bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post hoc analysis of sustained efficacy/tolerability of ≥12 cycles of omacetaxine mepesuccinate in chronic myeloid leukemia (CML).
Authors: Rea Delphine , Kantarjian Hagop M. , Wetzler Meir , Nicolini Franck E. , Lipton Jeffrey H. , Akard Luke Paul , Khoury Hanna Jean , Michallet Mauricette , Guerci-Bresler Agnès , Chuah Charles , Hellmann Andrzej , Legros Laurence , Warzocha Krzysztof , Parikh Purvish M. , Craig Adam , Cortes Jorge E. 
Published: March 2020

7066 Background: Subcutaneous omacetaxine mepesuccinate (OMA), a first-in-class cephalotaxine, inhibits protein synthesis independent of Bcr-Abl signaling. It showed clinical activity in 2 phase II, open-label CML trials, 1 in patients with a T315I Bcr-Abl mutation failing imatinib, and 1 in patients failing ≥2 tyrosine kinase inhibitors (TKIs). Methods: This post hoc analysis pooled patients with chronic phase (CP) or accelerated phase (AP) from the 2 trials. 28-day cycles of OMA 1.25 mg/m2BID were given ≤14 days for induction, ≤7 days as maintenance with dose delay/change as needed. Primary endpoints were major cytogenetic response (MCyR) for CP and complete hematologic response (CHR) for AP. Adverse events (AEs) were assessed. Results: Of 108 CP and 51 AP patients from the 2 trials, 31 (29%) CP and 7 (14%) AP patients received ≥12 cycles (Table). At baseline in the ≥12-cycle groups, most CP (median age 59 y) and AP patients (median age 67 y) had received hydroxyurea (17/31, 4/7) and ≥2 TKIs (22/31, 5/7), were not in CHR (22/31, 5/7), and were T315I positive (23/31, 3/7). As of March 31, 2012, 9 CP and 2 AP patients continued OMA treatment. Overall, mean days dosed per cycle were 6.1 for CP, 9.7 for AP; 5.3 and 8.9 at cycle 12. Grade 3/4 AEs occurred in 35/38 patients in this post hoc analysis, most in early cycles; 15/31 CP, 2/7 AP had grade ≥3 AEs first occurring at ≥12 cycles. Across all cycles, most common grade ≥3 AEs were thrombocytopenia (24/31 CP, 5/7 AP), anemia (16/31, 7/7), and neutropenia (17/31, 3/7).Nine patients receiving ≥12 cycles (5/31, 4/7) discontinued, most commonly due to disease progression (n=2). Conclusions: In this post hoc analysis of heavily pretreated CML-CP and CML-AP patients who had failed prior TKI therapy, efficacy was often durable for those who received OMA for ≥12 cycles. Most grade 3/4 AEs were hematologic and declined with time. Support: Teva BPP R and D, Inc. Clinical trial information: NCT00375219, NCT00462943.
Quality of life (QOL) and physical function in one-year adult and elderly survivors of acute myeloid leukemia (AML).
Authors: Alibhai Shabbir M.H. , Breunis Henriette , Timilshina Narhari , Minden Mark D. , Gupta Vikas , Buckstein Rena , Li Madeline , Tomlinson George A. , Brandwein Joseph 
Published: March 2020

7071 Background: The treatment of AML with intensive chemotherapy (IC) is associated with significant short-term toxicities. We previously showed similar impairments in QOL and physical function among younger (age 18-59) and older (age 60+) patients with AML at diagnosis, with similar recovery over 3 cycles of IC. We now comprehensively describe QOL and physical function recovery over 1 year from diagnosis. Methods: Younger and older AML patients undergoing IC without stem cell transplant were enrolled in a prospective, longitudinal study. Assessments were done at baseline (pre-IC) and at 7 time points over the next year. At each visit, patients completed the EORTC QLQ-C30 and the FACT-Fatigue to measure QOL and fatigue, respectively, in addition to 3 physical function tests (grip strength, 2-minute walk test (2MWT), and timed chair stands). Analyses involved multivariable linear regression analyses stratified by age group. Results: 243 patients were recruited (147 younger and 96 older, 56% male). Attrition was greater in older adults due to death or disease progression/relapse. Among patients remaining in remission after IC, global QOL and fatigue improved significantly over time (p<0.001 for both); trends were similar between older and younger patients. All 5 QOL domains improved or remained stable over time; the greatest improvements were seen in social function and role function and were similar in both age groups. Grip strength increased slightly over time (p=0.04) whereas both timed chair stands (p<0.001) and the 2MWT (p<0.001) had moderate to large improvements, with trends toward greater improvement in younger patients (p=0.07 and 0.09, respectively). Results were similar when missing data were imputed. Conclusions: Survivors of AML after successful conventional chemotherapy achieve significant improvements in QOL, fatigue, and physical function over time. The course of recovery is remarkably similar in younger and older AML patients, although significant attrition in older adults is a noteworthy limitation. These data suggest that appropriately selected older patients do well following IC for AML.
Omacetaxine mepesuccinate in chronic phase chronic myeloid leukemia (CML-CP): A post hoc analysis of myelosuppression.
Authors: Akard Luke Paul , Kantarjian Hagop M. , Nicolini Franck E. , Wetzler Meir , Lipton Jeffrey Howard , Baccarani Michele , Khoury Hanna Jean , Craig Adam , Cortes Jorge E. 
Published: March 2020

7073 Background: Omacetaxine mepesuccinate (OMA) was active in 2 CML trials of patients with T315I Bcr-Abl mutations or failing ≥2 tyrosine kinase inhibitors. Methods: Hematologic events/recovery were pooled from the 2 trials. OMA 1.25 mg/m2BID was given in 28-day cycles: ≤14 days induction, ≤7 days maintenance with dose delay/change as needed. Results: Of 108 patients, median exposure was 7.4 mos, with a median 3 cycle delays and 9 days dosing per patient. Of 91 patients receiving ≥2 cycles, 79 (87%) had ≥1 delay (366 delays in 729 cycles), most due to grade ≥3 thrombocytopenia. Median delay was longest early—peaking at 25 days in cycle 3. Predefined hematologic nadirs (see Table) were reached mostly in initial cycles and less after dose adjustments; 80 patients received blood products, 10 antibiotics. Most common lab grade 3/4 hematologic toxicities were thrombocytopenia (85%), neutropenia (81%), and anemia (62%). Grade 3/4 adverse events included 12 infections (6 treatment related, including 1 pneumonia, 1 sepsis) and 7 hemorrhages (1 related conjunctival, 1 postprocedural, 2 cerebral, 3 gastrointestinal [1 related]); 38 events were fatal (related: 1 pancytopenia, 2 sepsis, 2 unknown). There were 11 hematologic hospitalizations. Conclusions: In heavily pretreated CML-CP, myelosuppression was most common after initial OMA cycles, improved with dose adjustments, and rarely led to severe outcomes. Support: Teva BPP R&D, Inc. Clinical trial information: NCT00375219, NCT00462943. [Table: see text]
Variation in health-related quality of life (HRQOL) by line of therapy, age, and gender among patients with chronic lymphocytic leukemia.
Authors: Flowers Christopher , Farber Charles Michael , Flinn Ian , Grinblatt David L. , Kay Neil E. , Kipps Thomas J. , Kozloff Mark , Lamanna Nicole , Lerner Susan , Sharman Jeff Porter , Weiss Mark Adam , Swern Arlene S. , Khan Zeba M. , Street Thomas K. , Sullivan Kristen A. , Yu Ren , Pashos Chris L. 
Published: March 2020

7086 Background: The HRQOL of patients (pts) with chronic lymphocytic leukemia (CLL) has not been adequately delineated across patient, disease and treatment characteristics. We evaluated HRQOL of CLL pts undergoing treatment in the United States (US) by age, gender and line of therapy. Methods: Data were collected in Connect CLL, a prospective observational US registry. Physicians provided data on demographics, clinical characteristics and line of therapy at enrollment. HRQOL was self-reported by pts at enrollment using the Functional Assessment of Cancer Therapy-Leukemia, an instrument that yields a leukemia-specific total HRQOL score (FACT-Leu) and a cancer-specific total HRQOL score (FACT-G). Mean total scores were analyzed by line of therapy, age and gender. Statistical significance was ascertained by ANOVA using SAS 9.2. Multivariate analyses were conducted to assess the relative association of line of therapy, age and gender with HRQOL. Results: Among 1,252 pts enrolled from 161 geographically diverse centers (90% community, 8% academic, 2% veterans/military), pts were predominantly male (63%), white (89%) with mean age 69 yrs. Pts were categorized by line of therapy at enrollment: First 61%, Second 18%, Third 11%, Higher 9%; and by age group: <65 33%, 65-74 35%, 75+ 32%. Univariate analyses suggested that the total FACT-Leu score was significantly better in men than women (P=0.004); in pts aged 65-74 vs younger or older pts (P=0.033); and in pts initiating first-line treatment vs pts receiving subsequent treatments (P=0.0002). Similar results were found with the FACT-G score except that gender differences were not statistically significant. Multivariate analysis confirmed that line of therapy (P=0.007), gender (P<0.0001), and age group (P=0.039) were each associated with significant differences in the FACT-Leu total score. Conclusions: Results from the Connect CLL Registry indicate that HRQOL is better among pts initiating first-line therapy compared to pts initiating subsequent treatments, and that this remains true when age and gender are considered. Future analyses should determine how HRQOL may change over time relative to treatment and treatment response.
Inotuzumab ozogamicin (CMC-544) compared to chemotherapy in patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL): A retrospective comparison.
Authors: Faderl Stefan , Jain Nitin , O'Brien Susan Mary , Thomas Deborah A. , Ravandi Farhad , Jabbour Elias , Pierce Sherry , Kantarjian Hagop M. 
Published: March 2020

7095 Background: Modern multi-agent chemotherapy (CT) regimens result in complete remission (CR) rates of 80-90% and long-term survival rates of 40% in pts with ALL. The most common reason for treatment failure is relapse of the disease. Post-relapse therapies lead to second CR in 30-40% of pts with a 5-year survival of <10%. CD22 expression occurs in >90% of pts with ALL. Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody bound to a toxin, calecheamicin. We reported overall response rate of 57% with single-agent IO in R/R ALL (Kantarjian, Lancet Oncology 2012). Methods: We analyzed the outcomes of patients with R/R ALL treated with single-agent IO (n=90) vs. historical controls (n=292) treated with combination CT at our institution from 1990-2008. IO was dosed at 1.8 mg/m2 every 3-4 weeks (first 41 pts), and later weekly dosing (0.8 mg/m2 day 1, 0.5 mg/m2 on days 8 and 15, every 3-4 weeks). Fifty-percent of historical controls were treated with hyper-CVAD CT (n=147). Results: The median age in the IO cohort was 39.5 years (yrs) (range 4-84) and in the CT cohort was 37 yrs (range 14-81). Overall CR/CRp rate was 49% with IO vs. 29% with CT. In salvage 1, CR/CRp rate was significantly better with IO [66% vs. 40% with CT (p=0.007)]. When only hyper-CVAD-based regimens were included, the CR/CRp was not statistically different (66% with IO vs. 56% with hyper-CVAD, p=0.332). In salvage 1, the median overall survival (OS) was 9.2 months (mos) with IO vs. 6.2 mos with CT (p=0.06 compared with IO) vs. 7.9 mos with hyper-CVAD (p=0.48 compared with IO). In salvage 2, CR/CRp rate was better with IO vs. CT (44% vs. 16%, p=<0.001); OS was not different (4.3 mos vs. 2.5 mos, p=0.74). In salvage 3, CR/CRp rate was better with IO vs. CT (46% vs. 19%, p=0.03); OS was also better with IO vs. CT (6.6 mos vs. 2.6 mos, p=0.01). In salvage 4, CR/CRp rate was better with IO vs. CT (27% vs. 9%, p=0.01); OS was not statistically different (7.4 mos vs. 1.9 mos, p=0.09). Conclusions: In pts with R/R ALL, outcomes after single-agent IO are better than pts treated with CT alone. In addition, IO has fewer side effects than CT. IO has the potential to replace multi-agent CT as standard of care for treatment of pts with R/R ALL.
Autoimmune disorders in patients with B-cell chronic lymphocytic leukemia.
Authors: Duan-Porter Wei , Volkheimer Alicia D. , Davis Evan D. , Chen Youwei , Allgood Sallie , Weinberg J. Brice 
Published: March 2020

7103 Background: B-cell chronic lymphocytic leukemia (CLL) results from the accumulation and proliferation of malignant B cells with a predisposition for autoreactivity and autoimmune disease, particularly hematologic disorders such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). We sought to define the prevalence of autoimmune conditions and associated prognostic factors in our CLL cohort. Methods: We retrospectively reviewed the electronic medical records (EMR) of CLL patients at Duke University Medical Center (DUMC) and Durham VA Medical Center (DVAMC) for known diagnoses of autoimmune conditions, or clinical descriptions matching those disorders. Laboratory data confirming the diagnoses (e.g., Coombs test for AIHA) were verified directly in our EMR. IGVH mutation status, CD38 and ZAP-70 expression were previously determined. Results: We found 92 CLL patients with autoimmune disorders (21.4% prevalence), with higher numbers of both hematologic (58, 11.1%) and non-hematologic(42, 8.1%) conditions than previously published data [Barcellini et al. Haematologica (2006) 91:1689], although one series did show 9.7% of CLL patients with hematologic phenomena [Hamblin et al. J Clin Path (1986) 39:713-6]. CLL patients with AIHA and/or ITP had significantly shorter treatment-free survival [2.1 years (1-3.3)] and overall survival [11.9 years (9.6-15.8)] than those without [6.2 years (5.2-7.3) and 18.0 years (14.0-22.6), respectively]. 52% of CLL patients with autoimmunity had mutated IGVH (41/79 known results), 18% were CD38 positive (16/89) and 49% were ZAP-70 positive(39/80). In CLL patients without autoimmune disorders, the prevalence of mutated IGVH, and CD38 and ZAP-70 positivity were similar at 60% (219/364), 25% (99/395), and 47% (176/377), respectively. Conclusions: There is a higher prevalence of both hematologic and non-hematologic autoimmune disorders in our CLL cohort than previously reported. CLL patients with hematologic autoimmune disorders had shorter time to treatment and survival, compared to those without. There was no difference in frequency of mutated IGVH, CD38 or ZAP-70 expression between those patients with autoimmune conditions and those without.
Updated results from a randomized phase II dose-ranging study of the JAK2-selective inhibitor SAR302503 in patients with myelofibrosis (MF).
Authors: Pardanani Animesh Dev , Jamieson Catriona H. M. , Gabrail Nashat Y. , Lebedinsky Claudia , Gao Guozhi , Patki Abhay , Liu Feng , Tefferi Ayalew , Talpaz Moshe 
Published: March 2020

7109 Background: We previously reported results of treating MF patients with 3 cycles of 300, 400, or 500 mg of SAR302503 (NCT01420770; Blood 2012;120:21 Abs 2837). This is a report of efficacy and safety after 6 cycles. Methods: Patients ≥18 years of age with intermediate-2 or high-risk MF and splenomegaly were eligible. SAR302503 is administered orally, once a day in consecutive 4-week cycles until disease progression or unacceptable toxicity. Spleen response (≥35% reduction in spleen volume vs baseline) was assessed by MRI/CT (blinded independent central review). Results: 31 patients were enrolled (n=10 in the 300 and 400 mg groups; n=11 to 500 mg). Risk status was balanced in all but the 300 mg group (70% high-risk). Most patients were JAK2V617F positive (90%) and blood transfusion independent (81%). Spleen response rates at the end of cycle (EOC) 6 (secondary end point) were 30% (3/10) in the 300 mg group, 60% (6/10) with 400 mg, and 55% (6/11) with 500 mg compared with EOC 3 rates of 30%, 50%, and 64%, respectively. One patient on 500 mg who had a spleen response at EOC 3 (39% reduction), but not at EOC 6 (25% reduction) had dose reductions to 200 mg due to anemia. Median number of cycles was 13 (range, 2–17) and 24 patients have been on treatment >12 months. SAR302503 reduced baseline constitutional symptoms at the EOC 3, with the greatest responses for night sweats in 14/15 patients (93%), itching 10/14 (71%), early satiety and abdominal pain, each in 10/18 (56%). Most common adverse events were anemia and diarrhea, with grade 3–4 rates of 58% and 13%, respectively. The rate of grade 3–4 thrombocytopenia was 16%. There was no grade 3–4 neutropenia. The diarrhea rate tended to decrease after the first 2 treatment cycles. There have been no reports of withdrawal syndrome after stopping SAR302503. Median JAK2V617F allele burden was 93% at baseline, 87% at the EOC 3, and 78% at EOC 6 in 19/26 patients who had available samples. The expression of 22 of 97 cytokines was significantly regulated (≥1.5 fold difference; p<0.05) after cycle 1. Conclusions: In this Phase II trial, continued treatment with SAR302503 was associated with clinically meaningful reductions in splenomegaly. Symptom data will be updated. Clinical trial information: NCT01420770.
Modulation of plasma cytokines and its association with clinical response to treatment with the JAK2-selective inhibitor SAR302503 in myelofibrosis (MF).
Authors: Talpaz Moshe , Jamieson Catriona H. M. , Gabrail Nashat Y. , Lebedinsky Claudia , Liu Feng , Cao Hui , Tefferi Ayalew , Pardanani Animesh Dev 
Published: March 2020

7110 Background: Abnormal cytokine expression may represent an inflammatory response that contributes to the clinical phenotype of MF. Some constitutional symptoms (eg. fever, fatigue, pruritus, cachexia) are thought to be caused by elevated cytokines. In phase I/II studies, SAR302503 reduced splenomegaly and constitutional symptoms in patients with MF. Here, we report the effects of SAR302503 on the expression of 97 cytokines in MF patients enrolled in a Phase II study (NCT01420770) and the relationship to clinical response (spleen size), pharmacokinetic (PK) exposure, and body weight changes. Methods: Thirty-one patients were randomized to receive 300, 400, or 500 mg of SAR302503 orally, once daily, continuously in 4-week cycles. Plasma cytokines were measured at baseline and at the end of 4, 8, and 12 weeks of treatment using a microsphere-based immuno-multiplex assay (Rules Based Medicine). Results: Complete sample sets were available for 29/31 patients. A total of 28 cytokines predominantly involved in immune/inflammation pathways were regulated ≥1.5-fold (ANOVA P<0.05) and of these, 19 were regulated at all time points, indicating rapid and sustained modulation by JAK2 inhibition. At 4 weeks, 16 cytokines were down-regulated, including TNFα, IL-1RA, and IL-18, and 6 were up-regulated, including leptin, EPO, and adiponectin. Hierarchical clustering of the 22 regulated cytokines enriched patients into spleen responder (≥35% reduction in spleen volume by MRI) and non-responder groups, suggesting a link between cytokine modulation and clinical response. Moderate correlations (P<0.05) with spleen volume reduction at the end of week 12 were seen for a subset of regulated cytokines, including adiponectin and TNFα. Levels of the majority of the regulated cytokines tended to correlate with steady state PK exposure at week 4. A positive association with weight changes at week 24 were observed for leptin and adiponectin at week 4 (P<0.05). Conclusions: This analysis shows that SAR302503 treatment modulated the expression of circulating cytokines in MF patients in association with changes in clinical activity, PK exposure, and symptom improvement (weight gain). Clinical trial information: NCT01420770.
Exploring educational gaps in myelodysplastic syndromes in medical students and internal medicine residents: A dual-institution survey.
Authors: Coombs Catherine Callaghan , Wiese Kristin , deCastro Carlos , Shammo Jamile M. 
Published: March 2020

7118 Background: Myelodysplastic syndromes (MDS) are a heterogeneous and poorly understood group of disorders. Prior studies have focused on patient and provider understanding of these disorders; however, no study to our knowledge has been conducted to explore educational gaps of medical students and medicine residents. The hypothesis of this work is that MDS are poorly understood by trainees, but this could be improved after education. Methods: A nine question survey pertaining to definition, diagnosis, risk assessment and survival in MDS was sent to medical students and medicine residents a week prior to a lecture on MDS. At Duke, the lecture was a senior resident talk; at Rush, it was a medicine grand rounds by a hematology attending. The survey was resent to the initial groups 15 days after the lectures, but only those who attended the lecture were invited to take it. Results: At Duke, the response rate was 141 out of 255 (55%); at Rush, it was 65 out of 414 (16%). Responses for the questions were similar at both institutions with no statistical difference in the percent of correct responses by institution. 83.7% said that anemia was not a normal consequence of aging. 82.4% acknowledged that a bone marrow biopsy is required to diagnose MDS. 57.6% said anemia was the most common hematologic manifestation of MDS. 40.4% said that a hemoglobin of <10 should be referred to hematology. 36.1% said the bone marrow in MDS is hypercellular. 17.6% said MDS transforms to AML in 30% of cases. 11.2% identified MDS as a cause of macrocytic anemia. Only 11.1% identified MDS as a malignancy, and 5.5% identified the average survival of high-risk IPSS stage MDS as 0.4 years. In post-lecture surveys (n= 23), knowledge largely improved. However, given low number of responses, this reached statistical significance in only four of nine questions. Conclusions: MDS are poorly understood by both medical students and residents, especially in regard to the definition as a malignancy, prognosis, and risk of AML evolution. We propose that educational efforts aimed at early trainees would improve these knowledge deficits, in addition to the medical care of patients with MDS. The study is limited by the post-survey completion rate.