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.

Dasatinib in patients with chronic phase chronic myeloid leukemia (CP-CML) who are resistant or intolerant to imatinib: Results of the CA180013 ’START-C’ Study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6508-6508 ◽  
Author(s):  
A. Hochhaus ◽  
H. Kantarjian ◽  
M. Baccarani ◽  
F. Cervantes ◽  
T. Facon ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Response Analysis ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Imatinib Resistant ◽  
Grade 3 ◽  
Dose Reductions

6508 Background: Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases with proven preclinical and clinical activity against imatinib resistant BCR-ABL mutations. Methods: CA180013 is an open-label Phase II study of dasatinib in imatinib-resistant (IM-R) or -intolerant (IM-I) patients (pts) with CP-CML. Between February-August 2005, 424 pts were recruited from 75 centers worldwide. Dasatinib was given at 70 mg twice daily (BID) with dose escalation to 90 mg BID in pts lacking response, and dose reductions to 50 and 40 mg BID for toxicity. Evaluations were weekly blood counts for the first 12 weeks; bone marrow cytology and cytogenetics every 3 months. The primary endpoint was rate of major cytogenetic response (MCyR; ≤35% Philadelphia pos. metaphases) in IM-R pts. Results: Data are currently available from the first 186 pts (127 IM-R, 59 IM-I) accrued prior to May 12, 2005. Median age was 59 yrs (range 24–79); 46% were male. Median time from diagnosis of CML was 64 months. Of the IM-R pts, 72% received IM >3 yrs, and 72% had >600 mg/day of IM. Overall, 70% had received prior interferon alpha. 62 (33%) pts achieved a prior MCyR to IM. With ≥6 months of follow up, 168 (90%) pts had a complete hematologic response (CHR). MCyR were achieved in 83 (45%) pts including 40 (31%) of IM-R pts, and 43 (73%) of IM-I pts. Mutations in the BCR-ABL domain were found in 65/176 (37%) pts; 57 (88%) achieved CHR, and 24 (37%) MCyR. Molecular response analysis is ongoing. 160 (86%) pts remain on study without progression. Grade 3/4 neutropenia or thrombocytopenia was reported in 83 (45%) pts and 85 (46%) pts with onset after 4–8 weeks of therapy in most pts. Temporary dose interruptions occurred in 146 (78%), and dose reductions in 96 (52%) pts with a median daily of 108 (range 19–169) mg. Non-hematologic toxicity consisted mainly of Grade 1/2 diarrhea, headache, superficial edema, and pleural effusion, with ≤2% Grade 3/4. There was no cross-intolerance between dasatinib and IM. Conclusions: Dasatinib demonstrated substantial hematologic and cytogenetic activity in IM-R and IM-I pts with CP-CML. An updated analysis of 424 pts with ≥6 months of follow up will be presented. [Table: see text]

Efficacy of Dasatinib in Patients with Accelerated-Phase Chronic Myelogenous Leukemia with Resistance or Intolerance to Imatinib: 2-Year Follow-Up Data from START-A (CA180-005).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 470-470 ◽  
Author(s):  
Francois Guilhot ◽  
Jane F. Apperley ◽  
Dong-Wook Kim ◽  
Gianantonio Rosti ◽  
Xiaobin Yuan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Chronic Myelogenous Leukemia ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Imatinib Therapy ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Dasatinib (SPRYCEL®), a potent inhibitor of BCR-ABL and SRC-family kinases, has been shown to be effective and safe for patients with accelerated-phase chronic myelogenous leukemia (AP-CML) who are resistant or intolerant to imatinib. START-A is a 39-center, international study to which patients with AP-CML who failed prior imatinib therapy were enrolled between December 2004 and July 2005. Here we report an update of the efficacy and safety of dasatinib (70 mg BID) from this open-label study of 174 patients with imatinib-resistant (n=161) or -intolerant (n=13) AP-CML after a median follow-up of 14.1 mo (range 0.1–21.7). Dose escalation (100 mg BID) or reduction (50 or 40 mg BID) were allowed for a lack of response or toxicity, respectively. Median time from original diagnosis of CML was 82 mo (range 4–359). Prior therapy included interferon-α in 72% of patients and stem-cell transplantation (SCT) in 13%; 52% had received prior imatinib doses >600 mg/d and 59% treatment with imatinib for >3 years. Best response to prior imatinib therapy was complete hematologic response (CHR) in 79% of patients, major cytogenetic response (MCyR) in 33%, and complete cytogenetic response (CCyR) in 21%. CHRs were attained by 45% of patients, while MCyRs and CCyRs were seen in 39% and 32%, respectively. Responses were achieved irrespective of imatinib status (with MCyR of 39% for both imatinib-resistant and -intolerant subgroups), prior stem-cell transplantation (26% MCyR), or the presence of prior BCR-ABL mutations (with the exception of T315I) (40% MCyR for both the mutation-positive and -negative subgroups). Twelve-month progression-free survival and overall survival were 66% and 82%, respectively. Dose interruptions were required for 85% of patients and dose reduction for 65%; the average daily dose administered was 126 mg (range 32–196). Grade 3–4 neutropenia and thrombocytopenia were reported in 76% and 82% of patients. Non-hematologic toxicity was generally mild to moderate and consisted primarily of diarrhea (52% all grades, 8% grade 3–4), headache (29%, <1%), nausea (28%, <1%), pleural effusion (27%, 5%), fatigue (26%, 4%), and superficial edema (22%, 1%). Dasatinib is effective in patients with AP-CML following imatinib treatment failure and the overall benefit-risk evaluation is favorable in this poor prognosis population. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.

Treatment of Philadelphia Chromosome-Positive Early Chronic Phase Chronic Myelogenous Leukemia With Daily Doses of Interferon Alpha and Low-Dose Cytarabine

1999 ◽  
Vol 17 (1) ◽  
pp. 284-284 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Terry L. Smith ◽  
Mary Beth Rios ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Interferon Alpha ◽  
Low Dose ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Grade 3 ◽  
Low Dose Cytarabine

PURPOSE: To evaluate the efficacy of the combination of interferon alpha (IFN-α) and daily low-dose cytarabine (ara-C) in the treatment of patients with early chronic-phase chronic myelogenous leukemia (CML) (within 1 year of diagnosis). Improving the degree of hematologic and cytogenetic response in patients with Philadelphia chromosome (Ph)-positive CML may improve prognosis. Both IFN-α and ara-C induce cytogenetic responses as single-agent therapy in CML. PATIENTS AND METHODS: One hundred forty patients with Ph-positive early chronic-phase CML received subcutaneous injections of IFN-α 5 megaunits/m2 daily and ara-C 10 mg daily. Their median age was 46 years; 53% had good-risk disease, 33% had intermediate-risk disease, and 14% had poor-risk disease. Their results were compared with those of patients receiving IFN-α with or without intermittent ara-C (7 days/mo). RESULTS: A complete hematologic response (CHR) was achieved in 92% of patients. A cytogenetic response was seen in 74%: it was major in 50% (Ph-positive < 35%) and complete in 31% (Ph-positive 0%). With a median follow-up of 42 months, the 4-year estimated survival rate was 70% (95% confidence interval, 61% to 79%). Significant side effects included fatigue (43%; grade 3/4, 11%), weight loss (19%; grade 3/4, 11%), muscle and bone aches (20%; grade 3/4, 7%), oral ulcers (4%), diarrhea (6%), and neurologic changes (27%, grade 3/4, 6%). The median dose of IFN-α was 3.7 megaunits/m2 daily, mainly because of reductions for myelosuppression (70% of cases); the median ara-C dose was 7.5 mg daily. Prognostic risk groups were predictive for response to the IFN-α plus ara-C combination. The incidence of CHR was higher with IFN-α plus daily ara-C compared with IFN-α plus intermittent ara-C and IFN-α alone (no ara-C) (92% v 84% v 80%, P = .01), as were the incidences of cytogenetic response (74% v 73% v 58%; P = .003) and major cytogenetic response (50% v 38% v 38%; P = .06). The median time to achievement of major cytogenetic response was significantly shorter than that for previous IFN-α regimens (7 v 10 v 12 months; P < .01). However, with the present follow-up, the survival and time to blastic transformation were similar. CONCLUSION: The combination of IFN-α plus daily low-dose ara-C seems to be promising for the treatment of CML. High rates of CHR and cytogenetic response were observed with acceptable toxicity and a lower daily dose of IFN-α compared with our previous studies.

Dasatinib (SPRYCEL®) vs Escalated Dose of Imatinib (im) in Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Resistant to Imatinib: Results of the CA180-017 START-R Randomized Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 167-167 ◽  
Author(s):  
Neil Shah ◽  
R. Pasquini ◽  
P. Rousselot ◽  
S. Jootar ◽  
J. Holowiecki ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Dose Escalation ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Inadequate Response ◽  
Grade 3

Abstract Pts with CML resistant to im have few therapeutic options. A growing body of evidence suggests that treatment outcomes can be improved with increased potency of BCR-ABL inhibition. Escalating the dose of im to 800mg/day (d) can overcome some cases of im-resistance, but tolerability and durability of response are significant issues. Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL, SRC, and other kinases that is approximately 300 times more potent than im in vitro. Dasatinib has been shown to be effective and safe in pts with CML resistant or intolerant to im, leading to recent FDA approval. START-R is an international trial of dasatinib 70mg twice daily (BID) and im 800mg/d in pts with CP-CML resistant to prior im 400–600mg/d. Crossover was allowed upon confirmed progression or intolerance despite dose reduction (grade 3/4 non-hematologic toxicity). Dasatinib dose escalation to 90mg BID was allowed for inadequate response at 12 wks, and dose reduction to 50 or 40mg BID for toxicity. Dose reduction of im to 600mg/d was allowed for patients who had not previously received that dose. Major cytogenetic response (MCyR) rate at 12 weeks was the primary endpoint. From Feb–Nov 2005, 150 pts were randomized (2:1), 101 to dasatinib, 49 to im. MCyR to prior im had been seen in 28% of dasatinib and 29% of im pts. With a minimum follow-up of 10 mo, complete hematologic response (CHR) rate was 92% (93 dasatinib pts) vs 82% (40 im pts), and MCyR rate was 48% dasatinib vs 33% im. Of importance, the primary difference was the complete cytogenetic response (CCyR) rate of 35% (35/101) dasatinib vs 16% (8/49) im, suggesting that dasatinib can achieve deeper responses in this patient population. Of pts with no prior CyR to im, 44% (17/39) achieved a MCyR with dasatinib vs 7% (1/15) with higher dose im. MCyR rates of 40% to dasatinib and 20% to im were achieved in pts with baseline im-resistant BCR-ABL mutations, with 47% of dasatinib pts vs 0 im pts with difficult-to-treat P-loop mutations achieving a MCyR. Pts with no prior CyR to im were able to achieve MCyR with dasatinib, but dose escalation of im was not effective. 23% dasatinib pts vs 80% im pts had treatment failure (TF, defined as progression, lack of response, crossover for intolerance, or off treatment). Median time to TF was not reached for dasatinib, and was 3.5 mo (95% CI: 3.3-3.8) for im. 61 pts discontinued the initially assigned treatment, of whom 50 (12 dasatinib; 38 im) crossed over after progression, no response, or intolerance. Of 45 post-crossover pts (38 dasatinib; 7 im), 17 (45%) dasatinib pts achieved MCyR, but no (0%) im pts with 800mg/d achieved MCyR after crossover following dasatinib. Grade 3/4 non-hematologic toxicity was minimal in both arms. All grades of superficial edema and fluid retention were more common with im than dasatinib (41% im vs 15% dasatinib; and 43% im vs 28% dasatinib respectively), whereas pleural effusion was 13% (3% grade 3/4) dasatinib vs 0 im. Cytopenia was more frequent and severe with dasatinib. This is the first clinical trial in pts with CML to include both im and dasatinib arms. Based on nearly 1 year of follow-up, dasatinib clearly appears to be more effective in achieving MCyR than high-dose im in pts who fail 400–600mg/d im. An update with molecular response data and detailed mutational analysis will be presented.

Association of Hydroxyurea to Imatinib Is Effective in Patients with Chronic Myelogenous Leukemia Resistant to Imatinib Alone.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4693-4693 ◽  
Author(s):  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Ida Carmosino ◽  
Chiara Sarlo ◽  
Rosa De Cuia ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chronic Phase ◽  
Complete Response ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Hematological Toxicity ◽  
Imatinib Treatment ◽  
Duration Of Response ◽  
Wbc Count

Abstract The introduction of Imatinib in the treatment of Chronic Myelogenous Leukemia (CML) leads to the achievement of Complete Cytogenetic Response (CCR) in about 70% of patients: however, in the remaining 30% of patients there is a persistance of Ph+ cells also after standard (400 mg/day) and increased (600 mg/day) dose of Imatinib. These patients are thus cytogenetically resistant to Imatinib alone and their management is at present unclear. From 11/2002 to 11/2003, 10 patients in chronic phase (6 male and 4 female, median age 52.5 years, range 29 – 68 years) with persistance of 100% Ph+ cells (9 patients) or BCR/ABL + cells (1 patient with Ph- BCR/ABL+ CML at onset) after standard (at least 6 months of treatment) followed by increased dose (at least 3 months of treatment) of Imatinib alone, were considered resistant and added Hydroxyurea (HU) to Imatinib. Seven patients have been pretreated with IFN before Imatinib; median times from diagnosis and from Imatinib treatment to HU addition were 51 months (range 23 – 151) and 14 months (range 10 – 31), respectively. HU was given according to WBC count: patients with WBC < 10 x 109/l started HU at the dose of 1 g/day, patients with WBC > 10 x 109/l at the dose of 1.5 g/day. Imatinib was continued at the same previous dosage (600 mg/day in 6 patients and 400 mg/day in 4 patients who did not tolerate increased dosage for hematological toxicity). Three patients achieved a complete response (2 CCR after 3 and 12 months respectively and 1 molecular complete response after 9 months in the patient Ph- BCR/ABL+ at onset) and 1 patient achieved a partial CR (Ph+ < 33%) after 9 months: the remaining 6 patients were resistant with persistance of 100% Ph+ cells. Toxicity was mild and only 1 patient discontinued for 2 weeks the association due to transient thrombocytopenia: no extra-hematological toxicity has been recorded. After a median follow-up of 14 months (range 20 – 10), 2 patients (1 resistant and 1 after 5 months from the achievement of CCR) evolved in Blastic Phase (BP), 5 patients are in stable chronic phase with 100% Ph+ cells and 3 patients are still in response after 4,6 and 7 months respectively. In conclusion, the association of HU with Imatinib seems capable to induce cytogenetic response in at least one third of patients resistant to Imatinib alone, with minimal toxicity: a longer follow-up and a comparison with other associations is needed to evaluate the quality and duration of response in such group of patients.

Dasatinib Efficacy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Pre-Existing BCR-ABL Mutations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 449-449 ◽  
Author(s):  
Martin C Müller ◽  
Jorge Cortes ◽  
Dong-Wook Kim ◽  
Brian J. Druker ◽  
Philipp Erben ◽  
...  
Keyword(s):  
Amino Acids ◽  
Median Time ◽  
Chronic Phase ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Imatinib Resistant ◽  
Dasatinib Treatment

Abstract Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Across a series of phase II and III trials, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal response, or intolerance to imatinib. BCR-ABL mutations are an important cause of imatinib failure and suboptimal response. Here, the efficacy of dasatinib in patients with CML-CP who had baseline BCR-ABL mutations following imatinib treatment was analyzed using data from three trials (CA180-013, -017, and -034). Mutational assessment of the BCR-ABL kinase domain was performed using RT-PCR and direct sequencing of peripheral blood cell mRNA. Hematologic, cytogenetic, and molecular response rates were reported after ≥24 mos of follow-up. Duration of response, progression-free survival (PFS), and overall survival (OS; in 013/034) were calculated using Kaplan-Meier analysis, and rates were estimated at the 24-mo time point. Of 1,150 patients with CML-CP who received dasatinib, 1,043 had a baseline mutational assessment and were analyzed further. Of these, 402 patients (39%) had a BCR-ABL mutation, including 8% of 238 imatinib-intolerant and 48% of 805 imatinib-resistant patients. Excluding known polymorphisms, 64 different BCR-ABL mutations were detected affecting 49 amino acids, with G250 (n=61), M351 (n=54), M244 (n=46), F359 (n=42), H396 (n=37), Y253 (n=26), and E255 (n=25) most frequently affected. Dasatinib treatment in patients with or without a baseline BCR-ABL mutation, respectively, resulted in high rates of major cytogenetic response (MCyR; 56% vs 65%), complete cytogenetic response (CCyR; 44% vs 56%), major molecular response (MMR; 33% vs 45%); PFS (70% vs 83%), and OS (89% vs 94%) (Table). After 24 mos, CCyRs in patients with or without a BCR-ABL mutation had been maintained by 84% vs 85%, respectively, of those achieving this response. Among patients with mutations who received dasatinib 100 mg once daily, which has a more favorable clinical safety profile, efficacy and durability were similar (MCyR: 55%; CCyR: 41%; MMR: 36%; PFS: 73%; OS: 90%). In general, high response rates and durable responses were observed in patients with different mutation types, including highly imatinib-resistant mutations in amino acids L248, Y253, E255, F359, and H396. When responses were analyzed according to dasatinib cellular IC50 for individual BCR-ABL mutations, dasatinib efficacy was observed in 44 patients who had any of 5 imatinib-resistant mutations with a dasatinib cellular IC50 &gt;3 nM (Q252H, E255K/V, V299L, and F317L, excluding T315I), including MCyR in 34%, CCyR in 25%, MMR in 18%, PFS in 48%, and OS in 81%. Among patients whose mutations had a dasatinib IC50 ≤3 nM (n=254) or unknown IC50 (n=83), responses and durability were comparable to patients with no BCR-ABL mutation. As expected, few patients with a T315I mutation (IC50 &gt;200 nM; n=21) achieved a response. Among 70 patients with &gt;1 mutation, a MCyR was achieved in 53% and a CCyR in 37%. Among patients with mutational analysis at last follow-up (n=162), 42 (26%) retained a BCR-ABL mutation (20 retained a mutation with IC50 &gt;3 nM), 42 (26%) lost a mutation (5 lost a mutation with IC50 &gt;3 nM), and 44 (27%) developed a new mutation (39 developed a mutation with IC50 &gt;3 nM), with some patients counted in more than one category. Overall, this analysis demonstrates that dasatinib has broad efficacy against all BCR-ABL mutations except for T315l. For patients with BCR-ABL mutations, dasatinib treatment is associated with durable responses and favorable long-term outcomes. Table Analysis by dasatinib IC50 No BCR-ABL mutation BCR-ABL mutation BCR-ABL mutation treated with 100 mg QD &gt;3 nM (excl. T315I) 3 nM* Unknown IC50** Some patients had &gt;1 mutation. *Excluding patients with a concurrent mutation with dasatinib IC50 &gt;3 nM. **Excluding patients with a concurrent mutation with known dasatinib IC50. Patients, n 641 402 49 44 254 83 Response rates (≥24 mos of follow-up), % CHR 93 90 90 82 94 96 MCyR 65 56 55 34 58 73 CCyR 56 44 41 25 47 54 MMR 45 33 36 18 34 43 Median time to MCyR, mos 2.8 2.9 2.8 5.7 2.9 2.8 Median time to CcyR, mos 3.0 5.3 3.0 5.7 5.4 3.4 24-mo PFS (95% CI), % 83 (79.8–86.5) 70 (65.3–75.2) 73 (60.1–86.3) 48 (31.2–64.7) 73 (66.6–78.9) 89 (82.3–96.3) 24-mo OS (95% CI), % 94 (91.4– 95.7) 89 (85.1– 92.1) 90 (81.2– 98.3) 81 (68.8– 93.8) 90 (85.8– 94.2) 96 (91.2–100)

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]

Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome–positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 97-100 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Francis Giles ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Combination Regimens ◽  
Philadelphia Chromosome Positive

Abstract Fifty patients with Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in early chronic phase received imatinib mesylate, 400 mg orally daily. After a median follow-up of 9 months, 49 patients (98%) achieved a complete hematologic response and 45 patients (90%) achieved a major cytogenetic response, complete in 36 patients (72%). Compared with similar patients who received interferon-α with or without hydroxyurea or other interferon-α combination regimens, those receiving imatinib mesylate had higher incidences of complete and major (Ph &lt; 35%) cytogenetic responses at 3 months (34% and 74% versus 1%-4% and 9%-24%, respectively), 6 months (52% and 80% versus 3%-7% and 11%-28%, respectively), and 9 months (60% and 77% versus 5%-11% and 14%-30%, respectively; P &lt; .001). Competitive quantitative polymerase chain reaction (QPCR) studies at 9 months showed a median QPCR value (ratio of BCR-ABL/ABL transcripts × 100) of 0.59% overall and of 0.24% (range, 0.001%-29.5%) for complete cytogenetic response.

Dasatinib versus imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): DASISION 3-year follow-up.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6504-6504 ◽  
Author(s):  
Andreas Hochhaus ◽  
Neil P. Shah ◽  
Jorge E. Cortes ◽  
Michele Baccarani ◽  
M. Brigid Bradley-Garelik ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Cytogenetic Response ◽  
Transformation Rate ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Intent To Treat

6504 Background: In the phase 3 DASISION trial of dasatinib v IM in patients (pts) with newly diagnosed CML-CP, dasatinib had higher 12-month rates of complete cytogenetic response (CCyR) and major molecular response (MMR) (Kantarjian, NEJM 2010;362:2260). By 12 months confirmed CCyR (cCCyR) rates for dasatinib v IM were 77% v 66%, P=0.001, meeting the primary endpoint. Methods: Pts were randomized to receive dasatinib 100 mg once daily (QD; n=259) or IM 400 mg QD (n=260). Results: Minimum 24-month follow-up (median 26.6 months) is reported here. 24-month molecular response rates were higher for dasatinib v IM: MMR (BCR-ABL ≤0.1%) 64% v 46%, P<0.0001; MR4 (BCR-ABL ≤0.01%) 29% v 19%, P=0.0053; MR4.5 (BCR-ABL ≤0.0032%) 17% v 8%, P=0.0032. MMR rates were higher for dasatinib in all Hasford risk groups (high 73% v 56%; intermediate 61% v 50%; low 73% v 56%). Of pts who achieved MMR at 12 months, on dasatinib v IM, 97% v 92% had maintained their MMR at 24 months, respectively. Pts receiving dasatinib v IM had faster responses; median time to CCyR and MMR was 3.2 v 6.0 and 15 v 36 months, respectively. In an intent-to-treat analysis, fewer pts receiving dasatinib (n=9; 3.5%) transformed to accelerated/blast phase v IM (n=15; 5.8%) on study or during follow-up after discontinuation. 24-month overall and progression-free survival were similar for dasatinib v IM: 95.4% v 95.2% and 93.7% v 92.1% (follow-up is ongoing). Few additional adverse events (AEs) were reported between 12 and 24 months in both arms, with grade 3/4 nonhematologic AE rates ≤1%. In each arm, 10 pts had a BCR-ABL mutation detected at time of discontinuation. For dasatinib v IM, 23% v 25% discontinued treatment for drug-related AEs (7% v 5%), progression (5% v 7%), failure (3% v 4%), unrelated AEs (2% v <1%), death (2% v <1%), and other (4% v 8%). Few pts discontinued between 12 and 24 months for dasatinib (n=19; 7%) and IM (n=16; 6%). Conclusions: Updated data with minimum 36-month follow-up will be presented, including mutation analyses in pts who discontinued, progressed, or had suboptimal response. Pts receiving dasatinib had a lower transformation rate and higher molecular responses v pts receiving IM, supporting the use of dasatinib in newly diagnosed CML-CP.

Dasatinib (SPRYCEL®) in Patients (pts) with Chronic Myelogenous Leukemia in Accelerated Phase (AP-CML) That Is Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results of the CA180–005 ’START-A’ Phase II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2160-2160 ◽  
Author(s):  
Jorge Cortes ◽  
D.W. Kim ◽  
F. Guilhot ◽  
G. Rosti ◽  
R.T. Silver ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Mutational Analysis ◽  
Present Report ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Significant Activity ◽  
Hematologic Response ◽  
Grade 3

Abstract Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor that induces complete hematologic and cytogenetic remissions in pts in all phases of im-r or im-i CML. START-A is an open-label study of dasatinib in pts with im-r or im-i AP-CML. Preliminary results with early follow-up suggested significant activity. The present report updates the results of this study with a minimum of 9 months of follow-up. Dasatinib was given orally at 70 mg twice daily (BID). Dose escalation to 100 mg BID was allowed for inadequate initial response and reduction to 50 or 40 mg BID for persistent toxicity. Evaluation included weekly blood counts and monthly bone marrow including cytogenetics. Molecular evaluation of BCR-ABL transcript levels by real-time qPCR was performed at baseline and upon documentation of complete cytogenetic response. A total of 174 pts (161 im-r and 13 im-i) were enrolled between December 2004 and July 2005 in 39 centers worldwide. There were 96 (55%) males; median age was 57 years (range 22–86); median time from original diagnosis of CML was 82 months. Prior therapy included im in all pts (>600 mg/day in 91 (52%), im for >3 years in 103 (59%) pts, interferon in 126 (72%) pts, stem cell transplantation in 23 (13%) pts. Major cytogenetic response (MCyR) to prior im had been seen in 57 (33%) pts. The average daily dose (median across all pts) was 130 mg/day (range 44–199). Major hematologic response (MaHR) was documented in 110 (63%) pts with complete hematologic response in 75 (43%) and no evidence of leukemia in 35 (20%). At 9 months, 85% of pts have maintained their MaHR. MCyR was documented in 65 (37%) pts, complete in 49 (28%), partial in 16 (9%). Median progression-free survival (PFS) has not been reached; estimated PFS at 9 months is 70%. In the 94 pts with BCR-ABL mutations at baseline the MaHR rate was 69%. Generally, response rates were similar in the im-i and im-r groups. Cytopenias were significant with grade 3–4 thrombocytopenia and neutropenia in 82% and 76% of pts, respectively. Non-hematologic toxicities were generally mild to moderate. The most frequent (% any grade, % grade 3–4) were diarrhea (51%, 8%), headache (29%, 1%), fatigue (26%, 4%), fever (25%, 3%) and pleural effusion (25%, 3%). Pleural effusions were optimally managed with dose interruption and diuretics and/or pulse steroids. Dasatinib is highly effective in pts with im-r or im-i AP-CML with high rates of durable MaHR and MCyR. An updated analysis with at least 12 months of follow-up, including molecular response data and mutational analysis at time of progression, will be presented.

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