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.

Imatinib as Front-Line Treatment in Chronic Myelogenous Leukemia: How Important is the Achievement of Complete Cytogenetic Response after 3 Months?

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4271-4271
Author(s):  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Ida Carmosino ◽  
Federico Vozella ◽  
Paola Volpicelli ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Risk Score ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Imatinib Treatment ◽  
Front Line ◽  
Prognostic Role ◽  
Complete Cytogenetic Response ◽  
Pre Treatment

Abstract Abstract 4271 The achievement of Complete Cytogenetic Response (CCyR) (Ph+ cells 0%) with Imatinib treatment still remains the most important objective in Chronic Myelogenous Leukemia (CML) patients. According to The European Leukemia NET guidelines, CCyR should be achieved within the 12th month of treatment while at 3 months of treatment the goal should be complete haematological response. To address the prognostic role of the early achievement of CCyR, we revised 108 chronic phase CML patients [M/F 57/51, median age 54.9 years, interquartile range (IR) 40.8 – 68.1] treated with front-line Imatinib at our Institution from June 2002 to June 2008 who had evaluable karyotype after 3 months of treatment. At onset, median WBC and PLT counts were 78.4 × 109/l (IR 34.0 – 135.9) and 399 × 109/l (IR 282 – 585), respectively. Sokal risk score was low in 52 patients (48.1%), intermediate in 49 (45.4%) and high in 7 (6.5%); a short pre-treatment phase (< 3 months) with Hydroxyurea was administered to 94/108 patients (87%). After 3 months of Imatinib treatment, 84 patients (77.7%) achieved CCyR while 24 patients (22.3%) still presented Ph+ metaphases (median value 40%, IR 20 - 80) at cytogenetic analysis. At univariate analysis, factors with a negative prognostic impact on achievement of CCyR at 3 months were palpable spleen enlargement (p=0.002), WBC count at onset > 100.0 × 109/l (p=0.01) and pre-treatment with Hydroxyurea (p=0.032); on the contrary, sex, age, Sokal risk score and PLT value did not appear to affect early CCyR achievement. Among the 84 patients in CCyR after 3 months, there were 10 failures during follow-up (6 cytogenetic relapses, 2 molecular relapses and 2 evolution to blastic phase); among the 24 patients who did not achieve early CCyR, there were 12 failures during follow-up (9 primary resistances and 3 cytogenetic relapses). The difference in the incidence of failures during follow-up in the 2 groups was highly significant (p<0.001). In conclusion, the achievement of CCyR at 3 months seems unrelated to traditional prognostic factors (Sokal); furthermore, in our experience it appears to have an important prognostic role, as patients not achieving it showed a significantly higher rate of failures during the follow-up. Disclosures: No relevant conflicts of interest to declare.

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.

Incidence of Late Chronic Anemia in Newly Diagnosed Patients with Chronic Myelogenous Leukemia Responsive to Imatinib

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3769-3769
Author(s):  
Paola Volpicelli ◽  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Federico Vozella ◽  
Paola Finsinger ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Prolonged Treatment ◽  
Imatinib Treatment ◽  
Newly Diagnosed ◽  
Chronic Anemia ◽  
Significant Difference ◽  
Sokal Score

Abstract Abstract 3769 Anemia has been reported in about 5–8% of newly diagnosed patients with Chronic Myelogenous Leukemia (CML) treated with imatinib in the first 6 months of therapy, and has been generally regarded as transient like neutropenia and thrombocytopenia: in patients responsive to imatinib, however, it is still unclear if the prolonged treatment could induce the appearance of a late chronic anemia. To highlight this issue, we revised 104 CML patients (M/F 54/50, median age at diagnosis 58.0 years, interquartile range 43.3 – 70.2) treated at our Institution with 1st line imatinib therapy for at least 36 months and in stable complete cytogenetic response (CCyR). At the 36th month of imatinib treatment, a late chronic anemia (defined as Hb levels < 11 g/dl for > 6 months) was present in 16/104 patients (15.4%): the anemia was severe (Hb < 10 g/dl) in 10 patients (9.6%) and moderate/mild (Hb ≥ 10 < 11 g/dl) in 6 patients (5.8%). Clinical features at diagnosis of patients who had late chronic anemia at the 36th month compared to the remaining 88 patients without late anemia are shown in the Table: Hb < 11 g/dl at the 36th month Hb ≥ 11 g/dl at the 36th month p M/F 6/10 48/40 0.209 Median age (yrs) (IR) 68.0 (58.9 – 75.4) 56.6 (43.1 – 69.1) 0.016 Sokal Score: Low 3 44 0.002 Int 8 39 High 5 5 Median Hb (g/dl) (IR) 11.6 (10.4 – 13.3) 12.7 (11.2 – 13.8) 0.098 Median WBC (× 109/l) (IR) 79.0 (33.2 – 136.6) 60.5 (31.8 – 112.4) 0.423 Median PLTS (× 109/l) (IR) 624 (299 – 835) 412 (296 – 557) 0.122 All patients with late chronic anemia had a low reticulocyte count and 7/16 a condition of iron deficiency with reduced serum ferritin but no clinical and instrumental sign of chronic blood loss: in this latter group, oral iron supplementation was always ineffective. Four out 16 patients (25%) needed 1 or more red cell transfusions during the follow-up. At landmark analysis from the 36th month of imatinib treatment, there was no significant difference in the cumulative 4-year overall survival for patients with and for those without late chronic anemia (80%, 95% CI 44.8 – 100%, vs 94%, 95%CI 85.8 – 100%, respectively; p=0.068). In conclusion, the occurrence of a late chronic anemia during long-lasting treatment with imatinib has been observed in > 15% of our responsive patients and was severe in about 10% of cases: its occurrence seems more common in elderly patients with higher Sokal score at diagnosis. Late chronic anemia does not seem to affect OS, but the real impact should be evaluated on a large cohort of patients. Disclosures: Tafuri: Sigma Tau Pharmaceuticals: Research Funding.

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.

scholarly journals Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia

Blood ◽  
2002 ◽  
Vol 100 (5) ◽  
pp. 1590-1595 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Jorge E. Cortes ◽  
Sergio A. Giralt ◽  
Mary Beth Rios ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Imatinib Mesylate ◽  
Allogeneic Stem Cell Transplantation ◽  
Response Rate ◽  
Chronic Phase ◽  
Complete Response ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Blastic Phase

Twenty-eight adults with chronic myelogenous leukemia (CML) that had relapsed after allogeneic stem cell transplantation (SCT) received imatinib mesylate (400-1000 mg/d). Disease was in chronic phase in 5 patients, accelerated in 15, and blastic in 8 (7 medullary, 1 extramedullary); median time from transplantation to relapse was 9 months (range, 1-137 months). Thirteen patients had undergone salvage donor lymphocyte infusion (DLI) (median time from DLI to imatinib mesylate therapy, 4 months [range, 2-39 months]). The overall response rate was 79% (22 of 28 patients); the complete hematologic response (CHR) rate was 74% (17 of 23 patients), and the cytogenetic response rate was 58% (15 of 26 patients; complete response in 9 [35%] patients). CHR rates were 100% for chronic phase, 83% for accelerated phase, and 43% for blastic phase. The patient with extramedullary blastic disease achieved complete response. Cytogenetic response rates were 63% (12 of 19 patients) for chronic or accelerated phases (complete cytogenetic response in 8) and 43% for blastic phase (3 of 7 patients). At median follow-up of 15 months, 19 patients were alive, 9 with no evidence of disease. The 1-year estimated survival rate was 74%. Five patients had recurrence of grade 3 (3 patients) or grades 1 to 2 (2 patients) graft-versus-host disease (GVHD). Severe granulocytopenia developed in 43% of patients and thrombocytopenia in 27%; both conditions reversed with dose adjustments of imatinib mesylate. We conclude that imatinib mesylate effectively controlled CML that recurred after allogeneic SCT, but it was associated with side effects including myelosuppression and recurrence of severe GVHD.

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.

Four Years of Follow-Up of 1027 Patients with Late Chronic Phase (L-CP), Accelerated Phase (AP), or Blast Crisis (BC) Chronic Myeloid Leukemia (CML) Treated with Imatinib in Three Large Phase II Trials.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 23-23 ◽  
Author(s):  
Richard T. Silver ◽  
Moshe Talpaz ◽  
Charles L. Sawyers ◽  
Brian J. Druker ◽  
Andreas Hochhaus ◽  
...  
Keyword(s):  
Phase Ii ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Imatinib Treatment ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Phase Ii Studies ◽  
Large Phase

Abstract Background This report updates the results of 3 large phase II studies of the orally available BCR-ABL tyrosine kinase inhibitor imatinib for patients (pts) in AP, BC and late chronic phase (L-CP) CML failing prior interferon therapy (Kantarjan et al, ASH 2003; Talpaz et al, ASH 2003). Methods Between August 1999 and June 2000, 1027 pts were enrolled in phase II trials for CML in L-CP (n=532), AP (n=235) or BC (n=260). Pts in L-CP were treated with 400 mg/day and pts in AP or BC with either 400 or 600 mg/day. Dose escalation up to 800 mg/d was allowed in the late-chronic phase study. Pts with a confirmed diagnosis of AP (n=181), BC (n=229) and late-chronic phase (n=454) were evaluated for efficacy. All pts were evaluated for safety. The median time from initial diagnosis to study entry was 32 months for L-CP pts. Results As of 31-Jul-03, 5% patients with BC, 25% of CML-AP and 64% of L-CP patients still remain on treatment. At the recommended dose of 600 mg, an estimated 40% (AP) and 7% (BC) of patients remained progression-free at 36 months, and an estimated 55% (AP) and 14% (BC) patients were alive at 36 months after initiation of imatinib. The 3-year survival rates for pts with AP with a major cytogenetic response at 3 months were 85% vs. 52% for pts with no response (p<0.001). In L-CP patients with a median follow-up of 40 months, 65% of patients achieved a major cytogenetic response, which was complete in 52%. The cytogenetic responses were durable with an estimated 82% of the pts in continuos major cytogenetic response at 3 years. The estimated rates of progression-free survival and overall survival at 3 years were 80% and 88%. Pts with at least a minor cytogenetic response at 6 months ≤65% Ph+ cells) had an estimated 3-year survival rate of 96% vs. 86% for pts with a ( minimal response and 81% for pts with no cytogenetic response (p<0.001). Conclusion In large phase II studies, continuous imatinib treatment is safe and has improved progression-free survival of patients at all stages of CML. Responses to imatinib are durable and are predictive of long-term outcomes. These results will be further updated at the meeting using a data base lock planned for 20-Sept-04 (using data collected up to 31-July-04, i.e. more than 4 years after the last pts enrollment).

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)

Adherence to Imatinib Mesylate Treatment: Two Years Follow up

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4267-4267 ◽  
Author(s):  
Carlos A. Doti ◽  
German R Stemmelin ◽  
Elena Beatriz Moiraghi ◽  
María Gabriela Flores ◽  
Juan Garcia ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Complete Information ◽  
Cytogenetic Response ◽  
Hematological Toxicity ◽  
Control Group ◽  
Hematological Response ◽  
Complete Hematological Response

Abstract Background: Since the introduction of Imatinib (IM), the treatment of chronic myeloid leukemia (CML) experienced its most important change. As this drug became the first line for the treatment of CML, we learned that under-dosing was associated with a delay in achieving cytogenetic response and the development of acquired resistance. Last year we presented a case-control study that analyzed how compliance affects the cytogenetic response to Imatinib. This is an update of that data. Materials and Methods: Twenty-four patients with newly diagnosed Ph (+) chronic phase CML (CP-CML) were included and followed for 24 months. Patients received 400mg of IM and were asked to note down all taken doses, and reasons for non-compliance. Follow up visits were scheduled every 28–30 days and prescriptions were filled in order to last for only 30 days. During each visit, the medication was counted and non-adherence reasons were determined. Adverse events were graded according to the CTC and modifications in the Imatinib dose were only allowed with related adverse events with a CTC score ≥3. As a control group, we matched each case with a Phi + CP-CML patient from our data base of the same sex and similar age as the case patient. All control patients had to have complete information about dosing and response. They all received initial treatment with IM 400mg; thereafter, dose was adjusted according to each physician’s criteria. Compliance was measured as: mg prescribed/mg taken during the study period. Results: Twenty-four patients, 14 males median age 56 yo (range: 24–83), were included in the study. Three were lost to follow up, leaving only twenty-one for analysis of compliance. At the end of the first year, all patients had complete hematological response. Compliance during these 12 months was 96.1, which is clearly superior to the 80% reported in the setting of clinical trials. All patients had a complete hematological response, 89.9 achieved a major cytogenetic response (MCyR) and 87.4 a complete cytogenetic response (CCyR), compared to 60 of the control group with a MCyR (p=0.027) and 57.8 a CCyR (p=0.025). During the second year, four patients lost CCyR, three responded to an increase in IM dose and one progressed to an accelerated phase and died. Compliance fell slightly during this period to 90.86% which was reflected in 81.66% CCyR, which was still statistically higher than the 54% of major responses in the control group (p=0.033). In both groups, none of the patients not achieving MCyR at 12 months achieved MCyR at 24 months. Hematological toxicity was more frequently observed within the first 6 months of treatment and after the increase in dosage. Severity and incidence of adverse events were similar in both groups, and were the main reasons for interruption or reduction of IM dose in the control group. The only additional difference besides compliance between the two groups was the average IM dose prescribed during the duration of the study (cases group: 430mg – control group: 330mg). Conclusions: Adherence to Imatinib is associated with an improvement in cytogenetic response that can be seen even at two years after the start of therapy. Since outcome and development of resistance seem to be associated with compliance to therapy, emphasis should be put on maintaining treatment at an adequate dose for as long as possible.

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