bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute myeloid leukemia (AML) in adolescents and young adults (AYA): The M. D. Anderson Cancer Center (MDACC) experience
Authors: Pemmaraju N. , Kantarjian H. , Ravandi F. , O'Brien S. , Wierda W. , Thomas D. , Garcia-Manero G. , Borthakur G. , Pierce S. , Cortes J. 
Published: August 2020

7051 Background: AML is a heterogeneous group of hematopoietic neoplasms demonstrating clonal proliferation of myeloid precursors and is typically a disease of older adults. Little is known about outcomes of AYA with AML. Methods: We retrospectively analyzed all patients (pts) with AML treated at MDACC from 1965 to 2008. Pts ages 16 to 21 years (yrs) were defined as AYA. Results: Among 3,934 adult AML pts treated during this period, 163 pts (4%) were AYA with median age of 19 yrs. This cohort included 27 (17%) pts with Core Binding Factor (CBF)-AML [inv(16), t(8:21)] and 19 pts (12%) with acute promyelocytic leukemia (APL). Among the other pts, 50% had diploid cytogenetics, 11% had 5 or 7 abnormalities, 39% had other cytogenetic changes. Antecedent hematologic disorders were present in 33 pts (20%). Among 20 evaluated pts, FLT3 internal tandem duplication (ITD) was present in 4 pts and FLT3 kinase domain mutation was found in 2 pts. Complete remission (CR) rates were 89% for CBF AML, 79% for APL, and 75% for all other pts. Median survival for the total cohort was 1.7 yrs with 36% alive at 3 yrs, and median CR duration of 1.3 yrs (30% CR at 3 yrs). Outcome is better for pts with CBF leukemia (3 yr survival 56%, sustained CR 49%) and APL (3 yr survival 51%, sustained CR 36%) compared to other AML (3 yr survival 28%, sustained CR 24%). CR rates have improved from 71% in 1965–1984, to 85% in 1985–1994, and 83% after 1994. Similarly, overall survival (OS) has increased during the same time periods (3-yr survival 18%, 44%, and 53%, respectively) together with CR duration (3 yr CR duration 21%, 32% and 39%, respectively) as early mortality has decreased (11%, 8%, and 4%, respectively). To compare outcomes of AYA with older adults, we focused on those with diploid cytogenetics.CR for pts ages 16–21 was 81%, with 3 yr survival of 46%; for ages 22–45, CR was 75% and 3 yr survival 36%; for ages 46–60 CR was 68% with 3 yr survival 28%; and for pts age greater than 60, CR was 54% with 3 yr survival of 22%. Conclusions: The outcome of AYA pts with AML is significantly better than for older adults with AML. Despite the advances in treatments over time, there is still significant room for improvement, particularly among those AYA with AML other than CBF and APL. Exploration of new treatment options is needed in this patient population. No significant financial relationships to disclose.
Phase I trial of laromustine in combination with infusional ara-C in elderly patients over age 60 with newly diagnosed AML or high-grade MDS
Authors: Ritchie E. K. , Roboz G. , Hinchcliff K. , Curcio T. , Scandura J. , Feldman E. 
Published: August 2020

7054 Background: Laromustine is a novel sulfonylhydrazine-alkylating agent with activity in acute myeloid leukemia (AML). In vitro combinations of laromustine and cytarabine (ara-C) show synergistic cytotoxicity. Laromustine in phase I and II trials shows activity in patients with relapsed/refractory leukemia (1) and elderly patients with new AML (2). Major toxicites include infusion reactions, myelosuppression, and febrile neutropenia. Older patients had a CR rate on phase II trial of 31% (2). Based on this data, a phase I study to evaluate the safety and efficacy of combining escalating doses of laromustine with infusional ara-C in AML and MDS patients over 60. Comprehensive geriatric assessments (CGA) are performed as part of the study. Methods: Laromustine 300 mg/m2 (cohort 1, n = 6), 400 mg/m2 (cohort 2, n = 5) and 500 mg/m2 (cohort 3) was administered by IV infusion over 1 hour on day 1 in combination with ara-C 100 mg/m2/day as a continuous infusion for 7 days. Patients achieving CR after induction therapy were offered up to 2 cycles of consolidation therapy for a maximum cumulative laromustine dose of 1,000 mg/m2. All patients had CGA on days 1, 30, 60, and 90 consisting of validated scales for quality of life, nutrition, activities of daily living, mini-mental status, depression, and medical comorbidities. Results: During induction adverse events included grade 3–4 myelosuppression and febrile neutropenia. One patient had grade 2 dyspnea possibly related to drug and improved with a short course of steroids. GI toxicities included grade 1 mucositis, diarrhea, and nausea. After 2 consolidation cycles, there was possible drug-related pulmonary toxicity with 3 episodes of grade 3 hypoxia. All patients were treated with steroids and symptoms resolved. Two patients in cohort 1, and 2 patients in cohort 2 (n = 3) achieved CR. Data from CGA shows a decrease in depression scale score and increased self-assessment of health from baseline to 30 days post induction. There was decreased ability to perform instrumental activities of daily living at 30 days, but scores rebounded 90 days post induction. Conclusions: Preliminary data suggest laromustine and infusional ara-C is a feasible and active; updated data will be presented at the meeting. No significant financial relationships to disclose.
Inference of imatinib (IM) effects on leukemic stem cell (SC) compartment via mathematical modeling of IRIS treatment response data
Authors: Bottino D. , Chia Y. , Stein A. , Georgieva A. , Yu J. , Kahn J. , Helmlinger G. , Kalebic T. 
Published: August 2020

7056 Background: Continuous treatment of chronic phase CML (CML-CP) patients with imatinib (IM) induces durable responses in majority of patients with a decreasing rate of relapse (Hochhaus et al, Blood. 2007;110). We present a mechanistic mathematical model which uses 6-year follow up data from the International Randomized Study of Interferon Versus STI571 (IRIS) trial (O'Brien et al, N Engl J Med. 2003;348:994) to explore IM effects on leukemic stem cells (SCs) across the patient population. Methods: The model approximates hemopoiesis as a 4-stage process in which only the first stage, corresponding to the SC compartment, is capable of self-renewal. Leukemic SCs, early and late progenitors were assumed to have higher self-renewal and expansion/differentiation rates than their normal counterparts. Model parameters describing the patient population distributions of leukemic/total SC ratio at diagnosis and sensitivity of leukemic cells to IM, were then fitted to individual cytogenetic and molecular response (CR/MR) data from 200 randomly selected newly-diagnosed CML-CP patients with 6-year follow-up. Results: Based on our analysis, successful characterization of the wide range of clinically observed treatment responses requires the inhibition of the leukemic SC compartment by IM. The median predicted inhibition of the leukemic SC proliferation rate was 79%. The model further predicted that after 6 years of IM treatment, 45% of patients would achieve a leukemic/total SC ratio below 0.1. Conclusions: We have developed a mathematical model of IM effects on CML-CP based on 6-year CR and MR data from the IRIS trial. In contrast to prior reports (Michor et al, Nature. 2005;435), our modeling predicts that IM reduces the leukemic SC compartment in most CML-CP patients, which could provide a mechanistic rationale for the decreasing rate of relapse observed in the study population. [Table: see text]
Updated remission duration and survival results of single-agent clofarabine in previously untreated older adult patients with acute myelogenous leukemia (AML) unlikely to benefit from standard induction chemotherapy due to unfavorable baseline risk factor(s)
Authors: Erba H. P. , Kantarjian H. M. , Claxton D. F. , Arellano M. , Lyons R. M. , Kovacsovics T. J. , Gabrilove J. , Eckert S. , Faderl S. 
Published: August 2020

7062 Background: The CLASSIC II trial has previously reported an independently confirmed overall remission rate of 46% (38% CR and 8% CRp) and 30- and 60-day mortality rates of 9.8% and 16.1%, respectively (Blood 112: 558, 2008). We now report updated duration of remission (DOR), disease-free survival (DFS), and overall survival (OS). Methods: Single arm, multi-center, phase II, open-label, 2-stage study of patients with untreated AML, ≥60 years old, and at least one adverse prognostic factor: age ≥70 years, antecedent hematologic disorder (AHD), PS = 2, and/or intermediate/unfavorable risk karyotype. Clofarabine (CLO) administered days 1–5 at 30 mg/m2 during induction and 20 mg/m2 during re-induction/consolidation for maximum 6 cycles. Patients were followed for at least 6 months past remission (CR/CRp). Results: 116 patients enrolled and 112 in full analysis set. Median age 71 years. Median DOR (censored at alternative therapy) for CR/CRp was 56 weeks (95% CI, 33 weeks - not yet estimable [n/e]) and for CR 65 weeks (95% CI, 41 weeks - n/e). Median DFS (not censored at alternative therapy) for CR/CRp was 34 weeks (95% CI, 24 - 65 weeks). Median OS was 41 weeks (95% CI 28 - 53 weeks), for CR/CRp 59 weeks (95% CI, 50 weeks - n/e ), and for CR was 72 weeks (95% CI, 53 weeks - n/e) after median follow-up of 36 weeks (range, 1 - 85 weeks). Thirty-day mortality was 9.8% for all patients with 4.7% and 13% for age <70 and age ≥70 years, respectively. Conclusions: These data expand on the previously reported efficacy and safety data of single agent CLO in adult AML. Complete remissions appear durable (median >1 yr), and DFS and OS compare favorably to historical experience, particularly in patients with these adverse prognostic factors. These results suggest that single agent CLO is an effective and tolerable treatment option for older adult patients with untreated AML and 1 or more unfavorable baseline prognostic factor(s). [Table: see text]
Effect of nilotinib on the pharmacokinetics and pharmacodynamics of warfarin
Authors: Yin O. , Gallagher N. J. , Fischer D. , Zhao L. , Zhou W. , Golor G. , Schran H. 
Published: August 2020

7063 Background: Nilotinib, a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of CML-CP and CML-AP in patients resistant or intolerant to prior therapy including imatinib. Nilotinib has shown competitive inhibition of CYP2C9 in vitro, but its effect on CYP2C9 activity in human is unknown. This study evaluated the effects of nilotinib on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin, a sensitive CYP2C9 substrate, in healthy subjects. Methods: Twenty-four subjects (6F, 18M, age 21–65 years) were enrolled to receive a single oral 25 mg warfarin with either 800 mg nilotinib or matching placebo (administered 30 minutes after consumption of a high-fat meal) in a cross-over design. Serial blood samples were collected post-dose for determining nilotinib, S- and R-warfarin concentrations. Prothrombin time (PT) and international normalized ratio (INR) were determined as PD measures for warfarin. CYP2C9 genotyping was performed in all subjects using TaqMan assay. Results: Sixteen subjects were identified as CYP2C9 extensive metabolizers (EM) and 8 as intermediate metabolizers (IM), but none was poor metabolizer. PK parameters of S- and R-warfarin were found to be similar between two treatments (warfarin + nilotinib versus warfarin alone) for both EM and IM groups. The geometric mean ratios (90% CIs) for the Cmax and AUC0-∞ of S-warfarin in all subjects were 0.98 (0.95–1.02) and 1.03 (0.99–1.07), respectively, and for R-warfarin were 1.00 (0.96–1.04) and 1.02 (0.99–1.06) respectively. Mean ratios for the maximum value and AUC of PT were 1.00 (0.96–1.04) and 1.00 (0.98–1.02), respectively, and for INR were 1.00 (0.97–1.01) and 1.00 (0.99–1.01), respectively. Nilotinib Cmax was 1872±560 ng/mL, which is comparable to the mean steady-state Cmax in CML and GIST patients receiving 400 mg BID doses. Adverse effects observed following either treatment were generally consistent with the known safety profiles of both drugs, and there were no new safety issues observed. Conclusion: The study results demonstrate a lack of effect of nilotinib on the PK and PD of warfarin, suggesting nilotinib does not inhibit CYP2C9 activity in human subjects. These findings suggest that warfarin can be used with nilotinib concurrently without the risk of bleeding. [Table: see text]
Phase I dose escalation trial of sorafenib as a single agent for adults with relapsed and refractory acute leukemias
Authors: Pratz K. W. , Cho E. , Karp J. , Levis M. , Zhao M. , Rudek M. , Wright J. , Smith B. D. 
Published: August 2020

7065 Background: Sorafenib is a multikinase inhibitor with activity against B-raf, VEGF, and FLT3. Based on preclinical activity in FLT3 mutant AML, sorafenib was studied in refractory acute leukemia. Methods: The primary objective was to determine the safety and tolerability of sorafenib in refractory acute leukemias. Secondary objectives included pharmacokinetics (PK) and pharmacodynamic (PD) effects of sorafenib on FLT3 phosphorylation. Dose escalation began at 400 mg BIDx14days per month, and proceeded through 600 mg BID x 21 days per month. Plasma concentration of sorafenib and its primary metabolite sorafenib N-oxide were measured by LC/MS//MS method. The plasma inhibitory assay was used to measure target inhibition of phosphorylated FLT3 and phosphorylated Erk. Results: Fifteen patients (13 = AML, 2 = ALL) were enrolled (ages 37–85) and treated on three dosing schedules (400 mg BID x 14 d, 400 mg BID x 21 days, 600 mg BID x 21days) of single agent sorafenib. The maximally tolerated dose was 400 mg BID x 21 days per month. Grade 3 or greater toxicities were experienced in 55% of cycles, most common grade 3 or greater toxicities being fatigue (16%) and hypokalemia (13%). No patients met criteria for complete or partial response, but 11 of 15 (73%) patients experienced stable disease as best response, with 6 showing a reduction in bone marrow blasts after only one cycle, half of who experienced a >50% reduction in bone marrow blasts. Interestingly, 2 pts with FLT3-ITD mutations both showed marrow blast response (1 pt >50%). Sorafenib resulted in sustained complete inhibition of FLT3 and Erk as demonstrated in all patients assessed (n = 11). Importantly, this inhibition was maintained throughout treatment cycle and 3/5 pts had FLT3 inhibitory activity 7 days post their last dose. Correlative studies suggest sorafenib N-oxide is an active metabolite. Conclusions: Sorafenib is a potent inhibitor of FLT3 with favorable PK and PD properties. Clinical activity as a single agent was limited to transient reductions in bone marrow blast counts and dose escalation was limited due to toxicities. Based on PK data in conjunction with standard curves for inhibition of FLT3 by sorafenib in plasma, the minimum FLT3 inhibitory dose of sorafenib is likely less than 400 mg BID. No significant financial relationships to disclose.
Etoposide and mitoxantrone in newly diagnosed acute myeloid leukemia patients with persistent leukemia after a course of induction therapy with cytarabine and idarubicin
Authors: McHayleh W. M. , Redner R. , Sehgal R. , Raptis A. , Agha M. , Natale J. , Luong T. , Schlesselman J. J. , Foon K. , Boyiadzis M. 
Published: August 2020

7073 Background: The goal of induction chemotherapy in acute myeloid leukemia (AML) is complete remission with restoration of normal bone marrow. If residual leukemia is present after the first course of induction therapy, patients receive a second course identical to the first or receive a non-cross resistant antileukemic regimen. Methods: In a retrospective study of adult patients with newly-diagnosed AML treated at the University of Pittsburgh Cancer Institute between December 2002 and May 2008, we evaluated the efficacy and toxicity of mitoxantrone (10 mg/m2/d) and etoposide (100 mg/m2/d), both administered intravenously within 5 days as second course therapy of patients not responding to first-course induction therapy with cytarabine and idarubicin. Univariate and multivariate associations between patient characteristics and complete response (CR) were assessed by logistic regression, with overall- and relapse-free survival estimated by Kaplan-Meier analysis. Results: 74 AML patients (mean age 56 years, range: 18–73 years) completed treatment with etoposide and mitoxantrone; 29 (39%) achieved CR. Lower CR rate was associated with unfavorable cytogenetic risk status at diagnosis and higher percent blasts prior to treatment with mitoxantrone and etoposide. Ten (14%) patients died due to infectious complications. No grade 3 or 4 hepatic toxicities were observed. One patient developed grade 3 cardiac toxicity. Median duration of neutrophil recovery following therapy in patients achieving CR was 29 days. Median overall survival was 9.0 months (95% CI 5.8–14.9 months). The 29 patients who achieved CR received postremission therapy: 16 of these eventually relapsed, while 4 others died without evidence of relapse. Median duration of relapse-free survival in these 29 patients was 11.0 months (95% CI: 9.0–19.3 months). Conclusions: Our study suggests that the combination of etoposide and mitoxantorne is an active and well-tolerated regimen as second-course therapy in newly diagnosed AML patients who have persistent leukemia after a first course of induction therapy with cytarabine and idarubicin. No significant financial relationships to disclose.
Molecular responses with nilotinib 800 mg daily as first-line treatment of chronic myeloid leukemia in chronic phase: Results of a phase II trial of the GIMEMA CML WP
Authors: Martinelli G. , Castagnetti F. , Poerio A. , Breccia M. , Palandri F. , Alimena G. , Pane F. , Saglio G. , Baccarani M. , Rosti G. 
Published: August 2020

7074 Background: Nilotinib has a higher binding affinity and selectivity for Abl with respect to imatinib (IM). To investigate the efficacy and the safety of nilotinib 400 mg BID in untreated, early chronic phase (ECP) CML patients (pts), the GIMEMA CML WP is conducting a multicentric, phase II study trial (ClinicalTrials.gov NCT00481052 ). Methods: 73 pts have been enrolled between June 2007 and February 2008. The median age was 51 years (range 18–83). Median follow-up is currently 210 days (range 68–362). Results: All 73 pts and 48/73 (66%) completed 3 and 6 months on treatment, respectively. Response at 3 and 6 months (ITT): CHR rate was 100% and 98%, CCgR rate 78% and 96%, respectively. A MMR was achieved by 3% after 1 month on treatment, but this proportion rapidly increased to 22% after 2 months, 59% after 3 months and 74% after 6 months. One patient progressed at 6 months to accelerated-blastic phase with the T315I mutation. The median daily average dose was close to the intended dose, 789 mg (range 261 - 800); 34/73 pts (47%) interrupted nilotinib at least once, with a median interruption of 15 days (range 2–98). The dose of nilotinib at the last visit was 400 mg BID for 52 pts (71%), 400 mg daily for 20 pts (27%), and 200 mg daily for 1 patient (1%). AEs (grade 3/4) were manageable with appropriate dose adaptations: hematologic toxicity was recorded so far in 4 pts (5%); the most frequent biochemical laboratory abnormalities (grade 3) were total bilirubin increase (15%), GOT/GPT increase (11%), and lipase increase (4%). Only 1 episode of grade 4 lipase increase was recorded. It is noteworthy, considering the 48 cases with at least 6 months of follow-up, that the incidence of any grade 2 and 3 non-hematologic adverse event, decreased from 50% and 8% (first 3 months) to 23% and 6% (second trimester), respectively. In 16 pts (22%), transient and not clinically relevant ECG abnormalities have been recorded; 2 more pts (3%) revealed a transient and uneventful QTc prolongation (>450 but <499 msec). Conclusions: In ECP Ph-pos CML pts both cytogenetic and molecular responses to nilotinib are substantially faster than the responses to IM. Supported by: FIRB 2006. No significant financial relationships to disclose.
Chronic lymphocytic leukemia (CLL) coexistent with HIV: An increasing association?
Authors: Cole J. , Pantanowitz L. , Aboulafia D. M. 
Published: August 2020

7078 Background: In the era of highly active antiretroviral therapy (HAART) HIV-seropositive patients are living longer. With improvements in overall survival the frequency and pattern of malignancies seen in these patients are changing. CLL is the most common leukemia in Western countries, yet very little has been published regarding HIV coexistent with CLL. Therefore, the aim of this study was to evaluate the clinicopathological findings and outcome of HIV-associated CLL in a series of cases. Methods: Cases of HIV-associated CLL/small lymphocytic leukemia (SLL) were collected from the authors’ archives and published case reports (using PubMed search). Information regarding patient demographics (age, gender), mode of HIV acquisition, HAART use, immunosuppression (HIV Viral load [VL], CD4+ cell count), clinical presentation, pathology, and outcome were abstracted and analyzed. Results: A total of 6 patients were identified (4 personal cases, 2 published reports) with a median patient age of 60 years (range, 50–76), 5 of whom were male. Five were homosexual and 1 heterosexual. Five patients were on HAART. Immunologic parameters available for 4 patients showed a median CD4+ count of 930 cells/mm3 (range, 396–1374) and mean HIV VL of 2,103 copies/ml (range, <75–5,297). Persistent lymphocytosis was noted in 5 cases and 4 patients had persistent/progressive lymphadenopathy. CLL/SLL was diagnosed by lymph node biopsy (n = 1) and/or flow cytometry (n = 5). Two patients remained well without treatment and 4 required therapy due to either hemolytic anemia, CLL- induced renal failure, pancytopenia, or hypogammaglobulinemia with recurrent infections. One individual died of renal failure and two from infectious complications. Conclusions: CLL/SLL may occur in association with HIV infection in the elderly without significant concomitant immunosuppression. CLL-related complications in our small series were frequent (67%), including mortality (50%). Additional cases of CLL/SLL are anticipated as HIV-infected patients in the HAART era are reported to be living longer. The association between HIV and CLL is deserving of further attention and we encourage clinicians to report their findings. No significant financial relationships to disclose.