Comparison Between Patients With Philadelphia-Positive Chronic Phase Chronic Myeloid Leukemia Who Obtained a Complete Cytogenetic Response Within 1 Year of Imatinib Therapy and Those Who Achieved Such a Response After 12 Months of Treatment

2006 ◽  
Vol 24 (3) ◽  
pp. 454-459 ◽  
Author(s):  
Ilaria Iacobucci ◽  
Gianantonio Rosti ◽  
Marilina Amabile ◽  
Angela Poerio ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Complete Cytogenetic Response ◽  
Overall Survival Rates

Purpose Imatinib mesylate is a potent inhibitor of BCR-ABL, the constitutively active tyrosine kinase protein critical for the pathogenesis of chronic myeloid leukemia. Patients and Methods We reviewed 284 patients with late chronic-phase Philadelphia chromosome (Ph) –positive chronic myeloid leukemia treated with imatinib 400 mg daily after interferon-α failure. In a retrospective study, we evaluated the pattern and rapidity of the response to imatinib, comparing the cytogenetic and molecular responses, progression-free and overall survival rates in patients who obtained a complete cytogenetic response within 1 year of treatment (early responders), and in patients where a complete cytogenetic response was detected after 12 months (late responders). Results After 3 or 4 years of treatment, the molecular response of the late cytogenetic responders was similar to that of the early cytogenetic responders. At 36 months of treatment the amount of residual disease measured by standardized quantitative reverse-transcriptase polymerase chain reaction was 0.00047 in late responders versus 0.00022 in early responders, and at 48 months it was 0.00019 versus 0.00026 (median values, P value = nonsignificant). The estimated 4-year progression-free survival rate was 88% for early responders and 100% for late responders, while the estimated 4-year overall survival rates were 92% and 100% for early and late responders, respectively. Conclusion The sensitivity and the response (cytogenic and molecular) to imatinib may require 1 year or more. Long-term follow-up results continue to improve in terms of rates and durability of the complete cytogenetic response, major or complete molecular response, and progession-free and overall survival.

scholarly journals Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome–positive chronic myeloid leukemia patients with resistance or intolerance to imatinib

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. 4567-4576 ◽  
Author(s):  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Tim H. Brümmendorf ◽  
Dong-Wook Kim ◽  
Anna G. Turkina ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Complete Cytogenetic Response ◽  
Imatinib Resistant

Abstract Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinibintolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.

Imatinib for Newly Diagnosed Patients With Chronic Myeloid Leukemia: Incidence of Sustained Responses in an Intention-to-Treat Analysis

2008 ◽  
Vol 26 (20) ◽  
pp. 3358-3363 ◽  
Author(s):  
Hugues de Lavallade ◽  
Jane F. Apperley ◽  
Jamshid S. Khorashad ◽  
Dragana Milojkovic ◽  
Alistair G. Reid ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Newly Diagnosed

Purpose Imatinib is remarkably effective in treating newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). To date, most of the available data come from a single multicenter study in which some of the patients were censored for diverse reasons. Here, we report our experience in treating patients at a single institution in a setting where all events were recorded. Patients and Methods A total of 204 consecutive adult patients with newly diagnosed CML in CP received imatinib from June 2000 until August 2006. Response (hematologic, cytogenetic, and molecular), progression-free survival (PFS) and survival were evaluated. Results At 5 years, cumulative incidences of complete cytogenetic response (CCyR) and major molecular response (MMR) were 82.7% and 50.1%, respectively. Estimated overall survival and PFS were 83.2% and 82.7%, respectively. By 5 years, 25% of patients had discontinued imatinib treatment because of an unsatisfactory response and/or toxicity. The 5-year probability of remaining in major cytogenetic response while still receiving imatinib was 62.7%. Patients achieving a CCyR at 1 year had a better PFS and overall survival than those failing to reach CCyR, but achieving a MMR conferred no further advantage. The identification of a kinase domain mutation was the only factor predicting for loss of CCyR. Conclusion Imatinib is highly effective in most patients with CML-CP; patients who respond are likely to live substantially longer than those treated with earlier therapies. Achieving CCyR correlated with PFS and overall survival, but achieving MMR had no further predictive value. However, approximately one third of patients still need better therapy.

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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1911-1911
Author(s):  
Katia B.B. Pagnano ◽  
Eliana Cristina Martins Miranda ◽  
Marcia T Delamain ◽  
Gislaine OLIVEIRA Duarte ◽  
Erich Vinicius De Paula ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Rt Pcr ◽  
Molecular Responses ◽  
Free Survival ◽  
Complete Cytogenetic Response ◽  
Transcript Type

Abstract 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.

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

2021 ◽  
Vol 28 ◽  
pp. 107327482110017
Author(s):  
Ahmad Adel ◽  
Dina Abushanab ◽  
Anas Hamad ◽  
Mohammad Abdulla ◽  
Mohamed Izham ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cost Effective ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Complete Cytogenetic Response ◽  
Upfront Therapy

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.

scholarly journals The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. 4541-4546 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Jenny Shan ◽  
Alfonso Quintas-Cardama ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Major Determinant ◽  
Molecular Response ◽  
Complete Cytogenetic Response

Abstract We analyzed the association between achievement of early complete cytogenetic response (CCyR) and event-free survival (EFS) and overall survival (OS) in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with imatinib 400 mg (n = 73), or imatinib 800 mg daily (n = 208), or second- generation tyrosine kinase inhibitors (n = 154). The overall CCyR rates were 87%, 91%, and 96%, respectively (P = .06); and major molecular response (MMR) rates were 77%, 87%, and 89%, respectively (P = .05). Their 3-year EFS rates were 85%, 92%, and 97% (P = .01), and OS rates were 93%, 97%, and 100% (P = .18), respectively. By landmark analysis, patients with 3-, 6-, and 12-month CCyR had significantly better outcome: 3-year EFS rates of 98%, 97%, and 98% and OS rates of 99%, 99%, and 99%, respectively, compared with 83%, 72%, and 67% and 95%, 90%, and 94%, in patients who did not achieve a CCyR. Among patients achieving CCyR at 12 months, the depth of molecular response was not associated with differences in OS or EFS. In conclusion, second tyrosine kinase inhibitors induced higher rates of CCyR and MMR than imatinib. The achievement of early CCyR remains a major determinant of chronic myeloid leukemia outcome regardless of whether MMR is achieved or not.

scholarly journals Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

Leukemia ◽  
2021 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Chronic Phase ◽  
Individual Treatment ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Treatment Free Remission

AbstractIn the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-α treatment

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1039-1043 ◽  
Author(s):  
Andreas Hochhaus ◽  
Brian Druker ◽  
Charles Sawyers ◽  
Francois Guilhot ◽  
Charles A. Schiffer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Imatinib Treatment ◽  
Serious Adverse Events ◽  
Response Level

Abstract Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is the standard of care for chronic myeloid leukemia (CML). A phase 2 trial of imatinib in late chronic-phase (CP) CML after interferon-α (IFNα) failure enrolled 532 patients, 454 with a confirmed diagnosis of CP CML. Median time from diagnosis was 34 months; median duration of imatinib treatment was 65 months. Cumulative best rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were 67% and 57%, respectively. At the 5-year landmark, 184 (41%) of the 454 patients are in CCyR. At more than 6 years, 199 (44%) of the 454 patients remain on imatinib. Most responses occurred within 12 months of starting imatinib; however, some patients achieved initial MCyR and CCyR more than 5 years after imatinib initiation. Estimated rates of freedom from progression to accelerated phase (AP) and blastic phase (BP) and overall survival at 6 years were 61% and 76%, respectively. Both freedom from progression to AP/BP and overall survival (OS) were associated with cytogenetic response level at 12 months. No increase in rates of serious adverse events was observed with continuous use of imatinib for up to 6.5 years, compared with earlier time points. Imatinib continues to be an effective and safe therapy for patients with CP CML after failure of IFN.

A randomized study of interferon-α versus interferon-α and low-dose arabinosyl cytosine in chronic myeloid leukemia

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1527-1535 ◽  
Author(s):  
Michele Baccarani ◽  
Gianantonio Rosti ◽  
Antonio de Vivo ◽  
Francesca Bonifazi ◽  
Domenico Russo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Response Rate ◽  
Randomized Study ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Arabinosyl Cytosine

Interferon-α (IFN-α) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-α has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome–positive CML patients who were assigned at random to treatment with IFN-α2a alone or in combination with LDAC. The scheduled dose of IFN-α2a was 56IU/m2/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-α–plus–LDAC arm versus 55% in the IFN-α arm; P = .11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P = .003), and overall survival (5-year survival, 68% versus 65%; P = .77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-α versus IFN-α plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.

scholarly journals Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1141-1145 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Francis J. Giles ◽  
Kapil N. Bhalla ◽  
Javier Pinilla-Ibarz ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Study Endpoint ◽  
Primary Study ◽  
Molecular Response ◽  
Open Label ◽  
Imatinib Resistance ◽  
Abl Tyrosine Kinase

Abstract Nilotinib is a potent selective inhibitor of the BCR-ABL tyrosine kinase approved for use in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), and in CML-CP and CML-accelerated phase after imatinib failure. Nilotinib (400 mg twice daily) was approved on the basis of the initial results of this phase 2 open-label study. The primary study endpoint was the proportion of patients achieving major cytogenetic response (CyR). All patients were followed for ≥ 24 months or discontinued early. Of 321 patients, 124 (39%) continue on nilotinib treatment. Overall, 59% of patients achieved major CyR; this was complete CyR (CCyR) in 44%. Of patients achieving CCyR, 56% achieved major molecular response. CyRs were durable, with 84% of patients who achieved CCyR maintaining response at 24 months. The overall survival at 24 months was 87%. Adverse events were mostly mild to moderate, generally transient, and easily managed. This study indicates that nilotinib is effective, with a manageable safety profile, and can provide favorable long-term benefits for patients with CML-CP after imatinib failure. This trial was registered at www.clinicaltrials.gov as #NCT00109707.

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