Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 182-182 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Gautam Borthakur ◽  
Dan Jones ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Treatment Schedule ◽  
Molecular Response ◽  
Significant Activity ◽  
Efficacy And Safety ◽  
Significant Difference ◽  
Grade 3

Abstract Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCRABL and SRC with significant activity in pts with CML-CP resistant to or intolerant of imatinib (IM). We initiated a phase II trial to study efficacy and safety of dasatinib in pts with previously untreated CML-CP. Aims: To investigate the efficacy and safety of dasatinib as initial therapy for patients 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 previously untreated CML-CP were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD). Results: Fifty pts have been enrolled (25 on the QD schedule, 25 BID). Median age was 45 years (yrs) (range 18–76 yrs); 75% are Sokal low risk. Median follow-up is 24 months (mo). Overall, 44/45 (98%) evaluable patients achieved complete cytogenetic response [CCyR]. The CCyR rate at 3, 6 and 12 mo compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily: Percent with CCyR (No. evaluable) Mo on therapy Dasatinib Imatinib 400mg Imatinib 800mg P value 3 78 (45) 37 (49) 62 (202) 0.0003 6 93 (41) 54 (48) 82 (199) <0.0001 12 97 (35) 65 (48) 86 (197) 0.0001 18 88 (33) 68 (38) 89 (179) 0.004 24 80 (25) 70 (40) 88 (173) 0.006 MMR was achieved in 12/35 (34%) at 12 mo and 12/25 (48%) at 18 mo. One of 46 (2%) evaluable pts have achieved confirmed complete molecular response, and 1 other unconfirmed (ie, only achieved on their last assessment). Grade 3–4 non-hematologic toxicity (regardless of causality) included pruritus (13%), fatigue (6%), neuropathy (4%), and memory impairment (4%). Pleural effusion occurred in 21% evaluable pts (grade 3–4 in 2%). Grade 3–4 hematologic toxicity (transient) was thrombocytopenia in 11%, neutropenia in 21%, and anemia in 9%. Twenty-seven (54%) pts required transient treatment interruption. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3–4 toxicity by treatment schedule. Four pts came off study: 1 pts choice after 1 dose, 1 for toxicity (pleural effusion, QD schedule), and 2 lost response after multiple treatment interruptions (1 myelosuppression, 1 pleural effusion, both BID schedule). Two other pts have lost response because of non-compliance. 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 81%. Conclusion: Rapid CCyR occurs in most patients with previously untreated CML-CP treated with dasatinib frontline therapy with a favorable toxicity profile. Accrual to this trial continues.

Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 338-338 ◽  
Author(s):  
Jorge Cortes ◽  
Gautam Borthakur ◽  
Susan O'Brien ◽  
Dan Jones ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Research Funding ◽  
Initial Therapy ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Significant Activity ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Grade 3

Abstract Abstract 338 Dasatinib, a potent inhibitor of ABL and SRC, is approximately 300 times more potent than imatinib in vitro and has significant activity in pts with CML-CP resistant or intolerant of imatinib (IM). We initiated a phase II trial to study efficacy and safety of dasatinib in pts with previously untreated CML-CP. Aims: To investigate the efficacy and safety of dasatinib as initial therapy for patients with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response at 12 months (mo). Pts with previously untreated CML-CP within 6 months from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD). Results: Sixty-two pts have been enrolled (31 on the QD schedule, 31 BID). Median age was 47 years (yrs) (range 18–76 yrs). Median follow-up is 24 months (mo) (range, 1 to 39 mo). All 45 pts who were not in CHR at the start of therapy achieved CHR. Among 50 pts followed for at least 3 months, 49 (98%) achieved complete cytogenetic response (CCyR). Major molecular response has been achieved in 35 (70%), including 5 (10%) with complete molecular response. The CCyR rate at different timepoints (intention-to-treat) compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily: Major molecular response was achieved by 45% by 12 mo and 71% by 24 mo (corresponding rates with imatinib 400mg 34% and 55%, and with imatinib 800mg 58% and 66%, respectively). There was a trend for higher MMR rate with the QD schedule: overall 75% vs 65% (p=0.54), and by 12 months 52% and 38% (p=0.54). Grade 3-4 non-hematologic toxicity (regardless of causality) included fatigue (6%), pain (muscle or joint) (6%), dyspnea, neuropathy and memory impairment (5% each). Pleural effusion occurred in 13% evaluable pts (grade 3-4 in 2%). Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 10%, neutropenia 21%, and anemia 6%. Thirty (48%) of 62 pts required transient treatment interruptions. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3-4 toxicity by treatment schedule but there was a trend for less pleural effusion with QD (3%) vs BID (10%; p=0.26). Three pts lost CCyR: 2 because of non-compliance, 1 due to treatment interruption because of pleural effusion. 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 88%. All patients are alive. Conclusion: Rapid CCyR occurs in nearly all patients with previously untreated CML-CP treated with frontline dasatinib therapy; the MMR rate at 18 months was 71%, with a favorable toxicity profile. Because of favorable trends in response and toxicity, only QD arm will continue accrual. Disclosures: Cortes: BMS: Research Funding; Novartis: Research Funding; Wyeth: Research Funding. Off Label Use: Presentation will include use of dasatinib as initial therapy for CML, and indication for which dasatinib is not approved.. Borthakur:BMS: Speakers Bureau. O'Brien:BMS: Research Funding. Jabbour:BMS: Speakers Bureau; Novartis: Speakers Bureau. Ravandi:BMS: Consultancy, Honoraria, Research Funding. Kantarjian:Genzyme: Research Funding; BMS: Research Funding; MGI Pharma (Eisai): Research Funding; Novartis: Research Funding.

Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 30-30 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Dan Jones ◽  
Charles Koller ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Treatment Schedule ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Once Daily ◽  
Significant Difference ◽  
Grade 3

Abstract Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity in pts with CML-CP who are resistant to or intolerant of imatinib (IM), we initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio ≤ 0.05% in our lab) at 12 months (mo). All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD) schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed. Results: Thirty-seven pts have been enrolled between November 2005 and June 2007 (19 on the QD schedule, 18 BID). Median age was 41 years (yrs) (range 18–76 yrs). Nine (24%) of the pts were Sokal intermediate-risk and 3 (8%) were high-risk. Median baseline WBC count was 29.1 x 109/L (range 3.4–300.0). Three pts had clonal evolution at start of therapy. At 3 mo, complete hematologic response (CHR) was achieved in all pts,major cytogenetic response occurred 31/33 (94%), and complete cytogenetic response (CCyR) in 26/33 (79%) evaluable pts. After 6 mo of therapy, 30/32 (94%) evaluable pts had achieved CCyR. This compares favorably with results obtained in historical controls with IM at standard (400 mg) and high-dose (800 mg) at our institution: At 12 mo, 8/25 (32%) evaluable pts had achieved a major molecular response. Responses are similar in both treatment schedule groups. The most common non-hematologic adverse events (AE) included fatigue (n=22), musculoskeletal pain (n=20), headache (n=19), and dizziness (n=14), and were predominantly grade (grade 1–2). Grade 3–4 non-hematologic toxicity (regardless of causality) included headache, pain, rash, neuropathy and memory impairment (1 each). Pleural effusion occurred in 5 (14%) pts (all grade 1–2). Grade 3–4 hematologic toxicity (transient) included neutropenia in 4 (11%) pts, thrombocytopenia in 4 (11) pts, and anemia in (5%). With a median duration of therapy of 10 mo, 18 (49%) pts required transient treatment interruption, 14 due to non-hematologic toxicities, 3 due to hematologic toxicities, and 1 due to both. Sixteen pts (43%) have required dose reductions. The actual median daily dose for all pts was 100 mg; it was 100 mg for pts treated on the QD schedule, and 90 mg for those in the BID schedule. There is no significant difference in grade 3–4 toxicity by treatment schedule. Conclusion: Rapid, complete cytogenetic responses to dasatinib 100 mg/day occur in a high percentage of patients with previously untreated CML-CP. Once daily dosing appears to be associated with less toxicity. Accrual to this trial continues. Percent with CCyR (No. evaluable) Months on Therapy Dasatinib Imatinib 400 mg Imatinib 800 mg P value 3mo 79 (33) 37 (49) 62 (202) 0.0003 6mo 94 (32) 54 (48) 82 (199) <0.0001 12mo 100 (24) 65 (48) 86 (197) 0.0001

Results of a Phase II Trial of Dasatinib As Frontline Therapy for Chronic Myeloid Leukemia (CML) In Chronic Phase (CP)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1700-1700 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Hagop M. Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Cytogenetic Response ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Significant Activity ◽  
Grade 3

Abstract Abstract 1700 Background: Dasatinib is approximately 300 times more potent than imatinib (IM) in vitro and has significant activity in patients (pts) with CML-CP resistant to or intolerant of IM. In 2005 we initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP. Objective: To determine the outcome of pts with CML-CP treated with front-line dasatinib. The primary endpoint was attainment of major molecular response (MMR) at 12 months (mos). Methods: Pts with previously untreated CML-CP within 6 mos from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg twice daily (BID) or 100 mg once daily (QD). After 66 pts were accrued, the BID arm was closed and all subsequent pts were treated with 100 mg QD. No prior therapy was allowed except for IM for no more than 1 month, or hydroxyurea. Results: From November 2005 to June 2011, 99 pts have been enrolled (66 on the QD schedule, 33 BID). For the purposes of this analysis, we considered all pts with clonal evolution at baseline (n=6) as accelerated phase and excluded them from the present analysis, therefore leaving 93 pts (62QD, 31 BID) for review. Median age was 48 years (yrs) (range 18–82); 56% were male. Median baseline counts: WBC 22.95 K/uL, PB blasts 0%, BM blasts 3%, BM basophils 2%, and platelets 315; 21 pts (23%) had brief prior exposure to IM. Sokal score by distribution: Low (81%), Intermediate (14%), High (5%). Median follow-up is 29 mos (3–67). Of the 80 evaluable pts who were not in CHR at the start of therapy, 79 (98%) achieved CHR. Of 87 evaluable pts (ie, followed for at least 3 mos), 83 (95%) achieved complete cytogenetic response (CCyR). MMR has been achieved in 75 pts (86%), including 54 pts (67%) with complete molecular response (CMR; ≤0.0032% IS). At 6 mos, 79 (94%) pts had achieved a CCyR and 56 (68%) an MMR; corresponding figures at 12 mos are 95% and 73%, respectively. Grade 3–4 non-hematologic toxicity included fatigue (9%), pain and dyspnea (6% each), memory impairment (5%), headache and sensory neuropathy (4% each), nausea, cardiac arrhythmia, and neurologic (3% each) and diarrhea, visual, and pleural effusion (2% each). Grade 3–4 hematologic toxicity (transient) included thrombocytopenia 13%, neutropenia 24%, and anemia 9%. Fifty-two (56%) of 93 pts required transient treatment interruptions and 36 (39%) have required dose reductions. The actual median daily dose for all pts was 100 mg (20–140). Thirteen pts lost CCyR: (including 3 because of non-compliance and 2 transient losses, regained spontaneously). The 24-mo probability of event-free survival (EFS) is 93%.There have been no transformations or deaths on study. Twelve (13%) pts have discontinued therapy: 3 pt's choice, 1 lost to follow up, 4 toxicity (2 pleural effusion, 1 congestive heart failure, 1 headaches), and 4 for loss of major cytogenetic response (MCyR). Three pts have had mutation assessment upon discontinuation and no mutations were identified. Conclusion: Rapid CCyR occurs in nearly all pts with previously untreated CML-CP treated with frontline dasatinib therapy with a favorable toxicity profile. None of the patients have transformed to AP/BP confirming the efficacy of dasatinib as initial therapy for CML-CP. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Jabbour:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Ravandi:BMS: Honoraria, Research Funding. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Efficacy of Dasatinib in Patients with Chronic-Phase Chronic Myelogenous Leukemia with Resistance or Intolerance to Imatinib: 2-Year Follow-Up Data from START-C (CA180-013).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 734-734 ◽  
Author(s):  
Richard M. Stone ◽  
Hagop M. Kantarjian ◽  
Michele Baccarani ◽  
Jeffrey H. Lipton ◽  
Timothy Hughes ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Dasatinib (SPRYCEL®) is 325-fold more potent than imatinib against BCR-ABL in vitro and binds to BCR-ABL in both the inactive and active, oncogenic conformations. Dasatinib has been shown to be an effective treatment option for patients with imatinib-resistant or -intolerant chronic-phase chronic myelogenous leukemia (CP-CML). Here we report the extended follow-up of START-C, a 75-center, international study of dasatinib in 387 patients with CP-CML with resistance (n=288) or intolerance (n=99) to imatinib. Recruitment took place from February to July 2005. Dasatinib was administered on a 70-mg BID regimen; dose escalation (90 mg BID) or reduction (50 or 40 mg BID) were allowed for lack of response or toxicity, respectively. Median time from diagnosis of CML was 61 mo (range 32–50). Prior therapy included interferon-α in 65% of patients and stem-cell transplantation in 10%; 55% had received prior imatinib doses >600 mg and 53% treatment with imatinib for >3 years. Best response to prior imatinib therapy was complete hematologic response (CHR) in 82%, and complete (CCyR) and partial cytogenetic response (PCyR) in 19% and 18%, respectively. With a median follow-up of 15.2 mo, CHR was attained in 91% of patients (95% CI 87–93%), major cytogenetic response (MCyR) in 59% (95% CI 54–64%) (52% imatinib-resistant, 80% imatinib-intolerant), and CCyR in 49% (40% imatinib-resistant; 75% imatinib-intolerant). For patients with no prior MCyR to imatinib, 42% achieved a MCyR with dasatinib. A MCyR rate of 59% was recorded for patients with baseline BCR-ABL mutations; responses were seen across all mutations with the exception of T315I. MCyRs were durable, with only 7 of the 230 patients who had achieved a MCyR with dasatinib losing this response. Major molecular response rate (ie, a BCR-ABL/ABL ratio of <0.1% according to the international scale by RQ-PCR) at 12 mo was 25%. Progression-free survival at 15 mo was 90% while overall survival was 96%. Dose interruptions were required for 87% of patients and dose reduction for 73%; the average daily dose administered was 101 mg (range 11–171). Reports of grade 3–4 thrombocytopenia and neutropenia were documented for 48% and 49% of patients, respectively. Non-hematologic toxicity consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), and dyspnea (30%). Pleural effusion was experienced by 27% of patients; this was categorised as grade 1–2 in 21% and grade 3–4 in 6%. Dasatinib-induced cytogenetic responses remain durable in patients with CP-CML resistant or intolerant to imatinib. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.

Efficacy of Nilotinib (formerly AMN107) in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 446-446 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Dan Jones ◽  
Alessandra Ferrajoli ◽  
Marina Konopleva ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
P Value ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Treatment Interruptions ◽  
Grade 3

Abstract Background: Nilotinib is an oral tyrosine kinase inhibitor with high selectivity towards Bcr-Abl and approximately 30-fold more potent than imatinib, and is effective in patients with 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 initial therapy for patients 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 (or with &lt;1 months of therapy with imatinib) were eligible and received nilotinib 400mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also included. Results: Forty-nine pts have been treated for a median of 13 months (mo). The median age was 47 years (yrs) (range, 21 to 81); 69% are Sokal low risk. Eight (16%) had received imatinib for &lt;1 months. Overall, 46/48 (96%) of evaluable CP pts achieved a complete cytogenetic response [CCyR]. The rate of CCyR at 3, 6 and 12 mo for pts in CP compares favorably to those observed in historical controls treated with imatinib 400mg or 800 mg daily: Percent with CCyR (No. evaluable) Months on therapy Nilotinib Imatinib 400mg Imatinib 800mg P value 3 93 (45) 37 (49) 62 (202) &lt; 0.0001 6 100 (36) 54 (48) 82 (199) &lt; 0.0001 12 96 (27) 65 (48) 86 (197) 0.0003 18 92 (12) 68 (38) 89 (179) 0.0042 24 91 (11) 70 (40) 88 (173) 0.0151 MMR was observed in 45% at 6 mo and 52% at 12 mo. Two of 44 (5%) evaluable pts have achieved confirmed complete molecular response, and 3 others unconfirmed (ie, only achieved on their last assessment). Grade 3–4 hematologic toxicity (transient) included thrombocytopenia in 10%, neutropenia in 12%, and anemia in 2%. Grade 3–4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and lipase in 6%. 19 (36%) pts had transient treatment interruptions and 17 (32%) had dose reductions. The actual median dose is 800mg daily. Three pts have come off study: 1 pt’s choice and 2 because of toxicity (1 liver, 1 pericardial effusion). One of them (liver toxicity) transformed to blast phase shortly after coming off study. Estimated 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 95%. Conclusion: Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile. Accrual is ongoing.

Efficacy and Safety of Bosutinib (SKI-606) among Patients with Chronic Phase Ph+ Chronic Myelogenous Leukemia (CML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 733-733 ◽  
Author(s):  
J. Cortes ◽  
T. Bruemmendorf ◽  
H. Kantarjian ◽  
J. Khoury ◽  
G. Rosti ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Phase Ii ◽  
Inhibitory Activity ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Pleural Effusions ◽  
Imatinib Resistant

Abstract Bosutinib (SKI-606), an orally bioavailable dual Src/Abl inhibitor, shows inhibitory activity against Bcr-Abl 200 times more potent than imatinib, but has minimal inhibitory activity against platelet-derived growth factor receptor (PDGFR) or c-kit. In addition, it inhibits a wide variety of Bcr-Abl kinase domain mutants, except T315I. A phase I study in CML identified the phase II dose as 500 mg daily and showed evidence of clinical efficacy. We thus initiated the phase II portion of the study to investigate efficacy and safety of bosutinib in patients (pts) with chronic phase Ph+ CML who had failed imatinib therapy. We report preliminary data for 98 pts, median duration of treatment 5.1 mos (range 0.03–16.7 mos). Median age 56 yrs (range 18–86 yrs), 48% male. Prior therapy included interferon (40 pts), imatinib (98 pts), dasatinib (13 pts), nilotinib (4 pts), stem cell transplant (6 pts). Among pts who failed imatinib (with no other tyrosine kinase inhibitor), 57 were imatinib resistant, 21 pts were intolerant. Of 23 resistant pts evaluable for hematological response, 17 (74%) had complete hematological response (CHR). Of 36 evaluable imatinib-resistant pts, 15 (42%) achieved major cytogenetic response (MCyR) including 12 (33%) with complete cytogenetic response (CCyR). Among imatinib intolerant pts, 4 (57%) achieved MCyR and 3 (43%) CCyR; 5/6 (83%) pts evaluable for hematologic response achieved CHR. Among 8 pts who had previously received nilotinib or dasatinib, 3 (38%) achieved CHR, 2 (25%) MCyR. Among imatinib-resistant pts, median time to MCyR was 47.3 wks. Of 40 imatinib-resistant pts evaluable for molecular response, 13 (33%) achieved major molecular response, 6 (15%) of which were complete. Of 72 pts with samples tested for mutations, 19 different mutations were found in 27 pts (38%). CHR occurred in 4/5 pts with P-loop mutations and 14/17 with non-P-loop mutations; MCyR occurred in 1/4 pts and 8/19 pts, respectively. Treatment was generally well tolerated. Gr 3–4 hematologic laboratory abnormalities included thrombocytopenia in 9 pts (9%), neutropenia in 8 pts (8%), anemia in 1 pt (1%). The most common adverse events were gastrointestinal (nausea, vomiting, diarrhea) but these were usually gr 1–2, manageable and transient, reducing in frequency and severity after the first 3–4 wks of therapy. Gr 3–4 non-hematologic toxicity occurring in >5% of pts were diarrhea (n=6, 6%), increased ALT (n=6, 6%), rash (n=9, 9%). In most instances these events resolved with medical management and dose reduction allowing for continuation of therapy. 10 pts reported grade 1/2 edema. 1 pt had both pleural and pericardial effusions and 1 had pleural effusion, all gr 1/2 and considered unrelated to treatment. A single pt had gr 3 possibly related pleural effusion with concomitant pneumonia and pre-treatment history of recurrent pleural effusions. We conclude that bosutinib is effective in imatinib-resistant pts with chronic CML across a range of mutations and after the failure of other TKIs. The relative specificity without significant c-kit or PDGFR inhibition distinguishes bosutinib from other TKIs and may be responsible for the relatively favorable toxicity profile with only a small numbers of pts experiencing hematologic toxicity or pleural effusions/edema.

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 ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2282-2282 ◽  
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.

High-dose imatinib mesylate treatment in patients (Pts) with untreated early chronic phase (CP) chronic myeloid leukemia (CML): 2.5-year follow-up

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6535-6535 ◽  
Author(s):  
E. Aoki ◽  
H. Kantarjian ◽  
S. O’Brien ◽  
M. Talpaz ◽  
F. Giles ◽  
...  
Keyword(s):  
Standard Dose ◽  
Chronic Phase ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Molecular Responses ◽  
Pre Treatment ◽  
Grade 3

6535 Background: The standard dose (SD) of imatinib for CP CML is currently 400 mg daily, but higher doses (HD) may be more effective. We conducted 2 consecutive trials using HD imatinib (i.e., 400mg twice daily) in previously untreated early CP CML pts. This is an updated analysis of the longer follow-up. Methods: A total of 175 previously untreated pts received HD imatinib. We compared the results with a previous study using SD imatinib (400mg/day) in untreated pts with early CP CML (N=50). Results: Cytogenetic and molecular responses were evaluable in 222 pts (N=49 at SD, 173 at HD) and 217 pts (N=46 at SD, 171 at HD), respectively. In HD group, Sokal risk classification was good in 69%, intermediate in 29%, and poor in 11% of pts. There were no differences in pre-treatment characteristics between two groups. The median age was 48 years in both groups. Median follow-up is 53 months for SD and 30 months for HD group. Patients treated with HD had a higher rate of complete cytogenetic responses (90% vs 78% with SD, p=0.03) and these occurred earlier, with 69% achieving this response after 6 months of therapy vs 45% with SD (p=0.001). The cumulative incidence of major molecular response was significantly better in HD group (p=0.03), and this response was also observed earlier in HD group: at 12 months 54% in HD and 24% in SD group had achieved this response (p=0.001). At 24 months, 19/70 (27%) evaluable pts with HD versus 3/31 (10%) of pts in SD group achieved complete molecular remission. Four pts (2%) in HD group and 4 pts (8%) in SD group have progressed to advanced phases (p=0.05). There was a trend in favor of the HD group for transformation-free-survival but it was not statistically significant (p=0.07). Overall survival is excellent in both groups (24 month survival, 99% with HD vs 98% with SD; p=0.24). Grade 3 or 4 hematologic toxicity was more frequent in HD group whereas extramedullary toxicity was similar in two groups. The median actual dose in HD group was 800 mg at 12 months, with 39% patients requiring dose reduction at some point. Conclusions: High-dose imatinib provides higher rates of complete cytogenetic responses and earlier molecular responses with some increase myelosupression. The long-term benefit of earlier responses remains to be demonstrated. [Table: see text]

scholarly journals The Comparison of Dasatinib 70 Mg/Day to 100 Mg/Day in Newly Diagnosed Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): A Multicenter, Prospective, Randomized Controlled Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3615-3615
Author(s):  
Dan Yu ◽  
Zhuangzhi Yang ◽  
Hui Cheng ◽  
Rui Jiang ◽  
Jingming Guo ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Chronic Phase ◽  
Controlled Study ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Best Response ◽  
Significant Difference

Abstract Background: The purpose of this study is to compare efficacy and safety of patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline dasatinib 70 mg/day with those who received standard-dose dasatinib 100 mg/day. Method: From July 2019 to July 2021, 81 patients with newly diagnosed CML-CP were enrolled across 11 centers. All of the patients were randomly treated with dasatinib 70 mg/day (N=43) or standard-dose dasatinib 100 mg/day (N=38). Results: Among 81 enrolled patients, 16 patients were off study at different times for different reasons.All patients achieved hematological remission after 3 months of treatment, and the best response rates were 84.00% (21/25) and 88.89% (24/27) for 70mg/d and 100mg/d groups (P&gt;0.05).At 6 months, the best response, complete cytogenetic response (CCyR) and major molecular response (MMR) rate were 94.44% vs 92.86% (P &gt; 0.05), 94.44% vs 92.86% (P &gt; 0.05) and 55.56% vs 71.43% (P &gt; 0.05), respectively.At 9 months, the rates of CCyR and MMR were 90.91% vs 88.89% (P &gt; 0.05) and 66.67% vs 72.73% (P &gt; 0.05);CCyR and MMR by 12 months, respectively, were 90.91% vs 100.00% (P &gt; 0.05), 81.82% vs 80.00% (P &gt; 0.05).The adverse events (AEs) of the two groups were mild, and there was no significant difference (P &gt; 0.05).The most common grade ≥3 hematological AEs in 70 mg/d group were leukopenia (1/43), neutropenia (1/43) and anemia (2/43), and In 100mg/d group were leukopenia (4/38), neutropenia (6/38), anemia (3/38) and thrombocytopenia (3/38). Conclusions: Our study suggests that patients with newly diagnosed CML-CP treated with dasatinib 70 mg/day or 100 mg/day, there is no significant difference in efficacy and safety. Decreasing the dose of dasatinib can ensure the efficacy of patients, while reducing the economic burden of patients and increasing patient compliance. Disclosures No relevant conflicts of interest to declare.

scholarly journals Discontinuation of Dasatinib after Deep Molecular Response for over 2 Years in Patients with Chronic Myelogenous Leukemia and the Unique Profiles of Lymphocyte Subsets for Successful Discontinuation: A Prospective, Multicenter Japanese Trial (D-STOP Trial)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 791-791 ◽  
Author(s):  
Takashi Kumagai ◽  
Chiaki Nakaseko ◽  
Kaichi Nishiwaki ◽  
Chikashi Yoshida ◽  
Kazuteru Ohashi ◽  
...  
Keyword(s):  
Research Funding ◽  
Lymphocyte Subsets ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Consolidation Therapy ◽  
Cd8 Cells ◽  
Stop Trial ◽  
Significant Difference ◽  
Group B

Abstract Introduction The tyrosine kinase inhibitor (TKI), imatinib, dramatically improves the prognosis of chronic myelogenous leukemia (CML) by suppressing the function of BCR-ABL gene. It was shown that imatinib could be discontinued in a proportion of patients with CML who maintained deep molecular response (DMR) for at least 2 years. (Lancet Oncol. 2010; 11:p1029) Treatment with second generation TKI, dasatinib, after imatinib resistance/intolerance could also be discontinued after maintaining DMR for over 1 year in a proportion of patients with CML (Lancet Haematol. 2015; 2:p528). In this Japanese prospective multicenter trial (D-STOP trial by Shimousa Hematology and Kanto CML Study Groups, ClinicalTrials.gov Identifier: NCT01627132), we aimed to discontinue dasatinib in patients with CML who maintained DMR for over 2 years. Methods: Chronic phase CML patients treated with TKIs who had undetectable BCR-ABL1 mRNA were enrolled. After confirmation of undetectable BCR-ABL1 mRNA (International Scale <0.01%) using real-time quantitative polymerase chain reaction (RQ-PCR) in the central laboratory, the patient received additional dasatinib treatment for another 2 years as consolidation therapy. Patients who maintained DMR during the consolidation therapy proceeded to discontinue dasatinib. BCR-ABL1 mRNA was monitored every month in year 1 and every 3 months in year 2. Molecular relapse was defined as two successive positive RQ-PCRs for BCR-ABL1 within 1 month. The relapsed patients restarted dasatinib. The primary endpoint was treatment-free survival after 12 months of discontinuation. Lymphocyte subsets were analyzed using flow cytometry during and after the consolidation therapy. Results: Sixty-five patients received consolidation therapy, and 54 discontinued dasatinib treatment after maintenance of DMR for 2 years. Mean age of the patients was 54.2 (25-82) years, and median follow-up period after cessation of dasatinib was 16.2 (7-30) months. Twenty patients relapsed during the observation period. Using Kaplan-Meier analysis, the estimated overall treatment-free survival (TFS) was 62.9% (48.5-74.2) at 12 months (Fig.1). Most relapses occurred within 6 months after discontinuation of dasatinib. All relapsed patients responded again to dasatinib. There was no significant difference either in estimated TFS between males and females or Sokal scores at diagnosis. During the consolidation therapy, the proportion (%) of CD4+CD8−, CD3−CD56+, CD16+CD56+, and CD57+CD56+ cells among total lymphocytes were monitored using flow cytometry in patients who could discontinue dasatinib during the observation periods (group A) and those who relapsed (group B). At the start of the consolidation therapy, there was no significant difference between groups A and B (CD4+CD8−%: 33.6 vs 34.0, p = 0.89, CD3−CD56+%: 24.3 vs 24.1, p = 0.95; CD16+CD56+%: 22.1 vs 23.9, p = 0.57; CD57+CD56+%: 19.7 vs 21.8, p = 0.51, respectively). In group B, the proportion of CD4+CD8− cells gradually decreased, whereas CD3−CD56+, CD16+CD56+, and CD57+CD56+ cells gradually increased during the consolidation therapy. All four types of cells were relatively stable in group A. At the end of the consolidation therapy, there was a significant group difference in the proportion of these subsets (CD4+CD8−%: 29.6 vs 22.2, p = 0.018*; CD3−CD56+%: 25.9 vs 37.3, p < 0.01*; CD16+CD56+%: 23.2 vs 34.4, p < 0.01*; CD57+CD56+%: 21.9 vs 32.1, p < 0.001*; respectively). We concluded that patients with CD4+CD8− cells ≥23.1%, CD3−CD56+ cells ≤40.1%, CD16+CD56+ ≤35.6% or CD57+CD56+ ≤26.6% at the end of the consolidation therapy had significantly higher estimated overall TFS at 12 months than those without each condition (CD4+CD8−%: 84% vs 32%, p < 0.0001* (Fig.2); CD3−CD56+%: 77% vs 25%, p < 0.001* (Fig.3), CD16+CD56+%: 77% vs 25%, p < 0.0001*; CD57+CD56+%; 84% vs 46%, p < 0.01*, respectively). Although increased large granular lymphocytes and NK cells were reported to be associated with high responses to dasatinib (Int J Hematol. 2014; 99:p41), the unique profiles of lymphocyte subsets could predict successful discontinuation of dasatinib. Conclusion: Discontinuation of TKI in patients with chronic phase CML after consolidation therapy with dasatinib for 2 years was feasible with relatively high TFS. The unique profile of lymphocyte subsets might be able to predict successful discontinuation. Disclosures Kumagai: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Nakaseko:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding. Nishiwaki:Novartis: Research Funding. Yoshida:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Morita:Bristol-Myers Squibb: Speakers Bureau. Sakamoto:Takeda Pharmaceutical: Consultancy; Yakult: Other: Remuneration. Inokuchi:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

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