Azacitidine for Post-Remission Therapy in Elderly Patients with Acute Myeloid Leukemia : Final Results of the Qoless AZA-Amle Randomized Trial

Background: Elderly patients with acute myeloid leukemia (AML) experience a low complete remission (CR) rate following intensive chemotherapy, a short duration of CR and high treatment-related mortality. Median survival is 7-12 months. Several reports suggest that maintenance therapy may improve survival. In particular, a recent report (Huls G, et al. Blood 2019) has shown that azacitidine (Aza) maintenance treatment improves 1-year disease-free survival (DFS) when adjusted for cytogenetics at diagnosis and platelet (PLT) count at randomization. Aims: This phase III, randomized, multicenter trial assesses the efficacy of post-remission Aza treatment versus best supportive care (BSC) in 54 AML subjects >60 years of age in CR after homogeneous induction and consolidation chemotherapy. Primary endpoint is the difference in DFS at 2 and 5 years between arms; main secondary endpoints are the difference in overall survival (OS), the number and length of hospitalizations and quality of life (QoL). Methods: AML subjects with >30% blasts, "de novo" or evolving from myelodysplastic syndrome and fit for intensive chemotherapy, received 2 courses of "3+7" therapy (daunorubicin 40 mg/m2 daily days 1-3 and cytarabine 100 mg/m2 daily IV infusion days 1-7). Subjects obtaining a CR received cytarabine 800 mg/m2 3 hour infusion bid days 1-3 and were randomized 1:1 to receive BSC or Aza at 50 mg/m2 s.c./i.v. for 7 days every 28 days and dose increase after 1st cycle to 75 mg/ m2 for further 5 cycles, followed by cycles every 56 days for 4.5 years or until relapse. QoL was assessed by QOL-E and EORTC QLQ-C30. Results: 149 subjects were included of median age 69, interquartile range (IQR) 65-74 years, and male/female 78/71. Amongst subjects not reaching randomization, 59 were relapsed/refractory, 22 died, 10 refused to continue, 3 were excluded for protocol violation, and 1 was lost to follow-up. Randomized patients (27 Aza, 27 BSC) were in study until relapse. Median follow-up was 9.9 months (IQR: 3.2-22.5). At 2 years post-randomization, no deaths occurred and 21 subjects in the BSC arm (median DFS 9 months, 95% CI 0-20) relapsed versus 18 subjects in the Aza arm (median DFS 11 months, 95% CI 1-21; P=0.33; Fig.1a). There was an effect modification by age on the effect of Aza versus BSC on relapse (P for effect modification=0.02) so that the effect of AZA was not significant for subjects <65 years and 65-73 years (P=0.65 and P=0.66, respectively) but was significant in subjects >73 years (P=0.008, Fig.1b). Cytogenetic risk (P=0.84), minimal residual disease (P=0.97), and platelet (PLT) count (below/above 100 Gi/L, P=0.47) did not modify the effect of Aza on DFS. However, cytogenetic risk and PLT count were confounders: after data adjustment, the effect of Aza on DFS just failed to reach statistical significance [HR (Aza vs BSC): 0.53, 95% CI: 0.26-1.05, P=0.068] . At 5 years post-randomization, no subjects died; 2 subjects on Aza and 1 subject on BSC withdrew consent and 1 subject on Aza in CR withdrew for relapse of bladder cancer. In the BSC arm, 23 subjects relapsed (median DFS 9 months, 95% CI: 0-20) versus 20 Aza subjects (median 11 months, 95% CI: 1-21; P=0.31, Fig.1a).Similar to 2 years post-randomization, at 5 years post-randomization an effect modification by age on the effect of Aza versus BSC was confirmed (P for effect modification=0.01) and the effect of Aza was significant only in subjects >73 years of age (P=0.007, Fig.1b). Again, data adjustment for cytogenetic risk and PLT count strengthened the link between Aza and DFS [HR: 0.56, 95% CI: 0.29-1.07, P=0.08]. Grade 3-4 adverse events (mainly neutropenia) were more frequent in the Aza (41%) than in the BSC arm (4%, P=0.002). Two Aza subjects were hospitalized twice for adverse events for a total of 22 and 26 days, respectively, versus no hospitalization for BSC subjects. QOL-E scores were poor at diagnosis and improved significantly at randomization, with further improvement for physical well-being. EORTC QLQ-C30 symptoms improved progressively over time. In linear mixed model analyses, no significant effect of Aza versus BSC was found for any QoL domain, confirming safety of Aza versus BSC. Summary/Conclusion: With the limitation of a small trial, we conclude that post-remission Aza in elderly AML patients receiving standard induction-consolidation chemotherapy is safe and is well-tolerated. Noteworthy, in patients over 73 years of age, Aza significantly prolongs DFS up to 5 years. Figure Disclosures Oliva: Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Novartis: Consultancy, Speakers Bureau. Candoni:Merck SD: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Di Raimondo:Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding. Musto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mannina:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Martino:Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol myers squibb: Membership on an entity's Board of Directors or advisory committees. Alati:Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

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Quality of Life and Karnofsky Performance Status in Patients with Relapse or Refractory Primary Central Nervous System Lymphoma during Phase I/II Study of Tirabrutinib

Blood ◽

10.1182/blood-2021-146439 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4561-4561

Author(s):

Yasuhito Terui ◽

Yoshitaka Narita ◽

Motoo Nagane ◽

Kazuhiko Mishima ◽

Yoshiki Arakawa ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Karnofsky Performance Status ◽

Performance Status ◽

Central Nervous System Lymphoma ◽

Advisory Committees ◽

Chugai Pharmaceutical ◽

Eortc Qlq C30 ◽

Eortc Qlq

Abstract Background: Based on the results of a phase I/II study in Japan (Trial registration: JapicCTI-173646), tirabrutinib (TIR), a second-generation inhibitor of Bruton's tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL). We have previously reported overall response rate of 63.6% and manageable safety profile results of this study (Narita et al. Neuro Oncol. 2021;23(1):122-133). Further, one-year follow-up data after the last patient had enrolled showed that the effects of TIR persisted in r/r PCNSL patients (Mishima et al. Poster presented at the Society for Neuro-Oncology virtual conference; November 19-21, 2020). Here, based on this one-year follow-up data, we describe the Quality of Life (QoL) and Karnofsky Performance Status (KPS) in r/r PCNSL patients treated with TIR. Methods: Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with TIR once daily (QD) at a dose of 320 mg, 480 mg, or 480 mg upon fasting (480 mg fasted QD). TIR was administered in 28-day cycles, and treatment was continued until disease progression or clinically unacceptable toxicity was observed. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely QLQ-C30 (EORTC QLQ-C30), EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L). The QoL survey was conducted during the screening period, on Day 28 of Cycle 1, after every 2 cycles (i.e., after Day 1 of Cycle 3), after every 4 cycles (i.e., after Day 1 of Cycle 25), and at the end of treatment. KPS was measured during the screening period, on days 1, 8, 15, and 28 of Cycle 1, on day 1 of every cycle after Cycle 3, and at the end of treatment. Results: Forty-four patients were prospectively enrolled, and 20, 7, and 17 patients were treated with TIR at 320 mg QD, 480 mg QD, and 480 mg fasted QD, respectively. Median patient age was 60 years (range 29-86). Median follow-up period was 14.9 months (range, 1.4-27.7) for the entire cohort but was 19.1 months, 23.5 months, and 12.0 months for the 320 mg QD, 480 mg QD, and 480 mg fasted QD groups, respectively. At the time of data cutoff (February 25, 2020), 11 patients (25%) remained on treatment. Mean (SD) score for the global health status/QoL section of the EORTC QLQ-C30 was 50.9 (23.7) at baseline and remained relatively constant during treatment (Figure 1). This trend was also observed for emotional function, cognitive function, and fatigue sections of the EORTC QLQ-C30, for motor dysfunction, communication deficit, weakness of legs, and bladder control sections of the EORTC QLQ-BN20, and in items pertaining to self-care, usual activities, and anxiety/depression in the EQ-5D-3L. Median KPS was 80.0 (range, 70-100) at baseline, which remained unchanged during TIR treatment (Figure 2). Conclusion: QoL and KPS scores in r/r PCNSL patients were maintained during TIR administration, a new treatment option for r/r PCNSL, which does not lead to the deterioration of QoL and KPS. Figure 1 Figure 1. Disclosures Terui: Ono Pharmaceutical: Speakers Bureau; MSD: Speakers Bureau; Janssen: Speakers Bureau; Esai: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Celgene: Speakers Bureau; AbbVie: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Narita: Ono Pharmaceutical co.: Honoraria, Research Funding; Dainippon-Sumitomo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Stella-pharma: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Bayer: Research Funding; Ohara: Research Funding; Chugai Pharmaceutical co.: Honoraria; Novocure: Honoraria. Nagane: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Pfizer: Research Funding; MSD: Research Funding; Astellas: Research Funding; Nippon-Kayaku: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Shionogi: Research Funding; Otsuka: Research Funding; Ono Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novocure: Honoraria; Sumitomo Dainippon Pharma: Honoraria; RIEMSER: Membership on an entity's Board of Directors or advisory committees. Mishima: Ono Pharmaceutical Co: Research Funding; Astellas: Research Funding; HOYA Technosurgical Co.: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Research Funding; Medical U and A: Research Funding; Teijin Pharma: Research Funding; Eisai: Research Funding; MSD: Research Funding; Chugai: Research Funding. Arakawa: Sanofi: Research Funding; Carl Zeiss: Honoraria, Research Funding; Brainlab: Honoraria, Research Funding; Nihon Medi-Physics: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Philips: Research Funding; Siemens: Research Funding; Tanabe Mitsubishi: Research Funding; Chugai: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Meiji Seika: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Stryker: Research Funding; Astellas Pharma: Research Funding; Taiho Pharma: Research Funding; Nippon Kayaku: Honoraria; Novocure: Honoraria; UCB Japan: Honoraria; Integra Japan: Honoraria; Otsuka: Honoraria; Abbvie: Honoraria. Yonezawa: Eisai: Speakers Bureau; Ono Pharmaceutical co.: Speakers Bureau; Chugai Pharmaceutical co.: Speakers Bureau. Fukuhara: Celgene: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria; HUYA Bioscience International: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Zenyaku Kogyo: Honoraria; Bayer: Research Funding; AbbVie: Honoraria. Sugiyama: Daichi Sankyo Inc.: Consultancy; Ono Pharmaceutical Inc: Honoraria. Aoi: Ono Pharma USA, Inc.: Current Employment. Nishikawa: Novocure: Consultancy; Chugai: Honoraria, Research Funding; MSD: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono: Honoraria; Nihon-Kayaku: Honoraria. OffLabel Disclosure: Tirabrutinib. Clinical trial for PCNSL.

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Comparison of Overall Responses after Standard Induction with High Dose Daunorubicin Versus Standard Dose Daunorubicin with Gemtuzumab Ozogamicin in Favorable Risk Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-129166 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2636-2636

Author(s):

Chetasi Talati ◽

Ryan J Caddell ◽

Katherine Tobon ◽

Rami S. Komrokji ◽

Andrew T Kuykendall ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Statistical Significance ◽

Gemtuzumab Ozogamicin ◽

High Dose ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Remission Rates

Background: Patients with favorable risk acute myeloid leukemia (AML) by European LeukemiaNet (ELN) criteria are treated with intensive chemotherapy that yields high remission rates and is often curative. Intensive chemotherapy typically includes cytarabine and anthracycline (7+3) with high-dose daunorubicin (dauno 90mg/m2). When compared to 45mg/m2, dauno 90mg/m2 yields superior survival in younger, favorable risk AML patients. Since the re-approval of gemtuzumab ozogamicin (GO), standard practice now incorporates GO in the 7+3 backbone for favorable risk disease, however, it is typically with dauno 60mg/m2 rather than 90mg/m2. We aim to describe responses after 7+3 (dauno 90mg/m2) and 7+3 (dauno 60mg/m2) plus GO (7+3GO) in favorable risk AML. Methods: We retrospectively annotated 56 favorable risk AML patients (pts) who received upfront intensive chemotherapy at Moffitt Cancer Center between 2013 and 2019. They were divided in two cohorts: Cohort A) 7+3 with dauno 90mg/m2; Cohort B) 7+3 with dauno60mg/m2 plus GO at any time during induction or consolidation. Clinical and molecular data were abstracted for each patient in accordance with Institutional Board Review approved protocol. Overall response rates (ORR) included pts achieving complete remission (CR) with minimal residual disease negativity (CRMRD-), CR, CR with incomplete count recovery (CRi). MRD testing included quantitative Real-Time polymerase chain reaction (qRT-PCR) of t(8;21), inv(16) and nucleophosphin 1 (NPM1) tested at least after 2 cycles of intensive chemotherapy. Fisher's Exact method was used to determine significance for categorical variables. All p-values are two-sided. Results: Fifty-six pts were analyzed, including 41 in cohort A and 15 in cohort B. Pt demographics are noted in Table 1. In cohort B, 40.0% received GO on day 1 only (3mg/m2, capped or uncapped), 33.3% received fractionated dosing (3mg/m2 days 1,4,7) and 33.3% received GO during consolidation only. 39.3% of pts had inv(16), 23.2% had t(8;21)(q21.3q22) and 33.9% had mutated NPM1. In all 56 pts, ORR was 94.6%. ORR was 95.1% in cohort A and 93.3% in cohort B (p=0.79). CR rates were 85.4% in cohort A and 73.3% in cohort B (p=0.3) (Table 2). Rate of CRMRD- at any point was higher in cohort B vs cohort A, but did not reach statistical significance (45.8% vs. 20%, p=0.11). CRMRD- was significantly higher in pts with core binding factor (CBF) leukemia in cohort B vs cohort A (81.8% vs. 18.2%, p=0.008). The improvement in CRMRD- was seen in both inv(16) (A vs. B: 22.2% vs. 77.8%, p=0.049) and t(8;21) (0% vs. 100%, p=0.040). In pts with NPM1 mutations, a trend toward higher CRMRD- rates was noted in cohort B but this did not reach statistical significance (A vs. B: 40.0% vs. 100%, p=0.15). Although the median follow up time in cohort B is significantly shorter (12.3 mos in cohort B vs 38.3 mos in cohort A), no difference was observed in the 1-year EFS (68.4% in cohort A and 87.5% in cohort B (p=0.46)) or OS (83.0% in cohort A and 89.0% in cohort B (p=0.96)). No difference was seen in early mortality (30-day) between the two arms (7.3% and 6.7% in cohorts A and B, respectively (p=0.93)). Conclusions: We demonstrate that incorporation of GO to 7+3 with dauno 60mg/m2 yields comparable remission rates to 7+3 with dauno 90mg/m2. Importantly, GO based regimens produce higher rates of MRD negativity compared to 7+3 with dauno 90mg/m2 in CBF leukemia. Longer follow up is needed in order to accurately assess the impact of GO based regimens on overall survival outcomes and whether GO-induced higher MRD negativity rates will translate into superior survival for patients with favorable-risk cohort when compared to 7+3 with high dose daunorubicin. Disclosures Talati: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau. Komrokji:celgene: Consultancy; pfizer: Consultancy; DSI: Consultancy; Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau. Kuykendall:Janssen: Consultancy; Abbvie: Honoraria; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. Padron:Incyte: Research Funding. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy.

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Midostaurin in Adults with Newly Diagnosed FLT3-Mutation-Positive Acute Myeloid Leukemia Eligible for Standard Chemotherapy: Update from the Radius-X Midostaurin Expanded Access Program

Blood ◽

10.1182/blood-2018-99-113608 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4038-4038 ◽

Cited By ~ 1

Author(s):

Alexander E. Perl ◽

Kendra L. Sweet ◽

Gail J. Roboz ◽

Stephen A. Strickland ◽

Mark R. Litzow ◽

...

Keyword(s):

Febrile Neutropenia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Safety Data ◽

Newly Diagnosed ◽

Consolidation Chemotherapy ◽

Advisory Committees ◽

Acute Myeloid

Abstract Introduction: Midostaurin was the first multikinase inhibitor approved in combination with daunorubicin and cytarabine induction and high-dose cytarabine (HiDAC) consolidation chemotherapy for the treatment of adults with newly diagnosed FLT3-mutation-positive (mut+) acute myeloid leukemia (AML). Approval was largely based on the results from the phase 3 RATIFY trial; patients who received midostaurin had significantly improved overall and event-free survival than those who received placebo (Stone et al, N Engl J Med, 2017). RADIUS-X (NCT02624570) is an expanded treatment protocol (ETP) designed to provide access to midostaurin during the US Food and Drug Administration's review process and to extend the understanding of the safety and tolerability of midostaurin in patients with newly diagnosed FLT3-mut+ AML. The safety profile of midostaurin in preliminary data from RADIUS-X was consistent with that in the RATIFY study (Roboz et al, Blood, 2017 [abstract 1338]). Here we report updated safety data for midostaurin during induction and consolidation and safety data during the maintenance phase. Methods: In this open-label, single-arm ETP, patients (aged ≥18 years) received 1-2 cycles of induction therapy (cytarabine plus daunorubicin [60-90 mg/m2/day] or idarubicin [12 mg/m2/day]) and up to 4 cycles of HiDAC consolidation chemotherapy plus midostaurin (50 mg twice daily [bid] on days 8-21 of each 28-day cycle), followed by up to 12 months of single-agent midostaurin (50 mg bid on days 1-28). Patients could enroll at any point before completion of a second cycle of consolidation. Patients achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi) after induction proceeded to consolidation; patients who maintained a response were eligible to proceed to maintenance. The primary endpoints were safety and tolerability of midostaurin. Results: Of 111 patients screened, 103 were enrolled in the study: 47 during induction (46%) and 56 during consolidation (54%) (Figure). The median age was 58 y (range, 19-79 y); all patients were FLT3-mut+ (Table). Of 47 patients enrolled during induction, 15 received daunorubicin and 32 received idarubicin as the anthracycline. Of 35 patients who completed consolidation and entered maintenance, 9 had completed the protocol treatment and 3 remained on therapy at the data cutoff date (March 30, 2018). The CR/CRi rate for the induction phase was 74% (57% CR, 17% CRi). The relapse rate was 14% overall. The most common reason for study discontinuation was proceeding to transplant (overall, 52%; induction, 11%; consolidation, 42%; maintenance, 34%). The median duration of midostaurin exposure was 35 days (range, 3-426 days). Dose adjustment or interruption due to adverse events (AEs) occurred in 26 patients, most commonly due to febrile neutropenia (n=9) and gastrointestinal disorders (n=6). No new safety events were observed with longer follow-up. Most patients (99%) experienced ≥1 any-grade AE, mostly during induction and/or consolidation. Due to the timing of patient enrollment (up to the second cycle of consolidation), hematologic AEs were lower than reported in comparable studies. The most common AEs occurring in ≥20% of patients were febrile neutropenia (53%), nausea (42%), diarrhea (37%), anemia (36%), platelet count decreased (31%), fatigue (23%), headache (22%), and vomiting (22%). Serious AEs occurred in 50% of patients overall, most commonly febrile neutropenia (37%). AEs during induction were generally similar, regardless of anthracycline received. Overall, 9 patients discontinued due to AEs: 5 during induction (febrile neutropenia, blood bilirubin increased, electrocardiogram QT prolonged, renal impairment, and respiratory distress), 1 during consolidation (sepsis), and 1 during maintenance (leukocytosis). During maintenance, 16 of 35 patients (46%) reported any-grade AEs with midostaurin monotherapy; the most common any-grade and grade 3/4 AEs occurring in >1 patient were platelet count decrease (11% and 3%), nausea (9% and 0%), and oropharyngeal pain (6% and 0%).The rate of death during the study was low, with 1 death reported (disease progression). Conclusions: Midostaurin continued to demonstrate a manageable safety profile with longer follow-up and was associated with high transplant and low relapse rates. Maintenance therapy with midostaurin was well tolerated; no new safety signals were observed. Disclosures Perl: Daiichi Sankyo: Consultancy; Arog: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees. Sweet:Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Incyte: Research Funding; Bristol Myers Squibb: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Speakers Bureau. Roboz:Novartis: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Eisai: Consultancy; Janssen Pharmaceuticals: Consultancy; Argenx: Consultancy; Orsenix: Consultancy; Aphivena Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Jazz Pharmaceuticals: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Otsuka: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy; Janssen Pharmaceuticals: Consultancy; Bayer: Consultancy; Astex Pharmaceuticals: Consultancy; Eisai: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy. Strickland:Astellas Pharma: Consultancy; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Consultancy, Research Funding; Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bonifacio:Novartis: Employment. Haines:Novartis: Employment. Barbera:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals Corporation: Employment.

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Identifying Factors That Predict for Unplanned Readmissions for Acute Myeloid Leukemia Patients Receiving Consolidation Cytarabine Based Therapies

Blood ◽

10.1182/blood-2019-128807 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3433-3433

Author(s):

Caitlin Siebenaller ◽

Madeline Waldron ◽

Kelly Gaffney ◽

Brian P. Hobbs ◽

Ran Zhao ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Smoking Status ◽

Consolidation Therapy ◽

Peripheral Vascular ◽

Consolidation Chemotherapy ◽

Advisory Committees ◽

History Of ◽

Acute Myeloid

Background: Younger patients (pts) with acute myeloid leukemia (AML) who enter a remission after intensive induction chemotherapy routinely receive at least one cycle of consolidation therapy with high dose cytarabine (HiDAC). This is commonly administered over a five-day inpatient stay, after which pts are discharged home as their blood counts nadir. It is thus a natural consequence of therapy that readmission for febrile neutropenia (FN) occurs, which can impact measures of quality and value in this population. Precise descriptions of incidence, type, and severity of infection, if identified, are lacking, and thus it is unknown to what standard cancer centers should be held for anticipated readmission. We measured these rates, and attempted to identify predictive factors for readmission. Methods: Adult AML pts ≥ 18 years of age who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2019 were included. Our primary aim was to identify predictive factors for readmission after the first cycle of consolidation chemotherapy. The following pt characteristics and co-morbid conditions were analyzed: age, gender, body mass index (BMI), smoking status, AML cytogenetic risk status, history of diabetes, peripheral vascular disease, cardiovascular disease, chronic pulmonary disease, hepatic impairment, and other cancers. Secondary aims included: estimating rates of all-cause readmissions among all HiDAC cycles, defining the rate of FN readmissions, estimating rates of intensive care unit (ICU) admissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, prophylactic (ppx) medications used, and mortality. Statistical analyses interrogated potential risk factors for evidence of association with hospital readmission after the first cycle of consolidation chemotherapy. Results: We identified 182 AML pts who fit inclusion criteria. The median age was 50 years (range 19-73); 55% were female and 45% were male. Statistical analyses revealed no association with readmission after cycle 1 for cytogenetic risk (p=0.85), history of heart failure (p= 0.67), chronic pulmonary disease (p=1), connective tissue disease (p=0.53), cerebrovascular accident (p=0.63), diabetes (p=0.63), gender (p=0.07), history of lymphoma (p=0.53), other solid tumors (p=0.53), liver disease (p=1), myocardial infarction (p=0.71), peripheral vascular disease (p=1), or smoking status (p= 0.52). For 480 HiDAC cycles analyzed (88% at 3000 mg/m2), the overall readmission rate was 50% (242/480), of which 85% (205/242) were for FN. Those readmissions which were not FN were for cardiac complications (chest pain, EKG changes), non-neutropenic fevers or infections, neurotoxicity, bleeding or clotting events, or other symptoms associated with chemotherapy (nausea/vomiting, pain, etc.). Median time to FN hospital admission was 18 days (range 6-27) from the start of HiDAC. Of the 205 FN readmissions, 57% had documented infections. Of these infections, 41% were bacteremia, 23% fungal, 16% sepsis, 12% other bacterial, and 8% viral. Of 480 HiDAC cycles, ppx medications prescribed included: 92% fluoroquinolone (442/480), 81% anti-viral (389/480), 30 % anti-fungal (142/480), and 3% colony stimulating factor (14/480). Only 7% (14/205) of FN readmissions resulted in an ICU admission, and 1% (3/205) resulted in death. Conclusions: Approximately half of patients treated with consolidation therapy following intensive induction therapy can be expected to be readmitted to the hospital. The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable, however ICU admission and death associated with these complications are rare. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality. Disclosures Waldron: Amgen: Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding. Nazha:Incyte: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Gerds:Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees.

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Venetoclax and Azacitidine for Older Newly Diagnosed Patients with Acute Myeloid Leukemia: A Single-Institution Pilot Study Using Measurable Residual Disease to Guide Therapy

Blood ◽

10.1182/blood-2019-122120 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2638-2638 ◽

Cited By ~ 1

Author(s):

Amanda Winters ◽

Jonathan A Gutman ◽

Enkhtsetseg Purev ◽

Brett M. Stevens ◽

Shanshan Pei ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Residual Disease ◽

Refractory Disease ◽

Advisory Committees ◽

Ras Pathway ◽

Measurable Residual Disease ◽

Count Recovery

Background: Venetoclax (ven) was approved for older untreated acute myeloid leukemia (AML) patients due to high response rates and durable remissions. As a participating site in the dose escalation study, we observed deeper/more durable responses in some who received >400mg ven. We also noted 16/33 discontinued azacitidine (aza) after achieving a response; 9 relapsed and 7 remained in long term remission on ven only. Based on these observations, we designed a study that hypothesized: A)Higher initial doses of ven would allow deeper/more durable responses, and B)Multi modality high sensitivity measurable residual disease (MRD) testing could identify patients able to discontinue aza and remain on maintenance ven. Methods: This is an ongoing phase 2 study (NCT03466294) of 42 untreated AML patients ≥60 who decline/are ineligible for induction. Patients have adequate organ function and white blood cell counts <25x109/L (hydrea permitted). In cycle 1, patients receive aza 75mg/m2 on days (d) 1-7 and ven, escalated from 100 to 200 to 400 to 600mg on d 1-4. Ven continues at 600mg d 5-28 and bone marrow biopsies (BMBXs) are performed on d 8 and 28. Patients who achieve morphologic remission without count recovery have up to 14 days off therapy before subsequent cycles, with growth factor support; "upgraded" responses are recorded if count recovery occurs. Non responders discontinue or receive up to two additional cycles of aza and ven 600mg. Responders who remain MRD+ by multiparameter flow cytometry (MPFC, Hematologics) and/or digital droplet PCR (ddPCR) for as many identifiable diagnostic genes as possible also receive up to 2 additional cycles of aza and ven 600mg. MRD+ responders after 3 cycles continue aza and ven 400mg until toxicity/progression. Patients who experience MRD- responses at any time stop aza and continue ven 400mg daily (Fig 1). Results: 30 patients enrolled between May 2018 and July 2019; median age is 71 (60-88), 10% evolved from MDS and 10% and 73% had intermediate and unfavorable risk disease by ELN, respectively (Table 1). 732 adverse events (AEs) occurred; 46 (6%) were serious, the most common were neutropenic fever (37%) and pneumonia (13%). The most common >grade 2 related AEs were leukopenia (53%), thrombocytopenia (44%) and neutropenia (35%); there were no related grade 5 AEs. The overall response rate was 70% (21/30; CR=19, MLFS=2). Median number of cycles to achieve best response was 1. Significant blast reductions were seen on day 8; of the 28 with interpretable day 8 BMBXs, 10 achieved MLFS on day 8. 4 completed ≥1 cycle and were refractory. An additional 4 did not complete cycle 1: 1 died of disease and 3 elected to come off therapy (all subsequently died of disease). Four (19%) responders relapsed, after a median 180 days (27-279). With median follow up of 214 days, median response duration has not been reached. 10 patients died, after a median 65 days (29-256); 1/30 died within 30 days. Median overall survival has not been reached. Of the 26 who completed ≥1 cycle, 19 were MRD- by MPFC, including 18/19 who achieved CR. Of these 26, 3 were not monitored by ddPCR: for 2 patients this was due to the absence of detectable baseline mutations and for 1 patient it was due to refractory disease. The remaining 23 had ddPCR monitoring; 3 became MRD- by this modality (Fig 2). All 3 were also MRD- by MPFC and per protocol discontinued aza and initiated ven maintenance (Fig 1). MRD negativity by both parameters occurred after cycles 1, 2 and 3, respectively. One MRD- patient relapsed after 216 days; two remain in remission after 301 and 124 days. An additional 4 who achieved MRD+ responses discontinued aza at their insistence (and in violation of the protocol); 1 relapsed after 279 days, and 3 remain in ongoing remission. Univariate predictors of refractory disease were FAB M0/M1 (OR 0.070, p=0.02) and RAS pathway mutations (OR 14.25, p=0.02). Conclusions: Higher initial doses of ven are tolerated in this population. Blast reduction occurs quickly in many patients (day 8), for this low intensity regimen. Response rates are consistent with lower doses of ven. Very deep responses, as measured by highly sensitive MRD methods (MPFC and ddPCR are capable of sensitivity up to 0.02%), are attainable. Longer follow up time will determine if higher ven doses and MRD-driven decisions related to continuation of aza result in more durable responses. Increased maturation of blasts and RAS pathway mutations are predictors for refractory disease. Disclosures Lyle: Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo Incyte: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Pollyea:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Switching to Nilotinib Is Associated with Continued Deeper Molecular Responses in CML-CP Patients with Minimal Residual Disease After ≥ 2 Years On Imatinib: Enestcmr 2-Year Follow-up Results

Blood ◽

10.1182/blood.v120.21.694.694 ◽

2012 ◽

Vol 120 (21) ◽

pp. 694-694 ◽

Cited By ~ 2

Author(s):

Timothy P. Hughes ◽

Jeffrey H. Lipton ◽

Nelson Spector ◽

Brian Leber ◽

Ricardo Pasquini ◽

...

Keyword(s):

Board Of Directors ◽

Minimal Residual Disease ◽

Research Funding ◽

Residual Disease ◽

Molecular Response ◽

Advisory Committees ◽

Molecular Responses ◽

The Difference ◽

Minimal Residual

Abstract Abstract 694 Background: Superior rates of deeper molecular responses were achieved with nilotinib vs imatinib in patients newly diagnosed with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials—newly diagnosed patients (ENESTnd) trial. In addition, the 12-month (mo) analysis of the ENEST—complete molecular response (ENESTcmr) study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of major molecular response (MMR) and deeper molecular responses vs remaining on imatinib. Results from ENESTcmr are presented here with minimum 24 mo of patient follow-up. Methods: Patients with Ph+ CML-CP who had achieved complete cytogenetic responses but still had persistent BCR-ABL positivity by real-time quantitative polymerase chain reaction (RQ-PCR) after ≥ 2 years on imatinib were eligible. Patients (n = 207) were randomized to switch to nilotinib 400 mg twice daily (BID; n = 104) or to continue on the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103). Rates of MMR, MR4 (BCR-ABL ≤ 0.01% according to the International Scale [IS], corresponding to a 4-log reduction), MR4.5 (BCR-ABL ≤ 0.0032%IS, corresponding to 4.5-log reduction), and undetectable BCR-ABL via RQ-PCR with ≥ 4.5-log sensitivity were measured. Results: Among all randomized patients (intent-to-treat population), significantly more patients treated with nilotinib continued to achieve undetectable BCR-ABL by 24 mo (32.7% on nilotinib vs 16.5% on imatinib; P =.005; Table).The difference between the arms in achievement of this endpoint increased between 1 and 2 years (from 12.4% to 16.2%). The median time to MR4.5 and undetectable BCR-ABL was also significantly faster on nilotinib than on imatinib (P = .005 and .003, respectively). Cumulative rates of MR4.5 and undetectable BCR-ABL continued to be higher with nilotinib in patients without those responses at baseline, and the difference between arms appeared to increase over time. The safety profiles for nilotinib and imatinib were consistent with prior studies. By 24 mo, no patients in either arm progressed to accelerated phase/blast crisis. No patients on nilotinib died since the 12-mo analysis; 1 patient on imatinib died from metastatic prostate cancer in follow-up after discontinuation from the study. Conclusions: Switching to nilotinib led to significantly faster, deeper molecular responses in patients with minimal residual disease on long-term imatinib therapy. Since the 12-mo analysis, rates of deep molecular response (MR4.5 and undetectable BCR-ABL) have remained significantly higher in patients who did not have the response at baseline and were switched to nilotinib (vs those remaining on imatinib). In fact, the difference in favor of nilotinib increased between 1 and 2 years. These results suggest that switching to the more potent, selective tyrosine kinase inhibitor nilotinib is beneficial in patients with minimal residual disease after long-term imatinib therapy. Achievement of these deeper molecular responses (MR4.5 and undetectable BCR-ABL) after switching to nilotinib may enable a greater proportion of CML-CP patients to be eligible for future discontinuation studies. Cumulative rates of confirmed undetectable BCR-ABL by 24 mo will be presented as the confirmation assessments for several responders were not available at the time of this analysis. Disclosures: Hughes: Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding. Lipton:Novartis: Consultancy, Research Funding, Speakers Bureau. Spector:Novarits: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy. Leber:Novartis: Advisory Board Other, Honoraria, Speakers Bureau. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Purkayastha:Novartis Pharmaceuticals Corp: Employment. Collins:Novartis Pharmaceuticals Corp: Employment. Szczudlo:Novartis Pharmaceuticals Corp: Employment. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Transition of Chronic Myeloid Leukemia to Chronic Myelomonocytic Leukemia As a Tool to Observe Development of Chronic Myelomonocytic Leukemia

Blood ◽

10.1182/blood.v126.23.5223.5223 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5223-5223

Author(s):

Jamshid S Khorashad ◽

Srinivas K Tantravahi ◽

Dongqing Yan ◽

Anna M. Eiring ◽

Hannah M. Redwine ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Clonal Evolution ◽

Chronic Myelomonocytic Leukemia ◽

Imatinib Treatment ◽

Advisory Committees ◽

Clonal Architecture ◽

Myelomonocytic Leukemia

Abstract Introduction. Development of abnormal Philadelphia (Ph) negative clones following treatment of chronic myeloid leukemia (CML) patients with imatinib has been observed in 3 to 9% of patients. Here we report on a 77 year old male diagnosed with CML that responded to imatinib treatment and subsequently developed chronic myelomonocytic leukemia (CMML). He achieved major cytogenetic response within 3 months but this response coincided with the emergence of monocytosis diagnosed as CMML. Five months after starting imatinib treatment the patient succumbed to CMML. We analyzed five sequential samples to determine whether a chronological order of mutations defined the emergence of CMML and to characterize the clonal evolution of the CMML population. Materials and Method. Five samples (diagnostic and four follow up samples) were available for analysis. CMML mutations were identified by whole exome sequencing (WES) in CD14+ cells following the onset of CMML, using CD3+ cells as constitutional control. Mutations were validated by Sequenom MassARRAY and Sanger sequencing and quantified by pyrosequencing. Deep WES was performed on the diagnostic sample to determine whether the mutations were present at CML diagnosis. To determine the clonal architecture of the emerging CMML, colony formation assays were performed on the diagnostic and the next two follow-up samples (Samples 1-3). More than 100 colonies per sample were plucked for DNA and RNA isolation. The DNA from these colonies were tested for the presence of the confirmed CMML mutations and the RNA was used for detection of BCR-ABL1 transcript using a Taqman real time assay. Results. Four mutations were identified by Sequenom and WES throughout the patient's time course [KRASG12R, MSLNP462H, NTRK3V443I and EZH2I669M ]. Sequenom did not identify these at diagnosis while deep WES did. Clones derived from colony formation assay revealed three distinct clones present in all samples analysed. Clone 1 had only KRASG12R, clone 2 had KRASG12R, MSLNP462H, and NTRK3V443I, and clone 3 had all four mutations. All clones containing any of these four mutations were BCR/ABL1 negative. Analysis of clonal architecture indicated that KRASG12R was acquired first and EZH2I669M last, while MSLNP462H and NTRK3V443I were acquired in between. These CMML clones increased proportionately as clinical CML metamorphosed into clinical CMML after initiation of imatinib therapy. Consistent with the colony data, pyrosequencing revealed that the ratio between the mutants remained largely stable throughout the follow up period. Conclusion. This case illustrates how targeted therapy impacts clonal competition in a heterogeneous MPN. While the CML clone was dominant in the absence of imatinib, it was quickly outcompeted by the CMML clones upon initiation of imatinib therapy. The clonal architecture analysis, in combination with in vivo kinetics data, suggest that the KRASG12R mutation alone was able to produce a CMML phenotype as clones with just KRASG12R remained at a relatively stable ratio during follow up. Unexpectedly, acquisition of additional mutations, including EZH2I669M as the last mutational event identified in this patient, did not increase clonal competitiveness, at least in the peripheral blood. These data show that clonal evolution may not invariably increase clonal fitness, suggesting that factors other than Darwinian pressures contribute to clonal diversity in myeloproliferative neoplasms. Disclosures Deininger: Gilead: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Assessment of Patients Fitness at Diagnosis in Elderly Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.4012.4012 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4012-4012

Author(s):

Semra Aydin ◽

Ernesta Audisio ◽

Stefano D'Ardia ◽

Bernardino Allione ◽

Barbara Nicolino ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Perfect Agreement ◽

Medical Board ◽

Acute Myeloid

Abstract Background:Acute myeloid leukemia (AML) is a disease which predominantly affects patients with a median age at diagnosis over 65 years. The elderly population is highly heterogeneous and assessment strategies are needed to define the frailty profile. To date, evaluation of disease-related and patients specific factors in the context of clinic decision making has been largely subjective. Concerning AML therapy, several studies demonstrated improved survival for older patients receiving intensive induction chemotherapy compared to those receiving supportive care alone. Defining this subset of patients who are eligible or "fit" for intensive chemotherapy involves a great deal of subjectivity. Criteria yet have to be standardized across or within institutions. Aim:Aim of this study was to investigate the validity of four scores for assessment of patient fitness at diagnosis in parallel to physician evaluation. Further patient outcome according the respective evaluation was compared. Methods: In a single hematology center a total of 85 clinically and molecularly well characterized consecutive elderly (>60 years) patients with newly diagnosed AML were treated from 2012 to 2015 according to age, performance status and co-morbidities. Therapy response was defined according to ELN criteria. Therapy intensity decision was based on an initial haematologist evaluation followed by discussion of the patient case in an interdisciplinary board. Independently from the medical board, in parallel the local geriatric G8 screening tool, consisting of seven items from the Mini Nutritional Assessment (MNA) questionnaire and age, the HCT-CI comorbidity score as well as the AML scores proposed by the German Acute Myeloid Leukemia Cooperative Group, predicting probability of complete remission (CR) and early death (ED) were performed. Overall survival from diagnosis was compared between groups using the Cox model. Results:A total of 42 (49,4%) patients were evaluated "fit" by the medical board and treated by intensive chemotherapy ("7+3" regimen), whereas 4 patients (4,7%) underwent semi-intensive with hypomethylating agents and 39 patients (45,8%) received palliative therapy (low dose Cytarabine or Hydroxyurea). Twenty-six patients (30,6%) achieved a complete remission after induction chemotherapy, could follow consolidation chemotherapy and six of them underwent allogeneic hematopoietic stem cell transplantation. Fourty-four (51,8%) were non responders and 15 patients (17,6%) died during the first cycle. Overall, the median survival time was 6,7 months (95% CI 3,7-9,5). Primary physician care evaluation was able to define in a statistically significant manner a "fit" from an "unfit" patient. Median survival time from the "fit" patients was 10 moths (95%CI 5-not reached) compared to the "unfit" evaluated patients with 3,4 months (95%CI 1,4-5), p<0.001 with a HR (95%CI) of 3,18 (1,81 to 5,59). Parallel evaluation of patients unfitness according the proposed cut-point of the G8 (≤14), AML for CR (<40) and AML for ED (≥30) scores discriminated significantly patients survival with HRs equal to 3.03 (p<0,001), 2.11 (p=0,007) and 2.83 (p<0.001), respectively. The agreement between the frailty scores and physician evaluation on the prediction of fitness classification was analyzed by calculating the Cohens' Kappa. In this approach a Kappa level of 1,0 denotes perfect agreement. The agreement of was moderate for HCT-CI score and AML score for CR (0.47 and 0.46, respectively). The agreement was fair for G8 and AML score for ED (0.27 and 0.33, respectively). Summary/Conclusion: In conclusion, in the present AML cohort the applied frailty scores at diagnosis correlated significantly with the median overall survival. Since no perfect agreement was found respect to physician for fitness classification, frailty scores can help to improve the prognosis prediction. These results may encourage a following multi-centre analysis in order to increase the statistic power of the performed analysis. Disclosures Vitolo: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Gilead: Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures.

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Survey of Serum Aspergillus Antigen in Patients Undergoing Chemotherapy for Acute Myeloid Leukemia or Allogeneic Hematopoietic Stem Cell Transplantation: Role in Predicting Invasive Aspergillosis and in Modifying the Therapeutic Strategy

Blood ◽

10.1182/blood.v126.23.3428.3428 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3428-3428

Author(s):

Van Hung Tran ◽

Florence Persat ◽

Sophie Gardes ◽

Jeremy Monfray ◽

Sophie Ducastelle-Leprêtre ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Aspergillus Antigen ◽

Acute Myeloid

Abstract Introduction Invasive aspergillosis (IA) remains an important cause of mortality in immunocompromised acute myeloid leukemia (AML) patients receiving induction chemotherapy and in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological malignancies. Early diagnostic is critical and challenging given the efficacy and availability of several new anti-fungal therapies. In this study, we evaluated the performance of different factors in predicting the occurrence of IA, including the Aspergillus antigen galactomannan (GM) detection in sera. Methods We included all AML patients receiving induction chemotherapy and patients undergoing allo-HSCT for any hematological malignancy at our center between April 2006 and April 2014 with available data on Aspergillus antigen GM. Serologic detection of circulating GM fungal biomarker was considered during the 100 days following the first day of induction chemotherapy in AML patients or from the day of allo-HSCT. Usual follow-up included two GM tests per week, only patients with at least three serum GM results were considered. The GM tests have been performed routinely using the ELISA kit (Platelia Aspergillus antigen ELISA, Biorad), giving the results in index values. Demographic, GM index results and diagnostic data were collected. IA cases were classified as proven or probable according to the EORTC criteria. The value of the first antigen test, the delay to positivity, and the slope of the progression of the index value between the first two antigens concentrations were considered as predictors of IA. ROC curves for each predictor and their combination were performed and prognostic scores were established. Results A total of 775 patients were included : i) 292 AML patients, 153 (52%) males with a median age of 62 years (range: 17-79), 15% were classified as favorable, 8% as intermediate I, 18% as intermediate II and 59% as unfavorable according to cytogenetics and molecular markers; ii) 483 allo-HSCT patients, 293 (61%) were males, median age was 48 years (range: 18-70), among them 234 (48%) AML, 66 (14%) multiple myeloma, 46 (10%) Myelodysplastic syndromes, 38 (8%) Non-Hodgkin Lymphoma and the rest of patients had other hematological disorders; 233 (48 %) patients received reduced intensity conditioning and 250 (52%) myeloablative conditioning. The disease status at allo-HSCT was complete remission (CR) in 366 (76%) patients and the rest of patients were in less than CR. HSC source was peripheral blood in 42.2% (90 identical siblings, 150 10/10 matched unrelated, 54 9/10 mismatched unrelated), bone marrow in 42.6% (105 identical siblings, 162 10/10 matched unrelated, 45 9/10 mismatched unrelated) and cord blood in 15.2%. A total of 877 episodes with 16121 GM serum antigen results was considered (median: 18 GM tests per patient). During the follow-up, we identified 121 episodes with at least one positive GM test with a cumulative incidence at day 100 of 13.8%. We also diagnosed 48 IA (2 proven, 46 probable), with a cumulative incidence at day 100 of 5.5% in total, 7.2% in AML and 4.3% in allo-HSCT, respectively. We then classified the GM positive episodes in 82 false-positive (68%) and 39 true-positive episodes (32%) for IA, respectively. A majority of IA events occurred during the first 30 days of follow up, GM positivity showing a positive predictive value of 41% versus a negative predictive value of 99%. The three IA predicting factors had similar independent effects and their combinations were performed, allowing the establishment of an area under ROC of 0.79 (95% CI: 0.70-0.89). Cut off values of the first positive GM serum and slope were equal or higher than 1.04 and 0.04, respectively, and delay to positivity equal or less than 15 days. To simplify the practical use in clinical practice, the prognostic score defining the IA risk probability was defined as the number of predictors present (values from 0 to 3). This score was tested on positive follow-up giving values of 0, 1, 2 or higher for 45 (37%), 39 (32%) and 37 episodes (31%), respectively. A score superior or equal to 2 was indicative of IA in 62% of the cases (figure 1). Conclusion As IA has a significant impact on hematology patient's survival, this GM predictive score combining three predictors (value of the first antigen index, delay of positivity and slope of the index values) may help clinicians to conclude about starting an early preemptive IA treatment. Figure 1. Figure 1. Disclosures Nicolini: Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes

Blood ◽

10.1182/blood.v130.suppl_1.890.890 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 890-890

Author(s):

Andrew Wei ◽

Stephen A. Strickland ◽

Gail J. Roboz ◽

Jing-Zhou Hou ◽

Walter Fiedler ◽

...

Keyword(s):

Myeloid Leukemia ◽

Research Funding ◽

Low Dose ◽

Intensive Chemotherapy ◽

Employment Equity ◽

Advisory Committees ◽

Treatment Naïve ◽

Equity Ownership ◽

Low Dose Cytarabine

Abstract Background: Older patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy are unlikely to achieve remission with available therapy and have unacceptably short survival. Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of >60% combined with low-dose cytarabine (LDAC). Presented are long-term outcomes, including 1-year overall survival (OS) and biomarker analyses. Methods: This phase 1b/2, open-label study (NCT02287233) evaluates the safety and preliminary efficacy of orally administered VEN combined with LDAC in patients ≥65 years with previously untreated AML (except for hydroxyurea). Patients were ineligible for intensive chemotherapy because of comorbidity or other factors and had an ECOG performance score of 0-2, with adequate hepatic and renal function. Exclusion criteria were acute promyelocytic leukemia, active CNS involvement with AML, concominant use of moderate or strong CYP3A inhibitors, or prior treament with cytarabine for a preexisting myeloid disorder. Prior treatment for myelodysplastic syndrome (MDS) was allowed. In cycle 1, VEN was started at 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28. In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28. LDAC 20 mg/m2/day SQ was given on days 1-10 of each cycle. Preliminary efficacy was assessed as the overall response rate (ORR, which included complete remission [CR], CR with incomplete blood count recovery [CRi], and partial remission [PR]). Adverse events (AEs) and laboratory values were monitored. Exploratory analysis of biomarkers (eg, cytogenetics, molecular markers) was performed to identify potential predictors of clinical outcomes. Results: Data cutoff was May 30, 2017. All 71 patients were enrolled ≥1 year prior (46 [65%] male; median age, 74 years [range, 66-87 years]): 10 received VEN 800 mg and 61 received VEN 600 mg, the recommended phase 2 dose. Thirty-three patients (47%) had a history of antecedent hematologic disorder (AHD), most commonly MDS. Among 61 patients given VEN 600 mg, median time on VEN treatment was 6 months (range, <1 to 21 months). Thirty-eight (62%) of these patients achieved CR/CRi with a median duration of CR/CRi of 14.9 months (95% CI, 5.6 months to not reached [NR]; Figure). Best responses were 26% CR, 36% CRi, and 2% PR. Median OS was 11.4 months (95% CI, 5.7-15.7 months); the observed 12-month OS was 46% (95% CI, 33-58%). Only 1 patient has subsequently undergone bone marrow transplantation. Treatment-emergent grade 3/4 AEs (in ≥20% of 61 patients) were thrombocytopenia (59%), neutropenia (46%), febrile neutropenia (36%), anemia (28%), and decreased WBC count (26%). One case (2%) of tumor lysis syndrome occurred. Serious AEs (in ≥3 of 61 patients) were febrile neutropenia (20%), malignant neoplasm progression (13%), lung infection/pneumonia (13%), and sepsis (7%). The 30-day mortality rate was 3%; causes of death were disease progression (n=1) and lung infection (n=1). Common recurrent mutations in 53 patients who received VEN 600 mg are shown in the Table. All patients with an NPM1 mutation (including 3 with a co-mutation in FLT3-ITD) achieved CR/CRi. Patients with DNMT3A, FLT3-ITD, and SRSF2 mutations had CR/CRi rates of ≥75%, whereas those with TP53 mutations had the lowest CR/CRi rates of 44%. For patients with CR/CRi, median OS was 18.4 months (95% CI, 13.5 months to NR). The 12-month OS rate for patients in the 600-mg VEN cohort who achieved CR/CRi was 70.4% from Kaplan-Meier estimates, with 11 deaths. Among 19 patients who received study treatment ≥12 months, 17 remain alive. The longest, ongoing, disease-free follow-up after treatment completion is 12 months. Conclusions: The safety profile of VEN 600 mg/day plus LDAC was acceptable for elderly patients with treatment-naive AML who were ineligible for intensive chemotherapy. After ≥1 year of follow-up, the observed median OS was 11.4 months. This cohort included 44% (27/61) of patients with AHDs. Corelations of specified AML mutations with response and duration should be confirmed in later trials. Due to the observced CR/CRi rate of 62%, extended duration of response, and encouraging OS in a cohort of patients with particularly poor-risk features, the 600-mg dose of VEN combined with LDAC is being tested in an ongoing phase 3 study. Figure Figure. Disclosures Wei: AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria; AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees. Strickland: Boehringer-Ingelheim: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy; Tolero: Consultancy; Astellas: Consultancy; CTI BioPharma: Consultancy; Baxalta: Consultancy. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Hou: Teva Oncology, Seattle Genetics: Speakers Bureau. Fiedler: Amgen, Pfizer: Research Funding; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance; Amgen: Patents & Royalties; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Consultancy. Walter: ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding. Chyla: Abbvie: Employment, Equity Ownership. Popovic: AbbVie: Employment, Equity Ownership. Fakouhi: AbbVie: Employment, Equity Ownership. Shah: AbbVie: Employment, Equity Ownership. Dunbar: AbbVie: Employment, Equity Ownership. Xu: AbbVie: Employment, Equity Ownership. Mabry: AbbVie: Employment, Equity Ownership. Hayslip: AbbVie: Employment, Equity Ownership.

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