Loss of Major Molecular Response As a Trigger for Restarting Tyrosine Kinase Inhibitor Therapy in Patients With Chronic-Phase Chronic Myelogenous Leukemia Who Have Stopped Imatinib After Durable Undetectable Disease

2014 ◽  
Vol 32 (5) ◽  
pp. 424-430 ◽  
Author(s):  
Philippe Rousselot ◽  
Aude Charbonnier ◽  
Pascale Cony-Makhoul ◽  
Philippe Agape ◽  
Franck E. Nicolini ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Multicenter Observational Study ◽  
Tyrosine Kinase Inhibitor Therapy ◽  
Treatment Free Remission

Purpose More than half of patients with chronic-phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated loss of major molecular response (MMR) as a criterion for resuming therapy. Patients and Methods A multicenter observational study (A-STIM [According to Stop Imatinib]) evaluating MMR persistence was conducted in 80 patients with CP-CML who had stopped imatinib after prolonged CMR. Results Median time from imatinib initiation to discontinuation was 79 months (range, 30 to 145 months);median duration of CMR before imatinib discontinuation was 41 months (range, 24 to 96 months); median follow-up after discontinuation was 31 months (range, 8 to 92 months). Twenty-nine patients (36%) lost MMR after a median of 4 months off therapy (range, 2 to 17 months). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25% to 46%) at 12 months and 36% (95% CI, 26% to 47%) at 24 months, whereas probability of losing CMR was higher. Fluctuation of BCR-ABL transcript levels below the MMR threshold (≥ two consecutive positive values) was observed in 31% of patients after imatinib discontinuation. Treatment-free remission was estimated as 64% (95% CI, 54% to 75%) at 12 and 24 months and 61% (95% CI, 51% to 73%) at 36 months. Median to time to second CMR was estimated as 7.3 months in re-treated patients. Conclusion Loss of MMR is a practical and safe criterion for restarting therapy in patients with CML with prolonged CMR.

Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase Inhibitor Therapy in Early Chronic-Phase Chronic Myelogenous Leukemia

2017 ◽  
Vol 35 (2) ◽  
pp. 175-184 ◽  
Author(s):  
Sieghart Sopper ◽  
Satu Mustjoki ◽  
Deborah White ◽  
Timothy Hughes ◽  
Peter Valent ◽  
...  
Keyword(s):  
T Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Independent Validation ◽  
Tyrosine Kinase Inhibitor Therapy

Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry–based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts. Results T cells of patients with CML at diagnosis expressed low l-selectin (CD62L) levels, which was not a result of proportional aberrations of T-cell subsets. Low numbers of CD62L-expressing CD4+ and CD8+ T cells correlated with higher Sokal score, increased spleen size, and high leukocyte and peripheral-blood blast counts. At month 6 during nilotinib therapy, CD62L expression returned to levels of healthy individuals. The level of CD62L loss on T cells directly correlated with the extent of soluble CD62L (sCD62L) elevation. In parallel, the proteolytic activity of tumor necrosis factor α–converting enzyme (TACE; ADAM17, CD156b), the metalloproteinase shedding CD62L, was increased at diagnosis and significantly decreased during nilotinib treatment. High CD62L+ expression on both CD4+ and CD8+ T cells and, vice versa, low sCD62L levels at CML diagnosis were linked to superior molecular responses. These findings were corroborated in independent validation cohorts. Conclusion We demonstrate the prognostic impact of CD62L shedding from T cells and increased sCD62L plasma levels at CML diagnosis on molecular response to tyrosine kinase inhibitor therapy in early chronic-phase CML. Functionally, decreased CD62L may be a consequence of increased TACE-mediated CD62L cleavage and potentially impairs immune-cell function. Larger prospective studies are ongoing to confirm the prognostic relevance of this finding.

Imatinib Mesylate Discontinuation in Patients with Chronic Myelogenous Leukemia in Complete Molecular Remission: An Update Follow Up.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2154-2154 ◽  
Author(s):  
Francois-Xavier Mahon ◽  
Francoise Huguet ◽  
Gabriel Etienne ◽  
Delphine Réa ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Leukemic Cell ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Molecular Remission

Abstract The BCR-ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec) induces complete cytogenetic responses (CCR) in more than 85% of patients with chronic myelogenous leukemia (CML). However, patients in CCR relapse after imatinib interruption in case of detectable residual disease. In fact, less than 10% of patients achieve a molecular remission, defined by an undetectable residual disease using real time quantitative polymerase chain reaction (RTQ-PCR). We previously reported the outcome of CML patients in CCR after cessation of interferon-alpha during the pre-imatinib era. Seven (all with a negative PCR) out of 15 patients did not relapse (J Clin. Oncol.,20,2002:214–220). In the present study, we address the issue of the discontinuation of imatinib in CML with undetectable residual disease for more than 2 years in 15 patients. The median duration of RTQ-PCR negativity and imatinib therapy were respectively 32 months (24–46) and 45 months (32–56) before imatinib interruption. Eight patients displayed a molecular relapse with a detectable BCR-ABL transcript appearance between the first 6 months. Imatinib was then re-introduced and led to a novel molecular response in most patients. Seven other patients have still an undetectable level of BCR-ABL transcript after a median follow up of 20 months (9–24). With the assumption that the doubling time of a proliferative CML cell is 8 days, it will take a maximum of 6 months if only one leukemic cell persists and proliferates to reach 107 cells i.e corresponding to a residual disease detectable by RTQ-PCR. Relapses observed within 6 months may reflect the kinetic of undetectable dividing CML cells. Those cells may be eradicated or controlled in long term non relapsing patients described in our study.

Sustained Molecular Responses with Interferon α2a Maintenance Therapy after Imatinib Plus IFN Induction Treatment for Chronic Phase Chronic Myelogenous Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 28-28 ◽  
Author(s):  
Andreas Hochhaus ◽  
Andreas Neubauer ◽  
Martin C. Mueller ◽  
Simone Napieralski ◽  
Philipp Erben ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Maintenance Therapy ◽  
Chronic Myelogenous Leukemia ◽  
Significant Proportion ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Induction Treatment ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Interferon Α2a

Abstract Most patients with chronic myelogenous leukemia (CML) relapse after discontinuation of imatinib (IM, Glivec®/Gleevec™). Thus, current recommendations suggest a lifelong IM therapy even in complete molecular responders. However, in view of potential long term adverse effects there is a concern of tyrosine kinase inhibition. Hence, strategies to circumvent permanent kinase inhibitor therapy would be of substantial clinical value. Interferon α (IFN), in contrast to IM, elicits an autologous antileukemic immune response to control CML, and stopping IFN in complete cytogenetic responders is not associated with relapse in a significant proportion of patients. We therefore sought to determine efficacy and tolerability of an IFN maintenance immunotherapy after IM/IFN induction in newly diagnosed chronic phase CML patients. Twenty patients (14 m, 6 f; median age 44.6, range 23.5–74.1 years) have been investigated. Hasford score revealed low (n=13), intermediate (n=6), and high risk (n=1) diseases. IM therapy had been administered for 2.4 yrs (0.2–4.9), combined with PEG-IFNα2a (Pegasys®, n=17) or IFNα2a (Roferon®, n=3). Maintenance therapy consisted of PEG-IFN (n=16) or IFN (n=4). Dose was adjusted according to response and tolerability and ranged between 135 μg PEG-IFN every three weeks to 180 μg PEG-IFN once weekly week, or alternatively between 2 to 5*3 Mill IU IFN/week. IM was stopped due to side effects (n=5) or after the patient’s individual request and informed consent (n=15). At the time of imatinib withdrawal, 19 patients were in complete cytogenetic remission and one patient did not show any cytogenetic response. Major molecular response was determined in peripheral blood leukocytes of 16 patients, including one patient with undetectable BCR-ABL transcripts. After a median observation time of 1.2 yrs (range 0.1–3.1), 15 patients showed major molecular response, seven of them were complete. Improvement of molecular response was observed in seven and a stable situation in ten patients. By 6 weekly assessments of BCR-ABL expression gradual molecular relapse was observed in three patients. All relapsing patients responded to readministration of IM. At the time of IM withdrawal and during IFN maintenance therapy myeloblastin (proteinase-3, PR3) mRNA expression was determined and compared to glucose-6-phosphate dehydrogenase transcripts as internal standard. During IFN monotherapy, median ratios PR3/G6PD increased from 0.06% (range, 0.02–3.5) to 0.14% (0.03–1.4; p=0.03). IFN response was associated with the detection of autoreactive PR3 specific T-lymphocytes during IFN maintenance therapy determined by a tetramer assay in 7/8 patients, suggesting that PR3-specific cytotoxic T lymphocytes contribute to the IFN-mediated antileukemic immunity. In conclusion, we report a high rate of improved or continuous molecular remissions in 17 of 20 patients (85%) on IFN monotherapy after prior induction with IM/IFN. This suggests a previously unrecognized beneficial role for IFN in the maintenance therapy after IM-mediated debulking and may impact future CML therapy.

scholarly journals Molecular Monitoring of Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

2018 ◽  
Vol 4 (1) ◽  
pp. 1
Author(s):  
Mehrdad Payandeh ◽  
Mehrnoush Aeinfar ◽  
Saba Yari ◽  
Khirollah Yari ◽  
Masoud Sadeghi
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Median Duration ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Response To Therapy ◽  
Molecular Response ◽  
Molecular Monitoring ◽  
Tyrosine Kinase Inhibitor Therapy

Objective: Quantification of the BCR-ABL transcript is recommended to follow-up CML patients that treated by Imatinib mesylate (IM) as a tyrosine kinase inhibitor. BCR-ABL transcripts have been recognized as a molecular marker for response to therapy in CML patients (pts). Monitoring of this marker to be more effective for identifying optimal responses and can help to inform the decision to switch to alternative therapies. Quantitative reverse transcriptase PCR (Q-PCR) of BCR-ABL1 RNA is a critical laboratory technique for accurate and sensitive monitoring of the efficiency of tyrosine kinase inhibitor therapy. The aim of our study was to analyze the molecular response (MR) in Kurdish CML patients who are treated with Imatinib.Materials and Methods: We studied 60 blood samples from CML patients in chronic phase (CP), 36 females and 24 males, under IM treatment and monitored by Q-PCR on 12 months. The median duration of CML was 5 years (range: 1-15). The median duration of IM treatment was 4 years (range: 1-10). Results: 40% (24 pts), 28.33% (17 pts) and 15% (9 pts) and respectively had reached early molecular response (EMR) at 1.0-2.0 log, major molecular response (MMR) at 3.0 log and deep molecular response (DMR) at 4.0-5.0 log and also undetectable BCR‑ABL1 levels (CMR) were achieved in 16.67% (10 pts) at 12 months.Conclusion: We highlighted the possibility to use of Q-PCR as a warning at diagnosis, and may use to identify patients who could benefit from a more scrupulous follow-up.

scholarly journals Treatment Free Remission for Chronic Phase Chronic Myelogenous Leukemia Patients Who Stopped Tyrosine Kinase Inhibitor Therapy Due to Intolerance

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5919-5919
Author(s):  
Daulath Singh ◽  
Sucha Nand ◽  
Hanh Mai
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Median Treatment ◽  
The Past ◽  
Treatment Free Remission

Introduction: Chronic Myelogenous Leukemia (CML) is a myeloproliferative neoplasm that is often diagnosed in adults between the ages of 25-60. The outcome of the chronic phase CML has dramatically changed due to Tyrosine Kinase Inhibitor (TKI) therapy. There are well established guidelines from NCCN and ESMO on stopping TKI for patients achieving prolonged remissions with TKIs. We report clinical outcomes from a single tertiary care center in patients who stopped TKI therapy for reasons other than prolonged remission status. Methods: We retrospectively reviewed all the CML patients who were treated at our institution in the past 10 years (January 1st,2009 - December 31st,2018). We excluded patients who had accelerated or blast phase CML, atypical CML, patients on non-TKI therapy, and patients who received an allogeneic stem cell transplant. Results: A total of 117 patients were diagnosed with chronic phase CML at our institution in the past 10 years. Among the 117 patients, 12 of these discontinued TKI therapy. Six patients stopped TKI after achieving prolonged remission with TKI therapy and the remaining patients discontinued due to intolerance to treatment, fear of side effects, and loss of insurance. The median age of the whole cohort is 66 years (range 42-85). Six patients were male and 6 were females. Six patients were diagnosed with CML prior to year 2009 and rest after 2009. Prior to stopping, six patients received only 1 kind of TKI, 2 patients were treated with 2 types of TKIs, 2 patients received 3 types of TKIs, and 2 patients had 4 lines of TKIs (See Table). Cohort 1: 6 patients who stopped due to prolonged remission, median major molecular remission - MMR4 (BCR-ABL <0.01% IS by RT-PCR testing) prior to stopping TKI is 6 years (range 3-13 years). Of the six, only 1 relapsed (within 1 month of stopping) and was initiated back on the same TKI (imatinib). The relapsed patient has not achieved MMR4 level remission to date. Median treatment free remission for this cohort is 13 months (range 1-24 months). Cohort 2: Of those 6 patients who stopped TKI for other reasons: 4 stopped due to side effects/intolerance, 1 stopped due to fear of side effects after FDA label was updated, and 1 patient discontinued due to a loss of insurance. Median duration of MMR4 prior to stopping is 4 years (range 1-11 years). 5 of these 6 patients relapsed in the median time of 6 months (range 3-16 months). Of these 5, 4 were started back on the TKI therapy (three on the same TKI and one on a different TKI). Median treatment free remission for this cohort is 4 months (range 2-16 months). Conclusion: In this small cohort from a single institution's experience, CML patients who discontinued TKI therapy after achieving MMR4 for reasons other than prolonged remission have experienced poor outcomes including a higher rate of relapse and a shorter treatment free remission. We need studies with larger samples sizes and longer follow up to assess outcomes in patients stopping TKI therapy for various reasons. Disclosures No relevant conflicts of interest to declare.

Preliminary Activity of Nilotinib (AMN107), a Novel Selective Potent Oral Bcr-Abl Tyrosine Kinase Inhibitor, in Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Phase Chronic Myelogenous Leukemia (CML-CP).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2172-2172 ◽  
Author(s):  
Elias Jabbour ◽  
Jorge Cortes ◽  
Francis Giles ◽  
Susan O’Brien ◽  
Laurie Letvak ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Patient Choice ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Early Results ◽  
Grade 3

Nilotinib is a novel, highly selective oral Bcr-Abl inhibitor which is approximately 30-fold more potent than imatinib. High response rates with nilotinib were observed in all CML phases post imatinib failure. We evaluated the efficacy of nilotinib in newly diagnosed Ph-positive CML-CP. Thirteen patients with newly diagnosed Ph-positive CML-CP were treated with nilotinib 400 mg orally twice daily. The median age was 49 years (range, 24–72 years). The Sokal risk at pretreatment was low in 10 patients, intermediate in 2, and high in 1. The median follow-up is 8 months (range, 3–12 months). All patients have reached the 6-month evaluation. The rate of complete cytogenetic response [CGCR] (Ph 0%) at 3 and 6 months was 93% and 100%, respectively. This is compared with a CGCR at 3 months of 37% and with imatinib 400 mg/d and 61% with imatinib 800 mg/d (p=0.0002) and 54% and 85% at 6 months, respectively (p<0.0001), in historical data of newly diagnosed patients treated in studies at M. D. Anderson. Six patients were evaluable at 9 months and all were in CGCR. The median QPCR with nilotinib at 3, 6, and 9 months were, respectively, 3.4% (range, 0.02–29.5%), 1.8% (range, 0.004–9.13%), and 0.54% (range, 0.04–1.28%). At 3-month follow-up, major molecular response (BCR-ABL/ABL ratio<0.05%) was observed in 1/13 patients (8%) and in 6/11 (55%) at 6-month. Grade 3–4 myelosuppression was observed in 3 of the 13 patients and other grade 3–4 side effects in 3 patients (increased lipase in 2 and musculo-skeletal pain in 1). Four patients had their dose reduced to 400 mg daily due to extramedullary toxicity. Two patients were taken off after 6 and 8 months (patient choice) and switched to imatinib. In conclusion, early results with nilotinib 400 mg orally twice daily suggest significant efficacy manifested by complete cytogenetic responses in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile.

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

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 29-29 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Elias Jabbour ◽  
Alexandra Ferrajoli ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
P Value ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Major Molecular Response ◽  
Treatment Interruptions ◽  
Grade 3

Abstract Background: Nilotinib is a novel, oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl that is approximately 30-fold more potent than imatinib. High response rates have been reported with nilotinib therapy in CML after imatinib failure. Methods: We evaluated the efficacy of nilotinib as first line therapy in pts with newly diagnosed Ph-positive CML-CP. The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio ≤0.05% in our lab) at 12 months (mo). Results: Thirty-two pts have been treated with nilotinib 400 mg orally twice daily for a median of 5 months (mo) (range, 1 to 31 mo). The median age was 47 years (yrs) (range, 24–73 yrs). The Sokal risk at pretreatment was low in 21 (70%) pts, intermediate in 6 (20%), and high in 3 (10%). The rate of complete cytogenetic response [CCyR] (Ph 0%) at 3, 6 and 12 mo compares favorably to those observed in historical controls treated with imatinib 400 mg or 800 mg daily: The median QPCR with nilotinib at 3, 6, and 12 months were, respectively, 0.52% (range, 0.0–29.5%), 0.03% (range, 0.0–9.13%), and 0.09% (range, 0.0–16.21%). At 3 mo follow-up, major molecular response (MMR; BCR-ABL/ABL ratio ≤0.05%) was observed in 3/22 patients (14%), 7/13 (54%) at 6 mo, and 5/11 (45%) at 12 mo. 12-mo rates of MMR for the historical imatinib groups treated at 400 mg and 800 mg were 24% and 47%, respectively (p=0.02). None of the molecular responses has been lost while on therapy. Grade 3–4 neutropenia was observed in 2 (7%) pts, and thrombocytopenia in 1 (3%). Other grade 3–4 adverse events included elevation of lipase (n=3, 9%), or bilirubin (n=2; 6%), and amylase elevation, back pain, and infection (1 each). Twelve pts had transient treatment interruptions (median 11 days), most frequently due to pain (n=3; musculoskeletal 2, abdominal 1), lipase elevation (n=2). Seven patients had their dose reduced to 400 mg daily, 2 to 200 mg twice daily, and 1 to 200 mg daily due to extramedullary toxicity. Three patients decided to change therapy after 4, 6 and 8 months; 2 switched to imatinib and 1 received SCT. Conclusion: Nilotinib 400 mg orally twice daily suggest significant efficacy manifested by complete cytogenetic responses in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile. Percent with CCyR (No. evaluable) Months on Therapy Nilotinib Imatinib 400 mg Imatinib 800 mg P value 3mo 95 (22) 37 (49) 62 (202) < 0.0001 6mo 100 (13) 54 (48) 82 (199) <0.0001 12mo 100 (11) 65 (48) 86 (197) 0.0007

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.

Use of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in chronic phase (CML-CP)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7005-7005 ◽  
Author(s):  
E. L. Atallah ◽  
H. Kantarjian ◽  
S. O'Brien ◽  
D. Jones ◽  
G. Borthakur ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Poor Response ◽  
Treatment Interruption ◽  
Cytogenetic Response ◽  
Primary Objective ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Major Molecular Response

7005 Background: Dasatinib (formerly BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity in pts with imatinib (im) resistant/intolerant CML-CP, the present phase II trial was designed to study previously untreated CML-CP pts treated with dasatinib. The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio =0.05% by qPCR) at 12 months (mo). Methods: All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily or a 100 mg-once-daily schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed. Results: Of the 31 pts enrolled between 11/05 and 12/06; 52% were female; median age was 41 years (range 18–76). At 3 mo, complete hematologic response (CHR) and major cytogenetic response both occurred in 21 (81%) of 26 evaluable pts and complete cytogenetic response (CCyR) in 19 (73%) pts. After 6 mo of therapy, 20/21 (95%) evaluable pts had achieved CCyR. This compares favorably with a CCyR at 6 mo of 54% with im 400 mg/day and 85% with im 800 mg/day, in historical data of similar patients treated in studies at MD Anderson. At 9 mo, 4/15 (27%) evaluable pts had achieved a major molecular response. The most common non-hematologic adverse events (AE) included dyspnea (8 pts), fatigue (7 pts), muscle pain (6 pts), and headache (5 pts) and were predominantly grade (gr) 1–2. Pleural effusion occurred in only 3 pts (gr 1–2 in all). Grade 3–4 hematologic toxicity (transient) included anemia in 4 pts, neutropenia in 7 pts, and thrombocytopenia in 4 pts. With a median duration of therapy of 10 mo, 13 pts required transient treatment interruption, 9 due to non-hematologic toxicities, 3 due to hematologic toxicities, and 1 due to both. The actual median daily dose for all pts was 100mg. No difference in AEs has been observed between dose schedules. Conclusions: Rapid, complete cytogenetic responses to dasatinib 100 mg/day have been observed in a high percentage of patients with previously untreated CML- CP. Accrual to this trial continues. No significant financial relationships to disclose.

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