Ponatinib As Frontline Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Abstract Background: Ponatinib is a third generation tyrosine kinase inhibitor (TKI) that has demonstrated efficacy in patients (pts) with CML who have failed multiple therapies and those with a T315I mutation or other BCR-ABL mutations. In this study, we have assessed the efficacy and safety of ponatinib as a frontline therapy in pts with CML-CP. Methods: Fifty one pts with CML-CP were treated with ponatinib as initial therapy for CML in a single-arm, single-institution clinical trial. The starting dose of ponatinib was 45 mg orally daily in 43 pts and, after an amendment, 30 mg in 8 pts. Other eligibility criteria included age ≥18 yrs, ECOG PS 0-2, normal organ function, and absence of significant cardiac history or prior pancreatitis. Pts with clonal evolution at time of diagnosis were eligible without other evidence of accelerated phase. Dose reductions to 30mg/d, 15 mg/d, or 15 mg every other day were indicated for adverse events. Pts were followed with cytogenetic analysis and PCR every 3 months for the first 12 months, then every 6 months. Cytogenetic and molecular (by International Scale) response criteria were standard. Results: From May 2012 to June 2014, 51 pts were treated. The median age was 48 yrs (range, 21-75), 1 patient had clonal evolution, and 3 started therapy while in CHR. Sokal risk score was low in 69%, intermediate in 22% and high in 10%. The median follow-up was 15.6 months (range 5.6-23.7 months). Complete hematologic response (CHR) was achieved in 95% of pts, complete cytogenetic response (CCyR) in 95%, major molecular response (MMR) in 80%, molecular response 4.5-log (MR4.5) in 55% and undetectable BCR-ABL in 38%. At 3 months, 90% of 50 evaluable pts achieved CCyR, and at 6 months 93% of 45 evaluable pts had CCyR. The median transcript levels at 3 months was 0.096 and at 6 months 0.005. Rates of MMR at 3 and 6 months were 50% and 80%, and rates of undetectable BCR-ABL1 were 0% and 22%, respectively. None of the pts progressed, including no transformations to accelerated or blast phase and all pts were alive. Forty three (85%) pts required treatment interruptions. The median duration of treatment interruptions was 9 days (range, 1-48). The median dose for all pts was 30 mg/d. As of June 2014, all pts were taken off study – 38 per FDA recommendation for concerns of risk of thrombotic events and 13 due to adverse events. Of these 13 pts – 3 had vasoocclusive disease grade 3 (peripheral arterial disease, femoral artery thrombosis, gastrointestinal ischemia), 2 with acute coronary syndrome (grade 3), 2 had cerebrovascular events grade 3 (1 transient ischemic attack and 1 Moya Moya disease), 2 multiple toxicities, 1 grade 3 hypertension, 1 with resistance and grade 2 arthralgia, 1 grade 3 skin xerosis, 1 grade 4 myelosuppression. Cardiovascular events were observed in 24 (47%) pts, of which 11 had >1 cardiovascular event. Hypertension in 14 pts (7 were grade 3), chest pain in 8 (one pericarditis grade 2), acute coronary syndrome in 2 (grade 3), vasoocclusive disease in 3 (one suspected gastrointestinal ischemia; all grade 3), stroke in 3 (one TIA and one carotid arterial disease both grade 3), Raynaud’s phenomenon in 2 (grade 1-2), one each had toe cramps with tingling, palpitations, prolonged QTc. Non-cardiovascular adverse events included - skin rash in 35 (2 pts with grade 3/4), dry skin in 22 (all grade 1/2), lipase elevation in 32 (23 with grade 3/4), symptomatic grade 3 pancreatitis in 10 pts, constipation in 26 pts (all grade 1/2), and memory loss in 6 pts (all grade 1/2). Grade 3-4 myelosuppression occurred in 14 pts. Conclusion: Ponatinib therapy leads to fast and deep cytogenetic and molecular responses in pts with CML-CP. Cardiovascular toxicities, skin toxicity and lipase elevation were observed in several patients. Dose adjustment, regular monitoring and counselling of the pts for thromboembolic events can be used to manage pts on ponatinib. However, considering the risk of vascular thrombotic events and the availability of alternative options for these patients, the study has been terminated at the recommendation of the FDA. Disclosures Borthakur: Tetralogic Pharmaceuticals: Research Funding. Ravandi:Cellerant Therapeutics: Research Funding. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

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Ponatinib As Initial Therapy For Patients With Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Blood ◽

10.1182/blood.v122.21.1483.1483 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1483-1483 ◽

Cited By ~ 1

Author(s):

Jorge E. Cortes ◽

Gautam Borthakur ◽

Naveen Pemmaraju ◽

Naval Daver ◽

Alfonso Quintas-Cardama ◽

...

Keyword(s):

Abdominal Pain ◽

Adverse Events ◽

Research Funding ◽

Clonal Evolution ◽

Chronic Phase ◽

Initial Therapy ◽

Stopping Rules ◽

Molecular Response ◽

Treatment Interruptions ◽

Grade 3

Abstract Background Ponatinib has excellent clinical activity and an acceptable toxicity profile in patients with CML who have experienced resistance or intolerance to multiple tyrosine kinase inhibitors (TKI). In vitro, ponatinib at concentrations achieved in the clinic (40nM) prevents the emergence of resistant clones. We hypothesized that ponatinib could result in high rates of early responses and prevent resistance when used as frontline therapy for patients with CML-CP. Methods Patients with CML-CP were treated with ponatinib 45 mg orally daily as initial therapy for CML in a single-arm, single-institution clinical trial. Other eligibility included age ≥18 years (yrs), PS 0-2, normal organ function, and absence of significant cardiac history or prior pancreatitis. Patients with clonal evolution at time of diagnosis were eligible if no other evidence of accelerated phase. Dose adjustments were indicated for adverse events to 30mg/d, 15 mg/d, or 15 mg every other day. Patients were followed with cytogenetic analysis and PCR every 3 months for the first 12 months, then every 6 months. Cytogenetic and molecular (by International Scale) criteria were standard. Initial plan was for 50 patients to be treated with interim analysis and early stopping rules for efficacy and toxicity, with the primary endpoint being the rate of complete cytogenetic response (CCyR) at 6 months. Results From May 2012 to July 2013, 41 patients have been treated. The median age is 51 yrs (range, 21-75), and 1 patient had clonal evolution. Sokal risk score was low in 73%, intermediate in 17% and high in 10%. The median follow-up is 7.8 months. Overall, complete hematologic response (CHR) has been achieved in 87% of patients, CCyR in 89%, major molecular response (MMR) in 74% and molecular response 5-log (MR5) in 29%. At 3 months, 89% of 35 evaluable patients have achieved a CCyR, and at 6 month 93% of 27 evaluable patients have this response. The median transcript levels at 3 months is 0.091 and at 6 months 0.007. Rates of MMR at 3 and 6 months are 51% and 78%, respectively, and rates of MR5 are 0% and 22%. No patient has suffered progression, including no transformations to accelerated or blast phase and all patients are alive. Two patients have discontinued therapy: one for skin toxicity (lowest dose used 30mg/d) and one for persistent, recurrent idiosyncratic neutropenia (lowest dose used 15 mg every other day + filgrastim). Most common adverse events (AEs) of any grade are rash (61%), lipase elevation (56%), constipation (51%), dry skin (44%), abdominal pain (41%), and headache (39%), nearly all mostly grade 1-2. The most common grade 3/4 AEs have been lipase elevation in 39%, usually asymptomatic, with pancreatitis grade 3/4 in 15%. Other non-hematologic grade 3/4 AEs seen in more than 1 patient include elevated amylase (7%), abdominal pain (7%), hypertension (7%), rash (5%), and elevated ALT (5%). Grade 3-4 neutropenia or thrombocytopenia occurred in 10% each, transient in all except one. Twenty-nine (71%) patients have required treatment interruptions and 24 (59%) a dose reduction. The median duration of treatment interruptions is 9 days (range, 1-48). The median dose for all patients is 30mg daily. At 3 months 37% had reduced to 30mg or lower and at 6 months 56%. Conclusion Ponatinib is effective as initial therapy for CML-CP resulting in high rates of cytogenetic and molecular responses at early timepoints. Therapy with ponatinib is well tolerated with transient elevated lipase being the most common toxicity. In view of the frequency of dose reductions and considering the excellent responses achieved, the trial has been modified to explore 30 mg as initial dose. Disclosures: Cortes: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Off Label Use: Ponatinib is not approved for use as initial therapy for CML, only for patients who have developed resistane or intolerance. This presentation involves the use as initial therapy. Jabbour:Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. O'Brien:Ariad: Research Funding.

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Clinical Significance of Dose Reductions of Dasatanib and Nilotinib When Used As Frontline Therapy for Chronic Phase -Chronic Myeloid Leukemia (CML-CP) Does Not Affect Outcome,

Blood ◽

10.1182/blood.v118.21.3786.3786 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3786-3786

Author(s):

Asifa Malik ◽

Hagop M. Kantarjian ◽

Alfonso Quintas-Cardama ◽

Susan o'Brien ◽

Srdan Verstovsek ◽

...

Keyword(s):

Chest Pain ◽

Dose Reduction ◽

Research Funding ◽

Chronic Phase ◽

Molecular Response ◽

Median Dose ◽

Treatment Interruptions ◽

Frontline Therapy ◽

The Impact ◽

Dose Reductions

Abstract Abstract 3786 Background: Dasatinib and nilotinib are now standard frontline therapy for patients (pts) with CML-CP. Transient treatment interruptions and dose reductions occur frequently in pts treated with these agents, most frequently due to adverse events (AE). (Cortes et al. JCO 2010). The impact that such interruptions may have over the clinical outcome is not known. Aim: To determine the causes, frequency, and time to dose reductions of 2nd generation tyrosine kinase inhibitors (TKI), dasatinib and nilotinib when used as initial therapy for CML-CP and to investigate the impact that dose reduction has over outcome. Methods: We analyzed 204 pts with CML-CP treated with frontline dasatinib (n=99) at an initial dose of 100mg QD (n=66) or 50mg BID (n=33) or nilotinib at a starting dose of 400mg BID (n=105) in parallel trials. Data on dosing, treatment interruptions and reasons for dose adjustment were collected prospectively. The protocols included guidelines for treatment interruptions and dose reductions for drug-related grade 3–4 AEs, or persistent grade 2 AEs. Results: The median age for the 204 pts was 47 years (range, 17 to 86), 58% were males. A complete hematological response was achieved by 99%, complete cytogenetic response (CCyR) by 95%, major molecular response (MMR) by 87%, and complete molecular response (CMR; BCR-ABL/ABL â‰¤0.0032% IS) by 62%. A total of 71 pts (35%) required a dose reduction due to an AE, including 39/99 (39%) treated with dasatinib (23/66 -35%- at 100mg QD, 16/33 -48%- at 50mg BID) and 32/105 (30%) with nilotinib. Thirty-one pts (44%) required a second or subsequent dose reduction. The first dose reduction occurred within 3 months from start of therapy in 21 (54%) of pts treated with dasatinib while 18 (46%) (n=18) required it after 3 months. For pts treated with nilotinib 21 (66%) required a dose reduction within 3 months and 11 (34%) after 3 months of start of treatment. The most common AEs grade 2–4 leading to dose reductions on dasatanib included pleural effusion (n=24), headache (n=11), peripheral neuropathy (n=6), myelosuppression (n=6) (5 thrombocytopenia, 1 neutropenia), cough (n= 5), dizziness (n=4), generalized body pain (n=3), fatigue (n=3), rash (n=3), chest pain (n=2), anxiety/mood alteration(n=2), memory impairment (n=2), A.fib (n=2), and pneumonia, bradycardia, MI, CHF and depression (1 each) (>1 AE could be coded as reason for dose reduction if concomitant). For nilotinib causes were increased bilirubin (n=6), increased LFT's (n=6), myelosuppression (n=5) (2 thrombocytopenia, 3 neutropenia), rash (n=5), head ache (n=3), chest pain (n=3), lipase (n=2), bone pain (n=2), fatigue (n=2), nausea/vomiting (n=2), and bradycardia, pericarditis, PVC's, and abdominal pain (1 each). Only 3 pts had a re-escalation of dose after their dose reduction. Median dose for pts requiring a dose reduction on nilotinib was 400 mg/day (range was 200–400) and the median dose for dasatinib was 80mg/d (range 20–80mg/d). The outcome of patients with or without dose reduction is presented in Table 1. Conclusion: Although dose reductions are frequently required for pts with CML treated with dasatinib or nilotinib, dose reductions did not lead to adverse outcome. Dose adjustments can be used when required to manage AEs. This approach allows in most instances continuation of these highly effective therapies. Disclosures: Kantarjian: BMS: Research Funding; Novartis: Research Funding. Quintas-Cardama:Novartis: Consultancy; BMS: Consultancy. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Jabbour:BMS: Honoraria; Novartis: Honoraria. Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

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PF-114: A 4th Generation Tyrosine Kinase-Inhibitor for Chronic Phase Chronic Myeloid Leukaemia Including BCRABL1T315I

Blood ◽

10.1182/blood-2019-127951 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1638-1638 ◽

Cited By ~ 1

Author(s):

Anna G. Turkina ◽

Olga Vinogradova ◽

Elza Lomaia ◽

Evgeniya Shatokhina ◽

Oleg A. Shukhov ◽

...

Keyword(s):

Adverse Events ◽

Chronic Myeloid Leukaemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Myeloid Leukaemia ◽

Research Funding ◽

Kinase Inhibitor ◽

Molecular Response ◽

Travel Grant ◽

Grade 3

Background: PF-114 is a 4th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR-ABL1 isoforms including BCR-ABL1T315I. We present data from a phase-1 study in patients with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or with BCR-ABL1T315I (NCT02885766) with ≥6 months therapy. Methods: 3+3 dose-escalation study to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included safety and efficacy based on haematological, cytogenetic, and molecular criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 patients were enrolled. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given continuously. Median age was 50 years (range, 29-82 years). Median CML duration pre-study was 10 years (range, 0.3-23 years). All patients had baseline ECOG performance scores 0-1. Twelve patients had BCR-ABL1T315I. Patients were heavily pre-treated: 25 received ≥3 prior TKIs; 5 patients with BCR-ABL1T315I received 1 prior TKI. Interim analysis was conducted at follow-up of ≥6 months (cut-off date January 16th 2019). Therapy was ongoing in 17 patients at doses 200 mg (n=4), 300 mg (n=9), 400 mg (n=3) and 600 mg (n=1) with median duration of exposure of 7,4 (range, 4,6-26), 9,2 (range, 7,4-26), 9,2 (range, 8,3-9,2) and 9,2 months. Other patients discontinued because of progression (n=18), adverse events (n=6), consent withdrawal (n=4), participation in another study (n=3) or other reasons (n=3). The MTD was 600 mg with the grade-3 psoriasis-like skin lesions the DLT, which occurred during the first 28 days of treatment. Reversible grade-3 skin toxicity occurred in 11 patients at doses ≥400 mg. There were no other drug-related non-hematologic grade-3 toxicities except 1 grade-3 toxic hepatitis at 400 mg and there were no detectable effects on ankle-brachial index or vascular occlusive events. The best safety/efficacy dose was 300 mg/d with 6 of 11 patients achieving a major cytogenetic response (MCyR) and 4 of them - a major molecular response (MMR). Higher doses were less effective probably because of toxicity-related therapy interruptions and discontinuations. Five of 12 patients with BCR-ABL1T315I responded, 3 of which achieved a complete hematologic response and 4 achieved MCyR. Conclusion: PF-114 was safe and effective in patients with CML failing ≥2 TKIs or with BCR-ABL1T315I. The most effective dose was 300 mg/d. Five of 12 patients with BCR-ABL1T315I responded. A pivotal study is beginning. Disclosures Turkina: Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Lomaia:Novartis: Other: Travel Grant;Lecture fee; Pfizer: Other: Travel Grant. Shukhov:Pfizer: Consultancy; Novartis: Consultancy. Chelysheva:Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shikhbabaeva:Novartis: Consultancy; Fusion Pharma: Consultancy. Shuvaev:Fusion Pharma: Consultancy; Novartis: Consultancy; Pfize: Honoraria; BMS: Consultancy. Cortes:Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Ottmann:Roche: Honoraria; Pfizer: Honoraria; Fusion Pharma: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Mikhailov:Fusion Pharma: Employment. Novikov:Fusion Pharma: Employment. Shulgina:Fusion Pharma: Employment. Chilov:Fusion Pharma: Consultancy.

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Efficacy of Nilotinib in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP).

Blood ◽

10.1182/blood.v114.22.341.341 ◽

2009 ◽

Vol 114 (22) ◽

pp. 341-341 ◽

Cited By ~ 3

Author(s):

Jorge Cortes ◽

Susan O'Brien ◽

Dan Jones ◽

Elias Jabbour ◽

Marina Konopleva ◽

...

Keyword(s):

Adverse Events ◽

Research Funding ◽

Philadelphia Chromosome ◽

Myelogenous Leukemia ◽

Hematologic Toxicity ◽

Molecular Response ◽

Newly Diagnosed ◽

Blast Phase ◽

Line Therapy ◽

Grade 3

Abstract Abstract 341 Background: Nilotinib, an oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl and approximately 30-fold more potent than imatinib, is effective in CML after imatinib failure. We initiated a phase II study to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP. Aims: To investigate the efficacy and safety of nilotinib as first-line therapy for pts with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP within 6 mo from diagnosis were eligible and received nilotinib 400 mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also included. Results: Sixty-five pts (61 CP, 4 AP) have been treated for a median of 17 mo (range 1 to 43). The median age was 46 years (range 19 to 86). Among 48 pts who were not in CHR at the start, 47 (98%) achieved CHR (one discontinued after 2 weeks without adverse events). Among 51 pts followed for at least 3 mo, 50 (98%) achieved a complete cytogenetic response (CCyR). MMR has been achieved in 32 (63%) pts, including 12 (24%) with a complete molecular response. The rate of CCyR at different time points (intention-to-treat) for pts in CP compares favorably to that observed in historical controls treated with imatinib 400 mg or 800 mg daily: MMR was achieved by 55% at 12 mo and 53% at 24 mo (corresponding rates with imatinib 400 mg 34 and 55%, and with imatinib 800 mg 58% and 66%, respectively). Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 11%, neutropenia 12%, and anemia 5%. Grade 3-4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and lipase in 6%, and non-neutropenic fever in 6%. 24 (37%) pts had transient treatment interruptions and 11 (17%) had dose reductions. The actual median dose is 800 mg daily. Ten pts have discontinued therapy: 4 pts for toxicity, 2 because of transformation to accelerated or blast phase, and 4 for other reasons. 24 mo EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 90%. All patients are alive. Among pts in AP, 3 achieved CCyR (all of them sustained); one patient progressed to blast phase and died. Conclusion: Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 mo after the start of therapy and MMR in more than 50% at 12 months with a favorable toxicity profile. Disclosures: Cortes: BMS: Research Funding; Novartis: Research Funding; Wyeth: Research Funding. Off Label Use: Presentation will include use of nilotinib as initial therapy for CML, and indication for which nilotinib is not approved.. O'Brien:Novartis: Research Funding. Jones:Novartis: Research Funding, Speakers Bureau. Jabbour:Novartis: Speakers Bureau; BMS: Speakers Bureau. Borthakur:Novartis: Speakers Bureau. Kantarjian:Novartis: Research Funding; MGI Pharma (Eisai): Research Funding; Genzyme: Research Funding; BMS: Research Funding.

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Phase 1b Study of Otlertuzumab (TRU-016), an Anti-CD37 ADAPTIRTM Protein, in Combination with Rituximab in Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v124.21.4671.4671 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4671-4671 ◽

Cited By ~ 2

Author(s):

Kami J. Maddocks ◽

John Pagel ◽

John C. Byrd ◽

Scott Stromatt ◽

Farrukh Awan

Keyword(s):

Adverse Events ◽

Inflammatory Response ◽

Product Development ◽

Research Funding ◽

Response Rate ◽

Systemic Inflammatory Response ◽

Coronary Syndrome ◽

Phase 1B ◽

Grade 3 ◽

Related Reaction

Abstract Background: CD37 is a tetraspanin protein expressed on the surface of normal and transformed B cells across a wide range of maturational stages that mediates death signaling via SHP1. Otlertuzumab is a CD37-specific therapeutic protein built on the ADAPTIRTM(modular protein technology) platform that has shown significantly greater direct killing of CLL cells than rituximab and higher levels of Fc-mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. This phase 1b trial was conducted to evaluate the safety and efficacy of otlertuzumab in combination with rituximab in patients with CLL. Methods: Eligibility included CLL patients with adequate organ function, ECOG ≤2, and absolute neutrophil count ≥800/μL. Three cohorts have been enrolled. In the 1st cohort, 24 patients previously untreated patients who were considered ineligible for standard chemotherapy based on age, comorbidity or patient preference (naive) were enrolled and received IV infusion of otlertuzumab weekly for two 28-day cycles then once a month for 4 months. The first dose was 10 mg/kg and all subsequent doses were 20 mg/kg. In the 2nd cohort, 16 relapsed patients who had received 1-3 prior therapies were treated on the same dose and schedule as the 1st cohort except the first dose was 6 mg/kg. In the 3rd cohort, 16 naive patients received 6 mg/kg on Day 1 and 10 mg/kg on Days 8 and 15 and then monthly for 5 months. In all cohorts, rituximab (375 mg/m2 the first dose then 500 mg/m2) was administered after otlertuzumab by on the same schedule. Safety was evaluated using CTCAE and IWCLL 2008 Grading scale for Hematologic Toxicity in CLL Studies. Response was determined using the 1996 NCI and the 2008 IWCLL Criteria. Results: Patient characteristics and adverse events are shown in the table. All but 9 patients completed all cycles of therapy: 3 discontinued early due to progressive disease; 3 due to lack of response, and 3 due to AEs (reaction to allopurinol, systemic inflammatory response, and rash). Grade 3/4 neutropenia was reported in 9% of patients; the incidence of severe infections was low (9%). Serious adverse events occurred in 61% of pts and included infusion related reaction (28 pts, 2 grade 3, 26 ≤grade 2), febrile neutropenia (4 patients), infection (2 pneumonia and 1 each sinusitis and diverticulitis), pyrexia (2 patients), and deep vein thrombosis, lymph node pain, grade 1 acute coronary syndrome, atrial fibrillation, small intestinal obstruction, systemic inflammatory response syndrome, and hyperkalemia in 1 pt each. For the 20 mg/kg previously untreated patients (n=24) IWCLL response rate is 54% (8% CR); 1 patient is not yet evaluable. NCI response rate is 96% (38% CR). Median progression-free survival is 16 months. In the other 2 cohorts, patients have been followed from 1 to 5 months after end of treatment and response results will be presented at the meeting. Conclusions: The preliminary response rate with otlertuzumab in combination with rituximab is promising. This study is ongoing. The results for cohort 2 and 3 will be updated. The fourth cohort is currently being treated with otlertuzumab in combination with obinutuzumab instead of rituximab. Tablel 1Basic characteristics, therapeutic efficacy and CTCAE grade III/IV toxicity. Baseline Characteristics NaiveRelapsed20 mg/kg (n=24)10 mg/kg (n=16)20 mg/kg (n=16)Age, median (range)65 (27-85)62 (48-88)63(47-74)Male, n (%)13 (54)10 (63)9 (56)Β2 Microglobulin, mg/dL, median (range)3.5 (2-6)2.9 (1-6)4..0 (2-10)CIRS ≤6, n (%)14 (58)10 (63)11 (69)Rai III/IV, n (%)5 (21)5 (31)11 (69)del17p, n (%)2 (8)1 (6)5 (31)del11q, n (%)7 (29)2 (13)2 (13)del13q, n (%)13 (54)5 (31)7 (44)Trisomy 12, n (%)9 (38)4 (25)0Adverse Events, %Any Event10094100Any Grade 3/4 Event462563Any Serious Event756338Nonhematologic Events in ≥10% of patients*Infusion-related reaction67*5619Any infection583125Nausea331325Diarrhea331331Headache17625Hypertension171913*Cough13196Pyrexia131913MyelosuppressionNeutropenia*13019Thrombocytopenia000Anemia4019 *All grade 1/2 except 2 patients with Grade 3/4 infusion related reaction, 1 with Grade 3/4 hypertension, and 5 with Grade 4 neutropenia Disclosures Off Label Use: Ibrutinib is approved for previously treated MCL but was used as first-line therapy in 2 patients in this report.. Byrd:Emergent Product Development: Research Funding. Stromatt:Emergent Product Development: Employment. Awan:Lymphoma Research Foundation: Research Funding; Boehringer Ingelheim: Consultancy.

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Brentuximab Vedotin (BV) Plus Rituximab (R) As Frontline Therapy for Patients (Pts) with Epstein Barr Virus (EBV)+ and/or CD30+ Lymphoma: Phase I Results of an Ongoing Phase I-II Study

Blood ◽

10.1182/blood.v124.21.3096.3096 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3096-3096 ◽

Cited By ~ 7

Author(s):

Mitul Gandhi ◽

Shuo Ma ◽

Sonali M. Smith ◽

Chadi Nabhan ◽

Andrew M. Evens ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Dose Reduction ◽

Research Funding ◽

Response Data ◽

Best Response ◽

History Of ◽

Frontline Therapy ◽

Grade 3

Background Although there is no standardized frontline therapy for pts with post transplant lymphoproliferative disorder (PTLD), aggressive induction with chemoimmunotherapy (CIT) is associated in this population with excess toxicity (Choquet, 2007). Recent data support a risk-stratified sequential therapy approach, in which pts receive single-agent R, with aggressive CIT reserved for those not achieving complete response (CR; Trappe, 2012). However, only about 25-30% of pts treated by this method are spared aggressive CIT. Furthermore, elderly pts (eg, EBV-related DLBCL of elderly) and those with autoimmune disorders are prone to lymphoma sharing clinicopathological characteristics with PTLD, such as EBV, CD30, and CD20 coexpression. BV is a novel antibody-drug conjugate that received accelerated FDA approval based on high response rates in pts with relapsed/refractory CD30+ lymphoma. We hypothesized that a combination of BV and R would yield higher response rates than R alone, would limit exposure to CIT, and its attendant toxicity, in these pts. Methods We initiated a Phase I-II trial of the combination of BV and R in adults with previously untreated CD20+ NHL, with co-expression of EBV and/or CD30 (all at any level). Pts with central nervous system involvement, HIV infection, and those lacking history of immunodeficiency, were excluded. Induction consisted of R 375 mg/m2 days 1, 8, 15 22, and BV 1.2 mg/kg, days 1, 8, and 15, followed by restaging. Those with progressive (PD) or stable disease (SD) were removed from protocol and treated per local investigator (CIT recommended). Pts with partial response (PR) or CR could receive a second identical induction, followed by maintenance therapy (MT), or move directly to MT without consolidation. MT consisted of BV 1.8 mg/kg every 3 weeks and R 375 mg/m2 every 6 weeks for up to one year of total therapy. A standard 3 + 3 design was employed for Phase I, with provisional dose reduction in BV to 0.8 mg/kg. Toxicity data was defined using CTCAE 4.0. Response (Cheson, 2007) was assessed, at the end of induction, consolidation (if given), and after cycles 4 and 7 of BV. The primary objective in the phase I portion was to evaluate the safety of the combination of BV and R and to determine the recommended phase II dose (RP2D) of the combination. Results Toxicity and response data are available on seven pts (six treated in Phase I). Four were female, and median age was 61. Five pts had PTLD, diagnosed between 2 and 26 years from transplant, and two had pre-existing autoimmune disease with histories of iatrogenic immunosuppression. Patient characteristics and response data are summarized in Table 1. Five patients (71%) had a CR as best response. At median follow up of 9 months, no pts had PD or had died. One pt with SD as best response achieved CR after CIT, and another with SD declined further therapy but had not progressed at last follow up. Both pts with EBV+ serum by PCR at baseline cleared the virus during therapy. The most frequent Grade 3/4 adverse events (AE) observed were lymphopenia and neutropenia. The most frequent AE of any grade were anemia, transaminitis, and lymphopenia (Table 2). A dose reduction was not required after treatment of the first cohort, but an expansion cohort was requested by the Data/Safety Monitoring Committee for an episode of hyperbilirubinemia (primarly indirect and attributed to blood transfusion). No dose reductions were required during phase I, and the starting dose was the RP2D. Conclusions The combination of BV and R has an acceptable safety profile, appears efficacious and capable of sparing pts exposure to CIT, and warrants further evaluation in patients with CD30+ and/or EBV+ lymphomas with the RP2D idenfitied above. TABLE 1 Characteristics & Outcomes Pt Histology Stage IPI EBV (Serum) CD30 (IHC) Response(Induction) Best Response(Induction or MT) 1 P 4 2 + + CR CR 2* M 1 0 - + PR CR 3 M 3 3 - + PR CR 4 HL 3 1 - + CR CR 5* TCL 1 2 + - SD SD 6 M 4 1 - + SD SD 7 M 3 3 - + CR CR P: Polymorphic; M- Monomorphic large B cell like; TCL- T cell lymphoma; HL- Hodgkin's Like Lymphoma * Immunosuppression Related Lymphoma without history of solid organ transplant TABLE 2 Adverse events occurring in 50% or more of patients (total n=7) Adverse Event Grade 1 & 2 (n) Grade 3 & 4 (n) Anemia 5 1 Abdominal Pain 4 0 Diarrhea 3 0 Nausea 3 0 Fatigue 4 0 Elevated AST 3 2 Hyperbilirubinemia 2 1 Lymphopenia 1 4 Neutropenia 1 3 Anorexia 3 0 Hypoalbuminemia 5 0 Peripheral neuropathy 2 2 Disclosures Nabhan: Celgene: Honoraria, Research Funding. Petrich:Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics : Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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Pralatrexate Is Active in Cutaneous T-Cell Lymphoma (CTCL): Results of a Multicenter, Dose-Finding Trial.

Blood ◽

10.1182/blood.v114.22.919.919 ◽

2009 ◽

Vol 114 (22) ◽

pp. 919-919

Author(s):

Steven M. Horwitz ◽

Madeleine Duvic ◽

Youn Kim ◽

Jasmine M Zain ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Dose Reduction ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Single Agent ◽

Optimal Dose ◽

T Cell Lymphoma ◽

Grade 3

Abstract Abstract 919 Background: Pralatrexate enters cancer cells via the reduced folate carrier-1 (RFC-1) and is efficiently polyglutamated by folylpolyglutamyl synthetase (FPGS), leading to high intracellular retention. In a Phase 1/2 study of patients with hematologic malignancies, pralatrexate demonstrated activity in aggressive T-cell lymphoma with a maximum tolerated dose (MTD) of 30 mg/m2 once weekly for 6 of 7 weeks. The generally indolent course of CTCL may be better treated at lower doses in a maintenance fashion if a lower incidence and severity of adverse events can be achieved while preserving activity. PDX-010 is an open-label, single-agent, multicenter, Phase 1 dose-reduction trial in patients with relapsed or refractory CTCL. The primary objective is to identify an optimal dose and schedule of pralatrexate for these patients. Methods: Eligibility included mycosis fungoides (MF), Sézary syndrome (SS), and primary cutaneous anaplastic large cell lymphoma (ALCL); with disease progression after at least 1 prior systemic therapy. The pralatrexate dose and schedule started at 30 mg/m2 by IV push on 3 of 4 weeks and subsequent cohorts received reduced doses (20, 15, 10 mg/m2) and/or schedules (3/4 or 2/3 weeks) of pralatrexate based on tolerability. All patients received supplementation with vitamin B12 1 mg intramuscularly every 8-10 weeks and folic acid 1 mg orally once daily. As we sought a well tolerated regimen the definition of DLTs to trigger dose reduction included toxicities such as grade ≥ 3 neutropenia, grade ≥ 2 thrombocytopenia, febrile neutropenia, grade ≥ 2 mucositis/stomatitis, and any toxicity leading to dose omission or reduction in cycle 1. If DLT occurred and a response was seen, the following cohort was opened at the next lower dose or next less frequent schedule. Response was evaluated by modified severity-weighted adjustment tool (SWAT) every 2 cycles for 6 months and then every 4 cycles. For patients with lymph node involvement, scans were completed at baseline and upon clinical response or end of treatment, whichever occurred first. Results: Thirty-one patients received pralatrexate, with 18 (58%) men and median age of 57 yrs (range, 30-81). Patients had received a median of 6 prior therapies (range, 1-25). Cohorts at the following doses/schedules were enrolled: 30 mg/m2 x 3/4 weeks (n=2), 20 mg/m2 x 3/4 weeks (n=3), 20 mg/m2 x 2/3 weeks (n=7), 15 mg/m2 x 3/4 weeks (n=6), 15 mg/m2 x 2/3 weeks (n=3), and 10 mg/m2 x 3/4 weeks (n=10). Patients received pralatrexate for a median of 72 days (range, 7-491+); 4 patients received >10 cycles of treatment. The most common treatment-related adverse events (all grades) were mucositis (18 patients [58%]), nausea (14 patients [45%]), fatigue (14 patients [45%]), pyrexia (7 patients [23%]), vomiting (6 patients [19%]), anemia (6 patients [19%]), and edema (5 patients [16%]). Grade 3-4 treatment-related toxicities in >1 patient each were mucositis (4 patients [13%]) and anemia (2 patients [6%]). Mucositis was dose limiting (≥ grade 2) in 8 patients (26%). A total of 11 responses were observed, including 2 complete responses and 9 partial responses. In the 18 patients who received pralatrexate at a dose intensity of 15 mg/m2 x 3/4 weeks or greater, the objective response rate was 56% (10/18 patients). This appeared to be the threshold dose for substantial activity in CTCL, below which the incidence of responses decreased in this dose de-escalation trial. Conclusion: Pralatrexate shows impressive activity in the treatment of relapsed CTCL. The optimal dose and schedule that provided activity with tolerability for CTCL was determined to be pralatrexate 15 mg/m2 weekly on 3 of 4 weeks. This cohort is being expanded to better assess efficacy and durability. Disclosures: Horwitz: Allos Therapeutics, Inc: Consultancy, Research Funding. Duvic:Allos Therapeutics, Inc.: Research Funding. Lechowicz:Allos Therapeutics, Inc.: Consultancy. Fruchtman:Allos Therapeutics, Inc.: Employment.

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ENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Blood ◽

10.1182/blood.v116.21.207.207 ◽

2010 ◽

Vol 116 (21) ◽

pp. 207-207 ◽

Cited By ~ 18

Author(s):

Timothy P. Hughes ◽

Andreas Hochhaus ◽

Giuseppe Saglio ◽

Dong-Wook Kim ◽

Saengsuree Jootar ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clonal Evolution ◽

Molecular Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Free Survival ◽

Superior Efficacy ◽

Rate Of Progression

Abstract Abstract 207 Background: Results from the phase 3, international, randomized ENESTnd trial have demonstrated the superior efficacy of nilotinib over imatinib with significantly higher rates of major molecular response (MMR), complete cytogenetic response (CCyR), and with significantly lower rates of progression to AP/BC on treatment. Here, we present data with a median follow-up of 18 months. Methods: 846 CML-CP patients were randomized to nilotinib 300 mg twice daily (bid) (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg once daily (n=283). Primary endpoint was MMR (≤ 0.1% BCR-ABLIS) rate “at” 12 months, as previously presented. Key secondary endpoint was durable MMR at 24 months. Other endpoints assessed at 24 months include progression to AP/BC (with and without clonal evolution), event-free survival, progression-free survival, and overall survival (OS). Results: With a median follow-up of 18 months, the overall best MMR rate was superior for nilotinib 300 mg bid (66%, P < .0001) and nilotinib 400 mg bid (62%, P < .0001) compared with imatinib (40%). Superior rates of MMR were observed in both nilotinib arms compared with the imatinib arm across all Sokal risk groups (Table). The overall best rate of BCR-ABLIS ≤ 0.0032% (equivalent to complete molecular response, CMR) was superior for nilotinib 300 mg bid (21%, P < .0001) and nilotinib 400 mg bid (17%, P < .0001) compared with imatinib (6%). The overall best CCyR rate was superior for nilotinib 300 mg bid (85%, P < .001) and nilotinib 400 mg bid (82%, P=.017) compared with imatinib (74%). The superior efficacy of nilotinib was further demonstrated using the 2009 European LeukemiaNet (ELN) 12-month milestone in which fewer patients had suboptimal response or treatment failure on nilotinib 300 mg bid (2%, 3%) and nilotinib 400 mg bid (2%, 2%) vs imatinib (11%, 8%). Rates of progression to AP/BC on treatment were significantly lower for nilotinib 300 mg bid (0.7%, P=.006) and nilotinib 400 mg bid (0.4%, P=.003) compared with imatinib (4.2%). The rate of progression on treatment was also significantly lower for nilotinib when including clonal evolution as a criteria for progression (Table). There were fewer CML-related deaths on nilotinib 300 mg bid (n=2), and 400 mg bid (n=1) vs imatinib (n=8). Estimated OS rate (including data from follow-up after discontinuation) at 18 months was higher for nilotinib 300 mg bid (98.5%, P=.28) and nilotinib 400 mg bid (99.3%, P=.03) vs imatinib (96.9%). Both drugs were well-tolerated. Discontinuations due to adverse events or laboratory abnormalities were lowest for nilotinib 300 mg bid (7%) compared with nilotinib 400 mg bid (12%) and imatinib (9%). With longer follow up there has been minimal change in the occurrence of AEs. Minimum 24-month follow-up data for all patients will be presented. Conclusions: With longer follow-up, nilotinib was associated with a significantly lower rate of progression to AP/BC on treatment and lower rates of suboptimal response or treatment failure vs imatinib. Nilotinib resulted in fewer CML-related deaths and a higher OS rate vs imatinib. Nilotinib induced superior rates of MMR, CMR, and CCyR vs imatinib in patients with newly diagnosed CML-CP. Taken together, these data support nilotinib as a new standard of care for patients with newly diagnosed CML. Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Meyers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Hochhaus:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. le Coutre:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Clark:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Honoraria, Research Funding. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp:Novartis Pharma AG: Employment. Haque:Novartis: Employment. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

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Occurrence, Management, and Outcomes In Patients with Pleural Effusion During Dasatinib Treatment for Chronic-Phase Chronic Myeloid Leukemia (CML-CP) In the First-Line Setting: Analysis of the DASISION Trial

Blood ◽

10.1182/blood.v116.21.2282.2282 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2282-2282 ◽

Cited By ~ 2

Author(s):

Kimmo Porkka ◽

Michele Baccarani ◽

Andreas Hochhaus ◽

Hagop Kantarjian ◽

Satu Mustjoki ◽

...

Keyword(s):

Pleural Effusion ◽

Research Funding ◽

Chronic Phase ◽

Risk Scores ◽

Molecular Response ◽

Newly Diagnosed ◽

Once Daily ◽

Management Interventions ◽

Grade 3

Abstract Abstract 2282 Background: The Phase 3 DASISION trial comparing dasatinib 100 mg once daily with imatinib 400 mg once daily as initial treatment in patients (pts) with newly diagnosed CML-CP has demonstrated superior efficacy and favorable safety of dasatinib after a minimum of 12 months of follow-up (Kantarjian, H, et al. N Engl J Med 2010;362:2260). While fluid retention was more frequent with imatinib than with dasatinib, pleural effusion was seen only with dasatinib. Here, we provide a detailed analysis of pts experiencing pleural effusion, a clinically relevant adverse drug reaction. Methods: 519 pts with newly diagnosed, treatment-naive CML-CP (median disease duration of 1 month) were randomly assigned to either dasatinib 100 mg once daily (259 pts) or imatinib 400 mg one daily (260 pts). Key endpoints included complete cytogenetic response (CCyR), major molecular response (MMR) and safety. All pts were assessed by chest x-ray at baseline and at 6 months after randomization, or more frequently, if indicated clinically. Pts with pleural effusion at baseline were excluded. Pleural effusion was graded according to CTCAE version 3 (grade 1, asymptomatic; grade 2, symptomatic, up to 2 therapeutic thoracenteses; grade 3, symptomatic requiring supplemental oxygen, < 2 therapeutic thoracenteses; grade 4, life-threatening, hemodynamic instability). Results: After a minimum follow-up of 12 months with median treatment duration of 14.3 months (range, 0.3–25.8), 26 (10%, median age, 60 years) of the 258 dasatinib-treated pts (median age, 46 years) experienced pleural effusion. Of the pts with pleural effusion, 6 (23%) had low, 17 (65%) had intermediate and 3 (12%) had high Hasford risk scores. There were no grade 3 or 4 pleural effusion events. All events were grade 1(2%) or grade 2 (8%). Most events (n = 22, 85%) occurred more than 8 weeks after the start of study drug. In pts who had a pleural effusion, the median time to the event was 28 weeks (range, 4–88). Lymphocytosis (defined as peripheral blood lymphocyte count > 3.6 × 109/L) was noted in 11 (42%) of the 26 pts with pleural effusion, as compared to 46 (20%) of 232 pts with no pleural effusion. Pleural effusion was managed by dose modification and/or medical intervention. Therapy was interrupted in 19 pts, and the dose of dasatinib was reduced in 8 pts (4 pts, to 80 mg; 1 pt, to 70 mg; 3 pts, to 50 mg). Twelve pts received diuretics, 7 received corticosteroids, and only 1 pt underwent therapeutic thoracentesis. Only 3 pts (1.2%) discontinued therapy due to pleural effusion (grade 2). Eleven pts who continued dasatinib had resolution of their pleural effusion. Five pts had recurrent effusions. Of the 26 pts with pleural effusion, 24 (92%) achieved a CCyR and 17 (65%) achieved a MMR by 12 months of treatment; the corresponding CCyR and MMR rates in the total pt population were 83% and 46%, respectively Seven of the 8 pts with pleural effusion who reduced their dose achieved CCyR and MMR. Conclusion: In pts with newly diagnosed CML-CP treated with dasatinib as initial therapy, pleural effusion was mild to moderate in severity, and was manageable with dose interruption and/reduction and/or a short course of diuretics and/or corticosteroids. The occurrence of pleural effusion and management interventions did not negatively affect the achievement of CCyR or MMR. These findings are in line with data reported previously for second-line dasatinib in CML pts resistant or intolerant to imatinib (Porkka, K, et al. Cancer 2010;116:377). Furthermore, pleural effusion and peripheral lymphocytosis may be indicative of immune-mediated antitumor activity of dasatinib. Disclosures: Porkka: BMS, Novartis: Consultancy, Honoraria, Research Funding. Baccarani: Novartis, Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Brostol-Myers Squibb, Novartis: Consultancy, Research Funding. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Mustjoki: BMS, Novartis: Honoraria. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Zhu: Bristol-Myers Squibb: Employment. Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria.

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