Phase 1 study of polyethylene glycol formulation of interferon α-2B (Schering 54031) in Philadelphia chromosome–positive chronic myelogenous leukemia

Blood ◽  
2001 ◽  
Vol 98 (6) ◽  
pp. 1708-1713 ◽  
Author(s):  
Moshe Talpaz ◽  
Susan O'Brien ◽  
Esther Rose ◽  
Samir Gupta ◽  
Jianqin Shan ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Chronic Myelogenous Leukemia ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Phase 1 Study ◽  
Severe Fatigue ◽  
Complete Hematologic Response

Abstract Interferon α (IFN-α) therapy improves prognosis in Philadelphia chromosome (Ph)–positive chronic myelogenous leukemia (CML). Polyethylene glycol (PEG) attached to IFN-α prolongs its half-life and may offer better therapy. The aims of this phase 1 study were to define the maximal tolerated dose (MTD), dose-limiting toxicities (DLTs), and response with PEG IFN-α-2b. Twenty-seven adults with Ph+ CML in chronic or accelerated phases, in whom IFN-α treatment had failed, were studied. Patients had hematologic (9 patients) or cytogenetic resistance (12 patients) or intolerance to IFN-α (6 patients). PEG IFN-α-2b was given as a weekly subcutaneous injection starting at 0.75 μg/kg weekly and escalating to 1.5, 3, 4.5, 6, 7.5, and 9.0 μg/kg. The MTD was defined at 7.5 to 9 μg/kg; DLT included severe fatigue, neurotoxicity, liver function abnormalities, and myelosuppression. Longer administration of PEG IFN-α-2b resulted in chronic side effects not observed earlier, which defined the MTD and DLT. The proposed phase 2 dose of PEG IFN-α-2b was 6 μg/kg weekly. Among 19 patients with active disease, 7 (37%) achieved complete hematologic response (CHR); 2 (11%) had a cytogenetic response (complete). Among 8 patients treated in CHR, 7 (87%) improved cytogenetic response to complete (4 patients) or partial (3 patients). All 6 patients intolerant to IFN-α tolerated PEG IFN-α-2b; 4 improved their cytogenetic response. The results show that PEG IFN-α-2b is easier to deliver (once weekly), better tolerated, and perhaps more effective than IFN-α.

Dasatinib (BMS-354825) is active in Philadelphia chromosome–positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 497-499 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Claude Nicaise ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Src Kinase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Kinase Activation ◽  
Complete Hematologic Response

Abstract Developing strategies to counteract imatinib resistance constitutes a challenge in chronic myelogenous leukemia (CML). Therapy with the tyrosine kinase inhibitors nilotinib (AMN107) and dasatinib (BMS-354825) has produced high rates of hematologic and cytogenetic response. Src kinase activation has been linked to Bcr-Abl–mediated leukemogenesis and CML progression. In addition to binding Abl kinase with less stringent conformational requirements than imatinib, dasatinib is a potent Src kinase inhibitor. In the current study, we report on 23 patients with CML (19 of them in accelerated or blastic phases) treated with dasatinib after treatment failure with both imatinib and nilotinib. More than half (13; 57%) of 23 patients responded to dasatinib: 10 (43%) had a complete hematologic response (CHR), including 7 (30%) who had a cytogenetic response (2 complete, 4 partial, and 1 minor). These results suggest that dasatinib may be active in some patients after failure with both imatinib and nilotinib.

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 < 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 < .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.

A Phase 1/2 Study of SKI-606, a Dual Inhibitor of Src and Abl Kinases, in Adult Patients with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) or Acute Lymphocytic Leukemia (ALL) Relapsed, Refractory or Intolerant of Imatinib.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 168-168 ◽  
Author(s):  
Jorge Cortes ◽  
Hagop M. Kantarjian ◽  
Michele Baccarani ◽  
Tim H. Brummendorf ◽  
Delong Liu ◽  
...  
Keyword(s):  
Safety Profile ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Dual Inhibitor ◽  
Hematologic Response ◽  
Complete Cytogenetic Response ◽  
Imatinib Resistant ◽  
Complete Hematologic Response

Abstract SKI-606 is an orally available, dual Src/Abl kinase inhibitor shown to be 200-fold more potent than imatinib as an inhibitor of Bcr-Abl phosphorylation in biochemical assays. BaF3 cell lines and primary cells from pts expressing different imatinib-resistant Bcr-Abl mutant proteins are sensitive to SKI-606 in vitro. Unlike imatinib and dasatinib, SKI-606 exhibits no significant inhibition of c-kit or PDGFR. This differential selectivity may result in clinical benefit by altering the safety profile. In the phase 1 portion of this phase 1/2 study, pts in chronic phase with imatinib relapsed or refractory disease were eligible for treatment with SKI-606 once-daily dosing. 18 pts [median age: 62 yrs (range 27 – 72); 14 male; 4 female; median CML duration: 5.8 yrs (range 0.9 – 11.1); and median time on imatinib (n=16): 3.9 yrs (range 0.8 – 6.5)] have been enrolled in the following dose cohorts (mg/day): 400 (3 pts), 500 (3 pts) and 600 (12 pts), and have been on treatment for 30 to 192 days. 17/18 pts remain on study; 1 pt discontinued with disease progression. The following SKI-606-related AEs have been reported (n=15, G1/2): diarrhea (87%), nausea (33%), vomiting (20%), abdominal pain (13%), rash (13%), asthenia (13%), and increased AST/ALT levels (7%). 2 pts treated at 600 mg experienced a G3 toxicity: rash and thrombocytopenia. 5 pts (4 pts at 600 mg and 1 pt at 500 mg) had dose reductions for rash, thrombocytopenia, diarrhea, fever and increased AST/ALT levels. No pleural effusion or pulmonary edema has been reported. Of the 7 pts who entered the study in hematologic relapse and have completed 1 month of treatment, all have achieved complete hematologic response. Of the 7 pts on treatment ≥ 12 weeks (time of first cytogenetic assessment), 3 pts have achieved complete cytogenetic response and 1 pt a minimal cytogenetic response. 6/7 pts who have achieved complete hematologic response had pre-treatment imatinib-resistant Bcr-Abl mutations: M351T; F359V; T315I; F359(V,F); and 2 pts with multiple mutations [L248(L,V) and H396(H,R); H396(H,P) and E286(E,G) and M351(T,M)]. The 3 pts with complete cytogenetic response had mutations: M351T; M244V; and H396(H,P), E286(E,G) and M351(T,M). Based on the emergence of 1 DLT of G3 rash, and additional G2 GI and dermatologic toxicities observed at 600 mg, 500 mg has been selected as the dose for the phase 2 portion of the study. Patients in all phases of CML and Ph+ ALL are now being enrolled. SKI-606 is well tolerated in pts with CML, with a primarily GI and dermatologic safety profile, and with encouraging evidence of clinical activity in imatinib-resistant patients with complete hematologic and cytogenetic responses.

Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia.

1998 ◽  
Vol 16 (3) ◽  
pp. 882-889 ◽  
Author(s):  
S Sacchi ◽  
H M Kantarjian ◽  
T L Smith ◽  
S O'Brien ◽  
S Pierce ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Univariate Analysis ◽  
Group Analysis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Interferon Alfa ◽  
Myelogenous Leukemia ◽  
Costal Margin ◽  
Hematologic Response

PURPOSE To determine, in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) on interferon alfa (IFNalpha), whether combining pretreatment characteristics and early response profiles would distinguish patients with differential benefits that would allow better decisions on subsequent therapy. PATIENTS AND METHODS A total of 274 patients treated from 1982 through 1990 with IFNalpha regimens were analyzed. A second group of 137 patients treated with IFNalpha and low-dose cytarabine (ara-C) between 1990 and 1994 was later used to confirm the guidelines derived from the original study group analysis. Patients' pretreatment factors and response to IFNalpha therapy at 3, 6, and 12 months were analyzed in relation to subsequent achievement of major cytogenetic response. After univariate analysis of prognostic factors, a multivariate analysis selected, at 6 months, independent pretreatment factors that added to the response status in predicting subsequent outcome. The results were then applied at the 3- and 12-month periods and confirmed in the subsequent population. RESULTS Response to IFNalpha therapy at 3, 6, and 12 months was a significant predictor of later major cytogenetic response. The presence of splenomegaly > or = 5 cm below the costal margin (BCM) or thrombocytosis > or = 700 x 10(9)/L pretreatment added significant independent prediction to response. At 6 months, patients with a partial hematologic response (PHR) or resistant disease had a less than 10% chance of achieving a later major cytogenetic response, as were those in complete hematologic response (CHR) and who had pretreatment splenomegaly and thrombocytosis. Applying the model at 3 months showed that only patients with < or = PHR and pretreatment splenomegaly or thrombocytosis at 3 months had such a low major cytogenetic response rate. Finally, at 12 months, patients with CHR still had a 15% to 25% chance of having a major cytogenetic response later if they did not have pretreatment splenomegaly and thrombocytosis. CONCLUSION This analysis allows better selection of patients with Ph-positive CML on IFNalpha therapy for continuation of IFNalpha versus changing therapy early in the course of CML. For treatment programs that choose to change patients to other investigational therapies (eg, intensive chemotherapy and/or autologous stem-cell transplantation [SCT]), baseline outcome expectations are provided for patients continued on IFNalpha therapy, against which the results of new approaches can be compared.

scholarly journals Comparative Analysis of Autografting in Chronic Myelogenous Leukemia: Effects of Priming Regimen and Marrow or Blood Origin of Stem Cells

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1820-1831
Author(s):  
Catherine M. Verfaillie ◽  
Ravi Bhatia ◽  
Michael Steinbuch ◽  
Todd DeFor ◽  
Betsy Hirsch ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Disease Stage ◽  
Hla Dr ◽  
Before And After ◽  
American Society

The aims of this study were (1) to evaluate the effect of intermediate (cyclophosphamide alone) or intensive (mitoxantrone, cytosine arabinoside, cyclophosphamide) priming on the cytogenetic response in mobilized bone marrow (BM) or peripheral blood (PB) progenitors in patients with chronic myelogenous leukemia (CML), (2) to determine the incidence of cytogenetic remissions after mobilized progenitor transplantation in CML, and (3) to determine the effect of in vivo priming on the ability to select Philadelphia chromosome–negative (Ph-negative) CD34+HLA-DR− cells from mobilized BM or PB in quantities sufficient for transplantation. Between February 1994 and March 1997, 44 patients were enrolled in three sequential protocols. Although the duration of neutropenia after only cyclophosphamide mobilization was shorter, clinical morbidity for the intermediate and intensive priming protocols was similar. Cytogenetic responses in mobilized PB progenitors were similar after mobilization with either intermediate or intensive chemotherapy. The degree of Ph negativity in the mobilized product correlated with disease stage at the time of mobilization (early chronic phase [ECP] > late CP > accelerated phase). Cytogenetic responses after transplantation with mobilized progenitors obtained after the different regimens were similar. The cytogenetic status of the graft predicted the cytogenetic status of marrow obtained 3 weeks after transplantation whereas cytogenetic responses 3, 6, and 12 months after transplantation correlated with the number of BCR/ABL–negative CD34+HLA-DR−cells, but not the number of Ph-negative metaphases in the graft. In patients with ECP CML, mobilized PB collections yielded significantly more CD34+HLA-DR− cells than from steady state or mobilized BM. CD34+HLA-DR− cells were Ph negative and polyclonal (X-chromosome inactivation) in the majority of ECP CML patients, before and after mobilization and irrespective of the mobilization regimen. Because infusion of large numbers of Ph-negative CD34+HLA-DR− cells predicted superior outcome after transplantation, approaches in which CD34+HLA-DR− cells are selected from mobilized PB may result in longer lasting and clinically significant cytogenetic responses after transplantation. © 1998 by The American Society of Hematology.

Comparative Analysis of Autografting in Chronic Myelogenous Leukemia: Effects of Priming Regimen and Marrow or Blood Origin of Stem Cells

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1820-1831 ◽  
Author(s):  
Catherine M. Verfaillie ◽  
Ravi Bhatia ◽  
Michael Steinbuch ◽  
Todd DeFor ◽  
Betsy Hirsch ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Disease Stage ◽  
Hla Dr ◽  
Before And After ◽  
American Society

Abstract The aims of this study were (1) to evaluate the effect of intermediate (cyclophosphamide alone) or intensive (mitoxantrone, cytosine arabinoside, cyclophosphamide) priming on the cytogenetic response in mobilized bone marrow (BM) or peripheral blood (PB) progenitors in patients with chronic myelogenous leukemia (CML), (2) to determine the incidence of cytogenetic remissions after mobilized progenitor transplantation in CML, and (3) to determine the effect of in vivo priming on the ability to select Philadelphia chromosome–negative (Ph-negative) CD34+HLA-DR− cells from mobilized BM or PB in quantities sufficient for transplantation. Between February 1994 and March 1997, 44 patients were enrolled in three sequential protocols. Although the duration of neutropenia after only cyclophosphamide mobilization was shorter, clinical morbidity for the intermediate and intensive priming protocols was similar. Cytogenetic responses in mobilized PB progenitors were similar after mobilization with either intermediate or intensive chemotherapy. The degree of Ph negativity in the mobilized product correlated with disease stage at the time of mobilization (early chronic phase [ECP] &gt; late CP &gt; accelerated phase). Cytogenetic responses after transplantation with mobilized progenitors obtained after the different regimens were similar. The cytogenetic status of the graft predicted the cytogenetic status of marrow obtained 3 weeks after transplantation whereas cytogenetic responses 3, 6, and 12 months after transplantation correlated with the number of BCR/ABL–negative CD34+HLA-DR−cells, but not the number of Ph-negative metaphases in the graft. In patients with ECP CML, mobilized PB collections yielded significantly more CD34+HLA-DR− cells than from steady state or mobilized BM. CD34+HLA-DR− cells were Ph negative and polyclonal (X-chromosome inactivation) in the majority of ECP CML patients, before and after mobilization and irrespective of the mobilization regimen. Because infusion of large numbers of Ph-negative CD34+HLA-DR− cells predicted superior outcome after transplantation, approaches in which CD34+HLA-DR− cells are selected from mobilized PB may result in longer lasting and clinically significant cytogenetic responses after transplantation. © 1998 by The American Society of Hematology.

scholarly journals A randomized trial comparing interferon-alpha with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 906-916 ◽  
Author(s):  
K Ohnishi ◽  
R Ohno ◽  
M Tomonaga ◽  
N Kamada ◽  
K Onozawa ◽  
...  
Keyword(s):  
Survival Rate ◽  
Chronic Myelogenous Leukemia ◽  
Interferon Alpha ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Ifn Alpha ◽  
Significant Difference

Abstract A multicenter randomized study was conducted to compare the effect of interferon-alpha (IFN-alpha) with that of busulfan in newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase. From October 1988 to October 1991, 170 patients were randomized to receive either IFN-alpha or busulfan. Of 159 eligible patients, 31 (38.8%) of 80 patients in the IFN-alpha group and 43 (54.4%) of 79 patients in the busulfan group achieved complete hematologic remission, and 38.8% in the IFN-alpha group and 43.0% in the busulfan group achieved partial hematologic remission. A complete cytogenetic response was induced in seven (8.8%) of 80 patients treated with IFN-alpha and two (2.5%) of 79 patients treated with busulfan, and a partial cytogenetic response was 7.5% (6/80) and 2.5% (2/79), respectively. The difference in major (complete and partial) cytogenetic response between the two groups was significant (P = .046). At a median follow-up of 50 months, the predicted 5-year survival rate was 54% in the IFN-alpha group and 32% in the busulfan group (P = .0290), and the predicted 5-year rate of remaining in chronic phase was 41% in the IFN-alpha group and 29% in the busulfan group (P = .1165). As compared with the patients with no cytogenetic response, the patients with any cytogenetic response (complete, partial or minor) after the IFN-alpha or busulfan treatment were significantly superior in the duration of chronic phase (IFN-alpha group; P = .0017, busulfan group; P = .0010) even after correction for the time to response using the landmark analysis. However, there was no significant difference in survival rate in the IFN-alpha group (P = .1065). There was no significant difference in survival rate (P = .3923) and the duration of chronic phase (P = .6258) between the IFN- alpha and the busulfan group in the patients with a cytogenetic response (complete, partial or minor). These results demonstrate that IFN-alpha treatment produces a significantly superior cytogenetic response and survival rate as compared with the busulfan treatment, and unexpectedly, that busulfan can also eliminate Philadelphia chromosome positive clone in a few patients who showed prolonged survival rate and duration of chronic phase.

scholarly journals A randomized trial comparing interferon-alpha with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 906-916 ◽  
Author(s):  
K Ohnishi ◽  
R Ohno ◽  
M Tomonaga ◽  
N Kamada ◽  
K Onozawa ◽  
...  
Keyword(s):  
Survival Rate ◽  
Chronic Myelogenous Leukemia ◽  
Interferon Alpha ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Ifn Alpha ◽  
Significant Difference

A multicenter randomized study was conducted to compare the effect of interferon-alpha (IFN-alpha) with that of busulfan in newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase. From October 1988 to October 1991, 170 patients were randomized to receive either IFN-alpha or busulfan. Of 159 eligible patients, 31 (38.8%) of 80 patients in the IFN-alpha group and 43 (54.4%) of 79 patients in the busulfan group achieved complete hematologic remission, and 38.8% in the IFN-alpha group and 43.0% in the busulfan group achieved partial hematologic remission. A complete cytogenetic response was induced in seven (8.8%) of 80 patients treated with IFN-alpha and two (2.5%) of 79 patients treated with busulfan, and a partial cytogenetic response was 7.5% (6/80) and 2.5% (2/79), respectively. The difference in major (complete and partial) cytogenetic response between the two groups was significant (P = .046). At a median follow-up of 50 months, the predicted 5-year survival rate was 54% in the IFN-alpha group and 32% in the busulfan group (P = .0290), and the predicted 5-year rate of remaining in chronic phase was 41% in the IFN-alpha group and 29% in the busulfan group (P = .1165). As compared with the patients with no cytogenetic response, the patients with any cytogenetic response (complete, partial or minor) after the IFN-alpha or busulfan treatment were significantly superior in the duration of chronic phase (IFN-alpha group; P = .0017, busulfan group; P = .0010) even after correction for the time to response using the landmark analysis. However, there was no significant difference in survival rate in the IFN-alpha group (P = .1065). There was no significant difference in survival rate (P = .3923) and the duration of chronic phase (P = .6258) between the IFN- alpha and the busulfan group in the patients with a cytogenetic response (complete, partial or minor). These results demonstrate that IFN-alpha treatment produces a significantly superior cytogenetic response and survival rate as compared with the busulfan treatment, and unexpectedly, that busulfan can also eliminate Philadelphia chromosome positive clone in a few patients who showed prolonged survival rate and duration of chronic phase.

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.

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