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Purpose To study whether institutional clinical trial accrual volume affects clinical outcomes of younger (age less than 61 years) patients with acute myeloid leukemia. Patients and methods We investigated the impact of clinical trial accrual on response rates, early mortality and survival in patients with AML enrolled between 2002 and 2009 into two parallel cooperative group clinical trials SWOG S0106/ECOG-ACRIN E1900. Institutions were classified as low- (LAIs) (≤ 9 enrolled patients) or high-accruing institutions (HAIs) (≥10 enrolled patients). Fisher’s exact text and logistic regression analysis were used to analyze the response and early mortality rates. The effect of accrual volume on survival was analyzed by log-rank tests and Cox regression models. Results A total of 1252 patients from 152 institutions were included in the final analyses. The median clinical trial registrations in HAIs was 19 patients (range, 10 to 92) versus 3 (range, 1 to 9) patients in LAIs. In multivariate analyses, HAIs, as a quantitative covariate, was associated with improved complete remission rates (odds ratio (OR) 1.08, p = 0.0051), but no improvement median overall survival (HR 0.97, p = 0.065) or median event-free (hazard ratio (HR) 0.97, p = 0.05). Early mortality rates were similar between cohorts and academic affiliation had no impact on response rates or survival. Conclusion Clinical trial accrual volume, had an independent, albeit modest, impact on complete remission rates, but not on overall survival and event-free in younger patients with AML.

BACKGROUND: Outcomes of patients with acute promyelocytic leukemia (APL) have improved; however, a number of patients, particularly those with high-risk APL, still relapse despite all-trans-retinoic acid (ATRA) and arsenic-based therapies. We present single institution outcomes of autologous (auto) and allogenic (allo) hematopoietic cell transplantation (HCT) in patients with relapsed APL. PATIENTS AND METHODS: We retrospectively reviewed outcomes in patients with relapsed APL who underwent either auto- or allo- HCT at Moffitt Cancer Center from 1990 to 2018 utilizing the clinical data obtained from BMT Research & Analysis Information Network (BRAIN). Survival data were analyzed using Kaplan-Meier estimates. RESULTS: Autologous HCT Cohort: A total of 15 received auto-HCT with a median age at HCT of 39 (range, 21-60) years. Disease status at HCT were first complete remission (CR1) in 5 (33%) and CR2 in 10 (67%). Majority of patients (13/15, 87%) received busulfan/cyclophosphamide (Bu/Cy) conditioning and remaining (2/15, 13%) Bu/Cy/etoposide. All (n=15) patients received peripheral blood (PB) stem cell grafts. Median time to neutrophil engraftment was 11 (range, 10-14) days and platelet recovery was 14 (range 9-44) days. The median progression-free survival (PFS) for auto HCT was 12.9 (95% confidence interval (CI): 1.2-24.8) months. With a median follow up of 45.1 months for surviving patients, overall survival (OS) for auto HCT was 12.9 (95%CI: 0-27.8) years. At the time analysis, 8 patients were relapse-free. Allogeneic HCT Cohort: A total of 10 patients received allo HCT with a median age of 46 (range, 22-56) years at HCT. Disease status at allo HCT was CR2 in 2, CR3 in 6, and two had refractory disease. Two patients had prior auto HCT. Donor type was HLA-identical sibling=5; one antigen-mismatched sibling=1; HLA-matched unrelated donor=3; related haploidentical=1. Seven patients received peripheral blood graft and 3 received bone marrow graft. Conditioning regimen intensity was myeloablative in 7 (fludarabine/busulfan +/- anti-thymocyte globulin=3; Bu/Cy=3; cyclophosphamide/total body irradiation=1), and reduced intensity in 3 (fludarabine/melphalan=2; fludarabine/cyclophosphamide/total body irradiation=1). Seven patients received tacrolimus-based graft-versus-host disease (GVHD) prophylaxis. Median time of neutrophil engraftment was 15 (range, 12-22) days, and platelet engraftment was 22 (range, 15-28) days. The median PFS for allo HCT was 11.9 (95%CI: 2.1-21.6) months. With a median follow up of 48.2 months for surviving patients, median OS for allo HCT was 12.4 (95%CI: 4.8-19.9) months. At the time of analysis 4 patients were relapse-free. CONCLUSIONS: In our single center analysis, auto HCT for APL resulted in a durable remission and prolonged survival. Outcomes after allo HCT were suboptimal primarily due to their heavily pretreated condition and chemotherapy resistant disease. Further research on novel conditioning regimen and relapse prevention is needed to improve the outcomes of allo HCT in APL. Figure Disclosures Lancet: Jazz Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Consultancy; Daiichi-Sankyo: Consultancy; Pfizer: Consultancy. Sweet:Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Stemline: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; Agios: Consultancy; JAZZ: Consultancy; Incyte: Consultancy; pfizer: Consultancy; DSI: Consultancy; celgene: Consultancy. Bejanyan:Kiadis Pharma: Other: advisory board. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding.

Several prospective randomized trials comparing conditioning intensity before allogeneic hematopoietic cell transplantation (HCT) have been performed, with conflicting results. Although reduced-intensity conditioning (RIC) leads to lower treatment-related mortality (TRM), this is offset by higher rates of relapse. Long-term follow-up of randomized comparative trials are limited. Here we present long-term follow-up of a randomized comparison of myeloablative conditioning (MAC) compared with RIC before HCT for acute myelogenous leukemia (AML) or myelodysplasia (MDS). Long-term comparative analyses of overall survival, relapse, and relapse-free survival were performed. Patients age 18 to 65 years with

BACKGROUND: European LeukemiaNet (ELN) 2017 risk stratification by genetics is prognostic of outcomes in patients with acute myeloid leukemia (AML). However, the prognostic impact of the 2017 ELN genetic risk stratification after allogeneic hematopoietic cell transplantation (alloHCT) is not well established. OBJECTIVE: We examined the effect of 2017 ELN genetic risk stratification on alloHCT outcomes of AML. METHODS: We included 500 adult (≥18 years) AML patients in first (n=370) or second (n=130) complete remission receiving alloHCT from 2005 to 2016. Patients were classified into favorable (12%), intermediate (57%), and adverse (32%) 2017 ELN risk groups. The Cox proportional hazard model was used to conduct the multivariable analyses of leukemia-free survival (LFS) and overall survival (OS). Relapse and non-relapse mortality were analyzed by the Fine-Gray regression model. RESULTS: OS at 2 years was 72% in the favorable vs. 60% in the intermediate vs. 45% in the adverse risk groups (p

Busulfan (Bu)-containing regimens are commonly used in myeloablative conditioning regimens before allogeneic hematopoietic cell transplantation (HCT). Yet, there is considerable variability on how Bu is administered related to frequency (4 times a day [Q6] or daily [Q24]) and combinations with other chemotherapeutic agents (cyclophosphamide [Cy] or fludarabine [Flu]). We performed a prospective cohort study of recipients of Bu-based conditioning according to contemporary practices to compare different approaches (BuCy Q6, n = 495; BuFlu Q24, n = 331; BuCy Q24, n = 96; BuFlu Q6, n = 91) in patients with myeloid malignancies between 2009 and 2011. BuFlu Q24 recipients were more likely to be older and tended to have worse performance status and a higher comorbid burden. The cumulative incidences of hepatic veno-occlusive disease (P = .40), idiopathic pneumonia (P = .50), and seizures (P = .50) did not differ across groups. One-year HCT-related mortality ranged from 12% to 16% (P = .80), 3-year relapse incidence ranged from 32% to 36% (P = .80), and 3-year overall survival ranged from 51% to 58% (P = .20) across groups. This study demonstrates that HCT conditioning regimens using i.v. Bu Q6 or Q24 alone or in combination with Cy or Flu have similar outcomes in the myeloablative setting for treatment of myeloid malignancies.

Fatigue is common among cancer patients and adversely impacts quality of life. As such, it is important to measure fatigue accurately in a way that is not burdensome to patients. The 7-item Patient Reported Outcome Measurement Information System (PROMIS) Cancer Fatigue Short Form scale was recently developed using item response theory (IRT). The current study evaluated the psychometric properties of this scale in two samples of cancer patients using classical test theory (CTT).Two samples were used: 121 men with prostate cancer and 136 patients scheduled to undergo hematopoietic cell transplantation (HCT) for hematologic cancer. All participants completed the PROMIS Cancer Fatigue Short Form as well as validated measures of fatigue, vitality, and depression. HCT patients also completed measures of anxiety, perceived stress, and a clinical interview designed to identify cases of cancer-related fatigue.PROMIS Cancer Fatigue Short Form items loaded on a single factor (CFI=0.948) and the scale demonstrated good internal consistency reliability in both samples (Cronbach's alphas0.86). Correlations with psychosocial measures were significant (p values.0001) and in the expected direction, offering evidence for convergent and concurrent validity. PROMIS Fatigue scores were significantly higher in patients who met case definition criteria for cancer-related fatigue (p.0001), demonstrating criterion validity.The current study provides evidence that the PROMIS Cancer Fatigue Short Form is a reliable and valid measure of fatigue in cancer patients.

Transformative Leadership: A Model for Building a Comprehensive Cellular Therapy Program Partnership Introduction The third largest public safety net healthcare system in the United States established an outpatient Hematopoietic Cell Transplantation (HCT) program in 2007. In 2011, the Certificate of Need was obtained from the State of Florida to begin an inpatient (HCT) program. After ten years of low volumes leading to an inability to obtain allogeneic accreditation from the Foundation of Accreditation of Cellular Therapy (FACT), a transformative partnership for HCT was launched, in 2017, with a NCI designated comprehensive cancer center. The overall purpose of the partnership is to emulate the structure and quality of the NCI designated center's program and to increase patient access to HCT and other advanced cellular therapies in South Florida. Methods The HCT physicians and advanced practice providers are employed by the NCI center, but practice at the satellite campus. Essential program team members including the department administrator, HCT coordinators, quality program professionals, pharmacy, nursing and laboratory teams are employed by the public healthcare system. The partnership agreement is focused on quality indicators as the measure of success. A joint governance and a joint clinical operating committee, comprised of senior leadership from both institutions, were established to review metrics and quarterly outcomes, to ensure the partnership is meeting the clinical and operational program goals. Intellectual property including protocols, Standard Operating Procedures (SOP) for transplant, clinical pathways and quality initiatives are provided by the NCI center and adapted to fit the need of the program. The partnership also allows for a collaborative exchange of process improvements and best practices between operational areas including, information technology, managed care, revenue cycle, nursing, pharmacy, and laboratory. Joint educational activities include weekly grand rounds and monthly collaborative teleconferences for nursing, pharmacy, quality and coordination. Shared patient data allows for research activity between the two centers. Outcomes In the two years of partnership, the program has achieved FACT accreditation for autologous and allogeneic transplant. Prior to the partnership, the institution had referred out 149 patients for allogeneic transplant over the course of 10 years. Post-partnership, only three patients required referral for services the institution does not currently provide. Within one year of partnership launch, the program achieved certification as a National Marrow Donor Program Transplant Center and was approved as a center of excellence (COE) with three major managed care networks. Conclusion: Well-designed partnerships can allow for the establishment of accredited transplant and cellular therapy programs.

Haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy) is increasingly offered as a curative treatment for patients with hematological malignancies. In a recent registry study (Bashey et al. JCO 2017), peripheral blood (PB) as a graft source compared to bone marrow reduced the risk of relapse but increased acute and chronic GVHD after haplo-HCT with PTCy in combination with calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF). In this phase II trial we aimed to assess the efficacy of Sirolimus (Sir) in combination with PTCy and MMF as a CNI-free GVHD prophylaxis after PB haplo-HCT (NCT03018223). The primary end point was the cumulative incidence of grade II-IV acute GVHD at day 100 after HCT. With 32 evaluable patients enrolled, the study had a 90% power (α = 0.1) to demonstrate a reduction in 100-day grade II-IV acute GVHD from the historical benchmark of 40% (haplo-HCT and PTCy/Tac/MMF) to 20%. Sir was administrated from days +5 to +90 at target level of 8-14 ng/ml, followed by taper by day +180 in the absence of acute GVHD. A total of 32 patients with hematological malignancies were treated on trial 2/2017- 8/2018. The median age at HCT was 50 years (range, 23-75) and 59% of patients were racial/ethnic minorities. AML (50.0%) was the most common indication for HCT. The majority (66%) received myeloablative Fludarabine (Flu) and Busulfan (AUC of 5300), while 34% received non-myeloablative Flu/Cy/TBI 200 cGy. There were no graft failure events and the median time of neutrophil engraftment was 17 days (range, 12 - 30). With a median follow-up of 15.4 months, the primary endpoint was met with day 100 grade II-IV acute GVHD cumulative incidence of 18.8% (95% CI 7.5 - 34.0; grade III-IV = 9.4%). The cumulative incidence of 1-year NIH moderate/severe chronic GVHD was 20.0% (95% CI 7.9-36.0) (Figure). Only 3 patients required systemic glucocorticoids for chronic GVHD therapy. At last follow up, all immunosuppression was successfully discontinued in 43% (n=12) of all surviving study patients. The 1-year probability of non-relapse mortality was 19.7% (95% CI 7.8 - 35.5), relapse was 23.7% (95% CI 10.2 - 40.4), disease-free survival was 56.6% (95% CI 41.3 - 77.7) and overall survival was 70.2% (95% CI 55.5 - 88.6) for the entire cohort. These data demonstrate that PTCy/Sir/MMF GVHD prophylaxis effectively prevents grade II-IV acute GVHD after PB haplo-HCT and results in successful hematopoietic engraftment. Furthermore, the initial chronic GVHD, relapse and survival outcomes appear favorable. These findings warrant prospective comparison of PTCy/Sir/MMF with PTCy/Tac/MMF after PB haplo-HCT.

Disease Risk Index (DRI) and Hematopoietic Cell Transplant Comorbidity Index (HCT-CI) are independently validated and powerful pretransplant prognostic tools for overall survival (OS) of patients receiving allogeneic HCT (alloHCT) for hematological malignancies. Here we examined the prognostic significance of the DRI in conjunction with HCT-CI on OS among 341 elderly patients (≥60 years old) with AML (n=214) and MDS (n=127) who received alloHCT from 2005 to 2016. The median age at alloHCT for all patients was 66 (range, 60-76) years: 42% were age 60-64, 43% age 65-69 and 15% age ≥70. DRI classified patients as low/intermediate risk (LR/IR DRI, 63%) or high/very high risk (HR DRI, 37%). Nearly half of the patients had many comorbidities (HCT-CI ≥3) and 30% of all patients had lower Karnofsky Performance Status score (KPS Our findings suggest that most elderly patients with AML and MDS benefit from potentially curative alloHCT. Survival was worse for patients with combined high risk DRI and many comorbidities (HR DRI+ HCTCI ≥3). Thus, combining DRI and HCT-CI can serve as an effective pre-HCT tool to prognosticate survival after alloHCT. Age alone should not be a limiting factor in transplant decision making in otherwise eligible patients with AML and MDS.

Introduction Allogeneic stem cell transplant (alloSCT) provides pts with FLT3-ITD+ AML the highest likelihood of sustained remission, but relapse rates remain high. Post-SCT maintenance therapy may improve this outcome. Objective RADIUS, a randomized, open-label, phase 2 exploratory trial (NCT01883362) investigated whether SOC ± mido after alloSCT reduced relapse rates in pts with FLT3-ITD+ AML. Methods Eligible adults (aged 18-70 y) who had undergone myeloablative alloSCT in first complete remission (hematologic recovery and transfusion independence) were enrolled after engraftment and randomized 28 to 60 days after alloSCT to receive SOC ± mido 50 mg twice daily for up to 12 (4-week) cycles. The primary endpoint was relapse-free survival (RFS) at 18 mo after alloSCT; safety, pharmacokinetics (PK), in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay, overall survival (OS), and RFS at 24 mo after alloSCT were also assessed. The study was not adequately powered to detect a statistical difference between arms; a sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power if the incidence of relapse in the SOC + mido arm was 15%. Results 60 pts were randomized (30 per arm); 30 completed 12 cycles of therapy (14 with SOC; 16 with SOC + mido). The median dose intensity was 93 mg/day (range, 15-100 mg/day). Early discontinuations were similar between arms (15 with SOC; 13 with SOC + mido), often due to adverse events (AEs; 3% vs 27%) and consent withdrawal (20% vs 7%). 19 pts (63%) had mido dose modifications (84% due to AEs; concomitant CYP3A4 inhibitor, n = 1). With SOC alone, the estimated RFS (95% CI) at 18 mo was 76% (54%-88%) vs 89% (69%-96%) with SOC + mido (HR, 0.46 [95% CI, 0.12-1.86]; P = .27); the predicted relative reduction in the risk of relapse with the addition of mido was 54%. At 24 mo, OS (95% CI) was 85% with addition of mido (65%-94%) vs 76% with SOC alone (54%-89%) (P = .3418). PIA was evaluable in 28 pts in each arm; PK was evaluated in the SOC + mido arm. There was wide interpatient variability in trough levels of mido and its active metabolites ([CGP62221] + [CGP52421/5.4]) and in the degree of FLT3 inhibition. With mido, phosphorylated FLT3 (pFLT3) levels were With SOC and SOC + mido, AEs occurred in 87% and 100% of pts; serious AEs occurred in 57% and 30% of pts, respectively. 12 pts died on study (during follow-up phase; 8 with SOC and 4 with SOC + mido [n = 4 vs n = 2 due to AML disease progression]). Conclusion Mido as maintenance therapy was safely added for ≤ 1 y after alloSCT and, when added to SOC, reduced the predicted risk of relapse at 18 mo after alloSCT by 54% (vs SOC). Correlative analysis suggests that high levels of pFLT3 inhibition may positively influence outcomes.

For patients with acute myeloid leukemia from antecedent myelodysplastic syndrome particularly after azanucleoside treatment failure, outcome is poor. Here, we conducted a case-control study in these patients to compare the efficacy of CLAG-M induction (28 patients) versus standard 3+7 induction chemotherapy (24 patients). Response rates (P=0.014) and median overall survival (P=0.025) were 64% and 202 days (95% CI 37-367 days) versus 29% and 86 days (95% CI 36-136) in the CLAG-M and 3+7 cohorts, respectively. Median overall survival was 202 (95% CI 37-367 days) versus 86 days (95% CI 36-136) (P=0.025), respectively. CLAG-M has encouraging activity in this patient group.

European LeukemiaNet (ELN) 2017 updated prognostic system for acute myeloid leukemia (AML), which incorporates both cytogenetic and molecular risks, stratifying patients into 3 distinct genetic risk groups: favorable, intermediate and adverse. While most patients in favorable risk group can be cured with chemotherapy alone, the majority of patients in intermediate and adverse genetic risk groups are considered for curative allogeneic hematopoietic stem cell transplantation (alloHCT). However, the impact of ELN 2017 risk classification on survival of AML patients after alloHCT remains unclear. We examined the prognostic significance of ELN 2017 classification on 503 AML patients in first or second complete remission (373 CR1/ 130 CR2) receiving alloHCT at Moffitt Cancer Center) from 2005-2016. Patients were classified into favorable (n=58, 11.6%), intermediate (n=284, 56.8%) and adverse (n=158, 31.6%) ELN risk groups. The median age at alloHCT for the entire cohort was 55 years (range, 18-76 years) and 29% of all patients had many comorbidities (HCT ≥3) at transplant. Disease risk index (DRI) was low in 38 (7.6%), intermediate in 393 (78.6%) and high in 69 (13.8%) patients, and 22% (n=109) of all patients had secondary AML. Myeloablative conditioning was used in 77% (n=389) of patients, while 23% (n=114) received reduced-intensity conditioning regimen. HLA-matched unrelated donor (47%) was the most commonly used donor type, followed by matched related (27.7%) and mismatched donors (n=75, 9.8%). For the entire cohort, 2-year overall survival (OS) was 56% (52-60%) and leukemia-free survival (LFS) was 51% (47-55%). Patients with CR1 and CR2 status at alloHCT had similar OS (58% vs. 53%, p=0.17). We identified that ELN 2017 genetic risk is prognostic of OS after alloHCT in patients with AML: 72% (61-84%) in favorable risk vs. 60% (54-66%) in intermediate risk vs. 45% (38-53%) in adverse risk groups (p Our findings highlight the prognostic impact of ELN 2017 genetic risk on survival of AML patients undergoing alloHCT in CR1/CR2. Patients in the adverse risk group had higher risk of relapse and worse survival. Thus, ELN 2017 prognostic system can help identify AML patients in CR1/CR2 who can benefit from clinical trials offering relapse reduction strategies in order to improve their survival.

One limitation of reduced-intensity preparative regimens is potential for graft failure. We have developed a regimen that targets CD4(+) lymphodepletion to ensure early and durable engraftment. The primary endpoint was achievement of ≥50% CD3(+) donor chimerism by day +28. Forty-two patients (median age, 53 years; range, 29 to 73 years) received pentostatin 4 mg/m(2) i.v. on days -28, -21, and -14 when the CD4(+) cell count was100 cells/μL and on days -4 and -3 regardless of CD4(+) level. Rituximab 375 mg/m(2) was administered to patients with CD20(+) malignancies on days -21, -14, -7, +1, and +8. Busulfan 200 mg/m(2) i.v. was administered on days -4 and -2 at a dose to target a cumulative AUC dose of 16,000 (±10%) μmol·min/L. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 86% of patients. Donors were matched-related (47%), matched unrelated (43%), or mismatched unrelated (10%). Chronic lymphocytic leukemia (45%) and follicular non-Hodgkin lymphoma (14%) were the most common diagnoses. Disease status at initiation of the preparative regimen was complete remission in 22%, partial response in 55%, and stable/progression in 24%. The median percent CD4(+) cell count decrease from baseline (day -28) was 52% to day -21, 66% to day -14, 62% to day -7, and 91% to day 0. At day +28, all 42 patients (100%) had ≥50% CD3(+) donor chimerism. No patient experienced graft failure. Overall response rate was 82% (complete remisson, 67%). The day +100 cumulative incidence of grade II-IV acute GVHD was 59% (grade III-IV acute GVHD, 19%), and the 2 year cumulative incidence of chronic GVHD was 69% (moderate/severe, 58%). Nonrelapse mortality was 2% at day +100 and 17% at 2 years. Two-year PFS was 55%, and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse.

We aimed to evaluate the safety and efficacy of fludarabine (FLU) and pharmacokinetic-targeted busulfan (BU) as conditioning regimen for hematopoietic cell transplantation (HCT) in adult patients with acute lymphoid leukemia (ALL). Forty-four patients with ALL (27 in first complete remission [CR1] and 17 in more advanced disease stage: 4 with primary induction failure [PIF], 12 in CR2, and 1 in CR3) received FLU and pharmacokinetic-targeted BU as preparative therapy for HCT. Grafts were T-replete, filgrastim-mobilized peripheral blood stem cells (PBSC). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (TAC) and short-course methotrexate in 36 patients, TAC and sirolimus in 3, and TAC and mycophenolate mofetil in 5. Primary engraftment was achieved in all 44 patients. The cumulative incidence of transplant-related mortality (TRM) was 2% (95% confidence interval [CI] 0%-16%) at 100 days and 18% (95% CI 10%-34%) at 2 years. The 2-year cumulative incidence of relapse was 19% (95% CI 8%-41%) for those transplanted in CR1, and 48% (29%-80%) for those with more advanced disease. After a median follow-up of 32 months (range: 15-69 months), the 2-year overall survival (OS) was 54% (95% CI 39%-69%). Relapse-free survival (RFS) at 2 years was 63% (95% CI 45%-81%) for patients transplanted in CR1 and 34% (95% CI 11%-57%) for patients transplanted in more advanced disease. When compared to irradiation-containing regimens, FLU and PK-targeted BU appear safer and similarly effective in controlling ALL, providing a treatment option for adult patients with ALL.

There is no standard salvage regimen for AML. We retrospectively compared two commonly used regimens at our institution: CLAG and MEC. The complete response rate (CR) was 37.9% for CLAG (n=97) and 23.8% for MEC (n=65) (P=0.048), with median overall survival (OS) of 7.3 and 4.5 months, respectively (P=0.05). In primary refractory disease, CR was 45.5% for CLAG and 22.2% for MEC (P=0.09), with median OS of 11 and 4.5 months, respectively (P=0.07). In first relapse, CR was 36.8% and 25.9% (P=0.35) and median OS was 6.7 and 6.7 months, respectively (P=0.87). Our data support use of CLAG for RR-AML.

Disordered glucose metabolism is a common complication of glucocorticoid therapy for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT). We aimed to examine the impact of dysglycemia on outcomes in 173 recipients of HCT treated with glucocorticoids for aGVHD. A total of 147 of these patients contributed data to a landmark analysis performed at 12 weeks post-HCT. Median aGVHD onset was 21 days (range: 5–79) after transplant. Median duration of glucocorticoid therapy was 381 days (range: 15–1632). Glucose values were obtained from glucocorticoid initiation date to death or last follow-up, resulting in 11,588 total values. The median (range) for each parameter were: maximum 292 mg/dL (128–694), minimum 75 mg/dL (34–142), average 142 mg/dL (86–327), and standard deviation 46 mg/dL (12–108). Baseline diabetes mellitus predicted significantly greater maximum, mean, and standard deviation. With median follow-up of 20 months (range: 3–55), median overall survival (OS) was 33.7 months (95% confidence interval [CI] 16.4—not reached). On multivariable analysis, maximum, average, or standard deviation of glucose values predicted OS and maximum or average glucose values predicted nonrelapse mortality (NRM). Minimum glucose values of (0–60 mg/dL) were associated with worsened OS and increased NRM. Those patients treated with insulin or oral agents suffered significantly worse OS and increased NRM compared to patients who did not need therapy. Finally, those with sustained maximum values >200 mg/dL despite treatment suffered worse OS and increased NRM. These data suggest an independent adverse effect of dysglycemia in patients treated with glucocorticoids for aGVHD, and argue for stringent glycemic control in this setting.

Allogeneic hematopoietic cell transplantation in first complete remission (CR1) is considered the standard of care, and the only established therapy that offers a possibility of cure for patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Unfortunately, a number of patients, with suitable HLA-matched donors, are unable to receive an allograft because they fail to respond, or relapse shortly after induction chemotherapy. Incorporating imatinib during the induction/consolidation phase is facilitating a higher number of potentially curative allografts by improving both remission rates and/or the durability of responses in patients with Ph+ ALL. Imatinib and other tyrosine kinase inhibitors are also improving outcomes in elderly patients with Ph+ ALL, ineligible for allografting, when combined with glucocorticoids, and/or conventional chemotherapy. The addition of imatinib or other tyrosine kinase inhibitors to the therapeutic armamentarium of Ph+ ALL is reshaping the treatment algorithm and improving prognosis of this dreadful disease.

We evaluated the efficacy of FISH to detect chromosome anomalies in the evaluation of young (

s / Biol Blood Marrow Transplant 21 (2015) S114eS126 S124 Sarah Thirlwell , Kim Amtmann-Buettner . 1 BMT, Moffitt Cancer Center, Tampa, FL; 2 Professional Nursing Development, Moffitt Cancer Center, Tampa, FL; 3 Inpatient BMT, Moffitt Cancer Center, Tampa, FL; 4 Supportive Care Medicine, Moffitt Cancer Center, Tampa, FL; 5 Patient and Family Services, Moffitt Cancer Center, Tampa, FL Topic Significance & Study Purpose/Background/Rationale: BMT nurses deliver the treatments that can lead to patient and family acute and chronic suffering, and sometimes death, for the hope of cure and control of disease. In 2010, staff of our BMT Unit began demonstrating severe compassion fatigue (CF) with an increase in moral distress, nurse turnover rate, medical leave usage, conflict among staff, patients and families, and increased requests to Psychosocial Care for debriefing. Nursing Leadership, in partnership with other disciplines, recognized the need to address CF and create a plan to alleviate burnout and to increase nurses’ resiliency. Methods, Intervention, & Analysis: In 2011, the ProQOL5 survey, a valid CF assessment tool, was distributed to inpatient BMT nurses. The nurse manager then partnered with staff, Organizational Development, Social Work, Chaplaincy and Supportive Care Medicine to identify strategies to decrease CF among inpatient BMT nurses. A strategic plan was implemented to provide education about CF, to offer debriefing support, to hold skill-building sessions for resiliency and stress reduction techniques, to promote quality end-of-life care, and to improve workflow to promote selfcare. After implementation of the interventions, the ProQOL5 survey was repeated in 2013. Findings & Interpretation: Comparison of the results of the ProQOL5 surveys from 2011 to 2013 revealed improvement in the survey sub-domains of Compassion Satisfaction, Burnout, and Secondary Trauma. The result suggests that, when compared to standard compassion fatigue scores, BMT inpatient nurses experience slightly above average compassion satisfaction, low burnout as opposed to average burnout, and a low level of secondary trauma. Discussion & Implications: BMT nurses can experience severe compassion fatigue as a result of the care they deliver on a daily basis. A strategic and multimodal approach to alleviate CF can have a positive impact. Although the survey results did show improvement from 2011 to 2013, compassion fatigue is an ongoing concern for BMT nurses. Next steps include creation of a staff respite room on the BMT unit and the formation of a Code Lavender Team.

Intravenous busulfan (i.v. BU) has demonstrated safety when administered at 0.8 mg/kg per dose i.v. every 6 hours x 16 doses. We evaluated the safety and pharmacokinetics (PK) of giving the same total daily i.v. BU dose (3.2 mg/kg) either divided as a twice-daily infusion or as a single infusion to patients undergoing hematopoietic stem cell transplantation (HSCT). Twelve patients with hematologic malignant disease were treated; 7 patients had non-Hodgkin's lymphoma, 4 patients had acute myeloid leukemia, and 1 patient had chronic myelogenous leukemia. The first cohort (group A) received, on the basis of actual body weight, i.v. BU at 1.6 mg/kg per dose over 4 hours every 12 hours for 4 days (day -7 to day -4). The second cohort (group B) received 3.2 mg/kg per dose of i.v. BU (same total dose as group A) as a single infusion over 4 hours daily for 4 days. In both groups the i.v. BU was followed by cyclophosphamide 60 mg/kg daily for 2 days (day -3 and day -2). Blood specimens were collected on the first, fifth, and seventh doses for group A and on the first and fourth doses for group B to determine the disposition of i.v. BU. Peripheral blood stem cells (autologous in 7 cases and HLA-matched allogeneic in 5 cases) were given 2 days after completion of cyclophosphamide administration (day 0), and granulocyte colony-stimulating factor 5 microg/kg was started on the same day. GVHD prophylaxis consisted of tacrolimus plus methotrexate for recipients of allogeneic stem cells. One patient developed presumed fungal pneumonia and died of multisystem organ dysfunction on day +21 before hematologic reconstitution could be evaluated. Another was reported to have sudden death of undetermined cause at home on day 40. The remaining patients had engraftment (absolute neutrophil count >500/microL) at a median of 11 days and sustained platelet counts >20,000/microL at a median of 14 days. Significant regimen-related toxicity (grade III-IV) was limited to hepatic toxicity (2 cases) catheter infection (2 cases), epistaxis (3 cases), diarrhea (1 case), anorexia (1 case), mucositis (1 case), hyperglycemia (1 case), pneumonia (1 case), and sepsis (1). In group B there was 1 case of mild venoocclusive disease, which resolved without sequelae. No central nervous system or pulmonary toxicity was noted. Pharmacokinetic parameters, including clearance, half-life, maximum concentration, and area under the curve, demonstrated that the first dose profile was highly predictive of later dose PK profiles. No accumulation of the drug was noted. The change in dosing schedule did not increase toxicity or end-organ damage despite higher plasma concentration-times. Although further study for long-term efficacy is warranted, i.v. BU can be given safely with reproducible results on a twice-daily divided or single-daily dosing schedule to patients undergoing HSCT. Biol Blood Marrow Transplant 2002;8(9):486-92.

s / Biol Blood Marrow Transplant 21 (2015) S322eS354 S344 Teresa Field , Linda Kelley , Mohamed Kharfan-Dabaja , Frederick L. Locke , Asmita Mishra , Michael L. Nieder , Taiga Nishihori , Jose-Leonel Ochoa-Bayona , Lia Elena Perez , Marcie L. Riches , Claudio Anasetti . 1 Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2 Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Standard primary therapy for chronic graft vs. host disease (GVHD) is incompletely effective. Based on biologic insights implicating pathogenic B cells, we conducted a phase I-II trial examining the combination of standard ( 1mg/kg/day prednisone) glucocorticoid therapy with ofatumumab, a humanized anti-CD20 monoclonal antibody, for primary chronic GVHD therapy (NCT01680965). We here report the results of the phase I trial. Patients age 18 with NIH Consensus moderate-severe chronic GVHD newly requiring 1mg/kg/day prednisone were treated at three escalating dose levels (300mg, 700mg, and 1,000mg) of IV ofatumumab on day 1 and 14 of initial glucocorticoid therapy. Dose-limiting toxicity (DLT) was defined by the following: grade 4 infusion reactions, related grade 4 constitutional symptoms, related grade 3 organ toxicities, and grade 4 neutropenia lasting >14 days. Secondary endpoints included: adverse events, infectious complications, clinical response to therapy including reduction in prednisone dose, and serial measures of lymphocyte subsets and immunoglobulins. A total of 12 patients (median age 54, range 25-72) were treated (dose level 1: n1⁄43; level 2: n1⁄43; level 3: n1⁄46). At enrollment, overall chronic GVHD was moderate (n1⁄47) or severe (n1⁄45), with diverse organ involvement (skin: n1⁄48; mouth: n1⁄48; eye: n1⁄48; lung: n1⁄44; GI: n1⁄43; liver: n1⁄45; genital: n1⁄42; joint/fascia: n1⁄45), and both overlap (n1⁄47) and classic (n1⁄45) sub-types were represented. KPS was 80% in 11/12, median platelet count was 164 (range 92287), and median bilirubin 0.6 (range 0.2-0.9). Infusion of ofatumumab was well tolerated: Two infusion reactions (grades 2 and 3) occurred, resolved with supportive care, and all patients completed d1 and 14 infusions. No DLT was observed. From the total number of adverse events (n1⁄427), possibly related AE (n1⁄43) included grade 1 fatigue, grade 1 transaminitis, and grade 3 hand/foot cramping. Infectious complications were expected, and there were no cases of hepatitis B reactivation or progressive multifocal leukoencephalopathy (PML). At 3 months after therapy initiation, overall clinical response among evaluable patients was CR (n1⁄41), PR (n1⁄47), or SD (n1⁄41), and responses were sustained at 6 months (including one conversion from PR to CR). Encouraging reduction in prednisone dose was observed at 3 (median 89%, range 57-100%) and 6 months (median 93%, range 71-100%). Therapy produced significant B-lymphopenia (figure). Ofatumumab in combination with prednisone is safe, and phase II examination of efficacy is ongoing.

s / Biol Blood Marrow Transplant 21 (2015) S266eS321 S297 multivariate analysis using the LASSO approach to logistic regression analysis. Results: Of 134 allo-HSCTs, 29 (21.6%) patients experienced CMV viremia. Among these patients, median age was 51 years (range 27-67), with 48 episodes of viremia. Nine (31%) viremic patients developed CMV disease. CMV disease occurred at a median of 124 days post HSCT (range 61-322). Patients with CMV disease had a median of 2 viremic episodes before disease (range 1-4). Disease occurred at a median of 33 days from the start of the last viremic episode, and 75 days from the start of the first episode of viremia. On univariate analysis, factors associated with progression to CMV disease were: steroid-refractory acute GVHD (60 vs. 20%, p1⁄40.028); number of episodes of viremia >1x103 copies/mL (mean 2.4 vs 1.1, p1⁄40.016); longer duration of viremia (mean 38 vs. 22 days, p1⁄40.01); higher peak viral load (mean 4.49x105 vs. 8.31x103 copies/mL, p 1x103 copies/mL, a longer duration of viremia, and to have failed first-line pre-emptive ganciclovir therapy. This study, while limited, suggests that these risk factors may be predictive of CMV disease. Larger, prospective studies are needed to confirm these risk factors, some of which may be amenable to more aggressive anti-viral therapy.

Abstract 1333 In a prior retrospective analysis, we reported no adverse effects of pre-transplant 5-azacitidine on subsequent allogeneic hematopoietic cell transplantation (HCT) outcomes. We now report the results of a prospective observational clinical trial with the objective of evaluating HCT outcomes following pre-HCT therapy with 5-azacitidine. Twenty-three patients seen in consultation for HCT and medically eligible for a donor search were enrolled and received 5-azacitidine [75mg/m2 for 7 days every 4 weeks] until a suitable donor was identified. Four did not proceed to transplant for the following reasons: failure to obtain insurance approval due to patient age, failure of the pre-HCT organ evaluation although a donor was identified, CNS hemorrhage in setting of chronic anti-coagulation five days prior to HCT admission and one (62 years) declined HCT as only a HLA-A mismatched donor was available. Nineteen patients received a HCT following a myeloablative targeted busulfan fludarabine regimen. Median age at HCT was 57 years (25 – 67), 18 patients were older than 45 years, 7 older than 60 years. Disease at diagnosis was RCMD (3), RAEB2 (11), RAEB1 (3), CMML1 (1) and AMLM6 (1). IPSS at diagnosis was Int-1 (2), Int2 (9) and high (5), CMML1 (1), AMLM6 (1) and not evaluable (NE) (1). Cytogenetic risk was good (7), intermediate (5) and poor (7). Three patients had therapy related MDS. Patients received a median of 4 (1-6) cycles of 5-azacitidine. Median time from diagnosis (or time of progression and start of therapy in 2 patients) to HCT infusion was 195 days (107 – 350). Response to 5-azacitidine prior to HCT by the International Working Group 2006 criteria included partial response (8), stable disease (9) and 2 progressed. Two received leukemic induction chemotherapy prior to HCT. Disease status prior to HCT was RCMD (8), RAEB2 (2), RAEB1 (6), CMML1 (2) and AMLM6 (1). IPSS score prior to HCT was Low (1) Int-1 (6), Int2 (9) and poor (1) and CMML1 (2). Source of donor cells was peripheral blood siblings (7), matched unrelated donors (10) and mismatch unrelated donors (2). Median follow-up from HCT is 440 days (83-696). There are 3 patients who did not achieve remission (1) or relapsed (2) and 1 of the three remains alive with active disease. There are 3 non-relapse deaths, 2 due to infection and 1 due to GVHD. All deaths occurred between days 180 – 262. At one year OS is 69% (SE 0.12) and DFS is 63% (SE 0.12). In conclusion, pre-HCT 5-azacitidine was well tolerated, provided control of disease as a bridge to HCT and did not impose additional toxicity after allogeneic HCT with a promising 1 year progression-free survival. Controlled trials are needed to determine whether post-transplant relapse and survival are improved by pre-transplant 5-azacitidine. Disclosures: Field: Celgene: Research Funding. Perkins:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. Alsina:Celgene: Research Funding. List:Celgene: Research Funding. Anasetti:Celgene: Research Funding.

Abstract 3499 Intravenous busulfan (IV Bu) dosing in hematopoietic cell transplantation (HCT) conditioning regimens has been based largely on bioequivalence studies done with the oral dosage form. As systemic exposure to Bu has been correlated to both efficacy and toxicity, we used area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to IV Bu when given daily in combination with fludarabine as HCT conditioning. Three AUC levels were planned: 6000, 7500, and 9000 micromole*min/L, in cohorts of 20 patients (pts) each, with an additional 10 pts to be enrolled at the maximally tolerated AUC. To be included, pts had be 16–65 years old and have a hematologic malignancy, an HLA A, B, C, DRB1 8/8 or 7/8 matched related or unrelated donor, Karnofsky performance status 70–100%, and adequate organ function. The initial dose of IV Bu for the first AUC level was 170mg/m2/day on day -6 and day -5 then, on day -4 and day -3 doses were adjusted based on pharmacokinetic modeling after the first dose to achieve an average daily AUC of 6000. First doses for the subsequent cohorts were based on the linear correlation between AUC and dose in the previous cohort: 180mg/m2/day for AUC 7500 and 220mg/m2/day for AUC 9000, with dose adjustment on days -4 and -3 as described. Pharmacokinetic analysis was done after the day -3 dose to verify the accuracy of the dose adjustments. The first 20 pts in the AUC 6000 cohort (DL1) were coenrolled onto a randomized trial of GVHD prophylaxis (tacrolimus and methotrexate vs tacrolimus and mycophenolate mofetil) and were analyzed separately from a second cohort of 20 pts receiving an AUC 6000 (DL1A) and GVHD prophylaxis with tacrolimus and methotrexate. 20 pts were then enrolled onto AUC 7500 (DL2), followed by 3 pts on AUC 9000 (DL3). All DL3 pts had dose limiting toxicity so accrual to that level was stopped. An additional 9 pts have been treated to date on DL2 (5 of these are Disclosures: Perkins: PDL BioPharma: Research Funding. Off Label Use: IV busulfan was used in combination with fludarabine as conditioning prior to allogeneic hematopoietic cell transplantation in patients with a variety of hematologic malignancies. Field:PDL BioPharma: Research Funding.