Safety and Efficacy of Bosutinib in Fourth Line Therapy of Chronic Myeloid Leukemia Patients

Abstract BACKGROUND: Despite the excellent prognostic of chronic myeloid leukemia (CML) patients since the introduction of tyrosine kinase inhibitors (TKIs), approximately 50% of patients that are treated with TKIs will discontinue first line treatment due to lack of efficacy or intolerance. Once patients need a second line treatment, a considerable proportion of patients will need third or even fourth line therapy during further evolution. At this moment, there is a lack of data about real benefit of this group of patients. We have recently published our experience of 30 CML patients treated with bosutinib in 4th line. We present an update of the study where we have increased the number of patients, and the follow-up. The aim of this study is to present safety and efficacy data CML chronic phase patients treated with bosutinib in 4th line. METHODS: We have collected data from 59 CML patients treated with bosutinib in 4th line after resistance or intolerance to IM, NI and DA. 51 patients have been treated under the Spanish compassionate use program (36 centers) and 10 patients were treated in a single institution from United Kingdom. Median age of patients at diagnosis was 53 years. The percentage of low, intermediate and high risk Sokal groups were 47%, 37% and 16%. Median time TKIs exposure before bosutinib was 9 years. The most common indication (30/59) was intolerant to DA and NI. Patients' dispositions and main line characteristics are shown in table 1. RESULTS: Median follow-up was 14.3 months. All patients started bosutinib at 500mg/d, median dose of was 450mg/d. Overall probabilities to either achieve or maintain previous response were 96% (57/59), 62% (37/59), 40% (24/59) and 17% (10/59) for complete hematological response (CHR), complete cytogenetic response (CCyR), major molecular response (MMR) and MR4.5 respectively. However, probabilities to obtain responses (in patients without response evaluated at baseline) were 27% (7/26), 26% (12/45) and 12% (7/55) for CCyR, MMR and MR4.5. As expected, probabilities to obtain CCyR were lower for patients resistant to DA and NI patients than for patients intolerant to DA and NI (8% VS 44%). Event free survival (EFS) and progression free survival (PFS) probabilities were 50% and 83% by 27 month. Treatment was discontinued in 20/58 (34%), most frequent reasons being adverse events 9/59(15%), lack of efficacy 5/59 (8.5%), disease progression 2/59 (3.4%) and death 1/59 (1.7%). Two patients discontinued due to stem cell transplantation. The adverse events that led to treatment discontinuation were pleural effusion (3), diarrhea (2), rash, renal impairment, auricular fibrillation and liver enzyme elevation one patient each. Overall, bosutinib was well tolerated. Grade 3-4 hematological toxicities were 3%, 6% and 6% for anemia, thromboctytopenia and neutropenia. Most common non hematological side effects were diarrhea (39%, nauseas 13% and liver alterations 14% and pleural effusion 14%. CONCLUSIONS: Little is known about the therapeutic role of Bosutinib in 4th line. The series presented here is, to our knowledge, the largest being presented. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKIs. Table 1. IM+NI-I+DA-R (N=4) IM+NI-R+DA-R (N=18) IM+NI-I+DA-I (N=30) IM+NI-R+DA-I (N=7) Total (N=59) Sex, N (%) Male 2 (50) 11 (61.1) 16 (53.3) 2 (28.6) 31 (52.5) Median age of diagnosis, yr (range) 57.32 (50-64) 49.19 (23-73) 54.95 (21-89) 48.87 (26-68) 53.15 (21-89) Median age of Bosutinib initiation, yr (range) 69.13 (61-70) 62.27 (39-79) 64.85 (25-90) 64.79(35-74) 63.7 (25-9) Median follow up, months (range) 18.5(7.8-34.1) 8.4(1.22-36.1) 16.3(0.5-34.7) 23.4(3.3-28.9) 14.3(0.7-36.1) SOKAL Index at diagnosis, N (%) High 2(50.0) 4 (23.5) 1 (4.3) 1 (20) 8 (16.3) Intermediate 1 (25.0) 5 (29.4) 10(43.5) 2 (40) 18 (36.7) Low 1 (25.0) 8 (47.1) 12 (52.2) 2 (40) 23 (46.9) Median Time from first TKI to BOS, (yr, range) 10.3 (4.8-11.9) 9.3 (2.0-11.4) 8.8 (0.7-13.6) 8.2 (5.1-12.3) 8.8 (0.7-13.6) Median duration of prior therapy, months (range) Imatinib 38.8 (11.8-69.8) 32.6 (6.3-96.8) 26.2 (1.6-102.6) 23.1 (8.3-66.8) 28.8 (1.6-102.6) Dasatinib 21.5 (12.6-75) 21.8 (7.7-69) 31.4 (0.4-87.1) 23.7 (10.3-53.6) 23.44 (0.4-87.1) Nilotinib 19.1 (2.1-46.2) 16.7 (5-65.6) 8.9 (0.2-58.5) 30.9 (6.9-49.3) 14.3 (0.2-65.6) BOS: bosutinib, IM, imatinib; DA, dasatinib; NI, nilotinib, I: Intolerance, R: Resistant, Yr: year Disclosures García-Gutiérrez: Ariad: Consultancy; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Milojkovic:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Boque:Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria. Casado:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Jiménez:Pfizer: Consultancy, Honoraria. Giraldo:Pfizer: Consultancy. Steegmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Cost-Effectiveness of Imatinib Versus Interferon-α in the Treatment of Patients Newly Diagnosed with Chronic Myeloid Leukemia, under the Brazilian Public Healthcare System Perspective.

Blood ◽

10.1182/blood.v108.11.3314.3314 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3314-3314 ◽

Cited By ~ 2

Author(s):

Fábio Mataveli ◽

Alessandra Calabró ◽

Wellington Mendes ◽

Denizar Vianna ◽

Pedro Dorlhiac-Llacer ◽

...

Keyword(s):

Cost Effectiveness ◽

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Public Healthcare ◽

Line Treatment ◽

Newly Diagnosed ◽

First Line ◽

System Perspective

Abstract The 60-month follow-up data for patients randomized to imatinib in IRIS demonstrated significant clinical improvements in survival rates and QALYs gained (17,09 years;13,58 QALYs) in patients newly diagnosed with chronic myeloid leukemia (CML) and treated with imatinib in comparison to patients under interferon-alpha (INF-α) (9,10 years;6,31 QALYS) as first line therapy. Although reimbursed as second line therapy for chronic phase CML patients who did not respond to INF-α, imatinib was not considered for public reimbursement as first line treatment in Brazil based solely on drug costs. An economic evaluation of imatinib as first line treatment versus INF-α was performed under the Brazilian Public Heathcare System perspective, according to the long-term follow-up data from IRIS, literature recommendations and prior health technology assessment from the National Institute for Clinical Excellence (NICE) to consider long term follow-up survival and adverse events costs. This study was aimed to evaluate the cost-effectiveness of imatinib compared with IFN-α for first-line treatment of chronic myeloid leukemia under the Brazilian public healthcare system perspective. For the economic model, a base case of 100 patients for each treatment option was constructed focused on drug costs and adverse events. Drug costs were estimated based on the Brazilian public healthcare reimbursement payment (APAC-SUS) for chronic phase CML treatment. Febrile neutropenia (grade III and IV), depression, nausea and abnormal liver-function results were considered as adverse events. Clinical guidelines and protocols from two public hematology Brazilian centers, Fundação Pró-Sangue FM-USP and Instituto Nacional do Cancer, were used to estimate adverse events treatment costs. Adverse events frequency for all grades was based on data published by NICE and the Agency for Health Care Research and Quality. Due to the high crossover rate from INF-α to Imatinib group observed in the IRIS study (90% from INF-α to imatinib within a year of study entry) the estimated life time survival for INF-α treatment group was based on the European Study Group on Interferon in Chronic Myeloid Leukemia. Utilities values from the IRIS study were used for both groups. Annual discount rates were of 6% for costs and 1.5% for QALYs. The annual average costs for the treatment of adverse effects in the INF-α were 1.83 higher than the imatinib group. Adverse events lifetime costs for INF-α were 24% higher than imatinib, even tough imatinib granted a projected 6.3 years survival advantage over INF-α. The resulting incremental cost-effectiveness ratio (ICER) of imatinib, compared with IFNα, considering adverse events was US$ 18,637 per QALY gained. Assuming a conservative cost-effectiveness threshold of less than US$ 25,500, which is three times the GDP per capita in Brazil (US$ 8,500 in 2005), the ICER for imatinib compared with INF-α falls within the range considered by the World Heath Organization as a cost-effective fist line treatment for patients newly diagnosed with CML.

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Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 24-Month Minimum Follow-up Update

Blood ◽

10.1182/blood.v120.21.3785.3785 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3785-3785 ◽

Cited By ~ 1

Author(s):

H. Jean Khoury ◽

Carlo Gambacorti-Passerini ◽

Hagop M. Kantarjian ◽

Dong-Wook Kim ◽

David Marin ◽

...

Keyword(s):

Pleural Effusion ◽

Chronic Myeloid Leukemia ◽

Disease Progression ◽

Median Time ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

Grade 3

Abstract Abstract 3785 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. A total of 119 pts aged ≥18 y with prior imatinib (IM) failure plus dasatinib (DAS) resistance (n = 38), DAS intolerance (n = 50), nilotinib (NIL) resistance (n = 27), NIL intolerance (n = 1), or failure of DAS and NIL (n = 3) received BOS starting at 500 mg/d. Median age was 56 y (range, 20–79 y); 45% of pts were male; median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median BOS duration was 8.6 mo (range, 0.2–60.8 mo); 24% of pts are still on treatment. Dose escalation to BOS 600 mg/d occurred in 19% of pts. Time from last pt's first dose to data cutoff was 25 mo (median follow-up duration of 31.4 mo [range, 0.3–66.0 mo]). A confirmed complete hematologic response (CHR) was attained/maintained by 73% of evaluable pts (Table). The Kaplan-Meier (KM) probability of maintaining a CHR at 2 y was 67%. A major cytogenetic response (MCyR) was attained/maintained by 41%, including 32% with a complete cytogenetic response (CCyR). Among evaluable pts without a baseline CCyR, 36% (n = 37/102) achieved a MCyR, including 28 (28%) with a CCyR. The KM probability of maintaining a MCyR at 2 y was 71%. Of 86 pts with baseline mutation status, 40 (47%) pts had 19 unique Bcr-Abl kinase domain mutations, including 7 (8%) pts with T315I. Responses were seen across mutations (75% CHR, 43% MCyR excluding T315I), including those conferring resistance to other TKIs; responses in pts with T315I were low (29% CHR; 14% MCyR). Nine of 37 pts evaluated at baseline and treatment discontinuation had ≥1 new mutation (V299L, n = 4; L248V, n = 2; T315I, n = 2; F359C, n = 1; G250E, n = 1); 8 of 9 pts had discontinued BOS due to disease progression or lack of efficacy. On-treatment transformation to accelerated phase CML occurred in 5 (4%) pts after 16 to 428 d on study; no pt transformed to blast phase CML. KM-estimated on-treatment progression-free survival (PFS) at 2 y was 75%; KM-estimated overall survival (OS) at 2 y was 84% (Table). There were 23 (19%) deaths on study, with 6 deaths occurring ≤30 d after the last BOS dose. Most deaths were due to disease progression (n = 10 [8%]) or an adverse event (AE; n = 10 [8%]; including 1 treatment-related death due to gastrointestinal bleeding). Three deaths were due to unknown cause ≥509 d after the last BOS dose. Non-hematologic treatment-emergent AEs (TEAEs) seen in ≥20% of pts (all grades; grade 3/4) included diarrhea (82%; 8%), nausea (49%; 1%), vomiting (40%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (24%; 1%), and abdominal pain (20%; 1%). The incidence of individual TEAEs was generally similar across groups regardless of prior TKI exposure. Diarrhea TEAEs were predominantly grade 1/2, first reported early during treatment (median time to first event of 1.5 d [range, 1–210 d]), and transient (median event duration of 2 d [range, 1–524 d]). The incidence of pleural effusion was highest among DAS-intolerant pts (n = 11 [22%], including 3 pts with grade 3 events); for 9 of 11 pts pleural effusion had been indicated as a reason for intolerance to prior DAS. Grade 3/4 laboratory abnormalities reported in ≥10% of pts included thrombocytopenia (25%), neutropenia (19%), lymphopenia (17%), and hypermagnesemia (12%). Dose reductions and interruptions were used to manage AEs in 50% and 66% of pts. A total of 32 (27%) pts discontinued treatment due to an AE, most commonly hematologic events. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ≥24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ∼1 y earlier (Blood 2012;119:4303–12). n (%) IM + DAS-R IM + DAS-I IM + NIL-R IM + DAS ± NILa Total Evaluableb 37 49 25 4 115 CHR 23 (62) 39 (80) 19 (76) 3 (75) 84 (73) Evaluableb 36 44 26 4 110 MCyR 12 (33) 21 (48) 10 (39) 2 (50) 45 (41) CCyR 7 (19) 19 (43) 7 (27) 2 (50) 35 (32) Treated 38 50 27 4 119 PFS at 2 yc 70% 81% 79% 38% 75% OS at 2 yc 77% 85% 92% 75% 84% R, resistant; I, intolerant. a Includes 3 pts with prior exposure to all 3 TKIs and 1 NIL-I pt. KM rates may be unreliable due to the small number of pts in this cohort. b Received ≥1 dose of BOS and had a valid baseline response assessment. c Based on KM estimates Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Kantarjian:Pfizer: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marin:Novartis: Research Funding; BMS: Research Funding. Dorlhiac-Llacer:Novartis, Bristol Myer Squibb, Pfizer: Research Funding. Bullorsky:Novartis, BMS: Consultancy, Speakers Bureau. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Besson:Pfizer Inc: Employment. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

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Generic Imatinib in Chronic Myeloid Leukemia: Survival of the Cheapest

Blood ◽

10.1182/blood.v128.22.630.630 ◽

2016 ◽

Vol 128 (22) ◽

pp. 630-630 ◽

Cited By ~ 6

Author(s):

Danthala Madhav

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Imatinib Mesylate ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Quantitative Polymerase Chain Reaction ◽

Comparable Efficacy ◽

Molecular Response ◽

Free Survival

Abstract Introduction: The patent expiration of Imatinib mesylate (Glivec, ®Novaritis) on February 1, 2016, has brought the focus back on generic versions of the drug, and an opportunity to provide a safe and cost effective alternative. India has witnessed a mushrooming of home grown pharmaceutical companies, that have drawn on Darwinian theory to promote the concept of "survival of the cheapest", in pursuit of a deeper penetrance into the cash strapped population. The launch of Veenat (®NATCO pharma) at a fraction of the price of the innovator drug is a case in point. Objectives: To determine the molecular and cytogenetic responses, survival endpoints (event free survival (EFS), failure free survival (FFS), transformation free survival (TFS), overall survival (OS), and safety of innovator and generic brands of imatinib. Materials and Methods: In this retrospective analysis, data from 1,812 patients with chronic myeloid leukemia (CML) treated with frontline Imatinib mesylate (Innovator/Generic) at a single institution between 2008 and 2014 is included. Of these 1,812 patients, 445 were excluded due to inadequate data and follow up. Thus, data from 1,193 patients who were treated with Glivec (®Novartis), and 174 patients with Veenat (®NATCO) was available. Observations: A higher percentage of patients in the generic arm compared to the innovator arm, were in accelerated phase (9.7% vs 6.7%) and blast crisis (7.4% vs 3.7%), respectively.After a median follow up of 1,347 days, 805 (67.4%) patients achieved complete cytogenetic response (CCgR), 259 (21.7%) achieved major molecular response (MR3), and 205 (17.1%) achieved 4 log reduction in BCR ABL transcripts (MR4) in the innovator arm. After a median follow up of 1,220 days, 112 (64.3%), 24 (13.7%), and 42(24.1%) patients achieved a CCgR, MR3 and MR4 respectively, in the generic arm.Follow up assessments using real-time quantitative polymerase chain reaction (q-PCR) and/ or cytogenetic tests were not available in 230 (19.2%) and 40 (22.9%) patients, in the innovator and generic groups respectively, despite inclusion in a sponsorship program.Adherence to treatment was poor in 192 (16%) and 30 (17.2%) patients in the innovator and generic arms respectively. Results: In a fairly homogenous population of lower economic strata, on a free drug access program, the prime factors influencing adherence were low educational level, assumptions of "cure", recent bereavement, stigma of cancer diagnosis and repeated hospital visits. Transformation to accelerated/blast phase occurred in 7.7% and 7.4% of patients in the innovator and generic arms respectively. Testing for BCR-ABL1 mutations was done in 31 (17.8%) patients in the generic arm and 132(11%) patients in the innovator arm, after failure of treatment or suboptimal response. Mutations were identified in 14 (8%) patients in the generic arm and 52 (4.3%) patients in the innovator arm.The most common subsequent treatments chosen were, dose escalation (249 [20.8%] vs 30 [17.2%]), Nilotinib (26 [2.1%] vs 8 [4.5%]), Dasatinib (11 [0.9%] vs 9 [5.1%]) and hydroxyurea (11 [0.9%] and 4 [2.2%]) in the innovator and generic arms respectively. There was no difference in EFS (p=0.46), FFS (p=0.16), TFS (p=0.9), or OS (p=0.13) between the two groups. The frequency of reported grade 1, or 2 non-hematological adverse events which included musculoskeletal pain, muscle cramps, and peripheral edema, and hematological adverse events was comparable between the study groups. However, the incidence of grade 3 skin rash was higher in the generic group (2.8%) in comparison to the innovator group (0.2%). Conclusion: The findings of the present study showed comparable efficacy and safety of the generic and innovator versions of imatinib in the treatment of patients with chronic myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

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Frequency of Complete Molecular Response In Chronic Myeloid Leukemia Patients In Real Life Practice.

Blood ◽

10.1182/blood.v116.21.1227.1227 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1227-1227

Author(s):

Matthieu Decamp ◽

Dina Istasi ◽

Atchroue Johnsonansah ◽

Oumedaly Reman ◽

Xavier Levaltier ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Molecular Response ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Line Therapy ◽

Ifn Treatment ◽

Complete Molecular Response

Abstract Abstract 1227 Introduction: Scarce data are available on the frequency of complete molecular response (CMR) in chronic myeloid leukemia (CML) patients. The European Leukemia Net defined CMR lately as an undetectable transcript quantified by Real Time PCR and/or nested PCR in two consecutive blood samples of adequate quality, using strict sensitivity criteria (sensitivity > 10 4). CMR is the best response that we can achieve in CML patients. Generally it is obtained after hematopoietic stem cell transplantation (HSCT) but since the administration of tyrosine kinase inhibitors (TKI), the number of patients seen with CMR is continuously increasing. The aim of this study is to assess the frequency of CMR in CML patients, and study their characteristics. Methods: A retrospective study was conducted to collect epidemiological, clinical, therapeutic and laboratory data of CML patients followed in hospitals of the region of Basse Normandie in France. All CML patients who had been followed up, between 1999 and 2010, by molecular monitoring for their Bcr-Abl transcript level were included. Clinical and biological responses were defined according to the ELN 2009 recommendations. Results: 199 patients were included in this study, 154 were diagnosed during the study period. Median age at diagnosis was 54 years and 46% were females. 61.3% were diagnosed in the chronic phase while the accelerated and the blast crisis phase accounted for 10.5% and 0.02%. Among these patients, 2 had the p190 BCR-ABL transcript and 2 the p230 transcript type. 169 were still followed at the end of this study and the median follow up duration was 6,4 years. Out of these 199 patients 12 died and 18 were lost out of sight. Imatinb (IM) alone or Imatinib-based combined therapies in clinical trials, was administrated as a first line treatment in 51,2% of patients. Interferon (INF) alone or in association with other chemotherapy was the frontline therapy in 37,7%; 52% of them started IFN treatment before 2000 and 73% switched to IM. At the time of analysis 26.6% of patients achieved a complete molecular response and 39.7% obtained a major molecular response (MMR) as defined by the international scale; this figure is to be tempered by the fact that the follow up duration was less than 18 months for 9,5% of patients. CMR was obtained in 11 patients following HSCT. With IM as a first line therapy, 11 patients achieved CMR or had an undetectable transcript after a median duration of 43.3 months and lasted for 13.3 months. When IM was given as a second line therapy, 17 obtained a CMR or had an undetectable transcript, in this case the median time calculated starting from the second line treatment administration was 37,3 months and in half of them, it persisted for 28 months. Among these patients, two discontinued therapy and currently they are still on CMR, 24 and 18 months after IM arrest. There was no significant difference in the median CMR achievement duration between the first and second line IM therapy groups. CMR following IFN treatment had been observed in 8 patients, 7 of them stopped IFN and have been in CMR for more than 5 years since its discontinuation. Finally five patients achieved a CMR after administration of second generation TKI. Altogether, a total of 63 patients were followed up for undetectable BCR-ABL transcript. In 53, the transcript remained undetectable; whereas 10 had lost that level of molecular response; 7 of them had regressed to a MMR though they were under IM therapy; 2 lost the MMR, one of them after IM arrest and one progressed to acute leukemia. Conclusion: A significant proportion of patients is in CMR or at least had no detectable transcript. In case of TKI therapy, the response is obtained after continuous administration (median duration was 36 months) and is durable in most cases. In this study, few patients in CMR have discontinued treatment but maintained their CMR response. Unfortunately one stopped the treatment and relapsed rapidly. The maintenance of this level of response appears to be dependent on continued suppression of the Bcr-Abl clone by TKI. Disclosures: No relevant conflicts of interest to declare.

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Duration of Major Molecular Response and Discontinuation in Deep Molecular Response (MR4.5) Were Associated with Longer Treatment-Free Survival after Imatinib Discontinuation - Results from Two Prospective Brazilian Trials

Blood ◽

10.1182/blood-2019-125368 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1655-1655

Author(s):

Katia B Pagnano ◽

Fernanda S Seguro ◽

Eliana C Miranda ◽

Ana Beatriz Pascoal Lopes ◽

Andre Abdo ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Cox Regression ◽

Chronic Phase ◽

Molecular Response ◽

Free Survival ◽

Deep Molecular Response ◽

Treatment Free Remission

Several trials have demonstrated the feasibility of discontinuation of tyrosine kinase inhibitors (TKI) treatment in chronic myeloid leukemia (CML) patients (pts) with deep molecular response. Aims: to report the results of two Brazilian imatinib (IM) discontinuation trials and to evaluate factors impacting in treatment-free remission (TFR) and treatment-free survival (TFS) after IM discontinuation. Methods:Between September 2016 and January 2019, 60 CML pts were included in two ongoing phase II, single arm, prospective Brazilian discontinuation trials: Pilot Study of Discontinuation in Patients With Chronic Myeloid Leukemia With Deep Molecular Response - Evaluation of Pioglitazone in Treatment-free Remission (TFR) (EDI-PIO UNICAMP)(NCT02852486)and Imatinib Discontinuation in Patients With Chronic Myeloid Leukemia Chronic Phase With Sustained MR4log(USP) (NCT03239886). Inclusion criteria: age >18 years, chronic phase, minimum of 3 years of IM therapy, deep molecular response for ≥ 2 years (confirmed by 4 tests in the last 2 years, defined as MR4.0 in USP trial and MR4.5 in EDI-PIO). Patients participating in EDI-PIO trial used pioglitazone 30 mg/day plus IM for 3 months before IM discontinuation (n=30). After discontinuation, pts were monitored by quantitative RQ-PCR monthly in the first year, every 2 months in the second year and every 3 months in the third year. Criteria for IM re-initiation: loss of MMR (in one test), loss of cytogenetic response, loss of hematologic response, disease progression or confirmed loss of MR4.0 (this criteria used only in EDI-PIO trial). TFR was calculated from the date of discontinuation until first event (loss of MMR; IM reintroduction; death any cause or last follow-up); TFS was calculated from the date of IM discontinuation until reintroduction or last follow-up (censoring deaths not related to CML). Adverse events after IM discontinuation were reported according to CTCAE. Results:Data cut-off for analysis was February 2019. In the 1stanalysis 48 pts who discontinued IM in MR4.5 were analyzed. Patient's characteristics from EDIPIO (n=30) and USP (n=18) trials were: 57% vs. 67% male, median age of 55 (29-77) and 56 (33-95) years (29-95) at discontinuation; 16% and 33% had used previously Interferon; median duration of IM treatment of 10 (3-16) vs. 10 (5-15) years; median duration of MMR 95 (30-149) vs. 93 (57-130) months; MR4.0 was 90 (26-135) vs. 89 (30-123) months; and MR4.5 was 76 (23-135) vs. 75 (30-102) months; none variable had statistical difference.One patient died in MMR due to cardiac failure. TFR was 61% (95% CI 47-75) at 20 months. Sixteen (33%) out 48 re-initiated IM (2 with confirmed loss of MR4.0 and 14 with loss of MMR) in a median time of 20 (1-26) months. All relapsed pts recovered MMR after IM reintroduction, in a median time of 2 months (0-4). There was no transformation to advanced phases. No serious adverse events were reported during pioglitazone treatment. In the Cox regression the duration of MMR was associated with a longer TFR HR: 0.96 (beta-) (CI 95%:0.94-0.99, P= 0.006). Gender, age at diagnosis, age at discontinuation, treatment with pioglitazone, Sokal and EUTOS scores, BCR-ABL transcripts type, duration of IM therapy, duration of MR4.0 and MR4.5 and previous use of Interferon did not affect TFR.In the second analysis all 60 pts were included. TFS was 56% and was higher in pts who discontinued IM in sustained MR4.5 vs. MR4.0 (63% vs. 33%, P=0.04)(Figure). The independent factors for TFR in the multivariate analysis by Cox-regression were the duration of MMR [HR: 0.97 (beta-), 95%CI: 0.95-0.98, P=0.001] and intermediate/high risk Sokal [HR 3.14 95%CI: 1.08-9.11, P= 0.035]. Twenty-four out of 60 pts (40%) re-initiated IM (2 with confirmed loss of MR4.0 and 22 with loss of MMR).Adverse events occurred in 38 (63%) pts, 30% attributed to withdrawal syndrome. Some pts presented more than one event. Grade 1-2: arthralgia or muscular pain (17), hyperglycemia (4), hypertriglyceridemia (2), polycythemia (2), hypertension (3), and others (11). Four pts had grade 3-4 event: arthralgia (1), death for cardiac failure (1), abortion and hypertriglyceridemia (1). Conclusions:both trials demonstrated the feasibility and safety of IM discontinuation in pts in sustained deep molecular response. The duration of MMR was associated with a higher TFR and TFS rate. Imatinib discontinuation was more successful in pts in stable MR4.5. Figure Disclosures Pagnano: Pint Pharma: Consultancy; Abbvie: Consultancy; Sandoz: Consultancy. Delamain:Novartis: Honoraria.

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Physicians' Attitude Towards Selection of Second Line Therapy with Nilotinib and Dasatinib in Chronic Myeloid Leukemia Patients

Blood ◽

10.1182/blood.v128.22.5939.5939 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5939-5939

Author(s):

Fabio Efficace ◽

Gianantonio Rosti ◽

Francesco Cottone ◽

Laura Cannella ◽

Marco Vignetti ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Treatment Schedule ◽

Line Treatment ◽

Second Line ◽

Personality Profile ◽

Second Line Therapy ◽

Line Therapy ◽

Selection Of

Abstract Background: One of the main challenges in the treatment of chronic myeloid leukemia (CML) is the selection of second line therapy. While Nilotinib (NILO) and dasatinib (DASA) are available for use as second line treatment for several years, few evidence-based data is available on how physicians make decisions on the use of one drug over another. Aim: We performed a pilot study to describe which factors physicians consider most relevant when deciding therapy with either NILO or DASA in patients who previously failed or were intolerant to Imatinib (IMA) therapy. Patients and methods: Analyses are based on a sample 67 CML patients, recruited as part of a larger international study, who switched from IMA therapy to either NILO (N=36; 53.7%) or DASA (N=31; 46.3%). Patients had to be in second line treatment for at least three months to be eligible for this analysis. Also, in all participating centers, NILO and DASA should have been equally available for use. There were 15 physicians involved in the management of these patients and they were asked to complete an ad-hoc questionnaire investigating reasons based on which they made the decision to either use one drug over another. All questions were phrased as follows: "To what extent have the following issues been determinant to make a decision on which agent (NILO or DASA) to use for this patient?" All answers were rated on a four point likert-scale (ie, not at all, a little, quite a bit and very much). Items investigated were: 1) accessibility of the drug in the hospital; 2) cost of drug; 3) patients' comorbidities; 4) patients' age; 5) patients' personality profile; 6) discussion with patients about Pro and Cons; 7) different treatment schedule of drugs; 8) type of mutation during IMA therapy. Physician characteristics were also collected and analyzed. Other treatment-related variables were investigated such as main reason for changing of TKI (IMA intolerance or resistance), high grade adverse events (AEs) experienced during IMA treatment, or previous duration of IMA therapy. Results: Physicians' experience in treating CML patients was on average 14 years (range 4-32). Patient median age at the time of treatment switch was 47 and 55 years in the NILO and DASA group, respectively. Median time of duration of IMA therapy, before receiving second line therapy, was 1.4 years and 3.3 years for those who switched respectively to NILO or DASA. No differences existed between groups with regard to reasons for switching from IMA therapy (intolerance or resistance) or AEs reported with previous IMA therapy. The top issue considered as most relevant when making the decision was previous discussion with patients on advantages and disadvantages of drugs, being reported as "quite a bit" and "very much" important in 73% of evaluations. Cost of the drug was not considered relevant at all, in the selection of which drug to use, in 97% of the 69 evaluations considered. Also, type of mutation during IMA therapy was considered as of negligible relevance for the decision, but it should not be overlooked that mutations were detected in few patients. Patient's comorbidity or personality profile was quoted as a 'quite a bit' or 'very much' relevant reason for the selection of 2nd line TKI, respectively in 43% or 48% of all questionnaires. Low relevance was assigned to patient age and different treatment schedule: 'not at all' or 'a little' relevance was reported respectively in 64% and 70% of all questionnaires. The analysis of physician-reported grading distribution according to the type of second line treatment did not show any significant difference (no reason lead to a preferential selection of one drug), see table 1. Conclusions: No differences were detectablein selected factors, driving the decision to switch either to NILO or DASA when physicians consider switching from first line IMA therapy. Also, type of TKI selection does not seems to be guided by only one factor. Further research is needed to elucidate on potential reasons underlying clinical decision making in 2nd TKI selection. Disclosures Efficace: Seattle Genetics: Consultancy; TEVA: Consultancy, Research Funding; Lundbeck: Research Funding; Bristol Myers Squibb: Consultancy. Rosti:Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau. Breccia:Celgene: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Ariad: Honoraria. Baccarani:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau.

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Five-Year Outcome of 215 Newly Diagnosed Chronic Myeloid Leukemia Patients Treated Frontline with Nilotinib-Based Regimens: A Gimema CML Working Party Analysis

Blood ◽

10.1182/blood.v124.21.3141.3141 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3141-3141

Author(s):

Gabriele Gugliotta ◽

Fausto Castagnetti ◽

Massimo Breccia ◽

Luciano Levato ◽

Giovanna Rege-Cambrin ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Cytogenetic Response ◽

Molecular Response ◽

Newly Diagnosed ◽

Secondary Resistance ◽

Long Term Outcome ◽

Free Survival

Abstract Background. Nilotinib (NIL) is a potent and selective BCR-ABL inhibitor approved for the frontline treatment of chronic myeloid leukemia (CML) based on the results of the ENESTnd study. The sustained superiority of NIL vs. imatinib (IM) was confirmed after 5 years of follow-up (Hughes et al, abs. 677, EHA 2014). However, few data are available on patients (pts) treated frontline with NIL outside of Company-initiated trials. Objectives. To analyze the long-term outcome in a large, independent cohort of newly diagnosed CML pts treated frontline with NIL-based regimens. Methods. We analyzed 215 pts, enrolled in 2 multicenter phase II studies conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00481052 and NCT00769327) or treated at the Bologna University Hospital, with NIL 300 mg or 400 mg BID as initial treatment; 123 pts received a sequential treatment with NIL and IM (NIL-IM), with a 3-months (mos) rotation period (all patients received NIL in the first 3 mos). The median age was 53 years (range 18–86). Ten out of 215 pts (5%) had a high EUTOS score. The median follow-up was 57 mos (range 36–81 mos). We assessed: the rates of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR); the rates of optimal responders at each milestone according to ELN 2013 recommendations; the overall survival (OS; any death included), progression-free survival (PFS; progression to accelerated/blast phase [AP/BP] and deaths for any cause), failure-free survival (FFS; failures according to ELN 2013 recommendations and deaths for any cause), and event-free survival (EFS; events: failures, permanent discontinuation of NIL for any cause, including deaths). All analysis was made according to the intention-to-treat principle. Results. The cumulative rates of CCyR and MMR were 93% and 88%, respectively. At 3 mos, 82% of the pts were in Partial Cytogenetic Response and 90% had a BCR-ABL/ABL (IS) < 10%; at 6 mos, 86% were in CCyR and 83% had a BCR-ABL/ABL (IS) < 1%; at 12 mos, 72% were in MMR; all these pts were optimal responders according to ELN 2013 recommendations. Overall, 80 (37%) pts permanently discontinued NIL: 45 (21%) for adverse events or intolerance; 25 (12%) for failures; 7 (3%) while in stable MR4; 3 (1%) for other reasons. Cardiovascular adverse events (CVAE) were cause of permanent NIL discontinuation, after a median time of 37 mos, in 13 (6%) pts, and included 4 peripheral arterial occlusive diseases and 3 ischemic coronary diseases; only one pt died for CVAE. Nine (4.1%) pts progressed to AP/BP, 8/9 during the 1st year of therapy and one after 25 mos; all pts subsequently died (after a median of 13 mos, range 1-34 mos). NIL-resistant mutations were identified in 6 of these pts (4 T315I; 1 Y253H; 1 F359V); 7/9 progressions occurred in patients receiving NIL-IM. In addition, 6 pts were classified as failures at 3,6, or 12 mos according to ELN 2013 recommendations; afterwards, 10 pts developed a secondary resistance (3 loss of CHR, 3 loss of CCyR, and 4 confirmed loss of MMR). Overall, 17 (8%) pts died, in 7 cases for reasons unrelated to CML progression. The estimated 6-year OS, PFS, FFS, and EFS were 91%, 91%, 83%, and 59%, respectively. Conclusions. Our National experience showed that most pts treated frontline with NIL-based regimens were optimal responders according to ELN recommendations and that 91% of the patients were estimated to be alive and progression-free at 6 years. In particular, NIL alone was highly effective in the prevention of AP/BP. Considering that AP/BP had in most cases an early onset and an extremely poor prognosis, its prevention should be the priority of CML treatment, especially in the firsts 2-3 years. However, afterwards, the relatively high number of CVAE observed, suggests to focus, at least in selected patients, on strategies aimed at the prevention of CVAE (NIL dose reduction? switch to IM?). Acknowledgments. European LeukemiaNet, COFIN, Bologna University, BolognAIL Disclosures Gugliotta: Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy. Castagnetti:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Abruzzese:Novartis: Consultancy. Martinelli:ARIAD: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other. Baccarani:Novartis, BMS, Pfizer, Ariad: Consultancy, Honoraria, Speakers Bureau. Rosti:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy; Ariad: Consultancy; Pfizer: Consultancy.

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Frontline Tyrosine Kinase Inhibitors (TKI) As Initial Therapy for Patients with Chronic Myeloid Leukemia in Accelerated Phase (CML-AP),

Blood ◽

10.1182/blood.v118.21.3779.3779 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3779-3779

Author(s):

Maro Ohanian ◽

Hagop M. Kantarjian ◽

Alfonso Quintas-Cardama ◽

Susan O'Brien ◽

Srdan Verstovsek ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Research Funding ◽

Clonal Evolution ◽

Cytogenetic Response ◽

Initial Therapy ◽

Molecular Responses ◽

Free Survival

Abstract Abstract 3779 Background: Some patients (pts) with chronic myeloid leukemia (CML) present with features of accelerated phase (AP) at the time of diagnosis. Imatinib, dasatinib, and nilotinib are standard initial tyrosine kinase inhibitor (TKI) therapy for pts with CML in chronic phase (CP). For pts with accelerated phase CML (CML-AP), data is available mostly on treatment after failing previous therapies, and there is no available data on nilotinib and dasatinib as initial therapy for CML-AP. Aim: To describe efficacy of imatinib, dasatinib, and nilotinib as initial therapy for patients with CML-AP. Methods: Frontline TKI therapy was administered on consecutive or parallel clinical trials to 58 CML pts who presented with features of AP at the time of diagnosis, defined as blasts ≥15% (n=8), basophils ≥20%, (n=22), platelets <100×109/L (n=3), cytogenetic clonal evolution (n=22), or more than 1 feature (n=3). 36 pts received imatinib. 22 pts received a second generation TKI (2GTKI) (desatinib, n = 5 or nilotinib, n= 17). Results: A total of 58 pts were treated. Median age was 46 years (range 22 to 81). Pt characteristics were similar in all 4 treatment groups. With a median follow-up of 32 months (range 2 to 125), a complete hematologic response (CHR) was achieved in 93%, a partial cytogenetic response (PCyR) in 2 %, and a complete cytogenetic response (CCyR) in 82%. The rate of CCyR for evaluable patients treated with imatinib was 75%, and with 2GTKIs, 95%. Major molecular responses (MMR, BCR-ABL/ABL ≤0.1% IS) were achieved in 68% including complete molecular responses (CMR, BCR-ABL/ABL ≤0.0032% IS) in 49%. MMR rates for pts treated with imatinib were 66%, and with 2GTKIs, 71%. The median time to achieve a CCyR was 3 months, and a MMR, 9 months. The 12-month rate of CCyR was 74% with imatinib and 83% with 2GTKIs. The 12-month MMR rate was 52% for imatinib and 67% for 2GTKIs. Patients with clonal evolution as the only criterion for CML-AP had a 91% rate of CCyR compared to 76 % for those with other criteria (p=0.168). At 24 months from the start of therapy, event free survival (EFS) for all patients was 90% (imatinib 90%; 2GTKI 90%). 24-month transformation free survival (TFS) (survival free from transformation to blast phase) was 92% (imatinib 94%, 2GTKIs 90%). Overall survival at 24 months was 100% with both imatinib and 2GTKI's. We also analyzed the impact of early response on long-term outcome. The TFS rate at 24 months for those achieving a 12-month CCyR was 100% compared to 56% for those not achieving such responses. TFS was 100% for those with a MMR at 18 months and 60% for those without a MMR at 18 months. In total, 4 patients have transformed to BP. None of the patients who transformed had achieved CCyR by 12 months. At last follow-up, 34 patients remain on therapy. Reasons for discontinuation were treatment failure/disease progression in 8, toxicity in 1, and other reasons in 15. Conclusion: Patients with CML who present with features of AP at the time of diagnosis have an excellent outcome with TKIs, particularly 2GTKI. Those with clonal evolution as the only manifestation of AP have a particularly favorable outcome. TKIs should be considered standard initial therapy for patients with AP at the time of diagnosis. Disclosures: Kantarjian: Novartis: Consultancy; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding. Quintas-Cardama:Novartis: Consultancy; BMS: Consultancy. Ravandi:BMS: Honoraria; BMS: Honoraria; Bristol Meyers-Squibb: Research Funding. Jabbour:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

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Clinical Characteristics and Late-Line Treatment Patterns of Patients with Chronic Myeloid Leukemia Who Received 2 Prior Lines of Tyrosine Kinase Inhibitor Therapy in US Community Oncology Practices

Blood ◽

10.1182/blood-2021-152619 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 5036-5036

Author(s):

Pareshkumar Patel ◽

Aditya Raju ◽

Anna Coutinho ◽

Rodrigo Maegawa ◽

Orsolya Lunacsek ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Clinical Characteristics ◽

Treatment Options ◽

Treatment Patterns ◽

Line Treatment ◽

Publicly Traded ◽

Ecog Ps

Abstract BACKGROUND: Current treatment guidelines recommend tyrosine kinase inhibitors (TKIs) as first-line and second-line treatment options for patients with chronic myeloid leukemia (CML). 1,2 However, approximately 20% of CML patients fail to respond to the first- and second-generation TKIs, and evidence-based guidelines for late-line treatment options after failure/intolerance to TKIs are limited. 3,4 Therefore, this study sought to describe the clinical characteristics and real-world treatment patterns of CML patients who received 2 prior lines of TKI therapy. METHODS: A retrospective cohort design was utilized to identify adult CML patients who initiated a new line of therapy (LOT) after 2 prior lines of TKI therapy between 4/2013 and 12/2020 in the Florida Cancer Specialists network's electronic health records (EHR) database. The index LOT date was the start date of a new CML treatment regimen in LOT≥3 after 2 prior lines of TKI therapy. Patients were followed until 1 of the following occurred: death, loss to follow-up (last structured activity in EHR), or end of study period (3/31/2021). Demographic and clinical characteristics were captured during the baseline period starting 3 months prior to the initial CML diagnosis until the index LOT date and included age, gender, race, Eastern Cooperative Oncology Group performance status (ECOG PS) and comorbidity burden. Treatment patterns of all available LOTs from initial CML diagnosis were investigated and the following metrics were captured: regimen details of systemic CML therapies, duration of LOT, treatment-free interval. This study was descriptive in nature and no inferential statistics were computed. RESULTS: A total of 157 patients who initiated a new CML treatment regimen in LOT≥3 after 2 previous lines of TKI therapy were included in this study. The median age of the study sample at initial CML diagnosis was 63.8 years, 57.3% of the sample were male, and 50.3% were White. At index LOT, 46.5% of the sample had an ECOG PS score of 0-1, 5.1% had ECOG PS score of 2-4, and 48.4% had an unknown ECOG PS score. The majority of the sample initiated the index LOT in LOT 3 (n=151; 96.2%) vs in LOT 4 (n=6; 3.8%). The median duration of the index LOT was 6.6 months with median follow-up from index LOT being 23.0 months. After 2 prior lines of TKI therapy, 93.0% of the sample continued on TKIs only, 1.3% initiated a non-TKI CML drug, and 5.7% received a combination of CML drugs. Dasatinib (31.2%) and imatinib (30.6%) were the most commonly used TKIs in the index LOT. There was significant variability in the treatment sequences across LOTs, however, 50.3% of the sample restarted the same TKI in their index LOT which had been used in a prior LOT. A total of 65 patients (41.4%) initiated a new LOT after the index LOT, and the treatment-free interval following the index LOT was 1.8 months, on average. CONCLUSIONS: The majority of the CML patients who received 2 prior lines of TKI therapy continue to cycle through additional LOTs containing TKIs, and half of the patients restart the same TKI used in a prior LOT. The findings of this study highlight the need for better novel therapies that can fill the treatment gap for CML patients who are refractory or intolerant to TKIs. REFERENCES: 1. Deininger MW, Shah NP, Altman JK, et al. Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(10):1385-1415. 2. Hochhaus A, Saussele S, Rosti G, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv41-iv51. 3. Perrotti D, Jamieson C, Goldman J, et al. Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest. 2010;120(7):2254-2264. 4. Cortes J, Lang F. Third-line therapy for chronic myeloid leukemia: current status and future directions. J Hematol Oncol. 2021;14(1):44. Disclosures Patel: Novartis Pharmaceuticals Corporation: Research Funding. Raju: Xcenda LLC: Current Employment, Other: Xcenda LLC received research funding from Novartis Pharmaceuticals Corporation. Coutinho: Xcenda LLC: Current Employment, Other: Xcenda LLC received research funding from Novartis Pharmaceuticals Corporation. Maegawa: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company. Lunacsek: Xcenda LLC: Current Employment, Other: Xcenda LLC received research funding from Novartis Pharmaceuticals Corporation. Deyoung: Xcenda LLC: Current Employment, Other: Xcenda LLC received research funding from Novartis Pharmaceuticals Corporation. Iorga: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company. Cao: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company.

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