg or TBI 200cGy was added to HID transplants. All matched transplants received standard graft-versus-host disease (GVHD) prophylaxis (tacrolimus + methotrexate +/-ATG for MUDs), while HID group received PTCy-based GVHD prophylaxis. The cumulative incidence (CI) of non-relapse mortality (NRM), disease progression, and GVHD was estimated accounting for competing events. Regression analysis accounting for competing events was used to evaluate predictors of outcomes.Results: Patients' characteristics were well balanced in donor groups except for advanced stage 3-4 disease (HID 77% vs MRD 51%, p=0.03), use of FM100 regimen (HID 64% vs. MUD 11% vs. MRD 10%, p<0.001) and bone marrow graft (HID 84% vs. MUD 36% vs. MRD 2%, p<0.001) (Table 1). Engraftment was similar in HID, MUD and MRD (92%, 89% and 98%, respectively; p=0.7). The CI of grade III-IV aGVHD at 6-months in HID (reference), MUD and MRD was 4%, 14% (p=0.2) and 8% (p=0.5), and the 3-year cGVHD were 5%, 16% (p=0.2) and 26% (0.09), respectively. The 3-year relapse for the HID (reference), MUD and MRD groups was 15%, 21% (p=0.4) and 39% (p=0.04), respectively. The corresponding CI of NRM was 31%, 32% (p=0.9), and 10% (p=0.02). The 3-year PFS was equivalent in the 3 donor groups at 49% (HID, reference), 44% (MUD, HR=1.2, p=0.6), and 46% (MRD, HR=1.1, p=0.8). Similarly, overall survival (OS) did not differ with respective OS of 52% (HID, reference), 54% (MUD, HR=1.04, p=0.9), and 67% (MRD, HR=0.6, p=0.2) in the 3 groups. The 3-year GVHD-relapse free survival in HID (reference), MUD and MRD groups was 39%, 31% (p=0.3) and 24% (p=0.2) respectively. Patients receiving FM100 were older (median 57 vs. 46 years, p<0.01), more likely to receive HID transplant (48% vs 6%, p<0.01) and a bone marrow graft (55% vs 25%, p=0.01), and less likely (12% vs 35%, p=0.01) to be treated for HL. On univariate analysis, FM100 regimen showed a trend for improved PFS (HR=0.7, p=0.3) and less relapse (HR=0.4, p=0.1) compared to FM140 regimen with similar NRM (HR=0.9, p=0.8) and OS (HR=0.9, p=0.7). The 3-year PFS and OS for FM100 vs. FM140 was 57% vs 43%, and 64% vs 58%. In multivariate analysis (MV), factors associated with unfavorable PFS were NHL (HR=1.9, p=0.002) and >3 chemotherapy regimens (HR=1.8, p=0.01) received prior to transplant. Including donor type and melphalan dose in MV analysis did not alter these results.Conclusions: HID transplants have lower relapse rates and higher NRM comparing with MRDs, while no significant differences were seen comparing with MUDs, and similar survival compared with HLA matched transplants in patients with lymphoma receiving FM-based conditioning regimen. Our results suggest that FM100-based conditioning, which was used primarily in older individuals, is equivalent to FM140 and could be used as prefered standard conditioning regimen for ASCT for patients with lymphoma. Controlled studies are need to compare FM100 with FM140 conditioning and to evaluate PTCY-based GVHD prophylaxis in HLA matched transplants. [Display omitted] DisclosuresOran:ASTEX: Research Funding; AROG pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding. Shpall:Affirmed GmbH: Research Funding. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Westin:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

The effect of donor source on outcomes after second allogeneic hematopoietic cell transplantation for relapsed leukemia.

7044 Background: There is no standard treatment for patients with leukemia who relapse after allogeneic stem cell transplant (HCT). A second HCT (HCT2) may be the only possibly curable option; however, this is performed in few patients. We hypothesized that patient and transplant characteristics, such as donor source will affect outcomes. Methods: We retrospectively evaluated adult patients who received a HCT2 for relapsed leukemia or MDS at a single institution between 2000-2016. 85 patients underwent a HCT2 with an unmanipulated graft from a matched related (MRD, n = 21), matched unrelated (MUD, n = 40), or haploidentical (haplo, n = 24) donor, preceded by either a reduced intensity (RIC) or myeloablative conditioning (MAC) regimen. Results: The median age at HCT2 was 50 yrs and the median time between transplants was 448 days. Patients had relapsed AML (n = 62), ALL (n = 12), and MDS (n = 10). The median length of follow up for survivors was 22.3 months (range 3.9-131) with 20 patients alive in June 2016. 65 patients died; 32 from relapse, 21 from infection, 7 from GvHD, and 5 from organ failure. 1-year OS from HCT2 was 38.6%. For patients with MRD, MUD, haplo donors, 1 year OS was 52.3%, 33.3%, and 34.6% (p = 0.72). 1-year DFS in the entire cohort, MRD, MUD, and haplo groups was 26.4%, 14.3%, 34.8%, and 25.3% (p = 0.45). 1-year TRM was 36.2% and not different across these groups (p = 0.80). Univariate analyses of OS, DFS, and TRM based on patient, disease, and transplant characteristics showed an association with RIC and worse OS and DFS (HR 2.0, 95% CI 1.2-3.3; and HR 1.9, 1.2-3.1). Having &gt; 1 year between transplants was associated with lower TRM (HR 0.38, 0.19-0.77). Traditional risk factors like age, presence of active disease at HCT2, shorter time between transplants, and using the same donor from the first HCT were not otherwise significantly associated with OS, DFS, or TRM. Conclusions: Outcomes after HCT2 did not differ based on donor source. MAC is associated with better OS relative to RIC (1yr OS 51% vs 23%, p &lt; 0.01), DFS (1yr DFS 37% vs 12%, p &lt; 0.01), with similar TRM (1yr TRM 30% vs 47%, p = 0.12). Based on these data, serious consideration is necessary before using RIC regimens for HCT2 in patients with relapsed leukemia.

Favorable Immune Reconstitution Profile after Allogeneic Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Background: The administration of post-transplant high-dose cyclophosphamide (PTCy) has been shown to be an effective strategy for GvHD prophylaxis following allogeneic peripheral blood stem cell transplantation(PBSCT) from alternative donors. PTCy is toxic to allogeneic activated proliferating T lymphocytes, such as effector T cells. Conversely, it may not materially affect memory T cells.Methods: We evaluated immune reconstitution profile and transplant outcome in patients who received PBSCT with and without PTCy. PTCy was given on day +3 and +4 following haploidentical transplant (HAPLO), or only on day +3 following HLA-matched unrelated donor (MUD) transplant. No PTCy was given to patients with HLA-matched related donors (MRD). All patients received GvHD prophylaxis as tacrolimus (day +5 to +180) and MMF (day +5 to +35). Preparative regimens were myeloablative regimens (fludarabine/busulfan, fludarabine/TBI 12 Gy, or CY/TBI 12) in all patients except 4 patients (received fludarabine/melphalan). Immune reconstitution profile (IRP) was tested via serial flow cytometry analysis of peripheral blood lymphocytes after transplant were done on days +30, +100, and +180.Results: Data of 70 patients who underwent allogeneic PBSCT in our institution were analyzed in 3 groups; MRD (n=22), MUD (n=35), and HAPLO (n=13). The total cohort had 33 males (47%), and had median age of 52 years (range 20-70). All patients had hematological malignancy except one patient with HLH. The median duration of follow up was 6 months (range 1-17). The median day of neutrophil and platelet engraftment were 13, 12, 17 and 18, 15, 22 days for MRD, MUD and HAPLO groups respectively. The one-year overall survival of the whole group was 67% (95% confidence interval: 48-80) with no difference in OS among the 3 cohorts (log rank P value 0.4) (Figure 1). Lymphocyte and lymphocyte subset (T, B, NK) count recovery for MUD and HAPLO was significantly less (p<0.05) than MRD during the first month post-HSCT but these differences were statistically insignificant by day +60 and remained so through day +365. Recovery of both CD4+ and CD8+ naïve T cell (CD45RA+CD27+CD197+) population was generally slower for HAPLO patients during the first year and significantly less through day+ 180 for CD4+ T cells. As predicted, central memory (CD45RA-CD27+CD197+) CD4+ and CD8+ T cells remained proportionately equivalent at 40% and 28% respectively for all groups during the first year. The effector memory (CD45RA-CD27+CD197-) population was also proportionately consistent at 25% of total for both CD4+ and CD8+ subsets. Interestingly, the effector T cell population (CD45RA+CD27-CD197-) trended higher for all three recipient groups at each time point for both CD4+ and CD8+ populations increasing from 20% at one month to over 40% at one year.Conclusion: Post-PBSCT survival was not significantly different from alternative donor graft recipients and those that received MRD PBSCT. Lymphocyte recovery was impaired for the PTCy groups in the immediate post-PBSCT period but quickly recovered to that seen in MRD recipients. [Display omitted] DisclosuresSaad:Spectrum: Honoraria; American Porphyria foundation: Research Funding; Astellas: Research Funding; Alexion: Honoraria. Lamb:Incysus, Ltd: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The long-term outcome of reduced-intensity allogeneic stem cell transplantation from a matched related or unrelated donor, or haploidentical family donor in patients with leukemia: a retrospective analysis of data from the China RIC Cooperative Group.

This study compared 6-year follow-up data from patients undergoing reduced-intensity conditioning (RIC) transplantation with an HLA-matched related donor (MRD), an HLA-matched unrelated donor (MUD), or an HLA-haploidentical donor (HID) for leukemia. Four hundred and twenty-seven patients from the China RIC Cooperative Group were enrolled, including 301 in the MRD, 79 in the HID, and 47 in the MUD groups. The conditioning regimen involved fludarabine combined with anti-lymphocyte globulin and cyclophosphamide. Graft-versus-host disease (GVHD) prophylaxis was administered using cyclosporin A (CsA) and mycophenolate mofetil (MMF). Four hundred and nineteen patients achieved stable donor chimerism. The incidence of stage II-IV acute GVHD in the HID group was 44.3%, significantly higher than that in the MRD (23.6%) and MUD (19.1%) groups. The 1-year transplantation-related mortality (TRM) rates were 44.3, 17.6, and 21.3, respectively. Event-free survival (EFS) at 6years in the HID group was 36.7%, significantly lower than that of the MRD and MUD groups (59.1 and 66.0%, P < 0.001 and P = 0.001, respectively). For advanced leukemia, the relapse rate of the HID group was 18.5%, lower than that of the MRD group (37.5%, P = 0.05), but the EFS at 6years was 31.7 and 30.4% (P > 0.05), respectively. RIC transplantation with MRD and MUD had similar outcome in leukemia which is better than that with HID. RIC transplantation with HID had lower relapsed with higher TRM and GVHD rate, particularly in advanced leukemias. RIC transplantation with MRD and MUD had similar outcomes in leukemia and they were better than those with HID. RIC transplantation with HID had a lower relapse rate but higher TRM and GVHD rates, particularly in cases of advanced leukemia.

Comparable Results with Treosulfan Based Conditioning Regimen in Matched Related and Matched Unrelated Donor Transplants for Beta Thalassemia Major and the Challenges from India: A Single Center Experience

Background: Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for patients with thalassemia major. Majority of the patients undergoing transplants in India belongs to advanced Pesaro risk stratification and 2013 data from India using treosulfan based conditioning for matched related donor transplants (MRD) has showed an event free survival of 78.8 ± 6.0 at 3 years (Mathews et al. Plos One 2013). Advanced age and risk stratification is a deterrent in proceeding with matched unrelated donor (MUD) transplant in India. Since only 25-30 % of patients are likely to get a MRD, MUD transplant is a feasible option in the background of limited life expectancy in patients with thalassemia major. However, there is no data comparing MRD and matched unrelated donor (MUD) transplants from India.Method: This is a retrospective analysis to compare the outcomes between MRD and MUD transplants from a single institution. Events were defined as primary graft failure, graft rejection leading to recurrence of transfusion dependence or death.Results: A total of 123 patients with thalassemia major underwent MUD search in DKMS and DATRI registries. Fifteen (12%) and 13 (10%) patients found 10/10 HLA identical donors respectively and 4 (3%) of them had matches in both the registries. Very few patients underwent NMDP search due to cost constraints.Among the 36 patients who underwent stem cell transplantation, MRD group had 27 patients and MUD group has 9 patients. Base line characteristics of age, sex and Pesaro risk stratification were matched. (Table: 1) Majority of patients belonged to high risk category in both the groups. The conditioning regimens used in both the groups were thiotepa, fludarabine, and treosulfan (TreoFluT). All the MRD non-sibling transplants and MUD transplants also received antithymocyte globulin (ATG) as part of the conditioning regimen. All patients received HLA identical (10/10) grafts. In the MRD group, the stem cell source was 24 (89%), 2 (7%) and 1 (4%) from sibling, parent and 1st cousin respectively. The MUD grafts were procured from 3 different registries DKMS (German) 5 (56%), NMDP (US) 2 (22%) and DATRI (Indian) 2 (22%). Cyclosporine and short course methotrexate were used as Graft versus host disease (GVHD) prophylaxis in all the patientsMultiple challenges are involved in the availability and procurement of donor grafts from different registries. A special DCGI (Drug controller General of India) approval needs to be taken for every graft source procured from overseas. The estimated average cost of MRD transplant is 24000 US$ and MUD transplant is 48000 US$ for DKMS and DATRI grafts and 78000 US$ for NMDP grafts. Inspite of lower costs than the western countries, affordability is a major concern even if matched donors are available.Overall survival at 1 year in MRD and MUD groups was 84.3 ± 7.2% and 88.9 ± 10.5% at a median follow up of 20 (0-57) months and 13 (1-31) months respectively (p= 0.799) (Fig:1). The thalassemia free survival at 1 year was 84.3 ± 7.2% and 77.8 ± 13.9% with a median follow up of 20 (0-57) and 12 (1-31) months respectively (p= 0.732). (Fig: 2).Conclusion: Although the incidence of acute GVHD and chronic GVHD incidence are higher in the MUD transplant group, TreoFluT based conditioning for allogeneic stem cell transplantation with both matched related and unrelated donor graft source is a feasible option in beta thalassemia major patients even in high risk category from developing countries.Table 1Patient demographics and transplant characteristicsMRD (n= 27) n(%) Median(range)Mean ± SDMUD n=9 n(%) Median(range)Mean ± SDP-valueAge (yrs)10 (2-18)9 (2-18)0.502Sex: Male19 (70)6 (66)0.835Class I1 (4)2 (22)0.135Class II6 (22)3 (33)Class III20 (74)4 (44)Class III Vellore high risk11 (55)3 (75)0.693Stem cell sourcePBSC BM BM + CB BM + PBSC + CB23 (85) 2 (7) 1 (4) 1 (4)7 (78) 2 (22) 0 00.599Cell doseMNC/TNC x 108/Kg CD34 x 106/Kg8.04 (3.49 -14.6) 5.91 (0.23 -27.75)7.2 (2.83 -10.47) 8.47 (0.49 -21.6)0.782 0.381Acute GVHD6 (22)6 (66)0.014Grades I and II5 (19)4 (44)0.505Grades III and IV1 (4)2 (22)Classic acute GVHD5 (18)3 (33)0.287Persistent00Recurrent03 (33)Late onset1 (4)0Chronic GVHD6 (22)6 (67)0.014Classic Chronic GVH5 (18)3 (33)0.545Overlap syndrome1 (4)3 (33) [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effect of resolvin D1 on focal cerebral ischemia-reperfusion injury in rats

Objective To evaluate the effect of resolvin D1 on focal cerebral ischemia-reperfusion (I/R) injury in rats. Methods One hundred and twenty adult male Sprague-Dawley rats, aged 7 weeks, weighing 260-280 g, were randomly divided into 5 groups (n=24 each) using a random number table: sham operation group (group S) , group I/R, low-dose resolvin D1 group (group LRD) , medium-dose resolvin D1 group (group MRD) , and high-dose resolvin D1 group (group HRD) . Focal cerebral I/R was induced by right middle cerebral artery occlusion using a nylon thread inserted into internal carotid artery and advanced cranially until resistance was met.The occlusion was maintained for 2 h followed by 24 h reperfusion.In LRD, MRD and HRD groups, 0.03, 0.10, 0.30 nmol resolvin D1 5 μl was injected into the lateral cerebral ventricle at the beginning of reperfusion, respectively.Neurological deficits were evaluated at 24 h of reperfusion and scored.The rats were then sacrificed, and their brains were removed for determination of infarct volume (by TTC staining) , cerebral water content, Evans blue content and expression of matrix metalloproteinase-9 (MMP-9) in the ischemic cortex. Results Compared with group S, the neurological deficit scores, cerebral infarct volume, and cerebral water and Evans blue content were significantly increased, and the expression of MMP-9 was up-regulated in the other 4 groups.Compared with group I/R, the neurological deficit scores, cerebral infarct volume, and cerebral water and Evans blue content were significantly decreased, and the expression of MMP-9 was down-regulated in group MRD and group HRD, and no significant change was found in the parameters mentioned above in group LRD. Conclusion Resolvin D1 can attenuate focal cerebral I/R injury in rats, and down-regulation of MMP-9 expression and decrease in permeability of blood-brain barrier may be involved in the mechanism. Key words: Docosahexaenoic acids; Reperfusion injury; Cerebral

Prefrontal glucose metabolism in medication-resistant major depression.

Medication-resistant depression (MRD) is associated with poorer attentional performance and immense socioeconomic costs. We aimed to investigate the central pathophysiology of MRD, previously linked to impaired prefrontal cortex function. A total of 54 participants (22 with MRD, 16 with non-resistant depression, 16 healthy controls) were recruited. Non-MRD status was confirmed by a prospective 6-week antidepressant trial. All medication-free participants underwent a go/no-go task to study prefrontal cortical function (attention) and positron emission tomography scans to study regional cerebral glucose metabolism (rCMglu) at rest. The MRD group had worse attentional ratings and decreased rCMglu compared with the non-MRD and control groups. Attentional performance was positively associated with prefrontal cortex rCMglu. The prefrontal cortex differences between MRD and non-MRD groups remained after adjusting for past depressive episodes (F(1,35) = 4.154, P = 0.043). Pronounced hypofrontality, with the associated attentional deficits, has a key role in the neuropathology of medication-resistant depression.

Haploidentical Hematopoietic Stem Cell Transplantation without In Vitro T Cell Depletion for the Treatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

The role of haploidentical related allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) is not clear. We aimed to investigate the long-term survival of Ph+ ALL patients who underwent haploidentical donor (HID)-HSCT and to analyze the factors influencing relapse and survival after allo-HSCT. The study population included Ph+ ALL patients who underwent haploidentical related allo-HSCT. Additionally, Ph+ ALL patients who underwent HLA-matched related donor (MRD) transplants during the same period were included to compare outcomes. BCR-ABL transcript levels were analyzed by using real-time quantitative reverse transcription PCR. Clinical data from 139 Ph+ ALL patients who received allo-HSCT in our center were analyzed. Of these patients, 101 received HID transplants and 38 received MRD transplants. At a median follow-up of 36 months, 5-year disease-free survival (DFS) and overall survival (OS) rates in the HID transplant group were 65.8% and 74.0%, respectively. The 5-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) rates for the HID transplant group were 20.3% and 15.6%, respectively. In addition, there were no differences in OS, DFS, CIR, and NRM between the HID and MRD groups. Multivariate analysis showed that imatinib resistance was a significant factor influencing DFS and CIR in HID transplant patients. Haploidentical HSCT for the treatment of Ph+ ALL achieves promising long-term survival, which is comparable with that of HLA-MRD HSCT. Imatinib resistance is a negative predictor of relapse and DFS after allo-HSCT.

Gvhd Prophylaxis With Mycophenolate Mofetil and Calcineurin Inhibitor In Allogeneic Hematopoietic Cell Transplantation From HLA-Matched Siblings Or 7–8/8 HLA-Matched Unrelated Volunteer Donors: A Japanese, Multicenter, Phase II Trial

Background In allogeneic hematopoietic cell transplantation (allo-HCT), graft versus host disease (GVHD) remains a major cause of non-relapse mortality. Although methotrexate (MTX) combined with a calcineurin inhibitor (CI) is the current standard for GVHD prophylaxis, several recent studies have also reported the utility of mycophenolate mofetil (MMF) combined with CI, in terms of earlier hematological recovery and less mucositis with a similar incidence of GVHD. In Asian populations, however, there have been few prospective studies with MMF and CI as GVHD prophylaxis, and we thus carried out this Japanese multicenter prospective trial of allo-HCT with MMF and CI. Methods From April 2010 to September 2012, we prospectively registered patients with hematological malignancy who received their first T cell-replete allo-HCT from HLA-matched related donors (MRD group) or 8/8 or 7/8 matched unrelated volunteer donors (URD group). The primary endpoint was the cumulative incidence of grade II to IV acute GVHD at day 100. The expected and threshold incidences were 30% and 60% in MRD group, and 40% and 65% in URD group, respectively. With a statistical power of 80% and a one-sided, type I error of 5%, the each number of eligible patients required for these studies was calculated to be 17 and 25 in MRD and URD groups, respectively, and the each maximal number of registerable patients was set to be 30 and 45, respectively. As of June 2013, the primary endpoint for evaluation of all patients has been attained. As GVHD prophylaxis, MMF (500mg three times/day) and cyclosporine were used in MRD group, and MMF (1000mg three times/day) and tacrolimus were used in URD group. The MMF dose was tapered according to plan, starting on day 30–40 with cessation by day 100. The cyclosporine and tacrolimus were continued until days 60 and 100 and then tapered and stopped on days 150 and 180, respectively, unless GVHD developed. Results There were 20 patients (median age:47.5) in the MRD group and 31 patients (median age:45) in the URD group (HLA 8/8 matches:23, HLA 7/8 matches:8). In the MRD and URD groups, acute leukemia was present in 90% and 65%, and standard risk disease comprised 90% and 65%, respectively. In the MRD and URD groups, 75% (15/20) and 55% (17/31) received standard myeloablative conditioning (BuCy or CyTBI), and the remainder received reduced intensity conditioning (FluBu±TBI or FluMel±TBI). In the MRD group, peripheral blood stem cells and bone marrow were used in seven and 13 patients, respectively. In the URD group, all 31 patients received allo-HCT from a bone marrow donor. The cumulative incidences of grades II to IV and III to IV acute GVHD on day 100 were 45% (90% confidence interval [CI]:26.9-63.1) and 15% in the MRD group, respectively. The primary endpoint was not achieved in the MRD group, although the dose of MMF in the MRD group (1.5g/day) was lower than the URD group (3g/day). In contrast, the cumulative incidences of grades II to IV and III to IV acute GVHD on day 100 were 19.4% (90%CI:8.0-30.8) and 6.5% in the URD group, respectively. The primary endpoint was achieved in the setting of allo-HCT form URD. In the MRD and URD groups, cumulative incidences of neutrophil engraftment were 94.7% and 96.8%, and the median times to neutrophil engraftment were 12 days (range:10–13) and 13 days (range:8–26), respectively. Although one patient in the MRD group and 3 patients in the URD group experienced secondary graft failure, all of them recovered with dose adjustment of myelosuppressive drugs including MMF. Grade 3 stomatitis occurred only in 10% of the MRD group and 13% of the URD group, and there was no grade 4 stomatitis in either group. The cumulative incidences of late onset acute GVHD and chronic GVHD at one year were 12.5% and 37.5% in the MRD group, and 7.4% and 29.6% in URD group, respectively. With a median follow-up of 589 days in surviving patients, 1-year overall survival was 89.1% in the MRD group and 86.0% in the URD group. The 1-year cumulative incidences of non-relapse mortality and relapse were 10.9% and 11.9% in the MRD group, and 6.5% and 31.6% in URD group, respectively. Conclusion Our study confirmed that GVHD prophylaxis with MMF plus CI was associated with earlier hematological recovery and less mucositis. The use of MMF (3g/day) plus tacrolimus was a feasible and effective option as GVHD prevention in allo-HCT from 7/8 or 8/8 HLA-matched URD. Further studies will be needed to clarify the optimal dose of MMF in allo-HCT from MRD. Disclosures: Nakane: Chugai Pharma: Travel/accommodations/meeting expenses Other. Off Label Use: CellCept (mycophenolate mofetil). This drug was a primary drug to be evaluated for GVHD prophylaxis in this study. Nakamae:Chugai Pharma: Travel/accommodations/meeting expenses Other. Hino:Chugai Pharma: Honoraria, Research Funding, Travel/accommodations/meeting expenses Other.

Allogeneic Hematopoietic Stem Cell Transplantation From Haploidentical Donor After Reduced Intensity Conditioning Regimen Allows Promising Disease Control In Patients With Hematological Diseases

IntroductionAllogeneic hematopoietic stem cell transplantation (Allo-HSCT) from haploidentical donors (HID) as alternative donor is currently increasing for patients with hematological diseases. In this setting, post Allo-HSCT high dose Cyclophosphamide (Cy) allows the use of T-repleted graft from HID by decreasing early alloreactive T-cell, leading to low incidences of graft-versus-host disease (GVHD) and non-relapse mortality. However, the efficacy of this procedure is still a matter of debate. The aims of this study were to evaluate the efficacy of HID Allo-HSCT in a comparison with our historical control cohort of patients transplanted from matched related or unrelated donors. Patients and methodsWe report here the experience of HID Allo-HSCT prepared by reduced intensity conditioning (RIC) regimen and post infusion Cy (HID group; n=60) and compared outcome to that of historical control cohort of patients with hematological diseases (n=220) who underwent RIC Allo-HSCT from matched related donors (MRD group; n=110) or unrelated donors (UD group; n=110). The control cohort received RIC regimen based on Fludarabine (150 mg/m2 total dose over 5 days), intravenous Busulfan (6.4 mg/kg total dose over 2 days) and antithymocyte globulin (ATG; Thymoglobulin; 5 mg/kg total dose over 2 days). To better compare the results between these two heterogeneous cohorts of patients including different hematological diseases, we used the disease risk index (DRI) score recently published (Armand at al., Blood, 2012).Patient characteristics are illustrated in the Table 1. Although HID and MRD/UD groups were significantly different regarding age and graft source, they presented with similar disease risk profile when classified according to the DRI and comorbidities according to the HCT-CI. [Display omitted] ResultsIn the HID group, day-100 acute GVHD, overall incidence of chronic GVHD and 2-year NRM were 21%, 9% and 15% respectively. Regarding the disease control, with a median follow up of 17 months (range: 5-50), the 2-year cumulative incidence of relapse (CIR) was 23%, which is similar to the MRD and UD control groups (2-year CIR: MRD 31%; UD: 18%). The 2-year PFS and OS were 62% and 68% respectively in the HID group, 52% and 66% respectively in the MRD group and 55% and 56% respectively in the UD group. ConclusionsThese results suggest that RIC Allo-HSCT from HID allows promising anti-tumor effect that is comparable to our previous experience of Allo-HSCT from MRD or UD. We also confirm the low toxicity profile after HID Allo-HSCT. Taken together, these observations suggest that HID is a valuable alternative for patients with hematological diseases but no available MRD or UD. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Expression of tumor suppressor genes in diet‐induced liver injury: a model of the control of gene expression by gene‐specific CpG island methylation

A methyl‐deficient diet (MDD), lacking choline and folate and low in methionine, causes liver injury in rats. We investigated the effects of epigenetic factors on hepatic gene expression in the MDD model. Weanling, male Fisher 344 rats were assigned to receive: 1) control diet for 12 weeks, 2) MDD for 12 weeks, or 3) MDD for 9 weeks followed by methyl repletion with control diet for 3 weeks (MRD). Hepatic RNA and DNA were isolated from 3 rats per dietary group. Gene expression was assessed by microarray and RT‐PCR. Gene‐specific methylation was assessed by pyrosequencing. Microarray analysis revealed ≥4‐fold increase in expression of over 150 genes in the MDD group compared with the controls. Decreased expression toward control levels was observed in the MRD group for most of these genes, and was associated with recovery from liver injury. Among the genes that followed this pattern of expression were the tumor suppressor genes, glutathione‐S‐transferase pi 1 (GSTP1) and metallothionein 2A (MT2A). Methylation patterns of gene specific CpG islands for GSTP1 and MT2A followed inverse trends, with decreased levels of methylation associated with increased gene expression in the MDD group compared with the control and MRD groups. This model of liver injury shows upregulation of tumor suppressor genes associated with diet‐induced suppression of DNA methylation.Funding: American Cancer Society