A prospective analysis of clinical efficacy and safety in chronic myeloid leukemia-chronic phase patients with imatinib resistance or intolerance as evaluated using European LeukemiaNet 2013 criteria.

We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib-resistant or imatinib-intolerant chronic myeloid leukemia (CML). From 2009 to 2011, 54 CML-chronic phase (CP) patients with resistance (n = 40) or intolerance (n = 25) to imatinib were registered to undergo dasatinib treatment. Eleven patients showed both resistance and intolerance to imatinib. Coincidentally, the resistance criteria in this study were the same as a non-optimal response to tyrosine kinase inhibitors (TKIs) as defined in the European LeukemiaNet (ELN) 2013 recommendations. The overall incidence rate of major molecular response (MMR) at 12 months was 62.3% (n = 47). Forty patients with resistance to imatinib who were 'warning' and 'failure' patients based on the ELN 2013 recommendations were assessed; cumulative MMR and MR(4.5) rates were 62.5% (n = 39) and 21.0% (n = 40), respectively, at 12 months. Twelve patients who showed a BCR-ABL transcript level >1% on the international scale did not achieve a MMR or discontinued dasatinib treatment because of insufficient effects. With regard to safety issues, grade 3/4 non-hematologic adverse events (AEs) were infrequent. Patients with non-optimal responses (who meet ELN 2013 warning and failure criteria) to imatinib should be switched quickly to dasatinib, which is less toxic in CML-CP patients, to improve their prognoses. A BCR-ABL1 IS of <1% at 3 months of dasatinib administration is a landmark for good therapeutic outcome.

Murai K ，Akagi T ，Shimosegawa K ，Sugawara T ，Ishizawa K ，Ito S ，Murai K ，Motegi M ，Yokoyama H ，Noji H ，Tajima K ，Kimura J ，Chou T ，Ogawa K ，Harigae H ，Kubo K ，Oba K ，Sakamoto J ，Ishida Y ... -  《-》

Cross-Intolerance With Dasatinib Among Imatinib-Intolerant Patients With Chronic Phase Chronic Myeloid Leukemia.

BCR-ABL inhibitors have improved the prognosis of patients with chronic myeloid leukemia (CML). However, imatinib, the first approved BCR-ABL inhibitor, must be discontinued in many patients because of resistance or intolerance. The present retrospective, pooled analysis of phase II and III data explored the extent of cross-intolerance between imatinib and dasatinib, a second-generation BCR-ABL inhibitor, in 271 CML imatinib-intolerant patients. Overall, 47 patients (17%) had cross-intolerance to dasatinib, determined by recurrence of grade 3 or 4 adverse events (AEs). Of the 228 patients who discontinued imatinib because of nonhematologic intolerance, 10 (4%) experienced the same severe nonhematologic AEs with dasatinib, with 4 of these patients (2%) discontinuing dasatinib because of cross-intolerance. Of the 43 patients who discontinued imatinib because of hematologic intolerance, 37 (86%) experienced a recurrence of grade 3 or 4 hematologic AEs with dasatinib, with 8 patients (19%) discontinuing dasatinib because of cross-intolerance. Of the 43 patients taking dasatinib at the optimized dose of 100 mg/d, 1 (2%) discontinued therapy because of recurrence of nonhematologic AEs and 3 (7%) because of recurrence of hematologic AEs. With a median treatment duration of 22 months, the estimated rates of progression-free survival and overall survival at 2 years were greater for patients with nonhematologic versus hematologic intolerance to imatinib who switched to dasatinib (progression-free survival, 94% vs. 68%, respectively; overall survival, 98% vs. 88%, respectively). Dasatinib could be an appropriate treatment option for imatinib-intolerant patients with CML, with cross-intolerance resulting in discontinuation in a few patients.

Khoury HJ ，Goldberg SL ，Mauro MJ ，Stone RM ，Deininger MW ，Bradley-Garelik MB ，Mohamed H ，Guilhot F ... -  《-》

Dasatinib rapidly induces deep molecular response in chronic-phase chronic myeloid leukemia patients who achieved major molecular response with detectable levels of BCR-ABL1 transcripts by imatinib therapy.

Shiseki M ，Yoshida C ，Takezako N ，Ohwada A ，Kumagai T ，Nishiwaki K ，Horikoshi A ，Fukuda T ，Takano H ，Kouzai Y ，Tanaka J ，Morita S ，Sakamoto J ，Sakamaki H ，Inokuchi K ... -  《-》

Dasatinib-associated major molecular responses in patients with chronic myeloid leukemia in chronic phase following imatinib failure: response dynamics and predictive value.

Hochhaus A ，Müller MC ，Radich J ，Branford S ，Kantarjian HM ，Hanfstein B ，Rousselot P ，Kim DW ，Lipton JH ，Bleickardt E ，Lambert A ，Hughes TP ... -  《-》

Comparative Effectiveness of Newer Tyrosine Kinase Inhibitors Versus Imatinib in the First-Line Treatment of Chronic-Phase Chronic Myeloid Leukemia Across Risk Groups: A Systematic Review and Meta-Analysis of Eight Randomized Trials.

BCR-ABL1 tyrosine kinase inhibitors (TKIs) have significantly improved the survival outcomes for patients with chronic myeloid leukemia (CML). In addition to imatinib, 3 newer generation TKIs (NG-TKIs) have been approved as first-line treatment of chronic phase (CP)-CML. These have been preferably used in patients with CP-CML with a high Sokal or Hasford risk score. We performed a systematic review and meta-analysis to compare the outcomes with NG-TKIs as a category versus imatinib in patients with newly diagnosed CP-CML and to indirectly compare the efficacy of NG-TKIs among each other. Furthermore, we assessed the effect of the risk scores on the complete cytogenetic response (CCyR) and major molecular response (MMR). The eligible studies were limited to randomized controlled trials comparing the efficacy of first-line treatment using NG-TKIs versus imatinib in adult patients (aged ≥ 18 years) with CP-CML. The differences in the CCyR, progression-free survival, and overall survival between the NG-TKIs and imatinib were not statistically significant. NG-TKI-treated patients showed a significantly greater likelihood of MMR (relative risk [RR], 0.76; 95% confidence interval, 0.63-0.91; P = .003) and lower likelihood of progression to an accelerated phase/blast crisis (RR, 0.37; 95% confidence interval, 0.20-0.67; P = .001) than did imatinib-treated patients. Nilotinib, dasatinib, and radotinib showed significantly greater CCyR rates compared with bosutinib and ponatinib. All risk groups showed statistically equivalent benefits from NG-TKIs for the CCyR and MMR. In first-line treatment, the NG-TKIs as a category showed greater effectiveness in MMR and prevention of accelerated phase/blast crisis progression. Risk stratification was not found to affect the RR of CCyR and MMR.

Yun S ，Vincelette ND ，Segar JM ，Dong Y ，Shen Y ，Kim DW ，Abraham I ... -  《-》