Efficacy and Safety of Ixazomib Plus Lenalidomide and Dexamethasone Following Injectable PI-Based Therapy in Relapsed/Refractory Multiple Myeloma.

This nationwide, multicenter, open-label, single-arm study evaluated the efficacy and safety of the oral proteasome inhibitor (PI), ixazomib plus lenalidomide (LEN) and dexamethasone (DEX) (IRd) following injectable PI-based therapy for relapsed/refractory multiple myeloma (RRMM). Of 45 patients enrolled, 36 patients received IRd after achieving at least a minor response to 3 cycles of bortezomib or carfilzomib plus LEN + DEX (VRd, n=6; KRd, n=30). At median follow-up of 20.8 months, the 12-month event-free survival rate (primary endpoint) was 49% (90% CI: 35.9-62.0), counting 11 events of progressive disease/death, 8 dropouts and 4 missing response data. The 12-month progression-free survival (PFS) rate by Kaplan-Meier analysis (dropouts as censoring) was 74% (95% CI: 56-86). Median PFS and time to next treatment (95% CI) were 29.0 (21.3-NE) and 32.3 (14.9-35.4) months, respectively; median OS was not evaluable. The overall response rate was 73%, and 42% of patients had a very good partial response or better. Frequent (≥10% incidence) grade ≥3 treatment emergent adverse events were decreased neutrophil and platelet counts (n=7 [16%] each). Two deaths occurred (one during KRd treatment and one during IRd treatment), both due to pneumonia. IRd following injectable PI-based therapy was tolerable and efficacious in RRMM patients. TRIAL REGISTRATION NUMBER: NCT03416374; Date of registration: January 31, 2018.

Post-marketing surveillance of carfilzomib in Japanese patients with relapsed or refractory multiple myeloma.

Aim: To evaluate the safety and effectiveness of carfilzomib in a real-world setting. Methods: A post-marketing surveillance of Japanese patients with relapsed or refractory multiple myeloma who received carfilzomib treatment was performed. Results: Overall incidences of adverse events of any grade, ≥grade 3 treatment-related adverse events and serious adverse events were 63.5, 44.6 and 37.7% of patients, respectively. No new safety findings were observed. Treatment-related adverse events of special interest (≥5%) were hematological toxicities, infectious disease, cardiac disorders (including cardiac failure, myocardial infarction and QT prolongation), renal disorders, liver failure or liver dysfunction, and hypertension or hypertensive crisis. The overall response rate was 46.5%. Conclusion: Carfilzomib was found to be a safe and effective treatment for relapsed or refractory multiple myeloma in Japanese patients.

Carfilzomib is a medicine that was recently approved for the treatment of cancer of bone marrow (multiple myeloma) that comes back or does not respond to previous treatment (relapsed or refractory). Data gathered from the hospitals, where the medicine is commonly used, was used to generate evidence. We looked at how well carfilzomib works in Japanese participants and if it is safe. Overall, 63.5% of participants treated with carfilzomib had side effects and 37.7% had serious side effects. Death occurred in 3.1% of participants during the study. Decrease in bone marrow and blood cells, infections, heart and kidney disorder, liver failure or dysfunction, and high blood pressure occurred in 5% or more participants. In 46.5% of participants the tumors had disappeared or shrank. In Japanese participants, carfilzomib was found to be safe and effective treatment for cancer of bone marrow that comes back or does not respond to previous treatment.

A phase 2, open-label, multicenter study of ixazomib plus lenalidomide and dexamethasone in adult Japanese patients with relapsed and/or refractory multiple myeloma.

BACKGROUND: TOURMALINE-MM1 was a global study that demonstrated a significant improvement in progression-free survival with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone, in patients with relapsed and/or refractory multiple myeloma. The current study was conducted to evaluate further the efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients. METHODS: This phase 2, open-label, single-arm, multicenter study enrolled patients aged ≥ 20 years with relapsed and/or refractory multiple myeloma at 16 sites in Japan. Patients refractory to lenalidomide or proteasome inhibitor-based therapy at any line were excluded. The primary endpoint was the rate of very good partial response or better in the response-evaluable analysis set. Secondary endpoints were progression-free survival, overall response rate, duration of response, time to progression, overall survival and safety. RESULTS: In total, 34 patients were enrolled. The rate of very good partial response or better was 50.0% (95% confidence interval 31.9-68.1) and the overall response rate was 84.4% (95% confidence interval 67.2-94.7). Median progression-free survival was 22.0 months (95% confidence interval 17.3-not evaluable) and median overall survival was not estimable. The safety profile of ixazomib plus lenalidomide and dexamethasone in this study was similar to that in the TOURMALINE-MM1 study. CONCLUSIONS: The efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma are comparable with reported TOURMALINE-MM1 study results. CLINICALTRIALS. GOV IDENTIFIER: NCT02917941; date of registration September 28, 2016.

Phase I, multicenter, dose-escalation study of avadomide in adult Japanese patients with advanced malignancies.

Non-Hodgkin lymphoma (NHL) treated with chemoimmunotherapy has limited efficacy in some patients, resulting in relapsed or refractory disease. Avadomide (CC-122) is a novel cereblon-binding agent that exhibits antilymphoma and immune-modulation activities with a biological profile distinct from similar agents, such as lenalidomide. This phase I multicenter study evaluated avadomide in Japanese patients with advanced solid tumors or NHL. Fourteen patients with NHL and one with a solid tumor (esophageal carcinoma), were enrolled in four dose-escalation cohorts using a 3 + 3 design. Primary endpoints included safety, dose-limiting toxicities (DLT), maximum-tolerated dose and/or recommended phase II dose (RP2D), and pharmacokinetics. Secondary endpoints included overall response rate (ORR) and duration of response. One patient with NHL experienced DLT, which included face edema, pharyngeal edema, and tumor flare (all grade 1) that led to a dose reduction. Eleven patients had grade ≥3 treatment-emergent adverse events, most frequently decreased neutrophil count (33%) and decreased lymphocyte count (20%). The ORR in patients with NHL (n = 13) was 54%, including four complete and three partial responses. The best response for the solid tumor patient was progressive disease. Avadomide dose intensity was consistent across cohorts, and the 3-mg dose given five consecutive days/week was established as the RP2D. This phase I study identified a tolerable dose of avadomide, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with previously treated NHL.

Carfilzomib monotherapy in Japanese patients with relapsed or refractory multiple myeloma: A phase 1/2 study.

This multicenter, open-label phase 1/2 study evaluated single-agent carfilzomib in 50 heavily pretreated Japanese patients with relapsed/refractory multiple myeloma (median of five prior treatments). In phase 1, patients were dosed at three levels: 15, 20, or 20/27 mg/m2 . Maximum tolerated dosage was not reached at the tolerability evaluation. Patients in phase 2 were treated with 20/27 mg/m2 carfilzomib. Median duration of exposure to carfilzomib in the 20/27 mg/m2 group at this final analysis was 4.7 months (range: 0.3-39.4). Overall response rate in the 20/27 mg/m2 group, primary endpoint of the study, was 22.5% (n = 9) (95% confidence interval, 12.3-37.5) with 2.5% (n = 1) stringent complete response. Median progression-free survival and overall survival in the 20/27 mg/m2 group were 5.1 months (95% CI, 2.8-13.6) and 22.9 months (95% CI, 14.1-not estimable), respectively. Frequently occurring grade ≥3 adverse events in the 20/27 mg/m2 group included lymphopenia (72.5%), neutropenia (40.0%), and leukopenia (32.5%). Giving long-term carfilzomib monotherapy led to long-term overall survival for heavily pretreated multiple myeloma patients with a favorable safety profile. Carfilzomib monotherapy can be a good option for heavily pretreated multiple myeloma patients.

Evaluation of the Revised International Staging System (R-ISS) in Japanese patients with multiple myeloma.

In spite of recent development in the treatment armamentarium for multiple myeloma, overall survival (OS) still depends on risk status and sensitivity to treatment of each patient. We have evaluated the clinical relevance of the Revised International Staging System (R-ISS) by comparing it with the original ISS in 718 Japanese patients. The distribution of patients according to response was similar between the ISS and R-ISS stages. Treatment response was greatly influenced by initial treatment modalities and deeper response was observed more frequently in transplanted patients. The R-ISS discriminated the difference in OS between the stages more distinctly than the ISS (p = 9.0 × 10-15 and p = 4.0 × 10-10, respectively). Differences in OS were clarified by both R-ISS and ISS in non-transplanted patients (p = 2.4 × 10-12 and p = 1.4 × 10-8, respectively), but the ISS failed to distinguish the difference between the stages in transplanted patients (p = 0.13). In contrast, the R-ISS could at least discriminate the excellent prognosis of stage I patients whereas the distinction between stage II and III was not that clear (p = 0.033). The R-ISS stage II encompassed a large number of patients, and the prognosis was heterogeneous depending on the fulfillment of prognostic factors such as LDH and adverse cytogenetics. These results suggest that treatment factors and prognostic factors greatly affect the therapeutic response and outcome, and the R-ISS is superior to ISS in prognostication of both transplant-eligible and -ineligible patients in our current clinical practice.

Future projection of cancer patients with cardiovascular disease in Japan by the year 2039: a pilot study.

BACKGROUND: The number of cancer patients in Japan is estimated to rise to 3.5 million by 2025. The disease burden may be further complicated by comorbidities caused by cardiovascular disease (CVD). Predicting the number of cancer patients with CVD can help anticipate future resource needs. METHODS: We used statistics derived from the Niigata Cancer Center CVD Study (2015) as well as population estimates from the National Cancer Center's Cancer Registry and Statistics survey of 2017 for convenience. We simply multiplied the projected number of cancer patients through the year 2039 by the CVD prevalence in 2015, with patients classified by sex, age, and cancer type to estimate the number of cancer patients with CVD. RESULTS: The total number of Japanese cancer patients with CVD was 253,000 in 2015 and is predicted to increase rapidly by 30,000 in 2020 and peak at 313,000 in 2030-2034. Men will dominate the CVD population at 2.5-fold the number of women. The growth rate of the population with both cancer and CVD will be greater than that of the cancer-only population (1.23 vs 1.18, P < 0.001), and will comprise notably high proportions of patients with prostatic, breast, and uterine cancers (1.80, 1.57, and 1.66, P < 0.001, respectively). CONCLUSION: Future cancer patients will be older and more likely to have CVD. Although men will continue to dominate this population, the increase in the number of women will be pronounced. Cancer care providers should be trained to recognize CVD and provide any necessary interventions concurrently with cancer therapy.

Correction to: Future projection of cancer patients with cardiovascular disease in Japan by the year 2039: a pilot study.

n the original publication, in a title of Table 2.

Weekly carfilzomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma: A phase 1 and PK/PD trial.

This open-label multicenter phase 1 study evaluated the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of weekly carfilzomib and dexamethasone (Cd) in Japanese patients with relapsed or refractory multiple myeloma (RRMM). Carfilzomib was administered by 30-minute intravenous infusion on Days 1, 8 and 15 in a 28-day cycle starting at 20 mg/m2 on Day 1/Cycle 1 and 70 mg/m2 thereafter until progressive disease or unacceptable toxicity. Dexamethasone 40 mg was administered on Days 1, 8, 15 and 22 in Cycles 1-9 and on Days 1, 8 and 15 thereafter. Six patients were enrolled between March 2015 and June 2015. Patients had received a median of 4.5 (range, 4-8) prior regimens; all patients had previous therapies with bortezomib and immunomodulatory drugs. Of the 6 patients, 1 had a dose-limiting toxicity (DLT), and tolerability was confirmed. The DLT was grade 3 thrombotic microangiopathy, which was considered serious and occurred on Day 11/Cycle 1. All 6 patients (100%) experienced at least 1 grade ≥3 adverse event (AE). Two patients (33.3%) experienced AE (also considered adverse drug reactions) leading to study discontinuation: thrombotic microangiopathy (Day 11/Cycle 1) and thrombotic thrombocytopenic purpura (Day 6/Cycle 2). The overall response rate was 83.3% (95% confidence interval, 43.6-97.0). The weekly Cd regimen at a carfilzomib dose of 20/70 mg/m2 was well-tolerated among Japanese patients with RRMM. Our results could be the basis for the further development of carfilzomib treatment considering safety profiles including microangiopathy-related events and efficacy.

Pretreatment evaluation of fluorescence resonance energy transfer-based drug sensitivity test for patients with chronic myelogenous leukemia treated with dasatinib.

Tyrosine kinase inhibitors (TKI) are used for primary therapy in patients with newly diagnosed CML. However, a reliable method for optimal selection of a TKI from the viewpoint of drug sensitivity of CML cells has not been established. We have developed a FRET-based drug sensitivity test in which a CrkL-derived fluorescent biosensor efficiently quantifies the kinase activity of BCR-ABL of living cells and sensitively evaluates the inhibitory activity of a TKI against BCR-ABL. Here, we validated the utility of the FRET-based drug sensitivity test carried out at diagnosis for predicting the molecular efficacy. Sixty-two patients with newly diagnosed chronic phase CML were enrolled in this study and treated with dasatinib. Bone marrow cells at diagnosis were subjected to FRET analysis. The ΔFRET value was calculated by subtraction of FRET efficiency in the presence of dasatinib from that in the absence of dasatinib. Treatment response was evaluated every 3 months by the BCR-ABL1 International Scale. Based on the ΔFRET value and molecular response, a threshold of the ΔFRET value in the top 10% of FRET efficiency was set to 0.31. Patients with ΔFRET value ≥0.31 had significantly superior molecular responses (MMR at 6 and 9 months and both MR4 and MR4.5 at 6, 9, and 12 months) compared with the responses in patients with ΔFRET value <0.31. These results suggest that the FRET-based drug sensitivity test at diagnosis can predict early and deep molecular responses. This study is registered with UMIN Clinical Trials Registry (UMIN000006358).

Rapid reduction in BCR-ABL1 transcript predicts deep molecular response in dasatinib-treated chronic-phase chronic myeloid leukaemia patients.

OBJECTIVES: We conducted a phase-II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP) in Japan (IMIDAS PART 2 study). METHODS: Seventy-nine patients were administered 100 mg dasatinib once daily. We examined pretreatment and post-treatment influences of various factors. The BCR-ABL1 international scale (IS), halving time (HT) and reduction rate of BCR-ABL1 transcript within the initial 1 or 3 months of therapy (RR-BCR-ABL11m,3m ) were the post-treatment factors investigated to predict the molecular response. RESULTS: The estimated major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) rates were 77.2%, 49.4% and 35.4%, respectively, at 12 months. Grade 3/4 non-haematologic adverse events were infrequent. Multivariate analysis showed that age >65 years was significantly correlated with MR4.0 and MR4.5 (deep molecular response: DMR) at 12 months. All post-treatment factors at 3 months predicted DMR by univariate analysis. However, RR-BCR-ABL13m was the only significant landmark for predicting DMR by multivariate analysis. CONCLUSIONS: Primary treatment of CML-CP with dasatinib enabled early achievement of MMR and DMR, particularly in elderly patients, with high safety. Furthermore, RR-BCR-ABL13m was found to be a more useful predictor of DMR than HT-BCR-ABL1 and BCR-ABL1 IS.

Carfilzomib, lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan.

This is the first study in which the carfilzomib, lenalidomide and dexamethasone (KRd) regimen was evaluated in heavily pretreated multiple myeloma. This study is a multicenter, open-label phase 1 study of KRd in Japanese patients with relapsed or refractory multiple myeloma (RRMM) patients. The objectives were to evaluate the safety, tolerability, efficacy and pharmacokinetics of the regimen. Carfilzomib was administrated intravenously over 10 min on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. In cycle 1, the dosage for days 1 and 2 was 20 mg/m2 , followed by 27 mg/m2 . Lenalidomide and dexamethasone were administered at 25 mg (days 1-21) and 40 mg (days 1, 8, 15 and 22), respectively. Twenty-six patients were enrolled. Patients had received a median of four prior regimens and 88.5% and 61.5% received previous bortezomib and lenalidomide, respectively. High-risk cytogenetics were seen in 53.8% of patients. The overall response rate was 88.5%. A higher rate of hyperglycemia was observed than in a previous carfilzomib monotherapy study, but this was attributed to dexamethasone. Carfilzomib pharmacokinetics were not affected by lenalidomide and dexamethasone. The KRd regimen was well tolerated and showed efficacy in Japanese RRMM patients.

Comparison of Autologous and Unrelated Transplants for Cytogenetically Normal Acute Myelogenous Leukemia.

Allogeneic stem cell transplantation (SCT) from an HLA-matched sibling donor (MSD) is a postremission treatment that offers a potential cure for adults with cytogenetically normal (CN) acute myelogenous leukemia (AML) in first complete remission (CR1). The best alternative in the absence of an MSD remains unclear, however. The aim of this study was to retrospectively compare the outcomes of autologous peripheral blood stem cell transplantation (auto-PBSCT; n = 177) and allogeneic bone marrow transplantation (BMT) from an HLA-matched unrelated donor (MUD; n = 173) in adult patients with CN-AML/CR1. Both the multivariate analysis (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.71 to 1.97; P = .53) and propensity score models (HR, 1.40; 95% CI, 0.80 to 2.43; P = .24) indicated that the leukemia-free survival (LFS) rate of auto-PBSCT was not significantly different from that of MUD-BMT. These results suggest that in the absence of an available MSD, auto-PBSCT remains a viable alternative as postremission therapy in patients with CN-AML/CR1.

[Lenalidomide and low-dose dexamethasone therapy for Japanese patients with newly diagnosed multiple myeloma: updated results of the MM-025 study].

In a Japanese phase II study (MM-025), the efficacy and safety of lenalidomide plus low-dose dexamethasone (Rd) were confirmed at a median follow-up of 14.2 months in patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic stem cell transplantation. In the present report, we analyzed the follow-up data from the abovementioned study. Treatment was stopped for all 26 patients after a median follow-up of 31.3 months, and the median treatment duration was approximately 25 months. The overall response rate was 87.5%, and the complete response rate was 20.8%. The median duration of response and progression-free survival were 30.7 and 31.6 months, respectively. The median overall survival has not yet been reached. At least one grade 3/4 adverse event was experienced by 23 patients (88.5%), and 18 patients (69.2%) experienced serious adverse events. There were no treatment-related deaths. Therefore, the efficacy and safety of Rd were confirmed in transplant-ineligible Japanese patients with newly diagnosed multiple myeloma at the present follow-up period.

Lenalidomide and low-dose dexamethasone in Japanese patients with newly diagnosed multiple myeloma: A phase II study.

In the FIRST trial (MM-020), lenalidomide plus low-dose dexamethasone (Rd) reduced the risk of disease progression or death compared with combination melphalan-prednisone-thalidomide. As the FIRST trial did not include any Japanese patients, the efficacy and safety of continuous treatment with Rd was evaluated in 26 Japanese patients with newly diagnosed multiple myeloma (NDMM) in a single-arm, multicenter, open-label phase II trial (MM-025). Patients received lenalidomide on days 1-21 of each 28-day cycle, with a starting dose of 25 mg/day (dose adjusted for renal impairment), and 40 mg/day dexamethasone (dose adjusted for age) on days 1, 8, 15 and 22 of each 28-day cycle until disease progression or discontinuation for any reason. In the efficacy evaluable population, overall response rate was 87.5%, including 29.2% of patients who achieved a complete response/very good partial response. Median durations of response, progression-free survival and overall survival have not been reached. The most common grade 3-4 adverse events were neutropenia (23%) and anemia (19%). The efficacy and safety of Rd were consistent with data from larger studies, including the FIRST trial, thereby supporting the use of Rd continuous in Japanese patients with NDMM who are ineligible for stem cell transplantation.

A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma.

We conducted a phase 1/2 study of single-agent carfilzomib in Japanese patients with relapsed/refractory multiple myeloma. Safety, pharmacokinetics and pharmacodynamics of carfilzomib were examined in phase 1. The primary endpoint in phase 2 was the overall response rate (ORR). Carfilzomib was administered in a twice-weekly, consecutive-day dosing schedule. In Phase 1, doses of 15 or 20 mg/m(2) were administered on this schedule or 20 mg/m(2) on Days 1 and 2 of Cycle 1 and then 27 mg/m(2) in the 20/27 mg/m(2) cohort. Patients had a median of five prior therapies, including bortezomib and an immunomodulatory agent. The dose level did not reach the maximum tolerated dose. The most common adverse events were haematological. Notably, carfilzomib either induced new hypertension (n = 4) or aggravated previously existing hypertension (n = 6) in 10 of 50 patients. Four of the eight patients who previously experienced peripheral neuropathy (PN) experienced a recurrence with carfilzomib use, but no new cases of PN occurred. The ORR of the 20/27 mg/m(2) 40 patient cohort was similar to that in the pivotal US study. The dose was efficacious and tolerable in heavily pre-treated Japanese patients; however, meticulous control of hypertension may be necessary for further carfilzomib use.

Long-term follow-up results of a phase I/II study of melphalan, prednisolone and bortezomib in Japanese transplant-ineligible multiple myeloma patients (JPN-102).

The phase I/II study of melphalan-prednisolone-bortezomib (MPB) therapy in Japanese patients with previously untreated multiple myeloma (MM) who are ineligible for hematopoietic stem cell transplantation (JPN-102 trial) (registered between July 2008 and March 2011) showed an overall response rate in the MPB arm equivalent to that of the VISTA trial. In this study, we followed up the clinical data of 92 of the 101 patients registered in the JPN-102 trial to clarify the long-term outcomes of MPB therapy. The median follow-up period was 50.8 (0.9-66.1) months. The median age of this cohort was 72 (48-84) years. The median progression-free survival was 25.7 (95%CI: 21.3-33.9) months and the overall survival rates at 1, 3 and 5 years were 98, 86 and 76%, respectively. There was no significant difference in either progression-free survival or overall survival when comparing a total bortezomib amount of 39 mg/m2 or more being administered versus less than 39 mg/m2. The outcomes of the JPN-102 cohort appeared, at a minimum, to not be inferior to those of the MPB cohort in the VISTA trial. A prospective trial is needed to establish the MPB regimen as being suitable for Japanese patients with multiple myeloma.

Pomalidomide alone or in combination with dexamethasone in Japanese patients with refractory or relapsed and refractory multiple myeloma.

This phase 1, open-label, dose-escalation study investigated the tolerated dose (recommended dose), safety, efficacy, and pharmacokinetics of pomalidomide alone or pomalidomide plus low-dose dexamethasone in Japanese patients with refractory or relapsed and refractory multiple myeloma. Twelve patients were enrolled. Patients received pomalidomide 2 mg (Cohort 1) or 4 mg (Cohort 2) orally on day 1 and days 3-21 of a 28-day cycle. The tolerated dose of pomalidomide was determined to be 4 mg given on days 1-21 of a 28-day cycle. Efficacy outcomes with pomalidomide plus low-dose dexamethasone were consistent with those of previous studies. Responses (partial response or better) were achieved by three patients (25%; 1 [17%] in Cohort 1 and 2 [33%] in Cohort 2), and the median time to response was 6.4 months overall (9.0 months for Cohort 1 and 4.2 months for Cohort 2). The median progression-free survival was 5.5 months overall (5.1 months for Cohort 1 and not reached for Cohort 2). The most frequently occurring grade ≥3 adverse events were neutropenia (67%), anemia (25%), lymphopenia (25%), and pneumonia (25%), consistent with previous studies of pomalidomide plus low-dose dexamethasone in refractory or relapsed and refractory multiple myeloma. Further investigation of pomalidomide is recommended for Japanese patients with refractory or relapsed and refractory multiple myeloma. This study was registered with ClinicalTrials.gov (NCT01568294).

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.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.