Assessment of Dasatinib Versus Nilotinib as Upfront Therapy for Chronic Phase of Chronic Myeloid Leukemia in Qatar: A Cost-Effectiveness Analysis

Background: The economic outcome research of approved tyrosine kinase inhibitors for treating the chronic phase of chronic myeloid leukemia in developing is scarce. The aim of this study was to assess the cost-effectiveness of dasatinib and nilotinib for newly diagnosed chronic myeloid leukemia patients. Methods: A decision tree model was developed linking clinical effectiveness (defined as major molecular response) and/or complete cytogenetic response, utility, and cost data over a 12-month period. Patients are recruited from Qatar Cancer Registry. The probability of primary clinical outcome is calculated from DASISION (dasatinib) and ENESTnd (nilotinib) trials. Direct healthcare costs were derived from the national healthcare payer system, whereas adverse effects data were derived from local incident reporting system. Results: In the first-line treatments of chronic myeloid leukemia patients, nilotinib has greater major molecular response (39% nilotinib vs 12% dasatinib) and complete cytogenetic response (24% nilotinib vs 16% dastinib) response outcomes, and more adverse effects than dasatinib (13.3% vs 4%). Moreover, nilotinib is more cost-effective with annual costs (USD63,589.59) and after 12 months of follow-up. Despite the lower acquisition annual cost of dasatinib (USD59,486.30), the incremental cost-effectiveness ratio of nilotinib (vs dasatinib) per major molecular response/complete cytogenetic response achieved was USD15,481.10 per year. There were no cases in both arms that progressed to accelerated or blast phase. At a threshold of 3 times gross domestic product per capita of Qatar and according to World Health Organization recommendation, the nilotinib use is still cost-effective. Conclusion: Upfront therapy of chronic myeloid leukemia–chronic phase patients by nilotinib plan appears to be more cost-effective than dasatinib.

Pharmacokinetics, Efficacy and Safety of Bosutinib in a Pediatric Patient With Chronic Myeloid Leukemia

Bosutinib is a second-generation tyrosine kinase inhibitor indicated for treatment of chronic myeloid leukemia (CML) in adult patients. The safety and efficacy of bosutinib in patients younger than 18 years of age have not been established. We here report the case of a 4-year-old male with CML who was treated with bosutinib during coordination of human leukocyte antigen–matched unrelated bone-marrow transplantation because of insufficient responses to imatinib and dasatinib. The patient achieved a complete cytogenetic response immediately after starting bosutinib at 180 mg/day (290 mg/m2/day). Because toxicity was tolerable, the dose was increased to 200 mg/day (330 mg/m2/day). A complete cytogenetic response was maintained, but a major molecular response was not achieved 6 months after initiation of treatment with bosutinib. At steady state, maximum plasma concentration, minimum plasma concentration, and area under the plasma concentration-time curve were 89.2 ng/mL, 16.7 ng/mL, and 1017.4 ng·hr/mL, respectively, at 290 mg/m2/day; and 141.1 ng/mL, 18.9 ng/mL, and 1278.5 ng·hr/mL, respectively, at 330 mg/m2/day. To the best of our knowledge, this is the first case report to show the pharmacokinetics of bosutinib with efficacy and safety in a pediatric patient with CML. This rare case in a very young child with CML can also be valuable reference for clinical practice.

CHRONIC MYELOID LEUKEMIA COURSE IN PERSONS EXPOSED TO IONIZING RADIATION AS A RESULT OF THE CHORNOBYL ACCIDENT

Objective. Describe and characterize the peculiarities of the chronic myeloid leukemia (CML) course and response to treatment in patients irradiated as a result of the Chornobyl nuclear power plant (ChNPP) accident based on the assessment of clinical-laboratory and clinical parameters. Materials and methods. The CML patients (n = 33) exposed to ionizing radiation as a result of the ChNPP accident were enrolled. The comparison group consisted of CML patients (n = 725) with no history of radiation exposure. All patients were in the chronic phase of the disease. Clinical, hematological and molecular genetic research methods were applied. Results. Patients exposed to ionizing radiation as a result of the ChNPP accident had no differences in CML manifestation, as well as in classical genetic markers at the onset of the disease compared with patients with no history of radiation exposure. Reduction of tumor clone on imatinib therapy was significantly less effective in the patients exposed to ionizing radiation than in cases of no history of radiation exposure. Cases of primary resistance were statistically significantly prevalent in the ChNPP accident consequences clean-up workers while in the residents of radiologically contaminated areas a statistically significant increase in probability of loss of complete cytogenetic response (development of secondary resistance) to imatinib therapy was found. An association was found between the radiation exposure and probability of loss of complete cytogenetic response to imatinib therapy in this group of patients. Conclusion. The radiation exposure in the history even many years before the onset of CML is an unfavorable exogenous factor responsible for the development of resistance to imatinib therapy. Key words: chronic myeloid leukemia, ionizing radiation, tyrosine kinase inhibitors, response to treatment.

Pregnancy Outcomes in Chronic Myeloid Leukemia: A Single Center Experience

PURPOSE The aim of the current work was to report the effect of imatinib on pregnancy in patients with chronic myeloid leukemia (CML). METHODS Data were collected between January 1998 and December 2014. One hundred four patients met inclusion criteria, and we report the results of 104 pregnancies—conceived by the participant or partner—while being on imatinib therapy for CML. RESULTS Fifty-eight patients were male and 46 were female. Eighty-three patients, 20 patients, and one patient were had CML in the chronic phase, accelerated phase, or blast phase, respectively. Of 46 female patients, 21 underwent abortion (spontaneous, n = 36.9; elective termination, n = 8.6%). In the case of full-term pregnancy in the female partners of male patients with CML, all outcomes were uneventful. Of 46 female patients, 25 had full-term pregnancy outcomes. During the pre–imatinib era (total n = 6), patients were treated with hydroxyurea, interferon-alpha, and therapeutic leukapheresis. A total 10 of 19 pregnant patients continued on imatinib until their delivery and experienced the following outcomes: normal full-term deliveries (n = 7), preterm delivery (n = 1), omphalocele (n = 1), and craniosynostosis (n = 1). Of those who discontinued imatinib after counseling (n = 9), eight patients had full-term normal delivery, of which two patients required leukapheresis and one patient expired. All patients who continued on imatinib while pregnant were in complete cytogenetic response and major molecular response (MMR) before pregnancy, during pregnancy, and postpregnancy. Of nine patients who discontinued imatinib, two lost MMR during the third trimester and all of these patients were in complete cytogenetic response and MMR before pregnancy. CONCLUSION It is clear that there is no standard of care for the best treatment of CML in the case of pregnancy. Interferon and/or leukapheresis will be included as treatment options. Patients can have normal pregnancies even with the administration of imatinib at the risk of congenital anomalies, intervention for which can be done after birth.

CML Patients Outcome after TKI Discontinuation: A Single Institution Experience in the US

Chronic myeloid leukemia (CML) patients who achieve a complete cytogenetic response (CCyR) with tyrosine kinase inhibitor (TKI) have an expected survival rate comparable to that of the general population. It is practice to continue TKI therapy indefinitely. However, this chronic therapy may impact patient's lives either by its associated adverse events, or its influence on real-life events (eg. pregnancy, financial burden). Therefore, treatment discontinuation has been increasingly sought. Discontinuation of therapy for patients with sustained MR4.5 has been associated with 30-50% sustained molecular response in previous studies. However, patients may sometimes choose to discontinue therapy for various reasons regardless of the response. We retrospectively analyzed the outcome of 95 patients with CML who discontinued TKI therapy at a single institution. Median age at diagnosis was 50 years (range 26 - 75), 56 (59%) were females. Median follow up from diagnosis to treatment discontinuation was 120 months. TKI was the initial therapy in 62 patients (41 imatinib, 7 nilotinib, 12 dasatinib, 1 bosutinib, 1 ponatinib) and interferon in 33 patients (34%). At time of discontinuation, 67 patients (71%) were receiving their first TKI (48 imatinib, 6 nilotinib, 12 dasatinib, 1 ponatinib) while 25 (26%) and 3 (3%) patients were receiving their second and third TKI respectively. All patients achieved complete cytogenetic response (CCyR) and major molecular response (MMR) in a median of 3 (range 2-93) and 9 months (range 2-132) respectively. MR4.5 was achieved in 92 (97%) patients at a median of 17 months. Three patients had MMR as their best response. Patients received TKI for a median of 104 months (range 8-203) before discontinuation. Fifty two patients (54%) discontinued therapy due to adverse events, 27 (28%) electively due to sustained MR4.5, 7 (7%) due to pregnancy, 6 (6%) for financial reasons and 3 (3%) due to the occurrence of a second cancer. At time of discontinuation all patients were in CCyR; 90 patients (95%) were in MR4.5 and 5 patients (5%) in MMR. The median MR4.5 duration before discontinuation was 75 months (range 1-178); 84 had a sustained MR4.5 for at least 2 years and 59 for at least 5 years. After a median follow-up from treatment discontinuation of 23 months (0 to 113 months), 38 (40%) patients have lost their response at a median of 4 months (range 1-34) after discontinuation; 10 patients lost response after 12 months from discontinuation. Among patients with MR4.5 at discontinuation, molecular relapse occurred in 33 patients (37%) at a median of 4 months (range 1-34; 8 after 12 months from discontinuation). All 5 patients with MMR at discontinuation loss their response at a median of 8 months (range 2-14). Patients receiving imatinib, dasatinib or nilotinib had a median TKI treatment duration of 117, 64 and 65 months before discontinuation, and lost their response at a rate of 33%, 56% and 46%, respectively. Relapse rate for patients with MR4.5 sustained >2 years was 32%, whereas those with <2 years it was 82%; a similar analysis with cutoff of 5 years yielded a relapse rate of 15% and 77%, respectively. Among patients with b3a2 with MR4.5 at discontinuation, 35% lost response, compared to 33% for those with b2a2 and 53% for those with both b3a2 and b2a2. Twenty four relapsing patients were eventually retreated; 21 re-gained the response they had at the time of discontinuation in a median of 4.5 months after resumption of therapy. At last follow up, 82 (86%) patients were in MR4.5, 4 (4%) in MMR, 5 (5%) in CCyR, 3 (3%) in PCyR and 1 (1%) in mCyR. This analysis shows that patients with less than MR4.5 at time of discontinuation have higher risk of relapse. The lower percentage of relapse seen in patients who had been on imatinib likely represents the longer period of treatment before discontinuation compared to the 2nd generation TKIs. Late relapses (e.g., beyond a year) occur in a subset of patients. Although the majority of patients who lose their response after discontinuation respond to retreatment, treatment discontinuation is still not recommended outside clinical trials. Disclosures Jain: Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Genentech: Research Funding; Servier: Consultancy, Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Incyte: Research Funding; BMS: Research Funding. Daver:BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Research Funding; Kiromic: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. DiNardo:Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Influence of BCR-ABL Transcript Type on Outcome in Patients with Chronic-Phase Chronic Myeloid Leukemia Treated with Imatinib 400 Mg

The prognostic significance of BCR-ABL1 transcripts in chronic myeloid leukemia (CML) is controversial. A recent report demonstrated that patients with e13a2 transcripts have inferior outcomes with imatinib 400 mg and those patients with e14a2 or that express both transcripts have more chance of an optimal response and longer event-free and transformation-free survival, while others do not confirm this data.The aim of this study was to evaluate the impact of BCR-ABL transcript type in CML patients outcome.Patients and methods: all consecutive CML patients in chronic phase treated with imatinib 400 mg/day from February 2004 to January 2016 were enrolled. Patients' responses were monitored with cytogenetic analysis at 3, 6 and 12 months, then every six months until a complete cytogenetic response (CCR). Real-time polymerase chain reaction was assessed at baseline, then every 3 months for the first year until reaching a stable major molecular response, then every 3-6 months. Demographic and baseline disease characteristics were collected at diagnosis. The type of BCR-ABL1 transcript was evaluated by multiplex RT-PCR from cDNA synthesized from total leukocytes RNA at diagnosis. We included patients with BCR-ABL transcripts e13a2, e14a2, and with coexpression of e13a2 and e14a2. Statistical analysis: Event-free survival (EFS) was measured from the start of treatment until loss of complete hematologic response, loss of major cytogenetic response, progression to accelerated (AP) or blast phase (BC) or death from any cause at any time while on initial therapy. Overall survival (OS) was measured from the start of imatinib until to the date of death from any cause at any time or last follow-up. Transformation-free survival (TFS) was measured from the start of imatinib to transformation to AP or BC or deaths while on therapy. The differences between variables were analyzed by the χ2 and the Kruskal-Wallis tests for categorical and continuous variables. Survival probabilities were calculated using the Kaplan-Meier method and compared by the log-rank test. The Cox regression estimated the hazard ratio values. All analysis considering p-value < 0.05 and using SPSS 21.0 software. Results: A total of 190 patients were treated with imatinib 400 mg/day. Median age was 48 years (18-87) and Sokal risk was high in 47/151 patients (31%), intermediate in 55/151 (36%) and low in 49/151 (33%). Twenty patients were excluded from the analysis: 14 patients due to Interferon treatment before Imatinib; two patients that started imatinib after six months from diagnosis; two patients with e1a2 transcripts and two patients with no RT-PCR test available at diagnosis. The remaining 170 patients presented typical BCR-ABL1 transcripts: e13a2 (n=56; 33%), e14a2 (n=94; 55%) and both transcripts (n=20; 12%). A total of 44 (26%) patients discontinued imatinib and 24 (14%) switched to second-line tyrosine kinase inhibitor. No differences were observed in sex, age, leukocytes, hemoglobin and platelets count at diagnosis, Sokal or EUTOS score according to transcript type. The proportion of patients with e13a2, e14a2 and both achieving complete cytogenetic response at 6 months was 19/44 (43%); 42/60 (70%) and 9/14 (64%) (P=0.02); and at 12 months was 28/45 (62%); 47/60 (78%) and 11/14 (78%) (P=0.16). However, the proportion of patients with major or lower molecular responses at 18 months was 13/24 (54%), 25/36 (69%) and 6/9 (66%), which was not significantly different. There were no statistical difference in EFS, PFS, and OS among the e13a2, e14a2 and e14a2+e13a2 groups. However, there was a superior 10-year overall survival in patients with transcripts e13a2 compared to e14a2 (alone or coexpressed with e13a2) (93% vs. 73%, P=0.03), although the 5-year overall survival was 96% vs. 88%, respectively (P=NS). In the multivariate analysis, high/intermediate Sokal score and e14a3/e14a3+e14a2 were independent factors for poor OS (P=0.023 and 0.041, respectively).Conclusion: The type of BCR-ABL transcripts did not affect molecular responses. Although patients with e14a2 transcripts presented higher rates of CCR at 6 months, compared to e13a2 or both transcripts, at long term, there was a superior overall survival among patients with transcripts e13a2 compared to e14a2 (alone or coexpressed with e13a2). The biological mechanism responsible for that difference is not known and should be investigated in larger trials. Disclosures Pagnano: Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria.

Efficacy of nilotinib in a patient relapse after 9 years of imatinib treatment and in stable complete cytogenetic response

We report a case of a patient with chronic myeloid leukemia in chronic phase who was treated with interferon-alpha plus low dose of cytarabine for 5 years, achieving a partial cytogenetic response. In 2000, he started imatinib at 400 mg/day obtaining rapidly a complete cytogenetic response (CCyR) (after 6 months of treatment) and a “near” major molecular response (MMolR) with BCR-ABL transcript level waving from 0.13 to 0.15% (BCR-ABL/ABL%) during molecular follow-up performed in the subsequent 6 years. To further improve his molecular response, we associated to TKI an immune target therapy with a BCR-ABL derived peptide vaccine developed by us, obtaining a MMolR, confirmed during the following 12 months from the beginning of the vaccinations. Surprisingly, at 9 years from starting imatinib, we documented the loss of MMolR and CCyR. Clonal evolution, kinase domain mutations and reduced drug intake were excluded, thus the patient switched to nilotinb at 400 mg/BID: after 3 months of treatment he achieved CCyR and MMolR and after 6 months we documented also a complete molecular response (CMolR).