bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-institutional study of allogeneic bone marrow transplantation using myeloablative busulfan (Bu)/fludarabine (Flu) conditioning and short-course, single-agent graft-versus-host disease (GVHD) prophylaxis with high-dose, post-transplantation cyclophosphamide (PTCy).
Authors: Kanakry Christopher George , O'Donnell Paul V. , De Lima Marcos J.G. , Wei Wei , Furlong Terry , Medeot Marta , Jones Richard J. , Thall Peter F. , Andersson Borje , Luznik Leo 
Published: March 2020

7006 Background: The clinical efficacy of 1) myeloablative BuFlu and 2) PTCy as GVHD prophylaxis have been independently shown in multiple single-center studies. Here, we sought to combine these two promising strategies in the context of a multi-institutional clinical trial. Methods: IV Bu was given in pharmacokinetically adjusted doses to achieve a targeted steady-state concentration. PTCy at 50mg/kg on Days +3 and +4 was administered as sole GVHD prophylaxis. Ninety-two patients (median age 49, range 21-65) receiving HLA-matched allografts (49% related and 51% unrelated) were enrolled at three institutions: 42 at Johns Hopkins, 38 at Fred Hutchinson, and 12 at MD Anderson. Diagnoses included 37 patients with de novo AML (40%), 16 with secondary AML (17%), 15 with acute lymphoblastic leukemia (16%), 13 with myelodysplastic syndrome (14%), 5 with chronic myelogenous leukemia (5%), two with chronic myelomonocytic leukemia (2%), three with non-Hodgkin lymphoma (3%), and one with multiple myeloma (1%). Twenty-five patients (27%) were not in remission by morphologic criteria at the time of allogeneic transplantation and an additional 17 patients (18%) had flow cytometric, cytogenetic, or molecular evidence of disease. Results: Five patients (5.4%) had primary graft failure. The cumulative incidences of grades 2-4 and 3-4 acute GVHD were 51% and 16%, respectively, and the cumulative incidence of chronic GVHD was 14%. GVHD was the primary cause of death in two patients, and one patient died of veno-occlusive disease. The 100 day and 1 year non-relapse mortality were 9.8% and 16%, respectively. Relapse occurred in 24% of these high-risk patients. At 1 year, the EFS was 64% and the OS was 72%. For the 50 patients in complete remission without MRD, at 1 year the EFS was 77% and the OS was 78%. Conclusions: This multi-institutional trial confirms the efficacy of high-dose PTCy as single-agent GVHD prophylaxis and demonstrates that it can be safely and effectively combined with the myeloablative BuFlu conditioning regimen. Clinical trial information: NCT00809276.
Impact of allogeneic hematopoietic stem cell transplant (HSCT) on patients harboring the spliceosome mutation SRSF2.
Authors: Hamilton Betty Ky , Tabarroki Ali , Elson Paul , Hasrouni Edy , Visconte Valeria , Tench Shawnda , Kalaycio Matt E. , Sekeres Mikkael A. , Sobecks Ronald M. , Duong Hien Kim , Hill Brian Thomas , Bolwell Brian James , Copelan Edward Alan , Tiu Ramon Velasquez 
Published: March 2020

7008 Background: Molecular predictors of outcome are increasingly important in determining optimal therapy for myeloid neoplasms. Mutations (mut) in spliceosome genes U2AF1 and SRSF2 predict poor outcome in MDS and related diseases. The purpose of this study was to investigate the role of HCT on the prognostic impact of U2AF1 and SRSF2 in myeloid malignancies. Methods: 123 patients (pts) with MDS (33%), AML (51%), MPN (10%), and MDS/MPN (5%) receiving an allogeneic HCT from 2003-2012 for whom genomic DNA was available from a time when the disease was active, were evaluated for mut in U2AF1 and SRSF2 by direct sequencing. Data were analyzed using competing risks methods (relapse and non-relapse mortality, NRM), proportional hazards (overall survival, OS) and logistic regression models (GVHD). Results: Median time of follow up was 38 months (range 1.5-108). Median age at HCT was 51 yrs (range 18-71). 53 (43%) pts were in remission and 70 (57%) had active disease prior to HCT. 20 (16%) pts had low, 48 (39%) intermediate and 32 (26%) high risk cytogenetics respective to their disease, (per CALGB criteria for AML, IPSS-MF for MPN and IPSS-R for MDS), with missing data on 23 (19%) pts. 89 (72%) had myeloablative transplants, and 34 (28%) received reduced intensity regimens. 54 (44%) had related, 52 (42%) unrelated and 17 (14%) cord blood donors. SRSF2 mut were detected in 13 (11%) pts and U2AF1 in 2 (2%) pts. Due to the low incidence of U2AF1 mut in our cohort, further analysis was focused on SRSF2. There were no significant differences in baseline characteristics between mut and wild-type (wt) pts except SRSF2 mut tended to occur in older AML pts (median age 64 vs 50 yrs, p=0.0004). SRSF2 mut and wt had similar OS (p=0.95), relapse (p=0.28), NRM (p=0.45) and rates of acute (p=0.41) and chronic (p=0.67) GVHD. Results were similar, adjusting for factors such as age, disease type, cytogenetics, comorbidity, transplant type and stem cell source. Conclusions: SRSF2 has previously been associated with dismal outcomes in MDS pts, with 5 yr-OS of <20%. In this cohort of transplanted pts, SRSF2 mut had similar outcomes to wt, suggesting HSCT may compensate for the adverse impact of SRSF2.
Update on a phase I study of the selective PI3Kδ inhibitor idelalisib (GS-1101) in combination with rituximab and/or bendamustine in patients with relapsed or refractory CLL.
Authors: Barrientos Jacqueline Claudia , Furman Richard R. , Leonard John , Flinn Ian , Rai Kanti Roop , De Vos Sven , Schreeder Marshall T. , Wagner-Johnston Nina D. , Sharman Jeff Porter , Boyd Thomas E. , Fowler Nathan Hale , Holes Leanne , Johnson David Michael , Li Daniel , Dansey Roger D. , Jahn Thomas Michael , Coutre Steven E. 
Published: March 2020

7017 Background: PI3K-delta signaling is critical for proliferation, survival, homing and tissue retention of malignant B cells. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in pts with heavily pretreated CLL. Methods: This phase I study evaluated idelalisib continuously given at 150 mg BID in combination with rituximab (R, 375 mg/m2 every wk x 8), bendamustine (B, 70 or 90 mg/m2 x 2, every 4 wks x 6) or BR (every 4 wks x 6) for relapsed/refractory CLL. Pts still on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical response was evaluated according to published criteria (Hallek 2008; Cheson 2012). Results: 52 pts (23F/29M) with a median (range) age of 64 (41-87) years were enrolled. Adverse disease characteristics included bulky lymphadenopathy (62%), refractory disease (50%), multiple prior therapies (median 3, range: 1-14) with 96% receiving prior R and 44% receiving prior B. As of 14 Jan 2013, the median (range) treatment duration was 18 (1-33) months. 31/52 (60%) pts enrolled into the extension study; of those, 24/52 (46%) pts are continuing idelalisib treatment on the extension study. The ORR was 81%, with 1 CR, and a median (range) time to response of 1.9 (1.5-8.3) months. The 2-year PFS and OS were 62% and 85%, respectively. At 2 years follow up, 71% of responses were still enduring. There was no difference in outcomes for pts with <3 prior treatments (n=21) vs ≥3 prior treatments (n=31). The most common TEAEs (any Grade/≥Gr 3, independent of causality) included pyrexia (44%/6%), diarrhea (40%/14%), cough (31%/2%), fatigue (29%/2%), nausea (29%/0%). Pneumonia (any Gr/≥Gr 3) occurred in 15%/12% and rash was seen in 15%/0%. 10% of patients experienced ≥Gr 3 ALT/AST elevation based on laboratory values. Conclusions: A lack of overlapping toxicities allowed idelalisib to be co-administered with R, B, or BR, and all 3 combination regimens were highly active, resulting in durable tumor control in pts with heavily pretreated relapsed/refractory CLL. Phase III trials evaluating the efficacy of idelalisib in combination with R or BR are ongoing. Clinical trial information: NCT01088048.
The origin of GPI-AP deficient cells in MDS, MPD, and aplastic anemia and its significance in predicting leukemic transformation.
Authors: Pu Jeffrey J. , Spivak Jerry L. , Brodsky Robert A. , Moliterno Alison 
Published: March 2020

7032 Background: PNH is a clonal disorder originating from a multipotent hematopoietic stem cell (HSC) acquiring a PIG-A gene mutation. PIG-A mutation lead to glycosylphosphatidylinositol-anchor protein (GPI-AP) deficiency, which contributes to many manifestations of PNH. About 25% of MDS and MPD, and 60% of AA also harbor small population of PNH-like cells. It was observed that 1) 10-20% AA harboring PNH-like cells eventually transform into PNH; but MDS and MPD seldom evolve to PNH; 2) AA harboring PNH-like cells may have a better response to immunosuppressive therapy; and 3) PIG-A mutation frequency significantly increased in some human cell lines with genomic instability. However, the clinical significances of these PNH-like cells in MDS, MPD, and AA are unclear. Methods: We prospectively recruit MDS, MPD, and AA patients. Peripheral blood flow cytometry is used to identify GPI-AP deficient blood cells, a proaerolysin-resistant CFC assay is used to select GPI-AP deficient progenitor cells, a novel T cell enrichment assay with proaerolysin selection is used to expand GPI-AP deficient T cells, and RT-PCR assay and DNA sequencing assay are used to identify and analyze particular gene expression deficiency in GPI-AP biosynthesis. Results: Our preliminary data shows that PNH-like cells in AA arise from multipotent HSC harboring PIG-A mutation; in MDS initiated at progenitor harboring PIG-A mutations and are transient; and in MPD caused from PIG-Y gene transcriptional silencing. Interestingly, the PIG-A mutation frequency in 4 MDS harboring PNH-like cells were 10~100 times higher than healthy controls. Furthermore, these 4 MDS and 3 MPD harboring PNH-like cells rapidly transformed into acute myelogenous leukemia. Conclusions: The origins and the clonality of PNH-like cells are different among MPD, MDS, and AA. This may explain why AA often evolves into PNH, but MPD and MDS seldom transform into PNH. PNH-like cell population in MPD and MDS is a marker of genomic instability and may predict a risk of leukemic transformation.
Survival and cause of death in patients with refractory anemias.
Authors: Zhang Yue , Gould Rothberg Bonnie , Morgensztern Daniel 
Published: March 2020

7033 Background: Despite its common occurrence, there are few large population-based studies on low-grade myelodysplastic syndromes (MDS). We evaluated the outcomes for the two low-risk MDS subtypes. Methods: The Surveillance, Epidemiology and End Results (SEER) database was searched for patients with refractory anemia (RA) or RA with ringed sideroblasts (RARS), diagnosed between 2001 and 2009 with complete demographic information. Incidence rates were calculated from SEERStat 7.1. Overall survival (OS) and disease-specific survival (DSS) were calculated from diagnosis to death from any cause and death from MDS or acute leukemia, respectively. Univariate survival was estimated by the Kaplan-Meier method and curves compared by log rank. Univariate and multivariable Hazard ratios (HR) were calculated by Cox Proportional Hazards. Results: Among the 6,505 patients who met the inclusion criteria, there were 3,866 (59%) RA and 2,639 (41%) RARS. Age-adjusted incidence rates per 100,000 population for RA and RARS were 0.55 and 0.44 respectively. Medians OS for RA and RARS were 39 and 48 months respectively. Although RARS was associated with improved 5-year OS compared to RA (41.3% vs 37.7%; HR 0.86; 95% CI 0.81-0.92, p < 0.0001), there were no differences in 5-year DSS (74.2% vs 76.3%; HR 1.01, 95% CI 0.90-1.14, p = 0.41). Altogether, 2,112 deaths were accrued among RA patients and 1,352 among the RARS subclass. The number of deaths due to MDS or acute leukemia were 610 (28.8%) in RA and 457 (33.8%) in RARS. Acute leukemia was the cause of death in 190 (9.0%) RA patients and in 143 (10.6%) of RARS patients. Cardiovascular disease accounted for 25% of total deaths in RA and RARS. After adjusted for age, gender, race and year of diagnosis, RARS was associated with increased OS (HR 0.81; 0.76-0.87; p < 0.0001) but not DSS (HR 0.95; 0.84-1.07, p = 0.41). Conclusions: Both RA and RARS are indolent diseases with a high 5-year DSS and death occurring mostly from other causes, particularly cardiovascular disease. Although RARS was associated with better 5-year OS compared to RA, there were no differences in 5-year DSS.
The impact of sarcopenia on transplant-related complications and number of days spent in the hospital in patients with lymphoma.
Authors: Caram Megan Veresh , Couriel Daniel R. , Griggs Jennifer J. , Bellile Emily Light , Englesbe Michael 
Published: March 2020

7044 Background: Sarcopenia, a state of abnormally low muscle mass, has been found to be associated with more treatment-related complications and shorter overall survival in patients with different cancers. Sarcopenia can be reliably assessed with routine computerized tomography (CT). The objectives of the study were to determine whether sarcopenia is associated with the number of complications and the number of days spent in the hospital in patients undergoing autologous hematopoietic stem cell transplantation (autoSCT) for lymphoma. Methods: Adult patients treated for non-Hodgkin's or Hodgkin's lymphoma with autoSCT between 2/2005 – 6/2/2012 at the University of Michigan (U-M) Bone Marrow Transplant (BMT) Program were eligible for inclusion if a CT of the abdomen was performed within 60 days prior to autoSCT. Total psoas area and lean psoas area were calculated for each patient with cross-sectional area and density measurements taken at the level of the fourth lumbar vertebra using algorithms programmed in the Analytic Morphomics Lab at U-M. All analyses were completed using Poisson regression models controlling for age, gender, body mass index, Hematopoeitic-Cell Transplant Co-morbidity Index (HCT-CI), and Karnofsky performance status (KPS). Results: Total and lean psoas area were calculated in the 121 patients who met inclusion criteria. Men with greater psoas muscle measures experienced fewer complications and spent fewer days in the hospital during the autoSCT admission compared to men who were sarcopenic (complications β = -0.206, p=0.001; hospital treatment days β = -0.043, p=0.029). Sarcopenia did not play a role in outcomes in women. A strong association existed between sarcopenia and re-admission days within 100 days following autoSCT among both men (β = -1.183, p<0.0001) and women (β = -0.805, p<0.0001). Conclusions: Muscle mass is independently associated with complication rates and duration of hospitalization in patients undergoing autoSCT for lymphoma. CT-determined psoas muscle mass may be a valuable addition to other indices used to guide optimal treatment selection and serve as a potentially modifiable host factor to improve transplant-related outcomes.
MEDI-551, an anti-CD19 antibody active in chronic lymphocytic leukemia (CLL) patients previously treated with rituximab.
Authors: Hamadani Mehdi , Forero Andres , Kipps Thomas J. , Fanale Michelle A. , Cuneo Antonio , Perez de Oteyza Jaime , Gladstone Douglas , Goswami Trishna , Ibrahim Ramy A. , Liang Meina , Eck Steven , Elgeioushi Nairouz , Herbst Ronald , Cheson Bruce D. 
Published: March 2020

7045 Background: Anti-CD20 mAb therapy has provided survival advantage to patients (pts) with CLL; but pts invariably relapse after anti-CD20 therapy and new approaches are needed. The CLL cells of most pts express CD19, which are upregulated following anti-CD20 therapy. MEDI-551, an affinity-optimized anti-CD19 antibody, destroys malignant cells by Ab-dependent cellular cytotoxicity (ADCC) once bound to CD19. Methods: The activity and toxicity of single-agent MEDI-551 in CLL pts with prior rituximab administration was assessed in a phase 1/2, open-label, dose-escalation and expansion study (NCT00983619). Response was assessed using the 2008 Intl Working Group criteria. B-cell depletion was assessed with flow cytometry and confirmed with biomarker analyses (BAFF). Safety assessments included laboratory parameters and adverse events (AEs and serious AEs [SAEs]). Results: Of 91 pts with refractory B-cell malignancies included in the study, 26 had CLL. CLL pts had received a median of 6 prior therapies: 89% with chemotherapy, 27% with single-agent biologics. Within 3 cycles of MEDI-551 (3 mos), >60% of assessable pts achieved CD20+ B-cell depletion to <20 cell/uL. Decreases in circulating CD20+ and CD22+B cells were associated with concomitant increases in serum BAFF concentrations. Of 20 pts evaluable for response, 4 achieved partial response and 13 had stable disease. Commonly reported AEs were generally grade 1/2 and included infusion reactions (62%), nausea (23%), pyrexia (23%), and neutropenia (23%). Six SAEs were noted in 3 pts: 1 had infusion reaction and general health deterioration, another had subarachnoid hemorrhage (SAH), and a third had dyspnea, pyrexia, and back pain. Only infusion reaction was considered treatment related. Two treatment-unrelated events of general health deterioration and SAH resulted in death. Conclusions: Single-agent activity with a manageable toxicity profile was seen in CLL pts treated in this phase 1/2 study of MEDI-551. An ongoing phase 2 study of MEDI-551 in combination with bendamustine in relapsed CLL patients (NCT01466153) is evaluating clinical response to MEDI-551 and chemotherapy. This study was sponsored by MedImmune, LLC.
Association of prior epidemiologic exposures with cytogenetic risk in adult acute myeloid leukemia (AML).
Authors: Finn Laura Elizabeth , Sproat Lisa Ostrosky , Heckman Michael , Jiang Liuyan , Diehl Nancy N. , Ketterling Rhett P. , Valdez Riccardo , Foran James M. 
Published: March 2020

7047 Background: In addition to secondary AML (sAML), important lifestyle and environmental exposures associated with increased risk of AML development have been identified in recent case-control studies including obesity (BMI>30kg/m2), smoking, regular acetaminophen use, and rural/farm habitat. The association of these exposures with AML cytogenetic risk groups is unknown. We therefore evaluated relevant exposures in a cohort of 301 AML patients with confirmed central cytogenetics analysis diagnosed and treated at Mayo Clinic FL and AZ since 1995. Methods: Documented patient exposures were extracted from central electronic medical records, including: prior chemotherapy/radiation or hematologic malignancy, occupation, select medications, “toxins” (esp. benzene) and solid organ transplantation (SOT). Standard cytogenetic risk categories (including intermediate abnormal) were applied. The association of epidemiologic exposures with cytogenetic risk was evaluated on multivariable analysis using logistic regression models. Results: sAML was significantly associated with cytogenetic risk groups, as was prior SOT, healthcare occupation, farm habitat and toxin exposures [see Odds Ratios (OR), Table). In contrast, prior radiation for epithelial malignancies, smoking and BMI were not independently associated with specific cytogenetic risk categories. Conclusions: Specific epidemiologic exposures are significantly associated with AML cytogenetic risk categories suggesting a unique clinical phenotype. This supports a link to leukemogenesis and requires validation in a controlled prospective therapeutic study. [Table: see text]
Hematopoietic cell transplantation for refractory acute myeloid leukemia.
Authors: Im Annie P. , Gill Navkiranjit K. , Cunningham Diana E. , Agha Mounzer E. , Hou Jing-Zhou , Redner Robert , Boyiadzis Michael 
Published: March 2020

7059 Background: Hematopoietic cell transplantation (HCT) can be curative for patients with AML refractory to chemotherapy or re-induction after relapse. However, the role of HCT in this setting remains unclear. Our aim was to evaluate outcomes of HCT in these patients, and determine factors that may be predictive of complete remission (CR)/complete remission with incomplete count recovery (CRi) and overall survival (OS). Methods: Patients with relapsed AML who did not respond to re-induction or with primary induction failure (PIF) who received allogeneic HCT at University of Pittsburgh Cancer Institute 2000-2012 were identified. CR/CRi rates were calculated at day 30 and 100, and 3-year OS was determined using Kaplan Meier method. Cox proportional hazards regression was used to examine associations between factors of interest, and OS and CR/CRi. These included gender, age, relapse or PIF, 1° or 2° AML, cytogenetic risk, duration of CR1 (patients in relapse), performance status, number of induction cycles, circulating blasts, percentage of bone marrow (BM) blasts prior to HCT, matched unrelated or sibling donor, donor-recipient CMV status, and acute GVHD. Results: The study cohort consisted of 71 patients (median age 44 years, range 19-64) who underwent allogeneic HCT for refractory AML (relapse n=35, PIF n=36). At day 30, CR was 31% and CRi was 49%, for total 80% response rate. At day 100, 51% remained in CR/CRi. CR/CRi was associated with younger age (HR 1.26, p<0.001) and lower percentage BM blasts (HR 1.03, p=0.026). Three-year OS was 12.3% (5.6-21.8), and median OS was 0.57 years (0.35-0.75). Lower OS was associated with matched unrelated versus sibling donor (HR 1.74, 1.02-2.96) and older age (p<0.06). Of the 60 patients who were deceased, 38.6% died from progressive leukemia. Conclusions: Despite high CR/CRi rates after HCT for refractory AML, 3-year OS was low. Age and percentage BM blasts were significantly associated with CR/CRi. Only sibling donor was significantly associated with OS, though there was a trend for age. Though patients with refractory AML represent a high-risk group to undergo HCT, the high response rate through day 100 with subsequent disease-related mortality suggests a role for maintenance after HCT in this population.
Outcome of pregnancy in women on imatinib for CML.
Authors: Gundeti Sadashivudu , Goteke Vamshi Krishna Reddy , Maddi Rahul Narayan , Linga Vijay Gandhi , Digumarti Raghunadharao 
Published: March 2020

7061 Background: The use of imatinib (IM) now offers most patients with CML lengthy remissions and the hope of normal life expectancy. Majority of our CML patients are in the reproductive age group, and these improved survivals have resulted in issues relating to fertility and procreation. There is limited literature on the outcomes of pregnancy in women who continued IM during conception and through antenatal period. Methods: All women with CML who wished to conceive were counselled about the risks of pregnancy while on IM. They were given the choice of termination or stopping IM until delivery or continuing on IM with attendant risk to mother and baby. The records of all patients with CML treated with IM at our institute were retrospectively analysed over a period of 10 years. A total of 28 pregnancies in 25 women were documented. Only those women who were exposed to imatinib during conception and first trimester were included for this analysis. We report the outcome of 24 pregnancies in 22 women who had continued on IM in antenatal period. Results: Of the total of 24 pregnancies, 23 occurred in chronic phase and 1 in Blast phase. 21 of these conceptions occurred at IM dose of 400mg/ day, 1 at 600mg/ day and 2 at 800mg/ day. The median age at conception was 24.5 years (19-38). Mean time on IM at conception was 24.25 months (3-81). 19 patients (86.4%) were in CHR at conception and 11 of 22 patients (50%) attained complete cytogenetic response. The mean exposure to IM during pregnancy was 18.08 weeks (6-39 weeks).After explaining the pros and cons of continuation of pregnancy 6 women had stopped IM and 7 patients opted for termination of pregnancy. Conclusions: IM at higher dose appears to increase the risk of fetal loss. IM at standard dose of 400 mg does not appear to increase the incidence of congenital malformations or worsen foetal outcome. [Table: see text]