Impact of Imatinib Dose Escalation in Chronic Myeloid Leukemia Patients in Chronic Phase with Sub-Optimal Response or Failure with Imatinib 400 Mg.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3289-3289
Author(s):  
Katia BB Pagnano ◽  
Marcia T Delamain ◽  
Eliana C.M. Miranda ◽  
Vagner O Duarte ◽  
Brunna Eulálio Alves ◽  
...  
Keyword(s):  
Median Time ◽  
Dose Escalation ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Dose Increase ◽  
Free Survival ◽  
Optimal Response ◽  
Hematological Response

Abstract Abstract 3289 Poster Board III-1 Imatinib dose escalation has been used in sub-optimal response and therapeutic failure to imatinib in conventional doses. The aim of this study was to evaluate the efficacy of imatinib dose increase in CML patients in CP who did not achieve the best response to imatinib 400 mg QID. Patients and methods: All CML patients in CP treated in our institution with imatinib 400mg between March 2002 and December 2008 were evaluated. Imatinib was escalated to 600–800mg in cases with sub-optimal response or failure, according to Leukemia Net or IRIS Trial criteria. All survival curves were calculated from date of dose increase: overall survival (OS) until death or last follow-up, event free survival (EFS) until loss of complete hematological response (CHR) or major cytogenetic response (MCyR), progression to accelerated phase (AP) or blast crisis (BC) or death from any cause. Transformation free survival (TFS) was calculated from dose increase until progression to AP, BC or death. Results: 137 patients in CP were treated with imatinib 400 mg. Dose was escalated in 55 (40%) patients due to loss or failure to achieve CRH (13 = 24%); progression to BC (2 = 3.5%); no CCR (11 = 20%); loss of RCC (5 = 9%); CCR without major molecular response (MMR) after 18 months of imatinib (24 = 43.5%). Males: 37, females 18 cases. Median age: 44 (16–74) years. Twenty-eight patients (49%) were treated with imatinib as first line therapy and 51% had used IFN previously. Median time between diagnosis and imatinib start was 4.5 (0–94) months. Responses: 94% achieved CHR; 58% CCR and 34% MMR. After dose increase, 31 (56%) responded: 58% of the patients with previous sub-optimal molecular response achieved MMR. Among those who benefited from dose increase, only 3 cases lost the response: one with hematological resistance and two with cytogenetic resistance (2 lost CCR and one CHR). Seven out of 16 patients who increased dose due to cytogenetic failure (loss of response, failure and sub-optimal response) achieved response: one had partial cytogenetic response (PCyR) and 6 CCR. Five patients with hematological failure presented response: CHR (2), CCR (1), PCyR (1) and MMR (1). Patients with BC (2 cases) did not respond to dose escalation. TFS was 89% and 67% in 2 and 5 years, respectively. EFS was 71% and 64% in 2 and 5 years respectively. When stratified by the type of failure, EFS was 100%, 49% and 34% in the group with molecular sub-optimal response with median time of 22 (4–41) months, cytogenetic 17 (1.2–42) and hematological failure 7.7 (0.2–57), respectively (P<0.03). Conclusions: imatinib dose escalation was successful in molecular sub-optimal response. However, the patients who do not achieve MMR might be candidates to second line treatment. Patients who did not achieve cytogenetic or hematological response did worse with imatinib dose escalation. Disclosures: No relevant conflicts of interest to declare.

Impact of Imatinib Mesylate Dose Escalation on Resistance and Sub-Optimal Responses to Standard-Dose Therapy in Patients (pts) with Chronic Myeloid Leukemia (CML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1035-1035 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Ehab Atallah ◽  
Gautam Borthakur ◽  
William Wierda ◽  
...  
Keyword(s):  
Median Time ◽  
Dose Escalation ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Free Survival ◽  
Hematologic Response ◽  
Small Series ◽  
Better Than

Background: Dose escalation has been reported to be of benefit in some pts after standard-dose imatinib failure. This benefit is based on small series of pts with short follow-up. Although dose escalation is also recommended for pts with suboptimal response to imatinib (as defined by the European LeukemiaNet recommendations), the efficacy of this approach has not been reported. Methods: We assessed the long-term efficacy of dose escalation in 102 pts with CML in chronic phase who met the criteria of failure (n=85) or suboptimal (n=9) response to imatinib, or had their dose escalated by physician’s choice for responses better than suboptimal (n=8). Results: Median age was 52 years (range, 18–79). 89 pts were receiving imatinib after interferon failure and 13 as frontline therapy. Median time on imatinib before dose escalation was 19 mos (range, 3–87). Best response to standard-dose imatinib was complete cytogenetic response (CCyR) in 33 (32%), partial (PCyR) in 10 (10%), minor (mCyR) in 14 (14%), complete hematologic response (CHR) in 30 (29%), and partial hematologic response (PHR) in 1 (1%). 86 pts had their dose escalated from 400 to 800 mg/day and 24 from 300 to 600 mg[JC1]. Pts were followed for a median of 50 mos (range 3–83) from dose escalation. Among pts with criteria for failure, 45/61 (74%) treated for cytogenetic resistance (n=31) or relapse (n=30) responded, including complete molecular response (CMR) (n=2), major molecular response (MMR) (n=4), CCyR (n=24), PCyR (n=9), and minor CyR (n=6). Another 24 pts were treated for hematologic resistance (n=5) or relapse (n=19), and 13 (54%) responded: 1 MMR, 2 CCyR, 2 PCyR, 7 CHR, and 1 PHR. Median time to cytogenetic response was 9 mos (range, 2–54). 31/58 (53%) failure pts who responded to dose escalation relapsed after a median of 68 mos (range, 6–79), with relapses in 6/33 pts (18%) who achieved a CCyR. CCyR occurred in 31/77 (40%) pts who escalated to 800mg and 2/9 (22%) of those who escalated to 600mg (p=0.29). Among 9 pts with suboptimal response (8 no MMR at 18 mo, 1 no PCyR at 6 mos), 2 (22%) responded: 1 MMR and 1 PCyR. The later lost his response to minor CyR 2 years after escalation. Among 8 pts with response better than suboptimal, 6 (75%) improved their response to CMR (n=1) and MMR (n=3) from CCyR, and to CCyR (n=2) from PCyR at 3 and 9 mos,respectively. Table 1 summarizes responses and outcome for the 3 categories. Conclusion: Imatinib dose escalation can induce sustained molecular and cytogenetic responses in patients with failure or suboptimal response to standard-dose imatinib. Many of these responses can be durable. Table 1. Outcome after dose escalation (%) 2-year (%) from dose escalation CCyR MMR Transformation Event Loss CCyR EFS TFS EFS=Event-free survival; TFS=Transformation-free survival. * One evaluable pt not in CCyR at dose escalation. **4 evaluable pts not in CCyR at dose escalation Failure 33/85 (39) 7/85 (8) 9/58 (15) 31/58 (53) 6/33 (18) 85 86 Cytogenetic 30/61 (49) 6/61 (10) 4/40 (10) 15/40 (37) 5/30 (17) Hematologic 3/24 (12) 1/24 (4) 5/18 (28) 16/18 (89) 1/3 (33) Suboptimal 0/1* (0) 1/9 (11) 0 (0) 1 (11) 0 (0) 88 100 Other 4/4** (100) 4/8 (50) 0 (0) 0 (0) 0 (0) 100 100

Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3302-3302
Author(s):  
Massimo Breccia ◽  
Fabio Stagno ◽  
Roberto Latagliata ◽  
Paolo Vigneri ◽  
Laura Cannella ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Standard Dose ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

Efficacy of Nilotinib in EARLY Chronic PHASE CML Patients WHO Have Suboptimal Cytogenetic or Molecular Response to Imatinib. A Multicentric Retrospective Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4454-4454
Author(s):  
Luigia Luciano ◽  
Elisa Seneca ◽  
Mario Annunziata ◽  
Luca Pezzullo ◽  
Paolo Danise ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Second Generation ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Free Survival

Abstract Abstract 4454 The CML-CP suboptimal responders rappresent an eterogenous group of patients in which it is possible either to obtain an optimal renponse or to experiment a failure. The Clinical data of MDACC, Hammersmith Hospital and GIMEMA group showed that patients with suboptimal response at 6 and 12 months have worse long term outcomes than patients with optimal responses, particularly if the suboptimal response occurs early in the treatment, suggesting an advantage for pts with early major molecular response, expecially for event free survival and progression free survival. Moreover, recently, the German group has shown the benefit of early major molecular response on overall survival too. So earlier use of nilotinib or dasatinib in suboptimal CP CML may be beneficial in two potential ways: by promoting an early response, thereby potentially improving prognosis; by avoiding the development of treatment resistance. The clinical challenge in this setting would be to accurately identify patients who are likely to fail treatment with TKIs. This retrospective analysis was designed to explore the efficacy of the early switch to Nilotinib in patients with suboptimal responses to imatinib (IM) according to ELN raccomandations. In this multicentric retrospective study, 15 CML-CP patients with suboptimal response to IM within 24 months from diagnosis were evaluated: 4pts with a low, 3 with intermedied and 5 with high Sokal score. The best response to IM was CCyR for 6 pts, PCyR for one pt and Complete Hematological Response for 5 pts. As for suboptimal responses, 5 pts were defined in suboptimal cytogenetic response: 2 pts at 12 months and 2 pts at 6 months; 6pts were 18 months suboptimal molecular responders and 1 pt had a loss of CCyR at 12 months. All patients were switched to Nilotinib 400 mg twice daily. Bone marrow was done at baseline in all pts and at 3,6,12 and 18 months in cytogenetic suboptimal pts, while the molecular analysis was performed on peripheral blood every three months in all other pts. 12 pts have been treated with Nilotinib for a median of 17,5 months (range 3–37), 9 patients for ≥ 12 months. Before switching to Nilotinib, pts were treated with IM 400 mg once daily apart for 2 patients who needed an adjustment dose to 300 mg and 600 mg for toxicity and suboptimal response, respectively. Among 6 pts with suboptimal CyR, 4 obtained CCyR, 3 at 3 months and one at 6 months; 2 pts had any response at the milestones timepoints and they switched to another therapy. All pts with molecular suboptimal response obtained MMR at 3 months apart for one, who showed MMR at 12 months. Nilotinib was well tolerated in all 12 pts; only one developed a moderate transaminase elevation. A brief drug intrerruption was sufficient to manage this adverse event. Our data confirm that second generation TKIs give deeper and earlier responses also in second line treatment, garantendo optimal PFS and OS. In our serie infact, Nilotinib treatment results in high and relatively quick cytogenetic and molecular response rate in CML –CP-pts with suboptimal response to IM. These results demonstrate that the early switch to Nilotinib could be raccomanded in suboptimal responders in order to improve the outcome of this kind of pts and strongly suggest the second generation TKI as first line therapy in CML patients. A larger patient population and a longer period of observation could allow to confirm these preliminary data. Disclosures: No relevant conflicts of interest to declare.

Imatinib Mesylate Dose Escalation Improves Disease Response in Chronic-Phase Chronic Myeloid Leukaemia Patients after Cytogenetic or Molecular Suboptimal Responses to Standard Doses of Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1052-1052 ◽  
Author(s):  
Delphine Rea ◽  
Gabriel Etienne ◽  
Selim Corm ◽  
Pascale Cony-Makhoul ◽  
Martine Gardembas ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Median Duration ◽  
Dose Escalation ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Molecular Response ◽  
Dose Increase

Abstract In chronic phase-chronic myeloid leukemia (CP-CML), a complete cytogenetic response (CCR) along with a major molecular response (MMR) on imatinib mesylate (IM) at 400mg/d represents a strong factor predicting survival. Suboptimal cytogenetic responders (minimal or minor CR (mCR) by 6 months or partial CR (pCR) by 12 months, ELN) have a probability of further achievement of CCR of only 50%. Suboptimal molecular responders (CCR without MMR by 18 months, ELN) have a decreased probability of remaining event-free survivors when compared to optimal responders. Since non-randomized trials suggest that high-dose IM at CML diagnosis produces high rates of optimal responses, dose escalation can be recommended for suboptimal responders to standard dose of IM, but this strategy has not been yet evaluated. Here, we present the results from a series of 24 CP-CML patients who experienced IM-dose escalation for cytogenetic or molecular suboptimal response to standard doses of IM. Suboptimal cytogenetic responders (n=10) included 9 males, median age was 51.3 years-old (27.7–64.2), all were in early CP. Sokal scores were low (n=5), int (n=2), high (n=2) and unknown (n=1). All patients were treated with IM frontline at 400mg/d (n=9) or 600mg/d (n=1) and 2 received PEGIFN associated with IM at 400mg/d (withdrawn after 3 months for intolerance in 1). Prior to dose escalation, 7 patients were in pCR at 12 months and 3 in mCR at 6 months. The search for BCR-ABL mutations was negative in 6 patients tested. IM was increased to 600mg/d (n=7) or 800mg/d (n=3) after a median time of 13.7 months (5.6–15.2) on initial IM treatment. Median follow-up from IM at standard and escalated doses were respectively 28 (16.1–79.1) and 14.9 months (2.2–73.5). Of 9 patients with cytogenetic evaluation, 100% obtained CCR after a median duration of high-dose IM of 6.2 months (2.4–12.6). Five patients (50%) achieved a MMR after a median duration of high-dose IM of 9.7 months (2.9–45). Only one patient treated with PEGIFN and IM increased to 600mg/d obtained a complete molecular response (CMR) 19.9 months after high-dose IM. Suboptimal molecular responders (n=14) included 11 males, median age was 38.2 years-old (20.9–63.2), 9 were in early CP and 5 in late CP. Six had previously received IFN for a median of 4 months (4–53). Sokal scores were low (n=5), int (n=5), high (n=3) and unknown (n=1). All patients had received IM at 400mg/d, for a median duration of 27.3 months (16.7–73.3). BCR-ABL mutations were detected in 2/8 patients tested (M244V and Q252R). IM was increased to 600mg/d (n=13) or to 800mg/d (n=1). Median BCR-ABL prior to dose increase was 0.79% (0.15–3.06). Median follow-up from standard and escalated doses of IM were respectively 45.2 (26.9–85.9) and 12.5 months (3.3–38.1). Six patients (43%) obtained a MMR after a median of 6.7 months (2–25.4) of high-dose IM, including 1 with the M244V mutation. None achieved a CMR. To conclude, IM-dose escalation is beneficial to suboptimal cytogenetic responders with a rate of achievement of CCR and MMR of respectively 100 and 50%. Regarding molecular suboptimal responders, the rate of MMR after dose increase in only 43% and other strategies should be considered.

CD117 (c-kit) Expression On CD34+ Cells Participates In The Cytogenetic Response To Imatinib In CML Patients In First Chronic Phase

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3990-3990
Author(s):  
Jaroslaw Dybko ◽  
Ewa Medras ◽  
Olga Haus ◽  
Bozena Jazwiec ◽  
Joanna Urbaniak ◽  
...  
Keyword(s):  
Plasma Level ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Clonal Evolution ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Annexin V ◽  
Cytogenetic Response ◽  
Lower Percentage ◽  
Molecular Response

Abstract Background Chronic myeloid leukemia (CML) biology seemed to be perfectly explored especially at the beginning of tyrosine kinase inhibitors era (TKI). Later years with imatinib and second generation TKI showed variety of resistance mechanisms and it became obvious bcr-abl chimeric gene is not the only enemy to fight. Some studies assumed the decreased rate of programmed cell death (apoptotic) to be the primary mechanism by which BCR-ABL effects expansion of the leukemic clone in CML. Other studies showed the important role of patients adherence in achieving best possible response for imatinib. Imatinib plasma level was recognized as a useful tool for adherence evaluation. In this study we evaluate the expression of apoptotic marker, Annexin V in CD34+CD117+ cells of CML patients in first chronic phase treated with imatinib and try to find the correlation between this expression and cytogenetic response or imatinib plasma level. Patients The group of 54 CML patients (F/M = 30/24, median age, 50.5) in first chronic phase treated with imatinib (400 mg daily) was analyzed. The median time of treatment was 17 months (min. 12 months, max. 24 months. Only patients with the conventional translocation (Philadelphia chromosome) without additional chromosomal aberrations or clonal evolution during the treatment period were included in the study. Patients were categorized according to ELN criteria for cytogenetic response: complete cytogenetic response (CCyR) vs. no cytogenetic response (NCyR, defined as everything less than CCyR), and for molecular response: major molecular response (MMR) vs. no molecular response (NMR). Results In the cohort of 54 patients, 39 achieved CCyR in a median time of 12 months. Among these patients, 30 achieved MMR within the same time. Bone marrow CD34 positive cells were assessed for expression of CD117 and Annexin V in all groups of patients (CCyR with MMR, CCyR with NMR, and NCyR). The mean percentage of CD34+CD117+ cells was significantly higher in the NCyR group (7.67±5.62) in comparison with the CCyR group (2.27±1,78; p=0.002). The difference between MMR and NMR subgroups was not significant. While analyzing the CD34+CD117+ population, we found a significantly higher percentage of apoptotic cells (Annexin V positive) in the CCyR group (4.65±4.55) than in the NCyR group (1.67±1.22; p=0.004). Once again this difference was not significant between MMR and NMR subgroups. Serum imatinib levels were quantified in both CCyR and NCyR groups. We found higher values in the CCyR group (1244 μg/l±599) than in the NCyR group (1192 μg/l±593) but this difference was insignificant. Conclusions It was recently reported that c-kit must be inhibited to allow apoptosis of CML cells. Our results also correspond with these data. Not only was a lower percentage of CD34+CD117+ cells found in the CCyR group, but the fraction of these cells that were apoptotic was significantly greater compared with the NCyR group. Although other studies have indicated that trough plasma concentration of imatinib reflects clinical response in chronic phase of CML, we did not observe this. Our results showed higher imatinib levels in CCyR, but these data were insignificant. In conclusion, our results indicate that to achieve optimal treatment response in CML patients, c-kit kinase inhibition may be a requirement for successful proapoptotic activity of imatinib. Disclosures: No relevant conflicts of interest to declare.

Imatinib-Treated CML Patients With Discordant Response Between Cytogenetic and Molecular Tests At 3 and 6 Month Timepoints Have a Reduced Probability Of Subsequent Optimal Response: A Study From The “Gruppo Triveneto LMC”

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2732-2732
Author(s):  
Massimiliano Bonifacio ◽  
Gianni Binotto ◽  
Mario Tiribelli ◽  
Elisabetta Calistri ◽  
Elena Maino ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Rank Test ◽  
Molecular Response ◽  
Exact Test ◽  
Optimal Response ◽  
Molecular Tests ◽  
Sokal Score

Abstract Introduction The 2013 version of the European LeukemiaNet (ELN) recommendations for the management of chronic myeloid leukemia (CML) patients defines as optimal response the achievement of at least a partial cytogenetic response (PCyR) and/or BCR-ABL <=10% at 3 months, and of a complete cytogenetic response (CCyR) and/or BCR-ABL<1% at 6 months. Obtaining less than PCyR (i.e. Ph+ 36-95%) and/or BCR-ABL >10% at 3 months, and less than CCyR and/or BCR-ABL 1-10% at 6 months are regarded as warning. Patiens with discordant response between cytogenetic and molecular tests (e.g. PCyR and BCR-ABL >10% at 3 months) may be alternatively considered at the same timepoint as optimal or warning. Aims and Methods To evaluate the outcome of CML patients with discordant results between cytogenetic and molecular tests, we retrospectively analyzed our cohort of early chronic phase CML patients for which both cytogenetic and molecular responses were evaluable at 3 and/or 6 months. All patients received front-line imatinib 400 mg daily. PCyR and CCyR were defined as 1-35% and 0% Ph+ metaphases, respectively; major molecular response (MMR) was defined as BCR-ABL <=0.1%IS. Failure-free survival (FFS) was measured from the start of imatinib to the date of any of the following events: progression to accelerated or blastic phase (ABP), death for any cause at any time, imatinib dose increase (>=600 mg/day) or switch to nilotinib/dasatinib for primary or secondary hematologic or cytogenetic resistance. Cumulative responses and survival probabilities were estimated by the Kaplan-Meier method and compared by log rank test; differences among variables were evaluated by the Fisher's exact test. Results A total of 201 patients were analyzed. Median age at diagnosis was 55 (range 20-84) years. The distribution according to the Sokal score was: 86 (42.8%), 79 (39.3%) and 36 (17.9%) patients for low, intermediate and high risk, respectively. We observed that patients with concordant optimal (n=110) and discordant (n=19) results at the 3 month timepoint had significantly different chances of subsequent 6-month CCyR (88% vs 40%, p<.0001) and 12-month MMR (68% vs 12%, p<.0001), while there were no significant differences between patients with discordant or concordant warning (n=21) results (6-month CCyR 40% vs 14% and 12-month MMR 12% vs 0%, respectively). Also, patients with discordant results, compared to concordant optimal patients, had a significantly longer median time to CCyR (10.5 vs 3.5 months, p<.0001) and to MMR (49.6 vs 9.1 months, p<.0001), while there were no differences between discordant and concordant warning patients. Similarly, considering the 6-month timepoint, patients with discordant (n=28) results had a significantly inferior probability of subsequent 12-month MMR compared to concordant optimal (n=104) patients (16% vs 82%, p<.0001) but not different from concordant warning (n=38) cases (7%). Long-term FFS was significantly different between concordant optimal, discordant and concordant warning patients both considering the 3-month (82.8% vs 52.7% vs 9.6%, respectively) and the 6-month (90.4% vs 67.9% vs 23.7%, respectively) timepoints (figure). Conclusions Our results suggest that only CML patients with concordant cytogenetic and molecular optimal response at the earlier timepoints have an excellent probability of obtaining subsequent MMR and a favourable long-term FFS, while patients with at least one warning result should be carefully monitored, since their risk of treatment failure is higher. Disclosures: No relevant conflicts of interest to declare.

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)

Response and Outcomes to Nilotinib at 24 Months in Imatinib-Resistant Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) and Accelerated Phase (CML-AP) with and without BCR-ABL Mutations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1130-1130 ◽  
Author(s):  
Jerald P. Radich ◽  
Giovanni Martinelli ◽  
Andreas Hochhaus ◽  
Enrico Gottardi ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Advisory Committees ◽  
Imatinib Resistant

Abstract Abstract 1130 Poster Board I-152 Background Nilotinib is a selective and potent BCR-ABL inhibitor, with in vitro activity against most BCR-ABL mutants (excluding T315I) indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) CML in CPor AP resistant or -intolerant to prior therapy, including imatinib. In a previous analysis of nilotinib in patients with BCR-ABL mutations, mutations occurring at three specific amino acid residues (E255K/V, Y253H, and F359C/V) were shown to be associated with less favorable response to nilotinib. The current analysis is based on mature data with a minimum follow-up of 24-months for all patients. Outcomes of patients at 24 months were analyzed by mutation type. Methods Imatinib-resistant CML-CP (n = 200) and CML-AP (n = 93) patients were subdivided into the following mutational subsets: no mutation, sensitive mutations (including mutations with unknown in vitro IC50). or E255K/V, Y253H, or F359C/V mutations at baseline. Patients with mutations of unknown in vitro sensitivity were classified as sensitive in this analysis based on a previous finding that patients with these mutations responded similarly to nilotinib as patients with sensitive mutation. Patients with baseline T315I mutations were excluded from this analysis. Patient groups were analyzed for kinetics and durability of cytogenetic and molecular response to nilotinib, as well as event-free survival (EFS), defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to disease progression, or death, and overall survival (OS). Results In CML-CP and -AP patients with no mutation, sensitive mutations, or E255K/V, Y253H, or F359C/V mutations, hematologic, cytogenetic and molecular responses are provided in the Table. Overall, patients with no mutations responded similarly to patients with sensitive mutations, whereas patients with E255K/V, Y253H, or F359C/V mutations had less favorable responses. This correlation was observed in both CML-CP and CML-AP patients, respectively. Median time to CCyR was 3.3 months (range, 1.0–26.7) for CML-CP patients with no mutations, and 5.6 months (range, 0.9–22.1) for patients with sensitive mutations. At 24 months, CCyR was maintained in 74% of CML-CP patients with no mutation and in 84% of patients with sensitive mutations. One patient with CML-CP and an E255K mutation achieved CCyR at 25 months and maintained until last assessment at 30 months. Median time to MMR was similar at 5.6 months (range, 0.9–25.8) for CML-CP patients with no mutations and 5.6 months (range, 2.7–22.1) for patients with sensitive mutations. No patient with a less sensitive mutation achieved MMR. Median EFS and 24-month estimated OS rate are provided in the Table. Conclusions Imatinib-resistant CML-CP and CML-AP patients treated with nilotinib therapy with BCR-ABL mutations (excluding E255K/V, Y253H, or F359C/V) achieved rapid and durable cytogenetic responses, and estimated EFS and OS at 24 months similar to that of patients with no mutations, respectively. Patients with E255K/V, Y253H, or F359C/V mutations had lower and less-durable responses and shorter EFS than patients with sensitive mutations. Alternative therapies may be considered for patients with these uncommon mutations (E255K/V, Y253H, and F359C/V). Disclosures Radich: Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shou:Novartis: Employment. Haque:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau.

Maintaining Imatinib ≥600 Mg Daily in the First 12 Months of Chronic Phase CML Treatment Is Associated with Superior Event-Free Survival at 5 Years.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1125-1125 ◽  
Author(s):  
Michael P Osborn ◽  
Susan Branford ◽  
Deborah L White ◽  
John F Seymour ◽  
Ruth Columbus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Event Rates

Abstract Abstract 1125 Poster Board I-147 The Australasian Leukaemia and Lymphoma Group conducted a trial (TIDEL I) in 103 patients with newly diagnosed chronic phase CML, using imatinib 600 mg/day with dose escalation to 800 mg/day for suboptimal response. This was defined as failure to achieve (1) complete haematological response (CHR) at 3 months, (2) major cytogenetic response (MCR) at 6 months, (3) complete cytogenetic response (CCR) or molecular equivalent at 9 months, or (4) less than 0.01% (IS) BCR-ABL by RQ-PCR at 12 months. Here we report the outcomes with all surviving patients having been treated for at least 60 months. We aimed to determine whether the patient outcome at 60 months was predicted by the molecular response within the first 18 months of imatinib therapy. The outcomes for patients maintaining a dose of imatinib of ≥600 mg/day in the first 12 months was compared to those who were on a reduced dose for at least part of this time. Event-free survival (EFS) was defined as death from any cause, accelerated phase/blast crisis (AP/BC), and loss of CHR, MCR or CCR. The 103 patients included 66 males and 37 females with a median (±SD) age of 49 (±14) years. All patients had an ECOG performance status of 0-2 at enrolment. The 5-year EFS was 71%, transformation (AP/BC) free survival (TFS) was 95%, and overall survival was 87%. Of the 14 patients who died, 3 died in blast crisis, 2 from transplant-related complications, 8 from CML-unrelated causes, and the cause of death of 1 patient was unavailable. The annual rates of progression to AP/BC over 5 years were 3%, 1%, 0%, 1%, and 0%, while annual event rates were 13%, 8%, 8%, 1%, and 4%. CCR was achieved by 89% of patients by 60 months, while 72% achieved a major molecular response (MMR) by this time. In the first 12 months of treatment, 55% of patients maintained an imatinib dose of ≥600 mg/day (mean ±SD dose = 604 ±10 mg/day), while 45% were on <600 mg/day for at least part of this time (mean ±SD dose = 511 ±100 mg/day). EFS at 60 months was significantly higher in patients taking ≥600 mg/day compared with those who had been dose-reduced to <600 mg/day (89% vs 56%, P<0.001). Annual event rates for the ≥600 mg/day group were 6%, 2%, 2%, 0%, and 2%, while annual event rates for those on <600 mg/day were 14%, 16%, 16%, 8%, and 4%. By 60 months, 96% of patients who had been on ≥600 mg/day within the first 12 months had achieved CCR, while only 80% of those who had been on <600 mg/day had achieved this milestone (P<0.001). Log rank analysis of the achievement of MMR was also significant (P=0.03). Overall survival and TFS after 12 months were both similar between the dosing groups. There was no difference between the dosing groups' median age (50 vs 48 years, P=0.36) or Sokal score (1.04 vs 0.94, P=0.33) that may otherwise account for these results. The outcome was also determined for all patients dependent on the BCR-ABL levels at various assessment timepoints. Patients with a BCR-ABL level of <10% (IS) at 6 months (n=92) had an EFS of 78% at 60 months, while all of those with a level >10% (IS) (n=8) had an event (P<0.001). Patients with a level of ≤1% (IS) at 12 months (equivalent to CCR) (n=81) had an EFS of 75% compared with 25% (n=13) for those with levels >1% (IS) (P<0.001). At 18 months, a level ≤0.1% (IS) (n=58) conferred an EFS of 88%, while those who had failed to attain this depth of response (n=30) had an EFS of 60%. There was a significant difference in EFS between those who had achieved an MMR at 18 months and those who had achieved a CCR, but no MMR (88% vs 67%, P=0.03). In conclusion, our data suggest that patients maintaining a dose of ≥600mg in the first 12 months of imatinib therapy are more likely to achieve CCR and MMR, and superior EFS compared to those with a lower dose. This study also confirms that achieving an MMR by 18 months is associated with improved EFS. This emphasises the value of achieving a molecular response early in the treatment course, as well as adding weight to the evidence supporting the role of molecular monitoring in CML. Disclosures Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. White:Novartis and Britol-Myers Squibb: Research Funding. Seymour:Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Catalano:Roche: Honoraria, Research Funding, Travel grants. Mills:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding.

Prospective Exploratory Phase II Studies of A Rotating Regime of Nilotinib and Imatinib for Frontline Treatment of Philadelphia POSITIVE (Ph+) Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4972-4972 ◽  
Author(s):  
Giuseppe Saglio ◽  
Elisabetta Abruzzese ◽  
Giuliana Alimena ◽  
Monica Bocchia ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Chronic Phase ◽  
Disease Free Survival ◽  
Cytogenetic Response ◽  
Substantial Contribution ◽  
Free Survival ◽  
Complete Cytogenetic Response ◽  
Phase Ii Studies

Abstract Abstract 4972 The introduction of Imatinib (IM) and subsequently of Dasatinib and Nilotinib (NI) has made a substantial contribution to the therapy of all Ph+ leukemias. With IM alone, a complete cytogenetic response (CCgR) is achieved in about 75% of CML patients who are treated frontline, but about 15% of them loose the response in the first 3 years. A complete hematologic response (CHR) is achieved in almost all ALL patients, but about 50% of them relapse with BCR-ABL mutated clones within one year. With NI alone, a complete cytogenetic response is obtained in about 40% of Ph+ leukemia patients who are resistant to IM, and in more than 90% of early chronic phase, previously untreated, CML patients. NI is a derivative of IM, but has different pharmacokinetic and pharmacodynamic properties, and inhibits most of BCR-ABL mutants which are resistant to IM. Moreover, the toxicity profile of the two drugs is different. The administration of two tyrosine kinase inhibitors (TKIs) may increase the strength of initial therapy, so increasing the rate and the solidity of the response, and reducing the rate of failures. To test the feasibility and the validity of this hypothesis the GIMEMA CML WP designed a rotating regime of NI and IM to be tested front-line in patients with Ph+ CML, and in the patients with Ph+ ALL who are more than 60 years old. The first course is with NI 400 mg twice daily. The second course is with IM 400 mg once daily. A course lasts 3 months in CML, and 6 weeks in ALL. Treatment duration (study core) is 2 years in CML (8 courses), and 36 weeks in ALL (6 courses). The primary endpoint is event-free survival at 24 months in CML, and disease-free survival at 6 months in ALL. CML patients enrollment (n = 120) has been completed between February and August 2009. The results of the first interim analysis at 3 and 6 months will be presented. The enrollment of ALL patients will begin September 2009. Disclosures No relevant conflicts of interest to declare.

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