Matched Related Donor Recipients Research Articles

Allogeneic Hematopoietic Stem-Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen

Background: GATA2 deficiency is an increasingly recognized bone marrow failure syndrome responsible for: MonoMAC, monocytopenia with atypical mycobacterial infection (MAC); DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). GATA2 deficiency can be reversed by hematopoietic stem cell transplantation (HSCT). However, the intensity of conditioning required to ensure engraftment and reverse the myelodysplastic syndrome (MDS) characteristic of the disease remains controversial.Methods: We carried out a prospective study of allogeneic HSCT in 22 patients (mean age 26 years; range 17 to 45 years) with GATA2 deficiency, or the MonoMac syndrome, using a myeloablative, busulfan-based conditioning regimen. All 22 patients had MDS and two had AML. Eleven patients had clonal cytogenetic changes in the bone marrow. There were two matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor recipients. MRD and URD recipients received conditioning with 4 days of busulfan (days -6 to -3) to target an AUC between 3600 and 4800 min*microm/L and 4 days of fludarabine 40 mg/m2/day (days -6 to -3). Haploidentical related donor recipients received low-dose cyclophosphamide for two days (days -6 and -5), fludarabine 30 mg/m2/day for 5 days (days -6 to -2), 2-3 days of busulfan depending upon cytogenetics, along with 200 cGY total body irradiation (TBI) on day -1. MRD and URD recipients received tacrolimus and short course methotrexate for post-transplant graft-versus-host disease (GVHD) prophylaxis, whereas haploidentical recipients received high-dose post-transplant cyclophosphamide (PT/CY) followed by tacrolimus and mycophenolate mofetil for GVHD prophylaxis.Results: Nineteen of the 22 patients are alive with resolution of the clinical phenotype and correction of the bone marrow MDS with eradication of the cytogenetic changes at a median follow-up of 23 months (range, 6 to 48 months) giving an overall disease-free survival of 86 percent. The three deaths all occurred in the URD group. Of the three deaths, one resulted from refractory acute myelogenous leukemia (AML), and two from complications related to treatment for GVHD. There was a 26 percent incidence of grade III-IV acute GVHD (aGVHD) in the MRD and URD groups, and no grade III-IV aGVHD in the haploidentical related donor cohort. Similarly, there was a 46 percent incidence of chronic GVHD (cGVHD) in the MRD and URD cohort, whereas two of the 7 (28 percent) of the haploidentical related donor recipients had cGVHD.Conclusions: Despite overall disease-free survival of 86 percent with eradication of the clonal cytogenetic abnormalities in the bone marrow, GVHD remains a limitation in the MRD and URD cohorts treated with standard post-transplant tacrolimus/methotrexate prophylaxis for GVHD. We are currently de-escalating the busulfan dosing based on the AUC in all cohorts and incorporating PT/CY in the MRD and URD cohorts to decrease toxicity and reduce the incidence of aGVHD and cGVHD. Together with our previous studies using a nonmyeloablative regimen, it appears that when GATA2 deficiency patients are transplanted when they have a hypocellular bone marrow with MDS and without cytogenetic changes, a nonmyeloablative regimen results in reliable engraftment in GATA2 deficiency since the GATA2 deficient marrow has a proliferative disadvantage. However, with clonal progression and unfavorable cytogenetic changes and/or a hypercellular marrow, where the malignant clone has a proliferative advantage, a higher dose regimen results in more reliable engraftment and eradication of the clone. Studies to identify the precise level of conditioning for the stages of the disease are ongoing. DisclosuresNo relevant conflicts of interest to declare.

Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation for Pediatric Acute Myeloid Leukemia in the Contemporary Era

High risk or relapsed pediatric acute myeloid leukemia (AML) is potentially curable with allogeneic hematopoietic stem cell transplantation (HSCT). The use of a matched related donor (MRD) is the standard of care for these patients, but in the majority of patients a MRD is not available. Significant improvements have been made with supportive care practices, but there are limited outcome data for AML in pediatric patients transplanted in the contemporary era. We report retrospective results of HSCT in eighty-seven pediatric patients with high risk or relapsed AML performed at a single institution between 2008 and 2018. The median age at the time of HSCT was 8 years old (range: 0.6-20 years). More than 2/3rd of patients were in remission at time of HSCT with 43 patients (49%) transplanted in CR1 and 18 patients (21%) in CR2. Twenty six patients (30%) had active disease (defined as any evidence of disease) at the time of HSCT. Patients were transplanted using a matched related donor (MRD, n=21), a matched unrelated donor (MUD, n=25), a mismatched unrelated donor (MMUD, n=15), a haplo-identical donor (haplo, n=12) or an umbilical cord blood (UCB, n=14) graft. The majority of patients (78/87, 90%) received myeloablative conditioning while 9 patients (10%) received reduced intensity conditioning regimens. MRD and UCB graft recipients did not receive serotherapy. MUD, MMUD and haplo graft recipients (n=52) received serotherapy, the majority of whom received an alemtuzumab-based regimen, 42/52 (81%). Haplo-identical transplants were performed using CD34+ selected grafts. Three-year overall survival (OS) and disease free survival (DFS) for the entire cohort were 52% (95% CI: 41-62%) and 49% (95% CI: 38-59%) respectively. OS differed significantly according to disease status at time of transplant (p=0.018), with 3 year OS: 60%, (95% CI: 43-74%) for patients in CR1, 56%, (95% CI: 31-75%) for patients in CR2 and 34%, (95% CI: 17-52%) for patients with active disease. OS differed by donor type (p=0.058). OS was comparable for patients with MRD (71%, 95% CI: 46-86%) and 10/10 MUD (59%, 95% CI: 37-75%) (p=0.67). Patients with alternate donor sources had worse outcomes (MMUD 33%, 95% CI: 10-59%; UCB 43%, 95% CI: 18-66%; Haplo 33%, 95% CI: 10-59%) as compared to MRD (MMUD vs MRD, p=0.042, UCB vs MRD, p=0.046, haplo vs MRD p=0.017). There was a low incidence of Grade III-IV GVHD (8%, n=9) and extensive chronic GVHD (9%, n=7) likely secondary to the use of alemtuzumab-based conditioning regimens for MUD, MMUD and haplo donors. The 3-year non-relapse mortality was low at 11%, (95% CI: 5-19%). The primary cause of death was relapse, with a 3-year cumulative incidence of relapse of 40%, (95% CI: 30-50%). Patients with active disease at transplant had significantly higher cumulative incidence of relapse (sHR: 2.42, 95% CI: 1.18-4.95, p=0.016) compared to patients in remission. There was no difference in cumulative incidence of relapse between patients in CR1 and CR2 (p=0.598). In the contemporary era, outcomes after allogeneic HSCT are comparable for MRD and 10/10 MUD for pediatric AML. Myeloablative conditioning regimens that incorporated alemtuzumab were well tolerated with low rates of NRM and very low rates of acute and chronic GVHD. Relapse remains the major cause of treatment failure and future trials evaluating use of cellular therapies and targeted agents post-HSCT will be needed to improve current rates of relapse. Disclosures No relevant conflicts of interest to declare.

A Delayed Innate T Cell Reconstitution Is Associated with Epstein-Barr Virus Reactivation after Haploidentical Hematopoietic Stem Cell Transplantation Using Anti-Thymoglobulin and High-Dose Post-Transplant Cyclophosphamide

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) using a haploidentical donor (haplo-HCT) using post-transplant high-dose cyclophosphamide (PTCy) is increasingly used for patients lacking a matched related or unrelated donor. We recently noticed a relatively high incidence of infectious complications, especially Epstein-Barr virus (EBV) reactivation after haplo-HCT. However, the mechanisms underlying the increased incidence of this complication in the haplo-HCT setting are unknown. We hypothesized that the use of PTCy may be associated with a deficit in innate-like effector T cells essential for preventing EBV reactivation.This study aimed to analyze immune reconstitution following haplo-HCT using peripheral blood stem cells (PBSC) grafts and to evaluate the correlations with EBV reactivation and outcomes.Patients and Methods: One hundred and twenty-three consecutive patients who underwent allo-HCT for hematological malignancies between 2013 and 2016 were included in this single-center retrospective study. All patients received G-CSF mobilized PBSC grafts and ATG 2.5-5 mg/Kg total dose. All patients received a combination of cyclosporine A and mycophenolate mofetil for GvHD prophylaxis, except for patients with a matched related donor (MRD) who received cyclosporine A alone and patients with an haploidentical donor who received PTCy (50mg/kg/d at d3+/-d5). α/β T cells (CD3+, CD4+ and CD8+), γ/δ T cells (pan γ/δ and Vδ2+), mucosal-associated T cells wich express a highly restricted TCR comprising a semi-variant Vα7.2-Jα33 (MAIT), invariant NK T cells, NK cells, B cells, Tregs, monocytes subsets and dendritic cells (myeloid DC, plasmacytoid DC and Slan-DC) were analyzed by multi-color flow cytometry at months (M) 1, 3, 6 and 12 following allo-HCT. Clinical data [acute GvHD (aGvHD), relapse incidence, chronic GvHD (cGvHD), viral reactivations, bacterial and fungal infections, non-relapse mortality (NRM), progression-free survival (PFS), refined GvHD-free and progression-free survival (GPFS), overall survival (OS)] were assessed together with sequential quantitative evaluation of immune subsets.Results: Median age was 55 (range, 17-70) years, with 32 male patients (26%) receiving a graft from a female donor. Diagnoses were myeloid malignancies (66%) or lymphoid malignancies (34%). Thirty-three patients (27%) received a graft from a MRD, 65 from an unrelated donor (MUD, 53%), and 25 from a haplo-identical donor (20%). Thirty patients (24%) with refractory disease received a sequential conditioning regimen while the remaining (n=93, 76%) received a RIC/RTC regimen based on fludarabine, busulfan +/- thiotepa. At d180, the cumulative incidences (CIs) of grade II-IV and grade III-IV aGvHD were 34% and 5%, respectively. The 2 years CIs of cGvHD, extensive cGvHD and relapse were 23%, 8% and 17%, respectively. At 2 years, NRM was 7%, PFS was 77%, GPFS was 66% and OS was 83%. The rate of EBV reactivation was significantly increased in haplo-HCT recipients as compared to fully-matched donor recipients (respectively, 68% versus 26%, P< .001).At one month after allo-HCT, the median counts of all immune cells subsets (except monocytes) was significantly lower in haplo-HCT recipients as compared to MRD or MUD recipients. At 3 months, α/β T cells, iNK T cells, NK cells, B cells, Tregs and Slan-DC reached similar median counts in haplo-HCT recipients as compared to MRD or MUD recipients. In contrast, Vδ2+ T cells and MAIT cells median counts remained significantly lower at 3, 6 and 12 months in haplo-HCT recipients compared to MRD or MUD recipients (at M1, M3, M6, M12, the median Vδ2+ T cells counts were 0.05/µL, 0.24/µL, 1.38/µL and 2.97/µL, and MAIT cells were 0.07/µL, 0.70/µL, 1.00/µL and 1.21/µL, respectively). Lower Vδ2+ T-cells and MAIT cells counts at one month was associated with a significantly increased CI of EBV reactivation (respectively, P=.04 and P<.0001) in landmark study.Conclusion: Immunological reconstitution of innate T cells is significantly delayed after haplo-HCT and low-dose ATG and PTCy. This prolonged deficiency is associated with an increased risk of EBV reactivation. Development of new strategies for innate-T cells expansion are necessary after haplo-HCT. DisclosuresMohty:MaaT Pharma: Consultancy, Honoraria.

Allogeneic Hematopoietic Stem Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen

Allogeneic hematopoietic stem cell transplantation (HSCT) reverses the bone marrow failure syndrome due to GATA2 deficiency. The intensity of conditioning required to achieve reliable engraftment and prevent relapse remains unclear. Here, we describe the results of a prospective study of HSCT in 22 patients with GATA2 deficiency using a busulfan-based conditioning regimen. The study included 2 matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor (HRD) recipients. MRD and URD recipients received 4 days of busulfan and 4 days of fludarabine. HRD recipients received low-dose cyclophosphamide for 2 days, fludarabine for 5 days, 2 to 3 days of busulfan depending on cytogenetics, and 200 cGy total body irradiation. MRD and URD recipients received tacrolimus and short-course methotrexate for graft-versus-host disease (GVHD) prophylaxis. HRD recipients received high-dose post-transplant cyclophosphamide (PTCy) followed by tacrolimus and mycophenolate mofetil. At a median follow-up of 24 months (range, 9 to 50), 19 of 22 patients were alive with reversal of the disease phenotype and correction of the myelodysplastic syndrome, including eradication of cytogenetic abnormalities. Three patients died: 1 from refractory acute myelogenous leukemia, 1 from GVHD, and 1 from sepsis. There was a 26% incidence of grades III to IV acute GVHD in the MRD and URD groups and no grades III to IV acute GVHD in the HRD cohort. Similarly, there was a 46% incidence of chronic GVHD in the MRD and URD cohorts, whereas only 28% of HRD recipients developed chronic GVHD. Despite excellent overall disease-free survival (86%), GVHD remains a limitation using standard prophylaxis for GVHD. We are currently extending the use of PTCy to the MRD and URD cohorts to reduce GVHD.

Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Deficiency

Background:Mutations in the zinc finger transcription factor GATA2 are responsible for: MonoMAC, monocytopenia with atypical mycobacterial infection (MAC); DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). Allogeneic hematopoietic stem cell transplant (HSCT) represents the only definitive therapy for GATA2 deficiency.Methods: We carried out myeloablative allogeneic hematopoietic stem cell transplant (HSCT) on 24 patients (mean age 24.9 years; range 16 to 46 years) with mutations in GATA2, or the MonoMAC syndrome, during the preceding three years. Three matched related donor (MRD) recipients and 13 matched unrelated donor (URD) recipients received busulfan 3.2 mg/kg/day and fludarabine 40 mg/m2/day on day's -6, -5, -4, and -3. Eight haploidentical related donor recipients received cyclophosphamide 14.5 mg/kg on day's -6 and -5, fludarabine 30 mg/m2/day on day's -6 to -2, busulfan 3.2 mg/kg/day on day's -4 and -3, and 200 cGy TBI on day -1. The majority of the MRD and URD recipients (n=13) received tacrolimus and short course methotrexate post-transplant as graft-versus host disease (GVHD) prophylaxis; three URD, while three received post-transplant cyclophosphamide (PT/CY) on days + 3 and +4 followed by tacrolimus and mycophenolate mofetil as post-transplant immunosuppression for GVHD. All 8 haploidentical related donor recipients received PT/CY as described followed by tacrolimus/methotrexate.Results:Twenty-two of the 24 patients are alive and disease-free at a mean follow-up of 13 months (range, 2 to 36 months). One matched URD recipient died from persistent AML 110 days post-transplant, and one matched URD recipient died from GVHD 2 years post-transplant. Despite a previous history of MAC in 11 patients, including 3 patients with active MAC at the time of HSCT, there were no recurrences of MAC during or following HSCT. Similarly, 13 patients had MDS with cytogenetic abnormalities at the time of HSCT (trisomy 8, monosomy 7, 5q-, trisomy 1q), and all 13 had resolution of their cytogenetic abnormalities with no late relapses following HSCT. Three patients had lymphedema at the time of HSCT (Emberger syndrome), which was not reversed. Twenty-three of the 24 patients had complete reconstitution of the monocyte, NK, and B-lymphocyte compartments, which were severely deficient pre-transplant. One URD who received PT/CT had poor graft reconstitution and required a CD34+ donor cell boost three months post-transplant. Four of the 13 MRD and URD recipients who received tacrolimus/methotrexate developed grade III-IV acute GVHD, and 3 of the 7 who were more than one-year post-HSCT developed moderate to severe chronic GVHD. No haploidentical related donor recipient developed grade III-IV GVHD or moderate to severe chronic GVHD.Conclusions: Myeloablative HSCT in GATA2 deficiency results in uniform engraftment and reversal of the hematologic, cytogenetic, and clinical manifestations of clinical manifestations of GATA2 deficiency with low regimen-related toxicity, even in this cohort of patients with considerable co-morbidities. We are currently using PT/CY in MRD and URD recipients with normal, favorable, or intermediate cytogenetics with isolated trisomy 8 to reduce the incidence of acute and chronic GVHD. We anticipate that with HSCT earlier in the clinical course, before significant organ damage or clonal evolution of MDS to AML occurs, the outcome of allogeneic HSCT in patients with GATA2 deficiency will continue to improve. Haploidentical related donor transplant appears to be particularly well suited for this disease, especially when the disease presents as a hypocellular MDS with or without trisomy 8. DisclosuresNo relevant conflicts of interest to declare.

Transplantation from haploidentical donor is not inferior to that from identical sibling donor for patients with chronic myeloid leukemia in blast crisis or chronic phase from blast crisis.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for chronic myeloid leukemia (CML) patients in blast crisis (BC), and haploidentical donors (HID) are immediately available for most patients. We compared the outcomes of HID transplantation with those of matched related donor (MRD) transplantation in a cohort study. A total of 90 consecutive patients who received allogeneic HSCT because of CML-BC were investigated retrospectively. A total of 67 patients underwent transplantation from HID and 23 from MRD. Survival outcomes were compared between the two cohorts. Of the 90 patients, 86 patients were engrafted. Three-year overall survival (OS) and relapse-free survival (RFS) were comparable between HID and MRD recipients (OS: 60.0% vs 55.3%, respectively, P=.580; RFS: 51.1% vs 47.8%, respectively, P=.512). Three-year incidences of transplant-related mortality (TRM) and relapse did not differ between HID and MRD recipients (relapse: 21.0% vs 26.1%, respectively, P=.626; TRM: 27.9% vs 26.1%, respectively, P=.937). In multivariate analyses, previous chemotherapy history and not achieving CHR before HSCT are independent adverse predictors of OS. For CML-blast crisis or chronic phase from blast crisis patients, HID transplantation achieves comparable survival to MRD transplantation. HID donors can be regarded as regular donors for these special patients at selected centers.

Comparison of Post-Allogeneic Hematopoietic Cell Transplantation (HCT) Outcomes after Matched Related Donor Versus Matched Unrelated Donor HCT in Adults with Acute Lymphoblastic Leukemia

Allogeneic hematopoietic cell transplantation (HCT) is a potentially life-saving treatment for patients with acute lymphoblastic leukemia (ALL). About one-third of patients have a human leukocyte antigen (HLA) matched related donor (MRD), while the remaining two-thirds have either a fully HLA-matched (HLA-A, -B, -C, -DRB1 [8/8]) unrelated donor (MUD) or a MUD with a single HLA mismatch (7/8). Previous analyses by the CIBMTR have shown that MRD and MUD transplants produce similar survival outcomes for patients with acute myelogenous leukemia (AML) (Blood 2012; 119(17):3908-16), while donor source was an important predictor of outcomes in patients with myelodysplastic syndrome (MDS) (Blood 2013; 122(11):1974-82). Given that ALL represents the second most common indication for HCT, and recognizing the disease-specific nature of the impact of donor source on post-HCT outcomes previously described, we performed an analysis of outcomes after MRD versus MUD HCT in 1458 patients with ALL who underwent allogeneic HCT from 2000-2011 (MRD n=440, 8/8 MUD n=729, 7/8 MUD n=289). Median age was 37 years (18-69). Thirty-four percent were Philadelphia chromosome positive.Ten percent received reduced intensity conditioning (RIC). Twenty-three percent were transplanted in second complete remission (CR2).Seventy-four percent received peripheral blood stem cells. At 100 days post-HCT, the incidence of acute GVHD Grade B-D was significantly lower in MRD recipients than in 8/8 MUD or 7/8 MUD recipients (26%, 45%, 50%, respectively; p<0.001). In multivariate analysis, 8/8 MUD recipients had similar rates of transplant-related mortality (TRM) and overall survival (OS) (hazard ratio [HR] 1.16, p=0.225and HR 1.01, p=0.93, respectively) compared to MRD recipients; 7/8 MUD recipients had inferior TRM and OS when compared to both MRD recipients (HR 1.92, p<0.001 and HR 1.29, p=0.01, respectively) and 8/8 MUD recipients (HR 1.66, p<0.001 and HR 1.28, p=0.008, respectively).Recipients of peripheral blood transplants had inferior long-term survival (>24 months post-HCT) (HR=2.13, p=0.003) compared to bone marrow transplants. Compared to MRD, 8/8 MUD recipients had superior relapse rates (HR 0.77, p=0.02), while 7/8 MUD recipients had no difference (HR 0.75, p=0.05). There were no differences in leukemia-free survival (LFS) comparing 8/8 MUD recipients (HR 0.95, p=0.55) and 7/8 MUD recipients (HR 1.20, p=0.07) to MRD recipients (Table 2, Figure 1).Differences in survival were likely due to higher rates of acute GVHD and TRM in the 7/8 MUD group. We conclude that MRD and 8/8 MUD recipients have similar survival outcomes post-HCT, while 7/8 MUD recipients suffer inferior survival, demonstrating that donor source plays a large role in the quality of outcomes. While MRD remains the ideal donor source due to its lower incidence of acute GVHD,HCT from an 8/8 MUD is a good alternative to MRD transplant, given its comparable long-term survival outcomes. [Display omitted] [Display omitted] [Display omitted] DisclosuresSandmaier:Gilliad: Honoraria; ArevaMed: Honoraria; Jazz Pharmaceutical: Honoraria; Seattle Genetics: Honoraria; Abmit: Research Funding; Bellicum: Research Funding.

Recovery of CMV-Specific T Cells Following Alternative Donor Allogeneic Transplant with Post-Transplant Cyclophosphamide

Background: Post-transplant cyclophosphamide (PTCy) is increasingly used for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation (HCT) using alternative donors. However, immune reconstitution can be delayed posing an increased risk for CMV reactivation. We evaluated the outcomes of patients who received HCT-apheresis products comparing the impact of PTCy on lymphocyte recovery, CMV reactivation and CMV-specific CD8+ T cell recovery following haplo-identical (HAPLO), matched unrelated donor (MUD), and mismatched unrelated donor (mMUD) grafts vs. with conventional matched related donor (MRD) graft recipients.Methods: We examined 26 patients (median age, 49 years; range, 20-72 years) with advanced hematologic malignancies; n=5 (HAPLO); 6 (MRD); 15 (MUD). All patients received myeloablative conditioning regimens that was either busulfan- or total body irradiation (TBI)-based. PTCy (50 mg/kg/day) was administered on days +3 and +4 following HAPLO and on day +3 following MUD/mMUD transplant. Peripheral blood lymphocyte reconstitution and frequency of circulating CMV-directed CD8+ T cells was assessed (day ± 10 days) on post-transplant days +30, +60, and +90. Circulating anti-CMV T cell frequency was assessed using a phycoerythrin-tagged MHC dextramer against HLA-specific CMV pp65, IE-1, or pp50 peptides (Immudex; Copenhagen, DK) in combination with Tru-Count¨ tubes and fluorescent-labeled monoclonal antibodies against CD3, CD8, CD4, CD16/56, and CD19 (BD Biosciences; San Jose, CA). Anti-CMV CD8+ T cell immunity was defined as a CMV-dextramer (CMV/DEX) positive count of ≥7cells/ml. CMV reactivation was defined as a serologic titer of >500IU/mL. All patients with CMV reactivation received ganciclovir therapy until CMV titer became negative.Results: Day +30 total T cell recovery was significantly faster in MRD than CY-treated recipients (p=0.015) due principally to more robust CD8+ T cell recovery. CD4 T cell recovery remained below normal range in all groups through day +100. NK cells recovered to normal numbers at day +28 in all groups. Neither PTCy nor donor source significantly impacted the percentage of patients that recovered anti-CMV CD8+ T cells at each time interval (p = 0.8232). Excluding donors (D) and recipients (R) that were both negative, CMV/DEX+ T cells recovery was >7/mL in 4/5 MRD, 7/14 MUD, and 3/5 HAPLO by day +100. Among MRD recipients either D+ or R+ (n=5), 2 patients showed CMV reactivation within 40 days of transplant that was associated with <7 CMV/DEX+ T cells on day +30. Subsequent high (>90/mL) CMV/DEX T cell response in one patient shortened the duration of viremia to 10 days (vs. 16 days with poor responder) and 3 patients showed no CMV reactivation and a high CMV/DEX+ T cell response by day +60. For MUD CMV D+ and/or R+ recipients (n=14), 3 showed CMV reactivation within 50 days of transplant. All 3 patients had suboptimal CMV/DEX T cell response on day +30. Robust CMV/DEX+ T cell response on day +60 predicted shorter duration of viremia (20 days vs. average of 32 days). For HAPLO CMV D+ and/or R+ (n=5) recipients, 4 experienced CMV reactivation within 50 days of transplant. All patients had a <7 CMV/DEX+ T cells/mL +30. Robust CMV/DEX+ T cell response by day +60 was associated with shorter duration of viremia (range 7-21 days), while one patient with <7/mL CMV/DEX+ T cells had continued CMV viremia for 36 days.Conclusion: In this preliminary analysis, neither PTCy nor donor source significantly impacted the percentage of patients that recovered anti-CMV CD8+ T cells at each time interval. A weak CMV/DEX+ response (<7 cells/mL) on day +30 was consistent with increased risk of CMV reactivation (viremia) in all groups. A CMV/DEX+ T cell count ≥7 cells/mL was not immediately protective against CMV reactivation, but higher counts were associated with a shortened duration of viremia while on antiviral therapy. Conversely, subnormal counts were associated with a longer duration of viremia. This interim analysis suggests that CMV/DEX+ T cell enumeration is a useful biologic correlate for determining clinical response to antiviral therapy, and that donor-derived CMV specific T cell immunity is not further compromised with following PTCy in alternative donor HCT. DisclosuresNo relevant conflicts of interest to declare.

Use of Post-Transplant Cyclophosphamide (PTCy) with Mycophenolate Mofetil and Tacrolimus in HLA Matched Allogeneic Hematopoietic Cell Transplant Is Safe and Associated with Acceptable Transplant Outcomes

Background: The use of post-transplantation cyclophosphamide (PTCy) as a single agent for graft-versus-host disease (GVHD) prophylaxis in HLA matched transplant patients has had varied results. Two recent studies at Johns Hopkins University noted favorable incidences of both GVHD and non-relapse mortality (NRM) in both matched related and unrelated donor allogeneic hematopoietic cell transplant (allo-HCT) recipients (Kanakry CG, et al, JCO, 2013 and Kanakry CG et al, Blood, 2014). In contrast to this data, a phase II study at MD Anderson reported higher rates of grade II-IV acute GVHD and NRM, with worse overall survival in patients receiving PTCy as the sole GVHD prophylaxis compared to their matched cohort receiving a calcineurin-inhibitor (CNI) and methotrexate (MTX) as immunosuppression (Alousi AM et al, BBMT, 2015). Another study in Australia had to be stopped for safety reasons due to high GVHD and NRM when using PTCy as sole GVHD prophylaxis (Bradstock KF, BBMT, 2015). There is no published data on the use of MMF plus tacrolimus in combination with PTCy in HLA matched allo-HCT recipients. We hypothesized that addition of MMF and Tacrolimus to PTCy in HLA matched allo-HCT recipients will lead to significantly improved transplant outcomes. To answer this question we retrospectively analyzed data from patients who received this regimen at a single institution.Methods. We performed a retrospective analysis of 31 HLA matched allo-HCT patients who received PTCy at 50 mg/m2 on days +3 and +4 in addition to MMF and tacrolimus immunosuppression from December 2012 till June 2015 at Washington University School of Medicine in Saint Louis. All of these patients received G-CSF mobilized peripheral blood grafts. Patients included AML (n=13), ALL (n=5), MDS (n=5), CML (n=2), aplastic anemia (n=2) and NHL (n=1), myelofibrosis (n=1). Twelve of the patients underwent a matched related donor (MRD) transplant and 19 underwent a matched unrelated donor (MUD) transplant. Two of the MUD transplants had a HLA match grade of 8 of 10 and the other 17 were a 10 out of 10 match. Twenty-eight of the patients received a graft collected via peripheral blood stem cell mobilization and the other three had a donor graft collected via bone marrow harvest. Cumulative incidence of aGVHD was estimated using Gray's sub-distribution method to account for death without aGVHD as a competing event, and the cumulative incidences of non-relapse mortality (NRM) and relapse were estimated treating each other as competing event, while OS was estimated using Kaplan-Meier limit method.Results: This regimen was associated with acceptable GVHD in our patients. Incidence of grade II-IV acute GVHD was 28% (21.3% for MRD; 31.5% for MUD) at day 100 and 28% at 1 year. Incidence of Grade III-IV acute GVHD was 13.5% at both 100 days and 1 year. Limited chronic GVHD was 25.9% and extensive GVHD was 14.8% at 1 year. Similarly we found acceptable NRM and relapse in these patients, NRM was 10.2% and 19.7% at 100 days and 1 year respectively and cumulative incidence of relapse at 100 days and 1 year were 17.8% and 29.0% respectively. Overall survival at 1 year for all patients was 52%.Summary: Here we report favorable results from a regimen combining MMF and Tacrolimus on PTCy platform in HLA matched MRD and MUD transplant recipients. Relatively low GVHD and NRM results are particularly encouraging in view of almost exclusive use of G-CSF mobilized T cell replete grafts with much higher T cell content. Though limited by the relatively small number of patients, our results suggest combining MMF plus Tacrolimus with PTCy platform in HLA matched allogeneic transplant patients is safe and associated with acceptable transplant outcomes. DisclosuresVij:Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Uy:Novartis: Research Funding. Abboud:Teva Pharmaceuticals: Research Funding; Gerson Lehman Group: Consultancy; Merck: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Schroeder:Celgene: Other: Azacitidine provided for this trial by Celgene; Incyte: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy.

The Hierarchy of Alternative Donors for Allogeneic Hematopoietic Stem Cell Transplantation in Poor Risk AML in CR1: 10/10 Matched Unrelated Donors Still to be Preferred over Haplo-Identical Donors or Umbilical Cord Blood

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the most effective post-remission treatment (PRT) for prevention of relapse in poor risk acute myeloid leukemia (AML) in first complete remission (CR1). Most patients, however, lack a human leukocyte antigen (HLA) matched related donor (MRD). For these patients, 10/10 or 9/10 HLA-matched adult unrelated donors (MUDs) are considered preferred alternative donors, but results with haplo-identical donors (haplo) and alloHSCT using umbilical cord blood (UCBT) have gradually improved the last decade and these alternative donors/stem cells sources, with the advantage of rapid availability, are increasingly being applied. We set out to compare outcome in poor risk AML patients in CR1 proceeding to PRT by alloHSCT using either MRD, 10/10 or 9/10 MUDs, haplo or UCBT in order to establish the hierarchy of alternative donors/stem cell sources.2850 adult patients, transplanted between 2000 and 2012 and reported to the EBMT Acute Leukemia Working Party, with poor risk AML in CR1 receiving an alloHSCT using MRD (n=1716) or alternative donors, including 10/10 (n=635) or 9/10 MUDs (n=260), UCBT (n=142), or haplo (n=97) were eligible for this analysis. Poor risk AML was defined as either no CR after one cycle of induction chemotherapy, white blood cell count >100 x 109/L at diagnosis, or cytogenetic/molecular abnormalities associated with adverse risk, according to European LeukemiaNET classification. Endpoints of the study included 3-year overall survival (OS), relapse-free survival (RFS), and cumulative incidences of relapse and non-relapse mortality (NRM). Patient characteristics as well as time intervals from diagnosis to CR1 and from CR1 to transplant were evaluated and included in a multivariable analysis.Patient characteristics revealed no differences between the treatment groups with respect to the risk status of underlying AML. Recipients of haplo alloHSCT and UCBT were younger than MRD alloHSCT recipients (median ages, respectively, 43 and 45 versus 48 years, p<0.0001). The time interval from diagnosis to CR1 was longer for recipients of haplo alloHSCT as compared to MRD, MUD, or UCBT recipients (respectively: 65 versus 54, 51, and 55 days, p=0.013). The time interval between CR1 and transplant was longer for recipients of 10/10 and 9/10 MUD alloHSCT (respectively 113 and 137 days) as compared to UCBT (111 days) and haplo alloHSCT (106 days) versus MRD alloHSCT (79 days) (p<0.0001). 51% of patients needed more than 1 cycle of chemotherapy to obtain CR1 in all subgroups according to type of donor. Alternative donors were more frequently used in the recent years as compared to MRDs. Both reduced intensity conditioning and myeloablative conditioning (MAC) were applied, with a higher percentage of MAC in recipients of haplo alloHSCT (67%) and MRD alloHSCT (62%) versus patients receiving MUD alloHSCT (50%) and UCBT (44%). Prevention of GVHD differed, with more patients receiving in-vivo T-cell depletion before MUD and haplo alloHSCT (respectively 76% and 77%) versus 23% in MRD alloHSCT and 33% in UCBT.3 year OS following MRD alloHSCT was 56%, which did not differ from 10/10 MUD alloHSCT, but which differed significantly from 9/10 MUD (45%), UCBT (44%), and haplo alloHSCT (49%) (p=0.0007). Multivariable analysis confirmed the impact of type of donor and also showed that higher age and longer time from diagnosis to CR1 adversely impacted on OS. A longer time from CR1 to transplant was associated with better OS and less relapse. 3 year RFS was 51% and 50% following MRD and 10/10 MUD alloHSCT, respectively, which was significantly (p=0.0009) better than following UCBT (35%), haplo alloHSCT (39%), or 9/10 MUD alloHSCT (42%). NRM depended on donor type and estimated 36% and 25% after haplo alloHSCT and UCBT, respectively, versus 15% following MRD alloHSCT at 3 years. Relapse did not significantly differ by donor type in multivariable analysis.Collectively, these results suggest that alloHSCT with MRDs and 10/10 MUDs may still be preferred in patient with poor risk AML in CR1. Due to higher NRM, recipients of 9/10 MUD, UCBT, or haplo each showed a significant reduction of approximately 10% in OS and RFS as compared to MRD and 10/10 MUD alloHSCT. Therefore, the urge to immediately proceed to alloHSCT in poor risk AML might favor UCBT or haplo if the identification of 9/10 MUD is expected to be prolonged for months and a MRD or 10/10 MUD is not available. DisclosuresNo relevant conflicts of interest to declare.

Ultra Low-Dose IL-2 for GVHD Prophylaxis after Allogeneic Hematopoietic Stem Cell Transplantation Mediates Expansion of Regulatory T Cells without Diminishing Antiviral and Antileukemic Activity

GVHD after allogeneic hematopoietic stem cell transplantation (alloSCT) has been associated with low numbers of circulating CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs). Because Tregs express high levels of the interleukin (IL)-2 receptor, they may selectively expand in vivo in response to doses of IL-2 insufficient to stimulate T effector T-cell populations, thereby preventing GVHD. We prospectively evaluated the effects of ultra low-dose (ULD) IL-2 injections on Treg recovery in pediatric patients after alloSCT and compared this recovery with Treg reconstitution post alloSCT in patients without IL-2. Sixteen recipients of related (n = 12) or unrelated (n = 4) donor grafts received ULD IL-2 post hematopoietic stem cell transplantation (HSCT; 100,000-200,000 IU/m(2) ×3 per week), starting <day 30 and continuing for 6 to 12 weeks. No grade 3/4 toxicities were associated with ULD IL-2. CD4(+)CD25(+)FoxP3(+) Tregs increased from a mean of 4.8% (range, 0%-11.0%) pre IL-2 to 11.1% (range, 1.2%-31.1%) following therapy, with the greatest change occurring in the recipients of matched related donor (MRD) transplants. No IL-2 patients developed grade 2-4 acute GVHD (aGVHD), compared with 4 of 33 (12%) of the comparator group who did not receive IL-2. IL-2 recipients retained T cells reactive to viral and leukemia antigens, and in the MRD recipients, only 2 of 13 (15%) of the IL-2 patients developed viral infections versus 63% of the comparator group (P = 0.022). Hence, ULD IL-2 is well tolerated, expands a Treg population in vivo, and may be associated with a lower incidence of viral infections and GVHD.

Immune Reconstitution In Anti-Thymocyte Globulin Conditioned Unrelated Donor Stem Cell Transplantation

Anti-thymocyte globulin (ATG) is widely used for in vivo T cell depletion and immunomodulation in unrelated donor (URD) stem cell transplantation (SCT) to reduce the risk of graft vs. host disease (GVHD). However, despite the reduction in GVHD risk, outcomes are generally not superior to matched related donor (MRD) SCT conditioned without ATG. This is primarily because of defective immune reconstitution and high rates of opportunistic infections in ATG recipients. We have previously reported equivalent outcomes in URD SCT recipients conditioned with ATG when compared to MRD recipients. We now report immune reconstitution in an expanded cohort of these patients. Patients with AML, ALL, MDS, MPD (n=142) transplanted between 2004 and 2011 were included in this retrospective review. Seventy eight received either bone marrow or peripheral blood stem cell (PBSC) grafts from URD and received either 10 or 7.5 mg/kg rabbit ATG (Thymoglobulin, Sanofi-Aventis) during conditioning, those with MRD did not. Conditioning was myeloablative in all patients. Lymphoid recovery was equivalent in the two cohorts during the first year following SCT except in the first month (Figure), when URD recipients had lower absolute lymphocyte count (μ-URD=0.6x103/ μ L, μ-MRD=1.1; repeated measures mixed model p=0.022). Age, CD3/34 cell dose infused, stem cell source and conditioning intensity were not associated with ALC recovery post transplant. In a subset of patients lymphocyte subset enumeration was performed following withdrawal of immunosuppression, at an average 237 days post-SCT. ATG recipients had significantly lower mean CD4+ counts (μ-URD=267 (n=30), μ-MRD =434/ μ L (n=27); ANCOVA p = 0.003), however no significant differences were observed in CD3+, CD8+, CD19+ or CD56+ cell recovery. ATG recipients were significantly more likely to have complete donor T cell chimerism at 1 (OR = 12.5, CI= 2.4, 66.0, p = 0.001) and 2 months post-SCT (OR = 6.5 , CI=1.5, 27.4, p = 0.013), however by 9 months following SCT this trend had reversed with a greater likelihood of mixed T cell chimerism (OR > 100; p = 0.017), suggesting re-emergence of recipient derived T cell clones. Consequently, donor lymphocyte infusions were given significantly more often to ATG recipients (12/78) than to non-recipients (2/64) (OR = 5.64, CI = 1.21, 26.20, p=0.027). High grade CMV viremia (1000 copies/ μL) was significantly more likely in CMV sero-positive ATG recipients (n=18/55) than in non-recipients (n=7/48) (OR = 2.8, CI 1.1, 7.6, p = 0.032). Reduced intensity conditioning and PBSC were associated with higher CMV reactivation in ATG recipients and there was a lower likelihood of survival in these individuals than in those who did not receive ATG (HR: 0.53, CI: 0.31, 0.92; p = 0.024). EBV reactivation was observed more often in susceptible ATG recipients (n=22/58) than in non-recipients (n=5/43), (OR=4.6, CI=1.6, 13.6, p= 0.003). The median peak EBV viral load in ATG recipients (u=1545 copies/ μL, IQR: 288, 2,302) was significantly higher than in non-recipients (u=120 IQR: 57, 169, p = 0.005). PBSC stem cell source (p = 0.049) and HLA mismatch (p =< 0.001) were associated with EBV reactivation in ATG recipients but not in non-recipients. ATG recipients were also more likely to experience a fungal infection (OR=2.8, CI=1.1, 6.7, p=0.023). 1-month ALC was predictive of disease free survival whereby it had a significant negative effect on relapse (HR = 0.33; 95% CI: 0.16, 0.66; p = 0.002). As 1-month ALC increased by one-tenth, the odds of relapse decreased by over 3% and survival increased by 3%. In conclusion, high doses of ATG used during conditioning are associated with an early retardation of lymphoid recovery post-SCT, and with late mixed T cell chimerism accompanied by a delay in CD4+ T cell recovery. This is associated with a higher rate of viral reactivation in PBSC recipients and of fungal infections in general. Lower doses of ATG should be used in SCT and in ATG conditioned SCT, early intervention with DLI, particularly CD8+ cell depleted DLI as reported by others, may help restore T cell repertoire and improve SCT outcomes and survival. [Display omitted] Disclosures:Toor:Sanofi Avnetis: Research Funding.

Unrelated Donor Transplants for Older AML Patients Using a Low Dose TBI Containing Regimen Are As Efficacious As Related Donor Transplants, and Exhibit Favorable Outcomes for Intermediate Risk Disease.

Abstract 3119Hematopoietic stem cell transplants (HCT) for older patients with acute myelogenous leukemia (AML) have increased significantly over the past decade, associated with the use of reduced intensity conditioning (RIC) regimen. In the unrelated donor (URD) setting, anti-thymocyte globulin (ATG) has routinely been used to improve engraftment and decrease the incidence and severity of graft versus host disease (GVHD). We hypothesized that replacing ATG with low dose total body irradiation (TBI) during conditioning would provide sufficient immunosuppression to permit engraftment in older patients undergoing unrelated donor transplants for AML. Outcome data, including engraftment and GVHD rates were then compared to similar patients undergoing matched related donor (MRD) HCT for AML. Methods:Between 2007–2012, 50 patients (55–70 years, median 61 years) with AML in CR1 (n=41) or >CR1 (n=9) were prospectively enrolled on an IRB-approved clinical trial using a RIC regimen. Donors were either MRD (n=23), or URD (n=27) if a suitable MRD was not available. HLA matched donors were available in 39 of the 50 patients, with single antigen mismatched donors used in 11 (41%) URD cases. All patients were conditioned with fludarabine (160 mg/m2) + busulfan (6.4 mg/m2) [FluBu2]; URD recipients additionally received 200cGy TBI on day -1 pre-transplant. GVHD prophylaxis was tacrolimus and mycophenolate. Patients exhibited high risk (n=21) or intermediate risk (n=29) disease at initial diagnosis, as defined by cytogenetic and molecular criteria. High risk (HR) patients included those with either a FLT3 mutation, monosomy 5 or 7, 5q-, 7q-, t(6:9) or complex cytogenetics (> 3 abnormalities). Patients with t(8:21), t(16:16) or inv 16 were excluded from analysis. Stem cell sources included peripheral stem cells (n=49) or marrow (n=1). Results:For the entire cohort, the 1y and 3y relapse free survival (RFS) was 56% (95% CI: 43–69) and 43% (95% CI: 28–58) respectively, with 1y and 3y overall survival (OS) rates 58% (95% CI:46–74) and 44% (95% CI: 27–62%). There was no significant difference in 1y RFS between URD and MRD recipients [62±9.5% vs 48±11%] or 3y RFS [44±11% vs 40±12%], p = 0.42 (Figure). There was no difference in outcome by age, with 3y RFS 42.5±11% for patients 55–59 yrs (n=20) and 40±12% for patients 60–70 yrs (n=30), p =0.54. The median donor age was 37 yrs (range 19–50) for URD and 58 yrs (range 42–70) for MRD recipients. The median CD34 cell dose infused was 5.0 × 10(6)/kg in both cohorts [range URD: 1.2 –8.3 × 10(6), MRD: 1.9 –9.8 × 10(6)]. There was no difference in time to neutrophil engraftment, with both cohorts engrafting a median 12 days post-transplant. Primary graft failure occurred in 1 (3.4%) URD recipient, who received an HLA mismatched graft. No cases of secondary graft failure occurred in either cohort. Day 100 CD33 chimerism was all donor in all URD cases, and in 75% of MRD recipients. Grade 2–4 acute GVHD developed in 44% URD and 30% MRD respectively, with grade 3–4 acute GVHD in 7% URD and 10% MRD. Patients with intermediate risk disease experienced 1y and 3y RFS of 74±8.5% and 3-year RFS 62±10.5%, respectively. By comparison, transplant outcomes were poor for patients with high risk disease, with 1y and 3y RFS only 31±10% and 13±10% (Figure). Conclusion:Replacing ATG with low dose TBI in older AML patients undergoing RIC URD does not appear to compromise engraftment or increase GVHD rates. Survival is similar to that experienced by MRD recipients who are transplanted without either ATG or TBI. RFS for patients with high risk AML was poor, but patients with intermediate risk AML may benefit from this strategy when compared to historical results with non-transplant approaches for this patient population. [Display omitted] [Display omitted] Disclosures:Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; B.M.S.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Couriel:Therakos: Speakers Bureau; Merck: Speakers Bureau.

A Phase II Study of Allogeneic Transplantation for Older Patients with AML in First Complete Remission Using a Reduced Intensity Conditioning Regimen: Results From CALGB 100103/BMT CTN 0502

AbstractAbstract 230▪▪This icon denotes a clinically relevant abstractThe prognosis for patients (pts) with acute myeloid leukemia (AML) who are aged 60 years or older at the time of initial diagnosis is poor. Even for pts achieving a first complete remission (CR1), prospects for long-term survival are poor due to the very high risk of relapse. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with conventional chemotherapy when performed in younger pts with AML in CR1. However, the toxicity of this approach in older pts is prohibitive. A reduced intensity conditioning (RIC) regimen may mitigate the risk of early toxicity and while early results in older AML pts have been encouraging and suggest disease free survival (DFS) rates above 30% at 3 yrs (Farag et al, Biol Blood Marrow Transplant 2011), most data are retrospective and pts have not been treated uniformly. We therefore sought to determine the effectiveness of a uniform RIC regimen given to older pts with AML in CR1 on a prospective multi-center phase II trial conducted by the Alliance (formerly Cancer and Leukemia Group B (CALGB)) and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The study, activated in 2004, was initially limited to recipients of a matched related donor (MRD) graft but was amended in 2006 to include matched unrelated donor grafts (URD). The primary endpoint of the study was 2-year DFS. We hypothesized that DFS at 2-years would exceed 20% and powered the study to detect a 2-year DFS probability of 35% for URD recipients. We focused the primary analysis on URD recipients since the majority of older pts require an URD graft. Eligible pts were from 60–74 years old inclusive, had AML in CR1 following induction chemotherapy, availability of a 6/6 MRD or 8/8 URD, and absence of significant end-organ damage prior to transplantation. Adverse events (AE) were initially recorded according to NCI-CTCAE v3.0, amended to v4.0 in 10/2010. Accrual was completed in 12/2011. 132 pts were registered at 21 centers and 123 transplanted (MRD (47%); URD (53%). All donor grafts were mobilized and collected following G-CSF (PBSC). The median age of pts was 65 (range 60–74) and 76 pts (62%) were male. At diagnosis, 67% had an intermediate risk karyotype, 20% adverse risk, <1% favorable, and in 11% data were missing. More than 90% achieved CR following standard “7+3” based induction. CR1 was achieved after 1 (59%) or 2 (41%) induction cycles. Consolidation therapy was administered for one (50%) or two (24%) cycles and 17% received no consolidation with data missing in 9%. All but the initial 8 MRD recipients (who received fludarabine and busulfan alone) were conditioned with the same regimen containing fludarabine (30mg/m2/day × 5), busulfan (6.4mg/kg IV total dose), and antithymocyte globulin (ATG; thymoglobulin) (7.5mg/kg total dose). Only one case of primary graft failure was reported. With a median follow-up of 3.3 yrs, the results in the 123 transplanted pts are depicted below:EventCumulative incidence at 100 days* or 2yrs†95% CIAcute GVHD 2-49.4%*4.1–15%Acute GVHD 3-43.4%*1.2–6.7%Chronic GVHD26%†17–34%Relapse47%†37–57%Treatment related mortality (TRM)14%†7.2–21%EventProbability at 2 yrs95% CIDFS39%30–50%DFS URD only38%26–55%Overall survival (all pts)46%36–57%The rates of both acute and chronic GVHD as well as TRM were relatively low. There were 81 grade 3–5 non-hematologic AE recorded, including 7 grade 5 (4 infections, 1 each cardiac, pulmonary, and second malignancy). Relapse was the most common cause of death. In conclusion, the results of this first prospective US cooperative group trial conducted in a homogeneously treated group of older AML patients in CR1 demonstrate the feasibility and effectiveness of RIC allografting using MRD or URD PBSC grafts. DFS appears better following a RIC allograft compared to results achieved historically after conventional therapies, warranting prospective comparison in pts with contemporary cytogenetic and molecular disease characterization. Future research should also focus on preventing disease relapse after RIC allografting in this population. Disclosures:Devine:Sanofi: Honoraria, Research Funding. Off Label Use: Antithymocyte globulin for GVHD prophylaxis is included in the abstract. Vij:Millennium: Speakers Bureau. Shea:Otsuka: Research Funding.

Excellent survival after sibling or unrelated donor stem cell transplantation for chronic granulomatous disease

Matched related donor (MRD) hematopoietic stem cell transplantation (HSCT) is a successful treatment for chronic granulomatous disease (CGD), but the safety and efficacy of HSCT from unrelated donors is less certain. We evaluated the outcomes and overall survival in patients with CGD after HSCT. We report the outcomes for 11 children undergoing HSCT from an MRD (n = 4) or an HLA-matched unrelated donor (MUD) (n = 7); 9 children were boys, and the median age was 3.8 years (range, 1-13 years). We treated both X-linked (n = 9) and autosomal recessive (n = 2) disease. Nine children had serious clinical infections before transplantation. The conditioning regimens contained busulfan, cyclophosphamide, cytarabine, or fludarabine according to the donor used. All patients received alemtuzumab (anti-CD52 antibody). Additional graft-versus-host disease (GvHD) prophylaxis included cyclosporine and methotrexate for MUD recipients and cyclosporine and prednisone for MRD recipients. Neutrophil recovery took a median of 16 days (range, 12-40 days) and 18 days (range, 13-24 days) for MRD and MUD recipients, respectively. Full donor neutrophil engraftment occurred in 9 patients, and 2 had stable mixed chimerism; all patients had sustained correction of neutrophil oxidative burst defect. Four patients had grade I skin acute GVHD responding to topical treatment. No patient had grade II to IV acute GvHD or chronic GvHD. All patients are alive between 1 and 8 years after HSCT. For CGD, equivalent outcomes can be obtained with MRD or MUD stem cells, and HSCT should be considered an early treatment option.

Use of Rabbit Anti-Thymocyte Globulin for Conditioning in Matched Unrelated Donor Hematopoietic Cell Transplantation Provides Comparable Dose Dependant Outcomes to Matched Related Donor Recipients

Use of Rabbit Anti-Thymocyte Globulin for Conditioning in Matched Unrelated Donor Hematopoietic Cell Transplantation Provides Comparable Dose Dependant Outcomes to Matched Related Donor Recipients

A Retrospective Study of Alemtuzumab Level, T Cell Chimerism and Graft Versus Host Disease Using Intermediate Dose Alemtuzumab for Matched Related and Matched Unrelated Reduced Intensity Transplantation.

Abstract 3333Poster Board III-221Alemtuzumab (CAMPATH 1H) is a well established agent for effecting in vivo T cell depletion and prevention of GVHD in reduced intensity transplants. Many studies indicate that full dose alemtuzumab (100mg in 5 daily doses of 20mg) induces profound immunodeficiency, almost completely ablating GVHD in Fludarabine and Melphalan (FM) matched related donor (MRD) and matched unrelated donor (MUD) transplants. In contrast, FM conditioning alone exposes patients to a high burden of acute and chronic GVHD. Accordingly, many transplant centres have adopted policies of intermediate alemtuzumab dosing of 50mg or less. While the pharmacokinetics, rate of T cell engraftment and incidence of GVHD are well described using full dose alemtuzumab, much less is known about the in vivo action of alemtuzumab at intermediate doses. MethodsWe report our experience of alemtuzumab at 30mg (day -2) for MRD and 60mg (30mg day -4 and day -2) for MUD transplants, which was adopted as standard GVHD prophylaxis for FM transplantation at our centre in 2006. We avoided giving alemtuzumab on day -1, since there is a steep drop in alemtuzumab level in the first 24 hours after infusion and the timing of stem cell infusion may vary considerably, especially with unrelated donor grafts. From May 2006 to May 2009, 24 patients received MRD and 27 patients received MUD transplants. Post transplant serum samples were available from 19 MRD transplants and 15 MUD transplants at day +1. In addition, day +3 samples were identified from 10 patients previously transplanted with 100mg alemtuzumab, 10 MUD receiving 60mg and 10 MRD transplants receiving 30mg. All patients gave consent for clinical follow up and post transplant serum sampling for research purposes, according to protocols approved by the local research ethics committee of Northumberland and North Tyneside. Alemtuzumab concentration was measured by a validated flow cytometry assay, as previously described. ResultsThe mean (SEM) alemtuzumab concentration (micrograms/ml) on day +1 was 2.9 (0.3) after 30mg and 4.6 (0.6) after 60mg (t test p<0.01). On day +3 the levels were 2.4 (0.2); 4.0 (0.6); 8.4 (1.9) after 30mg, 60mg and historical controls of 100mg, respectively (p<0.05 between each dosing level). There were significant inverse correlations between patient surface area and alemtuzumab concentration by linear regression for both 30mg (r2 0.51 p<0.01) and 60mg dosing (r2 0.18 p<0.05). A trend for lower alemtuzumab with increasing cell dose was also observed, although this may be related indirectly to patient weight. All patients achieved >95% myeloid engraftment by day 100. Median (range) T cell engraftment was variable and significantly higher after MUD transplants: 70% (9-99%) than MRD transplants: 21% (5-85%; Mann Witney p <0.05). T cell chimerism was inversely correlated with alemtuzumab level in MRD transplants by linear regression (r2 0.37; p <0.05) but this trend was not apparent in MUD transplants. The incidence of acute GVHD was also greater after MUD transplantation at 47% (grade I or II) compared with 11% (grade I only) for MRD recipients. There was no significant relationship between GVHD grade and alemtuzumab level in either group. There were 2/24 non-relapse deaths after MRD and 3/27 following MUD transplantation; none were due to GVHD. The incidence of chronic GVHD is currently being evaluated. ConclusionThis analysis demonstrates predictable dose and surface-area relationships with alemtuzumab level in patients receiving FM conditioning. It also reveals that significantly less than 100mg alemtuzumab confers reliable GVHD prophylaxis in both MRD and MUD recipients, although at least twice the level of alemtuzumab is required to achieve comparable GVHD control in MUD transplants. Finally, it is notable that T cell chimerism at day 100 is directly related to alemtuzumab level at day +1 in MRD transplants. We conclude that optimisation of immune reconstitution and GVHD control using alemtuzumab in vivo depends upon due consideration of both recipient and donor factors, notably the size of the recipient and the origin of the graft. DisclosuresGroves:BioAnaLab: Employment. Hale:BioAnaLab: Employment, Equity Ownership.

A Retrospective Study of Patients Treated with Imatinib Mesylate Prior to Allogeneic Hematopoietic Stem Cell Transplant.

A retrospective study of CML allogeneic hematopoietic stem cell transplants (HSCT) at the FHCRC from January 2001 to April 2004 was conducted to address the impact of pre-transplant imatinib mesylate (IM) therapy on early treatment toxicity, non-relapse mortality (NRM), overall survival (OS), and relapse. Forty-eight patients, median age 40 years (range, 20–64), received IM prior to transplantation for a median duration of 9.5 months (range, 3–30). Twenty-nine patients received unrelated or mismatched donor HSCT and 19 patients received matched related donor (MRD) HSCT. Forty-four patients were in chronic phase (CP) and 4 patients in accelerated phase (AP) at the time of diagnosis and IM initiation. At transplantation 28 patients were in CP, 14 in AP, 3 in blast crisis (BC) remission, and 3 in BC. Patients were conditioned with busulfan and cytoxan (35) and cytoxan and total body irradiation (13). The median time to neutrophil engraftment for all patients was 16 days (range, 11–33). Median average bilirubin to day 20 and median maximum bilirubin to day 20 were used as an indicator of early transplant hepatotoxicity. These values were 1.0 (range 0.4–5.4) and 1.6 (range 0.6–11.4) for all patients, respectively. Among 48 patients 8 deaths occurred due to poor engraftment (1), diffuse alveolar hemorrhage (1), pneumonia (1), acute GVHD (2), myocardial infarction (1), refractory ITP (1), and fungal infection (1). Only one relapse occurred on day 553 in a CP patient who had no response to IM after 6 months of therapy prior to HSCT. For all patients 100-day survival was 92% (95%CI, 84–99%), one-year survival 85% (95% CI, 74–97%), and 1.5-year survival 73% (95%CI, 54–92%) with a median follow-up of 333 days (range 97–912 days). One of 19 MRD recipients died (at day 440) with a median follow-up among survivors of 291 days. One-year survival for unrelated or mismatched donor recipients was 77% (95% CI, 60–94%). One-year survival was 93% (median follow-up 345 days) for 28 CP patients and 70% (median follow-up 308 days) for 14 AP and 3 BC remission patients. All three patients transplanted in blast crisis are alive (follow-up 115–465 days). There was a suggestive association between time from diagnosis to transplant and mortality (P=0.10) for all patients. To assess the impact of IM response at transplant, patients were assigned to 1 of 5 response groups. One of 13 patients transplanted in complete cytogenetic response (CCyR) died (median follow-up 291 days). None of 9 patients (7 CP and 2 AP) with a major cytogenetic response (MCyR) to IM died (median follow-up 344 days). Three of 10 patients (2/8 CP and 1/2 AP) with no response to IM or with evidence of cytogenetic or hematologic relapse died (median follow-up 467 days). Two of 10 patients with evidence of clonal evolution on IM (median follow-up 354 days) and 2/6 patients who progressed to BC on IM (median follow-up 341 days) died.CONCLUSION: For all patients acute hepatotoxicity, one-year OS, and NRM appear similar to our Center's historical data. Patients achieving a CCyR or MCyR after IM therapy did particularly well, perhaps due to CP disease at HSCT and the shorter time to transplant (9 mo, range 3–29 mo). Poor IM response may serve as an indicator of poorer transplant outcome; however, more advanced disease at and longer time to transplantation (32 months, range 4–118 months) alone may explain the more adverse outcome.