Chronic myeloid leukemia patients who develop grade I/II pleural effusion under second-line dasatinib have better responses and outcomes than patients without pleural effusion

Eşkazan, Ahmet Emre; Karabacak, Deniz Eyice; Kurt, Enes Ali; Elverdi, Tuğrul; Yalniz, Fevzi F.; Salihoğlu, Ayşe; Ar, Muhlis Cem; Aydın, Şeniz Öngören; Başlar, Zafer; Ferhanoğlu, Burhan; Aydın, Yıldız; Tuzuner, Nukhet; Özbek, Uğur; Soysal, Teoman

doi:10.1016/j.leukres.2014.04.004

Cited by 33 publications

(26 citation statements)

References 26 publications

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“…Particularly for TKI-related PE, this AE was more common with dasatinib (28%) than with imatinib (0.8%); however with proper supportive measures, only 15 patients (6%) required permanent discontinuation of dasatinib due to PE. The generation of PE did not impair the ability of patients to obtain a response [11], and these findings were consistent with the data that when dasatinib was used after imatinib failure, in patients who experienced grade I/II PE under dasatinib, continuing dasatinib together with management strategies induced durable responses [12]. In addition to that, the number of patients quitting the study drug due to failure were similar in both arms [28 (11%) and 36 (14%) for the dasatinib and imatinib arms, respectively], and at the time of the analysis, the number of patients on each study arms were comparable [162 (63%) vs. 158 (61%) for the imatinib and dasatinib arms, respectively] [11].…”

Section: Dasatinib In the First-line Treatment Of Cml-cpsupporting

confidence: 88%

Tyrosine kinase inhibitor (TKI) therapy for newly-diagnosed patients with chronic myeloid leukemia: focusing on TKI discontinuation due to adverse events – is better always good?

Eşkazan

Özmen

2017

Expert Review of Hematology

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Section: Dasatinib In the First-line Treatment Of Cml-cpsupporting

confidence: 88%

Tyrosine kinase inhibitor (TKI) therapy for newly-diagnosed patients with chronic myeloid leukemia: focusing on TKI discontinuation due to adverse events – is better always good?

Eşkazan

Özmen

2017

Expert Review of Hematology

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“…Our observation that effusions were associated with both early and deep molecular response as well as improved CML outcomes is consistent with the literature and are likely indicative of potency of the TKI effect. 17,18 Management of effusions varied substantially between institutions reflecting a lack of a consensus approach to this adverse event. Approaches included dasatinib dose reduction, temporary or permanent cessation, steroids acutely and as maintenance, and diuretics.…”

Section: Discussionmentioning

confidence: 99%

The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia

et al. 2017

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Key Points• Prescribing appropriately for age and cardiovascular risk is likely to result in minimal permanent toxicity-related dasatinib cessation.• CML patients on dasatinib with pleural effusion are more likely to have achieved MR4.5 after 6-month therapy than those without effusion.Dasatinib has shown superiority over imatinib in achieving molecular responses (MRs) in chronic phase chronic myeloid leukemia but with a different toxicity profile, which may impact its overall benefit. Reported toxicities include pleural effusions and pulmonary hypertension, and although the incidence of these events is well described, response to therapy and impact of dose modifications on toxicity has not been comprehensively characterized in a real-world setting. We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic phase chronic myeloid leukemia patients at 17 Australian institutions. Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation.Age and dose were risk factors for pleural effusion (P , .01 and .047, respectively).Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced (P 5 .041); however, recurrence still occurred at 50 mg. Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions (P 5 .008). Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients. Dose reductions and temporary cessations had minimal impact on MR rates. Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.

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“…9 Radotinib was used at an initial dose of 2x400 mg/daily in the present study, and the most common grade 3-4 hematologic AE was thrombocytopenia, which was observed in 25% of the patients.…”

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confidence: 83%

Radotinib in the treatment of chronic phase chronic myeloid leukemia patients

Eşkazan

Soysal

2014

Haematologica

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We read with interest the article by Kim et al. 1 in which the authors provided the efficacy and safety data of radotinib (IY5511HCL), an oral BCR-ABL1-specific 2 nd generation tyrosine kinase inhibitor (TKI), in 77 patients with chronic phase-chronic myeloid leukemia (CP-CML) in a multinational phase II trial. After a median duration of radotinib exposure of approximately 12 months and a median follow up of 23.4 months, the complete cytogenetic response (CCyR) rate was 47% by 12 months, and the overall and progression-free survival rates at 12 months were 96.1% and 86.3%, respectively. Thrombocytopenia, hepatotoxicity, hyperbilirubinemia and hyperglycemia were the most common hematologic and non-hematologic adverse events (AEs). The authors implied that radotinib was effective and relatively well tolerated in patients with CP-CML, and CCyR rates were higher in patients without BCR-ABL1 mutations. 1Although most of the CP-CML patients do well under imatinib, some of them develop resistance, and BCR-ABL1 kinase domain mutations are detected in approximately 50% of patients with treatment failure and progression. Second generation TKIs (dasatinib and nilotinib) are used in patients who have intolerance and resistance to imatinib.3,4 In the study cohort, CCyR rate at 12 months was 47%, and the authors compared their results with dasatinib and nilotinib. They concluded that the efficacy of the study drug was comparable, and even favorable, to those observed with dasatinib 3 and nilotinib. 4 But these 2 studies which the authors mentioned have shorter followup durations than the present study, and when the other TKIs were used as a second-line treatment at longer followup periods the CCyR rates were similar to those of the present study: dasatinib 45%, 5 nilotinib 44%, 6 and bosutinib 41% 7. As expected, the response rates were higher in imatinib intolerant cases than in those who were resistant, 1 which has already been shown in the second-line dasatinib and nilotinib trials. 5,6 The authors concluded that in 5 patients with a BCR-ABL1 mutation which was less sensitive to nilotinib or dasatinib, 2 had gained major CyR. But there seems to be a problem in terms of efficacy of radotinib in patients with a mutated clone (n=14) because only 3 of these patients have responded to the study drug. Moreover, during follow up, 6 additional patients were found to harbor new mutations, including T315I. This is a major challenge for clinicians given that nearly half the patients with imatinib resistance have BCR-ABL1 mutations.Dasatinib and nilotinib are generally well tolerated but they do have AEs that appear in the short term or after a longer follow up.8 Their familiarity with these AEs allows physicians caring for CML patients to recognize and manage them.9 Radotinib was used at an initial dose of 2x400 mg/daily in the present study, and the most common grade 3-4 hematologic AE was thrombocytopenia, which was observed in 25% of the patients.1 Grade 1-2 hepatotoxicity was present in more than 70% of the patients, and the pe...

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Chronic myeloid leukemia patients who develop grade I/II pleural effusion under second-line dasatinib have better responses and outcomes than patients without pleural effusion

Cited by 33 publications

References 26 publications

Tyrosine kinase inhibitor (TKI) therapy for newly-diagnosed patients with chronic myeloid leukemia: focusing on TKI discontinuation due to adverse events – is better always good?

Tyrosine kinase inhibitor (TKI) therapy for newly-diagnosed patients with chronic myeloid leukemia: focusing on TKI discontinuation due to adverse events – is better always good?

The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia

Radotinib in the treatment of chronic phase chronic myeloid leukemia patients

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