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Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin <10 g/dl were included. Median age was 67 (45-88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia., (© 2021. The Author(s).)

Background: The Janus kinase (JAK) inhibitor ruxolitinib is the only approved therapy for patients with symptomatic myelofibrosis. After ruxolitinib failure, however, there are few therapeutic options. We assessed the efficacy and safety of momelotinib, a JAK 1 and JAK 2 inhibitor, versus best available therapy (BAT) in patients with myelofibrosis who had suboptimal responses or haematological toxic effects with ruxolitinib., Methods: In this randomised, phase 3, open-label trial, patients were screened for eligibility from 52 clinical centres in Canada, France, Germany, Israel, Italy, Spain, the UK, and the USA. Patients who had myelofibrosis and previous ruxolitinib treatment for at least 28 days who either required red blood cell transfusions while on ruxolitinib or ruxolitinib dose reduction to less than 20 mg twice a day with at least one of grade 3 thrombocytopenia, anaemia, or bleeding at grade 3 or worse, with palpable spleen of at least 5 cm and without grade 2 or greater peripheral neuropathy were included in the study. Patients were randomly assigned (2:1) to either 24 weeks of open-label momelotinib 200 mg once a day or BAT (which could include ruxolitinib, chemotherapy, steroids, no treatment, or other standard interventions), after which all patients could receive extended momelotinib treatment. Patients were randomly assigned to treatment by an interactive web response system and the randomisation was stratified by transfusion dependence and by baseline total symptom score (TSS). Results were analysed on an intention-to-treat basis. The primary endpoint was a reduction by at least 35% in the spleen volume at 24 weeks compared with baseline. Safety analyses included adverse event monitoring. The trial is registered with ClinicalTrials.gov, number NCT02101268., Findings: Between June 19, 2014, and July 28, 2016, 156 patients were recruited to the study; 104 received momelotinib and 52 received BAT. BAT was ruxolitinib in 46 (89%) of 52 patients. 73 (70%) of 104 patients in the momelotinib group and 40 (77%) of 52 patients in the BAT group completed the 24-week treatment phase. Seven (7%) of 104 patients in the momelotinib group and three (6%) of 52 in the BAT group had a reduction in the spleen volume by at least 35% compared with baseline (proportion difference [Cochran-Mantel-Haenszel method], 0·01; 95% CI -0·09 to 0·10), p=0·90). The most common grade 3 or worse adverse events were anaemia (14 [14%] of 104 in the momelotinib group vs seven [14%] of 52 in the BAT group), thrombocytopenia (seven [7%] vs three [6%]), and abdominal pain (one [1%] vs three [6%]). Peripheral neuropathy occurred in 11 (11%) of 104 patients receiving momelotinib (one of which was grade 3) and in no patients in the BAT group. Serious events were reported for 36 (35%) patients in the momelotinib group and 12 (23%) of patients in the BAT group. Deaths due to adverse events were reported for six patients (6%) receiving momelotinib (acute myeloid leukaemia [n=2], respiratory failure [n=2, with one considered possibly related to momelotinib], cardiac arrest [n=1, considered possibly related to momelotinib], and bacterial sepsis [n=1]); and four patients (8%) receiving BAT (lung adenocarcinoma [n=1], myelofibrosis [n=1], and sepsis [n=2])., Interpretation: In patients with myelofibrosis previously treated with ruxolitinib, momelotinib was not superior to BAT for the reduction of spleen size by at least 35% compared with baseline., Funding: Gilead Sciences, Inc., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naïve patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements. Results A ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and ruxolitinib, respectively, indicating that noninferiority was not met ( P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade ≥ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received ruxolitinib. Treatment-emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade ≤ 2) and 5% of patients who received ruxolitinib (all grade ≤ 3). Conclusion In JAKi-naïve patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was associated with a reduced transfusion requirement.

Patients in complete cytogenetic response (CCyR) with detectable BCR-ABL1 after ≥2 years on imatinib were randomized to nilotinib (400 mg twice daily, n = 104) or continued imatinib (n = 103) in the Evaluating Nilotinib Efficacy and Safety in clinical Trials-Complete Molecular Response (ENESTcmr) trial. By 1 and 2 years, confirmed undetectable BCR-ABL1 was achieved by 12.5% vs 5.8% (P = .108) and 22.1% vs 8.7% of patients in the nilotinib and imatinib arms, respectively (P = .0087). Among patients without molecular response 4.5 (BCR-ABL1(IS) ≤0.0032%; MR(4.5)) and those without major molecular response at study start, MR(4.5) by 2 years was achieved by 42.9% vs 20.8% and 29.2% vs 3.6% of patients in the nilotinib and imatinib arms, respectively. No patient in the nilotinib arm lost CCyR, vs 3 in the imatinib arm. Adverse events were more common in the nilotinib arm, as expected with the introduction of a new drug vs remaining on a well-tolerated drug. The safety profile of nilotinib was consistent with other reported studies. In summary, switching to nilotinib enabled more patients with chronic myeloid leukemia in chronic phase (CML-CP) to sustain lower levels of disease burden vs remaining on imatinib. This trial was registered at www.clinicaltrials.gov as #NCT00760877., (© 2014 by The American Society of Hematology.)

Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor for treatment of chronic myeloid leukemia (CML) following resistance/intolerance to prior therapy. Here, we report the data from the 2-year follow-up of a phase 1/2 open-label study evaluating the efficacy and safety of bosutinib as second-line therapy in 288 patients with chronic phase CML resistant (n = 200) or intolerant (n = 88) to imatinib. The cumulative response rates to bosutinib were as follows: 85% achieved/maintained complete hematologic response, 59% achieved/maintained major cytogenetic response (including 48% with complete cytogenetic response), and 35% achieved major molecular response. Responses were durable, with 2-year estimates of retaining response >70%. Two-year probabilities of progression-free survival and overall survival were 81% and 91%, respectively. The most common toxicities were primarily gastrointestinal adverse events (diarrhea [84%], nausea [45%], vomiting [37%]), which were primarily mild to moderate, typically transient, and first occurred early during treatment. Thrombocytopenia was the most common grade 3/4 hematologic laboratory abnormality (24%). Outcomes were generally similar among imatinib-resistant and imatinib-intolerant patients and did not differ with age. The longer-term results of the present analysis confirm that bosutinib is an effective and tolerable second-line therapy for patients with imatinib-resistant or imatinib-intolerant chronic phase CML. ClinicalTrials.gov Identifier: NCT00261846., (© 2014 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.)

In a randomized, phase III trial of nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal response or treatment failure on front-line imatinib than on nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or nilotinib 300 mg twice daily could enter an extension study to receive nilotinib 400 mg twice daily. After a 19-month median follow up, the safety profile of nilotinib 400 mg twice daily in patients switching from imatinib (n=35) was consistent with previous reports, and few new adverse events occurred in patients escalating from nilotinib 300 mg twice daily (n=19). Of patients previously treated with imatinib or nilotinib 300 mg twice daily, respectively, 15 of 26 (58%) and 2 of 6 (33%) without complete cytogenetic response at extension study entry, and 11 of 34 (32%) and 7 of 18 (39%) without major molecular response at extension study entry, achieved these responses at any time on nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response (clinicaltrials.gov identifiers: 00718263, 00471497 - extension)., (Copyright© Ferrata Storti Foundation.)

The function of the natural modulators of BCR-ABL-induced signaling pathways could influence the results to imatinib treatment. We assessed the association between single nucleotide polymorphisms (SNPs) on genes of the phosphatase family and the suppressors of cytokine signaling and the response to imatinib in 105 patients newly diagnosed with chronic-phase CML. SNPs in SOCS1 (rs243327) and PTPN22 (rs2476601) genes correlated with the risk of primary resistance to imatinib. A high-risk Sokal score, the T allele in PTPN22 SNP, and each copy of the C allele in SOCS1 SNP were adverse prognostic factors for failure-free survival (FFS). Based on such parameters, three risk groups were identified, with the 5-year FFS for each group being 95%, 75%, and 50%, respectively (P<0.001). A simple predictive model including Sokal score and genotype of SOCS1 and PTPN22 SNPs may be useful in the selection of the initial treatment in CML., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The association between seven polymorphisms in the genes hOCT1 and MDR1, encoding for imatinib transporter proteins, and the response to imatinib 400mg/daily was investigated in 65 patients newly diagnosed with chronic-phase chronic myeloid leukemia. The AA genotype at the rs6935207 hOCT1 polymorphic locus was not detected in patients with inadequate response to imatinib. The CC genotype at the rs1045642 (C3435T) MDR1 locus was associated with primary failure, whereas a T allele at the rs2032582 (G2677T/A) MDR1 locus seemed to protect from primary failure. Beside, the MDR1 haplotype 1236T-2677G-3435C was more frequently found in patients primarily resistant to imatinib., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Despite the favorable results of imatinib front line in chronic-phase chronic myeloid leukemia there is room for improvement., Design and Methods: Early intervention during imatinib therapy was undertaken in 210 adults with chronic-phase chronic myeloid leukemia less than three months from diagnosis (Sokal high risk: 16%). Patients received imatinib 400 mg/day. At three months, dose was increased if complete hematologic response was not achieved. At six months, patients in complete cytogenetic response were kept on 400 mg and the remainder randomized to higher imatinib dose or 400 mg plus interferon-alfa. At 18 months, randomized patients were switched to a 2(nd) generation tyrosine kinase inhibitor if not in complete cytogenetic response and imatinib dose increased in non-randomized patients not in major molecular response., Results: Seventy-two percent of patients started imatinib within one month from diagnosis. Median follow-up is 50.5 (range: 1.2-78) months. At three months 4 patients did not have complete hematologic response; at six months 73.8% were in complete cytogenetic response; among the remainder, 9 could not be randomized (toxicity or consent withdrawal), 17 were assigned to high imatinib dose, and 15 to 400 mg + interferon-alpha. The low number of randomized patients precluded comparison between the two arms. Cumulative response at three years was: complete hematologic response 98.6%, complete cytogenetic response 90% and major molecular response 82%. On an intention-to-treat basis, complete cytogenetic response was 78.8% at 18 months. At five years, survival was 97.5%, survival free from accelerated/blastic phase 94.3%, failure free survival 82.5%, and event free survival (including permanent imatinib discontinuation) 71.5%., Conclusions: These results indicate the benefit of early intervention during imatinib therapy (ClinicalTrials.gov Identifier: NCT00390897).

Chronic myeloid leukemia (CML) is driven by the BCR-ABL protein, which promotes the proliferation and viability of the leukemic cells. Moreover, BCR-ABL induces genomic instability that can contribute to the emergence of resistant clones to the ABL kinase inhibitors. It is currently unknown whether the inherited individual capability to repair DNA damage could affect the treatment results. To address this, a comprehensive analysis of single nucleotide polymorphisms (SNPs) on the nucleotide excision repair (NER) genes (ERCC2-ERCC8, RPA1-RPA3, LIG1, RAD23B, XPA, XPC) was performed in 92 chronic phase CML patients treated with imatinib upfront. ERCC5 and XPC SNPs correlated with the response to imatinib. Haplotype analysis of XPC showed that the wild-type haplotype (499C-939A) was associated with a better response to imatinib. Moreover, the 5-year failure free survival for CA carriers was significantly better than that of the non-CA carriers (98% vs. 73%; P = 0.02). In the multivariate logistic model with genetic data and clinical covariates, the hemoglobin (Hb) level and the XPC haplotype were independently associated with the treatment response, with patients having a Hb < or =11 g/dl (Odds ratio [OR] = 5.0, 95% confidence interval [CI] = 1.5-16.1) or a non-CA XPC haplotype (OR = 4.1, 95% CI = 1.6-10.6) being at higher risk of suboptimal response/treatment failure. Our findings suggest that genetic polymorphisms in the NER pathway may influence the results to imatinib treatment in CML., ((c) 2010 Wiley-Liss, Inc.)

Background: Expression of the pro-apoptotic BCL-2-interacting mediator (BIM) has recently been implicated in imatinib-induced apoptosis of BCR-ABL1(+) cells. However, the mechanisms involved in the regulation of BIM in CML and its role in the clinical setting have not been established., Design and Methods: We analysed the mRNA expression of BIM in 100 newly diagnosed patients with CML in chronic phase by Q-RT-PCR and the protein levels by Western blot analysis. Methylation status was analysed by bisulphite genomic sequencing and MSP. CML cell lines were treated with imatinib and 5-aza-2'-deoxycytidine, and were transfected with two different siRNAs against BIM and cell proliferation and apoptosis were analysed., Results: We demonstrated that down-regulation of BIM expression was present in 36% of the patients and was significantly associated with a lack of optimal response to imatinib as indicated by the decrease in cytogenetic and molecular responses at 6, 12 and 18 months in comparison with patients with normal BIM expression (p<0.05). Expression of BIM was mediated by promoter hypermethylation as demonstrated by restoration of BIM expression after treatment of CML cells with 5-aza-2'-deoxycytidine. Using CML cell lines with low and normal expression of BIM we further demonstrated that the expression of BIM is required for imatinib-induced CML apoptosis., Conclusion: Our data indicate that down-regulation of BIM is epigenetically controlled by methylation in a percentage of CML patients and has an unfavourable prognostic impact, and that the combination of imatinib with a de-methylating agent may result in improved responses in patients with decreased expression of BIM.

Imatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM(+)) and 900 subjects who did not receive IM before HCT (IM(-)) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM(+) and IM(-) groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT.

Dasatinib, a potent inhibitor of BCR-ABL in vitro, is effective for patients with chronic myelogenous leukemia (CML) resistant or intolerant to imatinib. To provide a more definitive assessment of dasatinib in chronic-phase (CP)-CML, we report extended follow-up of a phase II trial, presenting data for the entire patient cohort (N=387). Dasatinib (70 mg) twice daily was administered to patients with imatinib-resistant or -intolerant CP-CML. With median follow-up of 15.2 months (treatment duration, <1-18.4 months), a complete hematologic response was attained or maintained in 91% of patients. A major cytogenetic response (MCyR) was attained or maintained by 59% (52% imatinib resistant and 80% imatinib intolerant); this was complete in 49% of patients (40% imatinib resistant and 75% imatinib intolerant). Of 230 patients achieving an MCyR, 7 experienced disease progression. Fifteen-month progression-free survival was 90% while overall survival was 96%. Grade 3/4 thrombocytopenia and neutropenia were reported in 48 and 49% of patients, respectively. Non-hematologic toxicity (any grade) consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), dyspnea (30%) and pleural effusion (27%). Pleural effusions were classified as grade 3 in 6% of reported events, with no incidence of grade 4. Dasatinib is associated with high response rates in patients with imatinib-resistant or -intolerant CP-CML.

Nilotinib, an orally bioavailable, selective Bcr-Abl tyrosine kinase inhibitor, is 30-fold more potent than imatinib in pre-clinical models, and overcomes most imatinib resistant BCR-ABL mutations. In this phase 2 open-label study, 400 mg nilotinib was administered orally twice daily to 280 patients with Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia in chronic phase (CML-CP) after imatinib failure or intolerance. Patients had at least 6 months of follow-up and were evaluated for hematologic and cytogenetic responses, as well as for safety and overall survival. At 6 months, the rate of major cytogenetic response (Ph < or = 35%) was 48%: complete (Ph = 0%) in 31%, and partial (Ph = 1%-35%) in 16%. The estimated survival at 12 months was 95%. Nilotinib was effective in patients harboring BCR-ABL mutations associated with imatinib resistance (except T315I), and also in patients with a resistance mechanism independent of BCR-ABL mutations. Adverse events were mostly mild to moderate, and there was minimal cross-intolerance with imatinib. Grades 3 to 4 neutropenia and thrombocytopenia were observed in 29% of patients; pleural or pericardial effusions were observed in 1% (none were severe). In summary, nilotinib is highly active and safe in patients with CML-CP after imatinib failure or intolerance. This clinical trial is registered at http://clinicaltrials.gov as ID no. NCT00109707.

Although imatinib induces marked responses in patients with chronic myeloid leukemia (CML), resistance is increasingly problematic, and treatment options for imatinib-resistant or -intolerant CML are limited. Dasatinib, a novel, highly potent, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, induced cytogenetic responses in a phase 1 study in imatinib-resistant or -intolerant CML and was well tolerated. Initial results are presented from a phase 2 study of 186 patients with imatinib-resistant or -intolerant chronic-phase CML (CML-CP) designed to further establish the efficacy and safety of dasatinib (70 mg twice daily). At 8-months' follow-up, dasatinib induced notable responses, with 90% and 52% of patients achieving complete hematologic and major cytogenetic responses (MCyR), respectively. Responses were long lasting: only 2% of patients achieving MCyR progressed or died. Importantly, comparable responses were achieved by patients carrying BCR-ABL mutations conferring imatinib resistance. Dasatinib also induced molecular responses, reducing BCR-ABL/ABL transcript ratios from 66% at baseline to 2.6% at 9 months. Nonhematologic adverse events were generally mild to moderate, and most cytopenias were effectively managed with dose modifications. Cross-intolerance with imatinib was not evident. To conclude, dasatinib induces notable responses in imatinib-resistant or -intolerant CML-CP, is well tolerated, and represents a promising therapeutic option for these patients. This trial was registered at www.clinicaltrials.gov as CA180013.

Background: The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy., Methods: We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events., Results: The median follow-up was 60 months. Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P<0.001). Grade 3 or 4 adverse events diminished over time, and there was no clinically significant change in the profile of adverse events., Conclusions: After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients. (ClinicalTrials.gov number, NCT00006343 [ClinicalTrials.gov].), (Copyright 2006 Massachusetts Medical Society.)

Background and Objectives: Imatinib mesylate has recently been shown to be highly effective in chronic-phase chronic myeloid leukemia (CML). The results of imatinib treatment in chronic-phase CML patients resistant or intolerant to interferon (IFN) and the factors predicting therapeutic response and progression-free survival were analyzed., Design and Methods: One hundred and fifty patients with chronic-phase CML resistant (n=111) or intolerant (n=39) to IFN were treated with imatinib. Prognostic factors for response and disease progression were assessed by multivariate analysis., Results: The median time from diagnosis was 43 months (0.5-188), median IFN therapy 21.5 months (0.5-140) and median follow-up from starting imatinib 13.6 months (range: 3-23). Complete hematologic response was achieved in 96 of 97 patients. Complete, partial and minor cytogenetic responses were present in 44%, 22%, and 8% of patients at 12 months. Grade III-IV neutropenia, thrombocytopenia, and anemia developed in 33%, 16%, and 6% of patients, respectively. Sixty-five patients discontinued treatment for a median of 4 weeks (1-36) due to toxicity. The rate of progression-free survival (lack of accelerated/blastic phase with persistent response) was 89.2% (95% CI: 84-94.4) at 12 months and 80.2% (95% CI: 72.2-88.2) at 18 months. Platelets > 450x10(9)/L and treatment discontinuation > 4 weeks were associated with a lower rate of major (complete plus partial) cytogenetic response. Patients in Sokal's high-risk group and those who did not achieve a major cytogenetic response had significantly shorter progression-free survival., Interpretation and Conclusions: Imatinib is highly effective in chronic-phase CML patients resistant or intolerant to IFN, especially in those with normal platelet counts and in those not requiring prolonged treatment discontinuation due to neutropenia.

A 58-year-old woman with chronic myeloid leukemia (CML), and previous intolerance to interferon was treated with the BCR-ABL tyrosine kinase protein inhibitor imatinib mesylate. Coincidentally, with the start of treatment, the patient developed acute renal failure, with acute tubular necrosis being observed on histopathology. Imatinib was stopped and three hemodialysis sessions were performed, which was followed by a progressive improvement of the renal function and normalization of the urine output. One year later the patient still has mild chronic renal failure and remains in chronic phase of CML on hydroxyurea treatment.

Background: Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML., Methods: We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients). Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression., Results: After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1 percent (95 percent confidence interval, 84.1 to 90.0) in the imatinib group and 34.7 percent (95 percent confidence interval, 29.3 to 40.0) in the group given interferon alfa plus cytarabine (P<0.001). The estimated rates of complete cytogenetic response were 76.2 percent (95 percent confidence interval, 72.5 to 79.9) and 14.5 percent (95 percent confidence interval, 10.5 to 18.5), respectively (P<0.001). At 18 months, the estimated rate of freedom from progression to accelerated-phase or blast-crisis CML was 96.7 percent in the imatinib group and 91.5 percent in the combination-therapy group (P<0.001). Imatinib was better tolerated than combination therapy., Conclusions: In terms of hematologic and cytogenetic responses, tolerability, and the likelihood of progression to accelerated-phase or blast-crisis CML, imatinib was superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML., (Copyright 2003 Massachusetts Medical Society)

Imatinib mesylate (STI571) is a highly effective and well-tolerated treatment for patients with chronic-phase chronic myeloid leukaemia (CML), but information on its efficacy and tolerance in intensively pretreated patients is scarce. Thirty-three chronic-phase CML patients who were resistant or intolerant to interferon (IFN) and had been previously submitted to autologous stem cell transplantation were treated with imatinib for a median of 14 months (range: 6-19 months). Seven patients were in haematological response (HR) at the start of treatment; the remaining 26 attained a HR at a median of 3 weeks (range: 1-4 weeks). Major cytogenetic response rates at 3, 6 and 12 months were 42%, 45% and 55%, respectively, including 21%, 24% and 33% complete responses. Grade 3-4 neutropenia, thrombocytopenia and anaemia developed in 33%, 27% and 12% of patients respectively. Non-haematological toxicity included superficial oedema (21% of patients), gastrointestinal symptoms (18%), muscle cramps (15%), skin rash and liver enzyme increase (3% each). These results were not significantly different from those in 65 chronic-phase CML patients, resistant or intolerant to interferon without a previous ASCT, who were included in the same protocol. Imatinib mesylate is effective and safe in chronic-phase CML patients with a previous history of intensive treatment.

Imatinib mesylate (STI571, Gleevec, Glivec, a selective inhibitor of the BCR-ABL tyrosine kinase causative of chronic myeloid leukemia (CML), represents the paradigm of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a targeted molecular therapy. Phase II clinical trials have shown marked therapeutic activity of imatinib in all evolutive phases of CML, but notably in the chronic phase, where it induces complete hematological responses in almost 100% of patients resistant or intolerant to interferon, with a major cytogenetic response rate of 60%, including 41% complete cytogenetic responses. The preliminary results of an ongoing phase III multicenter randomized study comparing imatinib with interferon plus cytarabine as first-line treatment for CML favor imatinib in terms of efficacy and safety. If confirmed with longer follow-up,these results would establish imatinib as the choice therapy for the majority of CML patients, with allogeneic transplantation being restricted as initial therapy only to younger patients with a family donor. Longer follow-up will answer some questions, such as those on long-term safety, durability of the responses, whether these will translate into a survival prolongation and the possibility of molecular responses. In addition, further information on the mechanisms involved in the primary and acquired resistance to imatinib is needed. Besides the Bcr-Abl protein, the drug is also active against other tyrosine kinases, such as Abl, the stem-cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this sense, it must be pointed out that imatinib has shown a remarkable activity in gastrointestinal stromal tumors., (Copyright 2002 Prous Science)