bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term outcomes of high-dose therapy using busulfan, etoposide, and cyclophosphamide followed by allogeneic hematopoietic cell transplantation for patients with high-risk or advanced stages of myeloid malignancies
Authors: Naik S. G. , Negrin R. , Laport G. , Miklos D. , Shizuru J. , Arai S. , Blume K. , Wong R. , Lowsky R. , Johnston L.
Published: August 2020

7033

Patients (pts) with high risk (HR) or advanced myeloid malignancies have limited effective treatment options. These include high-dose therapy followed by allogeneic hematopoietic cell transplantation (HCT). We report a single institution long-term follow-up of 96 pts, median age 50 (20–60) yrs, who received HLA matched related HCT between 1992 and 2007. All pts were treated with a uniform preparatory regimen: busulfan 16.0 mg/kg (d-8 to-5), etoposide 60mg/kg (d-4), cyclophosphamide 60mg/kg (d-2), and graft-versus-host-disease (GVHD) prophylaxis of cyclosporine and prednisone. Disease status at transplantation was induction failure (IF) acute myeloid leukemia (AML) (n = 10), HR AML in 1st complete remission (CR1) n = 11, in CR2 (n = 5), in CR3 (n = 2), relapsed refractory (RR) AML (n = 14), chronic myeloid leukemia (CML) in second chronic phase (n = 6), blast crisis (n = 2), myelofibrosis (n = 6), myeloproliferative disorders (n = 2), and MDS (n = 38). Thirty-six % (n = 35) of pts received bone marrow while 64 % (n = 61) received G-CSF mobilized peripheral blood mononuclear cells (PBMC). With a median follow up of 5.6 yrs (1.6–14.6 yrs) actuarial 5-year overall survival (OS) was 32% (95% CI 22–42%) and 5-year probability for freedom from progression (FFP) was 64% (95% CI 52%-76%). Relapse rate was 32% at 1 year and remained at 36% (95%CI 24%-48%) at 2 and 5 years with no further increase in relapse beyond two years. Non-relapse mortality (NRM) was 29 % (95% CI 20%5–38%) at day 100 and 39% (95% CI 29%-49%) at one yr. Cumulative incidence of acute (grade 3–4) and chronic GVHD was 28% (95% CI 19%-37%) and 38% (95% CI 24%-52%), respectively. There was no statistically significant difference in OS; 31% versus 32% (p = 0.89) or FFP 71% versus 60% (p = 0.29) for recipients of BM versus PBMC with similar results in IF and RR AML. These results confirm that pts with high-risk or advanced myeloid malignancies can achieve long-term survival following myeloablative allogeneic HCT with aggressive conditioning. Relapse and acute GVHD remain significant causes of mortality. Strategies to augment graft-versus-tumor reactions and reduce GVHD remain essential for improving long-term outcomes.

No significant financial relationships to disclose.
Clinical improvement with a novel CD20 mAb, ofatumumab, in fludarabine-refractory chronic lymphocytic leukemia (CLL) also refractory to alemtuzumab or with bulky lymphadenopathy
Authors: Kipps T. J. , Österborg A. , Mayer J. , Stilgenbauer S. , Hellmann A. , Williams C. D. , Furman R. , Chan G. , Russell C. , Wierda W. G.
Published: August 2020

7043

Background: Patients (pts) with CLL refractory tofludarabine and alemtuzumab (double-refractory, DR) or refractory to fludarabine with bulky (>5 cm) lymphadenopathy (bulky fludarabine-refractory, BFR) have a poor prognosis. Ofatumumab is a human mAb specific for a distinctive small-loop epitope of CD20 that appears more potent than rituximab in eliciting complement-dependent lysis of B cells in vitro. We report, for the first time, results from the planned interim analysis of the clinical benefit observed in pts with DR or BFR CLL treated with ofatumumab in an international pivotal clinical study. Methods: Pts with DR or BFR CLL received 8 weekly then 4 monthly ofatumumab infusions (Dose 1, 300 mg; Doses 2–12, 2,000 mg). Primary endpoint was overall response rate (ORR; 1996 NCI-WG criteria), as assessed by an Independent Review Committee, over 24 wks. Results: Of 138 treated pts (DR: N = 59; BFR: N = 79; median age 64 and 62 yrs, respectively), 63% had Rai stage III/IV disease at screening. Pts had a median of 5 prior therapies. ORR (99% CI) was 58% (40, 74%) in the DR and 47% (32, 62%) in the BFR groups, and median overall survival (95% CI) was 13.7 mo (9.4, NR) and 15.4 mo (10.2, 20.2), respectively. Resolution of disease symptoms (maintained for ≥2 mo) were observed in a large proportion of pts (Table), including in pts considered nonresponders by NCI-WG criteria. Improvements in hematologic values were also observed in some pts with abnormal baseline values, particularly for platelet counts. Pts with thrombocytopenia at baseline (n = 73) experienced sustained increases in median platelet counts from 65 × 109/L to over 100 × 109/L by Wk 8; a similar pattern of rapid improvement was observed in Hgb values. Conclusions: Ofatumumab as single-agent achieves high ORR, and improves disease symptoms and hematologic parameters in heavily pretreated pts with DR and BFR disease who lack standard treatment options.

[Table: see text]

[Table: see text]
Comorbidity description using the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) in elderly de novo poor-risk AML patients (pts) treated with laromustine
Authors: Schiller G. J. , O'Brien S. M. , Vey N. , Pigneux A. , DeAngelo D. J. , Karp J. E. , Hudak D. , Kell J. , Stuart R. K. , Giles F. J.
Published: August 2020

7050

Background: Treatment of older pts with AML is often complicated by comorbidities and pts with comorbidities are often underrepresented in clinical trials. The HCT-CI, which was developed in pts receiving allogeneic SCT, has been applied to pts receiving induction therapy for AML in an effort to assist in therapeutic and investigational decisions (Kantarjian 2006; Etienne 2007; Giles 2007). HCT-CI scores have been shown to be predictive of early death and survival in pts ≥ 60 years receiving induction therapy for AML, with early death rates of 3%, 11%, and 29% for pts with HCT-CI scores of 0, 1–2, and ≥ 3, respectively (Giles 2007). Methods: 140 pts age ≥ 60 with poor risk de novo AML from two phase II studies were scored for comorbidity by HCT-CI. In these studies, poor risk was defined by the presence of at least one risk factor: age ≥ 70, ECOG PS = 2, unfavorable cytogenetics, or cardiac, pulmonary, or hepatic dysfunction. All pts received induction therapy with 600 mg/m2 laromustine as a single 30–60 min infusion. A second induction cycle could be administered to pts with PR or hematologic improvement. Pts with CR or CRp were able to receive consolidation with laromustine 400 mg/m2 (Study CLI-033) or araC 400 mg/m2/day CIV for 5 days (Study CLI-043). Results: HCT-CI score was 0 in 7 (5%) pts, 1–2 in 19 (14%), and ≥ 3 in 114 (81%). The median HCT-CI score was 5 (range 0–13). The most common comorbidities were cardiac (42%), severe pulmonary (39%), infection (35%), and arrhythmia (31%). 52 (37%) of all pts achieved a CR/CRp; 39/114 (34%) of pts with HCT-CI score ≥ 3 achieved a CR/CRp. Deaths within 30 days of first induction were observed in 0/7 pts with HCT-CI score 0, 4/19 (21%) with score 1–2, and 16/114 (14%) with score ≥ 3. Overall survival at 12 months was 43%, 14%, and 21% for pts with HCT-CI scores of 0, 1–2, and ≥ 3, respectively. Conclusions: The majority (81%) of these older poor risk AML pts treated with laromustine had a HCT-CI score ≥ 3, confirming the poor risk nature of this patient group. The induction death rate for pts treated with laromustine and with HCT-CI score ≥ 3 was lower than that reported for a group of pts with HCT-CI score ≥ 3 treated with standard induction chemotherapy (14% vs 29%; Giles 2007).

[Table: see text]
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.
Functional assessment of performance status in patients with myelofibrosis (MF): Utility and feasibility of the 6-minute walk test (6MWT)
Authors: Mesa R. A. , Kantarjian H. , Tefferi A. , Cheville A. , Pardanani A. , Levy R. , Erickson-Viitanen S. , Thomas D. , Cortes J. , Borthakur G. , Verstovsek S.
Published: August 2020

7083

Background: Patients with Myelofibrosis (MF) suffer from significant fatigue, constitutional symptoms and splenomegaly (Mesa et. al. Cancer 2007) not improved by current therapy. The 6MWT measures functional status in cardio-pulmonary clinical trials. We undertook a prospective feasibility study of the 6MWT in MF patients for use in therapeutic clinical trials. Methods: MF patients (able to walk, normal vitals, not on a JAK2 inhibitor) were eligible. Baseline features and the MF symptom assessment form (MFSAF: Mesa et. al. Blood 2008) was administered. The 6MWT was administered in standardized fashion (American Thoracic Society: observed laps of a 30 - 35 meter long course, indoors, level, without encouragement), and then repeated for further validation. Results: Safety of the 6MWT: Fifty five MF patients were enrolled with only 2 patients (3%) stopping the 6MWT early secondary to fatigue. There were no adverse events attributable to undergoing the 6MWT in test subjects. Results of the 6MWT: Current results of our ongoing study demonstrate compared to age matched healthy volunteer controls, males with MF walk approximately 90 meters less and females with MF walk approximately 60 meters less (Table). Correlation of 6MWT Results to Patient Reported Symptoms (MFSAF): Results from the MFSAF demonstrated the fatigue (as assessed by the brief fatigue inventory (Medoza et. al. Cancer 1999) embedded in the MFSAF) showed patients with a higher BFI (i.e., more fatigued) had more impairment in the 6MWT than those with low BFI scores. Symptomatic burden as assessed by the MFSAF were typical for MF, correlation of individual symptom severity with 6MWT will require a larger trial for adequate power. Conclusions: The 6MWT can be safely performed in un-selected MF patients, and demonstrates a functional deficit compared to published controls. Validation of the ability of the 6MWT to measure functional improvements in MF patients as a response to novel therapy trials is planned.

[Table: see text]

No significant financial relationships to disclose.
Persistence of complete molecular remission in chronic myeloid leukemia after imatinib discontinuation: Interim analysis of the STIM trial
Authors: Mahon FX F. , Rea D. , Guilhot F. , Legros L. , Guilhot J. , Aton E. , Dulucq S. , Reiffers J. , Rousselot P.
Published: August 2020

7084

Background: Imatinib (IM) has greatly improved survival in chronic myeloid leukemia (CML). However, IM must be continued for an indefinite period of time. A multicenter trial “Stop Imatinib” (STIM) was initiated in July 2007, in order to evaluate the persistence of complete molecular remission (CMR) after stopping IM and determine factors associated with CMR persistence. Methods: Inclusion criteria were IM treatment duration ≥3 years and sustained CMR, defined as BCR-ABL transcripts below a detection threshold of a 5-log reduction (undetectable by RQ-PCR) for ≥2 years. Molecular relapse was defined as RQ-PCR positivity confirmed on 2 successive occasions. In case of relapse, pts were rechallenged with IM at 400 mg daily. Molecular monitoring was performed according to international recommendations. Results: Sixty-nine pts were recruited among which 60 with a follow-up >1 month, including 22 males and 38 females. Median age was 62 (29–80), 31 pts had been treated with IFN prior to IM and 29 with IM frontline (de novo). Median follow-up was 5 months (1–16). Relapse occurred in 37 pts within 6 months of IM discontinuation. Only 1 pt relapsed after 6 months (M7). All patients in molecular relapse were sensitive to IM reintroduction. At last follow-up in December 2008, CMR was sustained in 8 pts at M14 and 3 pts at M16. No differences in terms of demography, duration of IM treatment and CMR duration were found between pts who relapsed and those who did not. At M9, the probability of persistent CMR was 46% (95% CI: 32–59%), 53% (95% CI: 33–69%) for previously IFN-treated pts and 39% (95% CI: 20–58%) for de novo pts (p = 0.54). A trend for a lower probability of relapse in low Sokal score pts was observed. Conclusions: Our data confirm that CMR can be long-lasting after discontinuation of IM. Using stringent criteria, it is possible to stop IM in patients with sustained CMR, even in those treated with IM as a single agent. Updated follow-up will be presented.

No significant financial relationships to disclose.
Treatment patterns of chronic myelogenous leukemia patients with suboptimal responses to imatinib
Authors: Guérin A. , Guo A. , Williams D. , Yu A. P. , Wu E. , Latremouille-Viau D. , Tsaneva M. , Signorovitch J. , Griffin J. D.
Published: August 2020

7090

Background: Imatinib is the first-line therapy for Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Patients with suboptimal responses may have the dose of imatinib escalated or may be switched to an alternative kinase inhibitor such as dasatinib. The aim of this study is to examine the real-world treatment patterns of imatinib and dasatinib in CML patients. Methods: Two large U.S. administrative claims databases from January 1999 to March 2008 were combined (MarketScan and Ingenix Impact) to extract de-identified information of patients diagnosed with CML (ICD-9 code: 205.1) who were initiated on imatinib. Patients were followed from the first observed imatinib prescription to the end of data availability. Patients who increased imatinib dose to >400 mg/day were defined as dose escalators, while patients who initiated on imatinib and further switched to dasatinib were considered as switchers. Rates of imatinib dose escalation and switching to dasatinib were estimated. Kaplan-Meier (KM) survival analyses were used to estimate the rate of imatinib discontinuation, defined as a lack of imatinib supply for at least 90 days. Among switchers, the rate of switching back to imatinib was also estimated using KM survival analysis. Results: Among the 5,159 CML patients initiated with imatinib, 1,144 patients either had dose escalation of imatinib (839) or were switched to dasatinib (305) during the study period. Of the 5,159 patients, 12.1% patients discontinued imatinib by the end of the first year, and 25.4% discontinued by the end of the third year. Among the 305 switchers, 115 (37.7%) had an imatinib dose increase prior to the switch, and 66 (21.6%) were escalated to 800 mg of imatinib before switching. 51 patients (16.7%) had used imatinib for <6 months before switching, and 17.1% switched back to imatinib within 6 months of dasatinib treatment. Conclusions: This study showed that great variability was observed in the real world treatment pattern of CML patients. Most CML patients who initiated on imatinib did not dose increase or switch during the study period. Of those who switched to dasatinib, most did not attempt to increase the dose before switching, and a sizeable portion of patients had to switch back to imatinib.

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Mortality and hospitalization in myelodysplastic syndromes (MDS) using the SEER-Medicare linked database
Authors: Lindquist K. , Danese M. , Knopf K. , Mikhael J.
Published: August 2020

7091

Background: Mortality in patients with MDS is high, and most require transfusions, emergency department (ED) visits, and hospitalizations. The relationship between these outcomes with the key complications of MDS (anemia, neutropenia, thrombocytopenia) has not been well studied. Methods: Patients who were ≥ 66 years at MDS diagnosis in 2001 or 2002 were identified from SEER registries. Those with both Medicare Part A and B were followed until death or the end of 2005. Mortality, transfusions, ED visits, and hospitalizations were based on Medicare data. The presence of complications was based on diagnosis codes, transfusions, and medication use. Kaplan-Meier incidence was estimated for each outcome. Factors associated with each outcome were based on multivariable Cox models with baseline age, gender, race, co-morbidity level, socio-economic status indicators, and time-varying covariates for each complication. Results: In 1,863 MDS patients, the 3-month incidence of transfusion, ED and hospitalization was 45%, 41%, and 62%, and 3-year incidence was 75%, 87%, and 91% respectively. Median survival was 22 months. The 3-year incidence of anemia, thrombocytopenia and neutropenia was 89%, 37%, and 15% respectively. See table for multivariate results. Conclusions: Starting shortly after diagnosis, MDS patients have high rates of transfusions, ED visits, and hospitalizations. Diagnoses of anemia, neutropenia, and thrombocytopenia are strongly associated with this utilization. The presence of anemia and thrombocytopenia are important independent risk factors for death.

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Adverse events associated with escalating imatinib versus switching to dasatinib in patients with chronic myelegenous leukemia
Authors: Wu E. , Guo A. , Williams D. , Guérin A. , Yu A. P. , Latremouille-Viau D. , Tsaneva M. , Signorovitch J. , Griffin J. D. , Bollu V.
Published: August 2020

7092

Background: After initial therapy with imatinib, some chronic myelegenous leukemia (CML) patients may require dose escalation or switching to another BCR/ABL kinase inhibitor to achieve the desired response. This study compared adverse events associated with either escalation of imatinib or switching to dasatinib. Methods: Two large administrative claims databases were combined (MarketScan and Ingenix Impact) to extract deidentified information on 17,382 patients diagnosed with CML (ICD-9 code: 205.1) from January 1999 to March 2008. 474 patients (dose escalators) had their dose of imatinib increased at some point to >400 mg/day but were never given dasatinib, while 175 patients were switched to dasatinib with or without dose escalation of imatinib (switchers). Patients were followed from the index date to treatment discontinuation or end of eligibility. Cox proportional-hazard models were used to compare the risk of common adverse events (AEs) associated with escalation or switching to dasatinib, controlling for demographics, imatinib treatment patterns, and prior therapies at baseline. Patients with the studied AEs at baseline were excluded from analyses of the corresponding AEs. Results: Switchers experienced significantly higher risk of the following AEs than escalators: fluid retention (HR 3.22 p < 0.0001), pleural effusion (HR 4.90 p < 0.0001), thrombocytopenia (HR 3.25 p = 0.0044), neutropenia (HR 3.40 p = 0.0009), and some non-hematologic adverse events (HR 2.38 p < 0.0001), dyspnea (HR 4.02 p < 0.0001), constipation (HR 5.79 p = 0.0041), nausea and vomiting (HR 2.40 p = 0.0100), and congestive heart failure (HR 5.01 p < 0.0001). No statistically significant differences in risk of other common AEs associated with imatinib and dasatinib were identified. Conclusions: 15.4% of CML patients treated with ≤400mg of imatinib initially either had dose escalation or switch to dasatinib. Significantly more AEs were associated to those who switched to dasatinib than those who dose escalated. Further study is warranted to examine the causality of the difference in these AEs.

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Lymphocyte reconstitution in multiple myeloma patients after allogeneic G-CSF-mobilized hematopoietic progenitor cells transplantation from HLA-identical siblings
Authors: Martino M. , Fedele R. , Irrera G. , Messina G. , Cuzzola M. , Gareffa C. , Console G. , Dattola A. , Iacopino P.
Published: August 2020

7098

Background: Allogeneic transplantation of G-CSF-mobilized hematopoietic progenitor cells (HPC) results in rapid and complete engraftment in a large proportion of patients and in relatively fast immune recovery. Methods : We have analyzed by flow cytometry the immune reconstitution in 19 patients (pts) affected by multiple myeloma undergone to allogeneic HPC transplant from HLA-identical related donors after nonmyeloablative conditioning regimen with fludarabine 90 mg/m2 and cyclophosphamide 900 mg/m2. In each patient a comparable number of mononuclear cells, CD3+ T lymphocytes and CD34+ progenitor cells was infused. To evaluate the kinetics of the immune reconstitution, the overall number of total lymphocytes, T, B and NK cells of each patient were assessed before and 1, 2, 3, 6, 12, 18, 24, 30, 36 months after allogeneic HPC transplant. Results: Overall T cell reconstitution was in all the pts at 3 months, since at that time the CD3+ T cell median number was 880 cells/microl (r. 589–1,357). However, in all pts high numbers of CD3+ T cells were achieved at 12 months after transplant (median 1,326 cells/microl, r. 850–2,309). The CD4+ T cell median number was 281 cells/microl (r. 185–433) at 6 months, 391 cells/microl (r. 303–505) at 12 months, 603 cells/microl (r. 433–736) at 18 months. The CD8+ T cell median number was increased from the transplant to 18 months in which it was 1,489 cells/microl (r. 760–1,976). The decrease of CD8+ T cells with the normalization of CD4+/CD8+ ratio was observed at 30 months when CD4+ T cells were 650 cells/microl (r. 370–989) and CD8+ T cells were 690 cells/microl (r. 445–1,743). B cells recovery was observed at 18 months with a median number of 194 cells/microl (r. 40–404). The faster reconstitution was documented for NK cells with a median number of 314 cells/microl (r. 61–647) at 2 months. Conclusions: the complete immune reconstitution in our pts was achieved at 30 months after transplant. Our objective is to evaluate if this slow immune recovery is associated with a high incidence of infectious diseases and a low incidence of chronic GVHD.

No significant financial relationships to disclose.
Plerixafor (AMD3100) in myeloma and lymphoma patients undergoing autologous stem cell transplantation
Authors: Moreb J. S. , Salmasinia D. , Cline C. , Rosenau E.
Published: August 2020

7100

Background: Poor peripheral blood stem cell (PBSC) mobilization has been reported as an obstacle to autologous stem cell transplant (ASCT). Plerixafor (AMD3100) has been recently approved as a mobilization agent for PBSC in the setting of ASCT. Methods: We retrospectively analyzed the data on patients who received plerixafor in our institution over two-year period. Four lymphoma patients received the drug in their first cycle of mobilization and 17 patients (hard to mobilize, HTM) as a rescue after failing to achieve cell target using G-CSF alone. These patients include 8 multiple myeloma (MM) and 9 lymphoma patients. A control group of 26 randomly picked MM and lymphoma patients who were good mobilizers and received ASCT during the same period were used for comparison. Results: Sixteen of the 17 HTM patients proceeded to ASCT with median CD34+ cell dose of 3.68 X 106/kg (range, 1.88–5.01 X 106), and two of them had tandem transplants. All MM patients achieved minimum cell dose for two ASCTs. One MM patient died of progressive disease prior to ASCT. In comparison to the control group, plerixafor patients tended to have lower median CD34+ cell dose/kg collected and higher number of apheresis days, however the content of CFU-GM/kg on 1st day of apheresis was either equal or higher in the plerixafor group versus the control. The length of hospital stay, number of serious bacterial infection, time to granulocyte engraftment (AGC > 500) and long-term hematopoietic recovery at ≥ 12 mo post ASCT were not different among the two groups. Time to platelet recovery > 20,000/mm3 was similar for the MM patients, while more delayed for the plerixafor mobilized lymphoma patients (24 versus 12 days in the control group). One lymphoma patient in the control died of transplant-related complications before engraftment and none in the plerixafor group. Disease relapse at 12 months post ASCT was 0 and 10 % for plerixafor and control MM patients, respectively, and 46 and 20 % for lymphoma patients. However, the overall survival for both groups was not significantly different. Conclusions: all poor mobilizers were able to obtain adequate transplant CD34+ cell dose by using plerixafor and G-CSF. In general, patients mobilized with plerixafor had similar post transplant course and long-term outcome.

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Analyzing white blood cell subpopulation for quick and simple predictors for autologous stem cell collection
Authors: Gao Y. , Lim S. , Gao F. , Ng J. , Phoon Y. , Tham C. , Quek R. , Tao M.
Published: August 2020

7101

Background: For patients undergoing peripheral stem cell harvesting, the current standard predictor for successful harvest is the peripheral blood (PB)CD34 count, which may have a slow turn-around time. Daily monitoring of CD34 count may not be cost-effective. This study aims to identify simple hematological parameters that can be used to predict for a single day CD 34+ stem cell yield of at least 1 x 10(6)/kg. Methods: 57 patients with lymphoproliferative malignancies who underwent autologous stem cell (ASC) harvesting were studied following DHAP, ICE or ESHAP chemotherapy. Eight main parameters were investigated to predict for a single day CD34 stem cell yield above 1x10(6)/kg: PB CD34+ cells, absolute monocyte count (AMC), AMC ratio, total white count (WBC), absolute lymphocyte count (ALC), ALC ratio, immature granulocyte count (IMC), IMC ratio and non-neutrophil cells (NNC). NNC was calculated by subtracting absolute neutrophil count from the total white count. The ratios were calculated by dividing the respective values on the first day of harvest with the values on the day before mobilizing chemotherapy started. Results: Linear regression showed a strong correlation between stem cell yield and CD34+ cells (R2=0.79, p<0.001), IMC ratio (R2=0.51, p<0.001) and AMC ratio (R2= 0.46, P<0.001). WBC and AMC showed a wide dispersion of results and were not reliable predictors of CD34 yield. On multivariate analysis, an IMC > 1 (p=0.03) and AMC ratio > 1 (p=0.002), ALC ratio > 1 (p=0.03) were independently predictive of a single day CD34 stem cell yield exceeding 1x10(6)/kgConclusions: Incorporating simple, routine hematolgic indices such as ALC and AMC ratio into a simple formula can be used to predict for ASC collection in addition to CD34+ count. This may be particularly useful when the turn-around-time to attain enumeration of CD34+ cells is slow or delayed on the same day of collection.

No significant financial relationships to disclose.