scholarly journals The Clinical Significance of Achieving Different Levels of Cytogenetic Response in Patients With Chronic Phase Chronic Myeloid Leukemia After Failure to Front-Line Therapy: Is Complete Cytogenetic Response the Only Desirable Endpoint?

2011 ◽  
Vol 11 (5) ◽  
pp. 421-426 ◽  
Author(s):  
Jorge Cortes ◽  
Alfonso Quintas-Cardama ◽  
Elias Jabbour ◽  
Susan O'Brien ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Significance ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Front Line ◽  
Complete Cytogenetic Response ◽  
Line Therapy ◽  
Different Levels

scholarly journals Nilotinib early switch efficacy in non-optimal responder CML patient after first line imatinib treatment

2015 ◽  
Vol 5 (6S) ◽  
pp. 11-16
Author(s):  
Ferdinando Porretto
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutational Analysis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Imatinib Treatment ◽  
First Line ◽  
Complete Cytogenetic Response ◽  
First Line Therapy ◽  
Line Therapy

We report a case of a patient with chronic myeloid leukemia in chronic phase who was treated with Imatinib as first line therapy. He showed a suboptimal response by 2006 ELN criteria after six months, for this reason we performed a mutational analysis that showed the mutation F486S. Due to this finding we made an early switch to Nilotinib (Nil); patients started Nil at 300 bid mg/day obtaining at six month a complete cytogenetic response (CCyR) and a MMolR (RQ-PCR ratio BCR-ABL1/ABL1%IS: 0.05). The patient is now on 24 months Nil treatment showing a RQ-PCR ratio BCR-ABL1/ABL1%IS: 0.004.

scholarly journals Predictive value of early molecular response in patients with chronic myeloid leukemia treated with first-line dasatinib

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 291-294 ◽  
Author(s):  
David Marin ◽  
Corinne Hedgley ◽  
Richard E. Clark ◽  
Jane Apperley ◽  
Letizia Foroni ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Predictive Value ◽  
Myeloid Leukemia ◽  
Transcript Level ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
First Line ◽  
Complete Cytogenetic Response ◽  
First Line Therapy ◽  
Line Therapy

Abstract Dasatinib is effective therapy for newly diagnosed patients with chronic myeloid leukemia, but not all patients respond well. We analyzed the outcome of patients treated with dasatinib as first-line therapy to identify patients who are more likely to fare poorly. The 8.6% of patients who at 3 months had a BCR-ABL1/ABL1 ratio > 10% had a significantly worse 2-year cumulative incidence of complete cytogenetic response (58.8% vs 96.6%, P < .001) and molecular responses than the remaining patients with a lower transcript levels. The predictive value of the 3-month transcript level could be improved using the dasatinib-specific transcript level cut-offs, namely, 2.2%, 0.92%, and 0.57% for complete cytogenetic response, 3 log and 4.5 log reductions in the transcript level, respectively. The study was registered at www.clinicaltrials.gov as #NCT01460693.

Better Molecular Response (MR) to Imatinib (IM) in Early Chronic Phase (CP) Versus Late CP Chronic Myeloid Leukemia (CML) Patients (pts) in Complete Cytogenetic Response (CCR): A Comparison at 24 Months of 2 Clinical Trials of the GIMEMA Working Party on CML on Behalf of the GIMEMA Working Party on Chronic Myeloid Leukemia (GIMEMA-CML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1096-1096 ◽  
Author(s):  
Angela Poerio ◽  
Marilina Amabile ◽  
Ilaria Iacobucci ◽  
Simona Soverini ◽  
Sabrina Colarossi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Nested Pcr ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Working Party ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Molecular Response ◽  
Front Line ◽  
Log Reduction

Abstract We sought to determine the differences in molecular response between early and late CP pts with CML who achieved a CCR after treatment with IM at the standard dose of 400mg/d. We studied 2 different cohorts of patients in CCR: 67/191 (35%) pts after α-Interferon (α-IFN) failure enrolled on the CML/002/STI571 protocol 53/76 (70%) pts treated front line with a combination of IM and pegilated IFN-α (PEG-IFN) enrolled on the CML/011/STI571 protocol Cytogenetic response was monitored on bone marrow (BM) metaphases and molecular response was assessed by real time RT-PCR (TaqMan) BM and peripheral blood (PB) samples, collected at baseline, 3, 6, 9 and 12 months during the first year, and every 6 months thereafter. Molecular response was expressed as the ratio between BCR/ABL and β2-microglobulin (β2-M) x100. The lowest level of detectability of the method was 10−5. Negative results (i.e. undetectable transcript) were confirmed by nested PCR performed 4 times (sensitivity 10−6). For the purpose of this analysis, a major molecular response (MMR) was defined as a BCR-ABL/β2M value &lt;0.0001%, which turned out to be roughly equivalent to a 3-log reduction and a complete molecular response (CMR) was defined as negative (undetectable) BCR/ABL levels confirmed by nested PCR. We observed a progressive decrease of the amount of BCR/ABL transcript in pts who achieved a CCR. At 24 months the median reduction in BCR/ABL transcript level was: a 3-log reduction in late CP pts a 4-log reduction in early CP pts In the latter group of pts MR was assessed also at 36 months. So we observed that 36 months after the first dose of IM and PEG-IFN pts who were still in CCR had the median value of BCR/ABL transcript of 0.00001% both in BM and PB. Therefore all these pts achieved a MMR. However only 8/53 (4%) pts were in CMR (undetectable BCR/ABL at least once as assessed by nested PCR). We conclude that front-line treatment with IM results in a better quality MR (4-log reduction in BCR/ABL transcript levels in early CP pts, as against a 3-log reduction in late CP pts). Figure Figure

Clinical Significance of Deeper Molecular Responses with Four Modalities of Tyrosine Kinase Inhibitors As Frontline Therapy for Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 164-164 ◽  
Author(s):  
Lorenzo Falchi ◽  
Hagop M. Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Susan O'Brien ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Significance ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Initial Therapy ◽  
Molecular Responses ◽  
Free Survival

Abstract Abstract 164 Background: The achievement of a major molecular remission (MMR) after imatinib therapy in pts with chronic myeloid leukemia (CML) in chronic phase (CP) predicts for decreased risk of events, but has little impact in overall survival (OS) among patients with complete cytogenetic response (CCyR). Deeper molecular responses (MR), including undetectable transcripts, are frequently sought in patients with CML treated with tyrosine kinase inhibitors (TKI), but the prognostic significance of these responses is not known. Objectives: To determine the long-term clinical significance of achieving deeper level of MR achieved after therapy with TKI for CML in CP. Methods: Pts were included in clinical trials for initial therapy for CML with one of the following modalities: imatinib 400mg/day (IM400), imatinib 800mg/day (IM800), nilotinib (NILO) and dasatinib (DASA). We defined the level of MR as MMR, MR4, MR4.5 and undetectable transcripts (UND), corresponding to an ABL/BCR-ABL ratio (International Scale) of ≤0.1%, ≤0.01%, ≤0.0032%, and undetectable transcripts (minimum sensitivity 4.5-log), respectively. Results: A total of 495 pts were treated: 83 pts with IM400, 204 with IM800, 106 with NILO and 102 with DASA. At presentation leukocyte counts were higher in the NILO group (41.5 vs 22.2, 27.5 and 27×109/L for IM400, IM800 and DASA pts). All other patient characteristics were equally distributed across the 4 treatment groups. After a median follow-up of 73 months (2 to 142), complete cytogenetic response (CCyR) was achieved in 88%. CCyR rates for IM400, IM800, NILO and DASA pts were 82%, 88%, 90% and 90%, respectively. Best level of MR for the entire population was: <MMR in 17% of pts, MMR in 13%, MR4 in 5%, MR4.5 in 19%, UND in 44%. In IM400 pts MR was <MMR in 28% of pts, MMR in 10%, MR4 in 8%, MR4.5 in 14%, UND in 40%. In IM800 pts MR was <MMR in 14% of pts, MMR in 8%, MR4 in 5%, MR4.5 in 19%, UND in 54%. In NILO pts MR was <MMR in 18% of pts, MMR in 20%, MR4 in 7%, MR4.5 in 22%, UND in 33%. In DASA pts MR was <MMR in 18% of pts, MMR in 18%, MR4 in 7%, MR4.5 in 23%, UND in 39%. There was a trend for earlier achievement of MR with NILO: median times to MMR, MR4, MR4.5 and UND were 12, 17.4, 17.9 and 25.1 months, respectively, for IM400 pts; 5.8, 8.7, 11.8 and 23.7 months, respectively, for IM800 pts; 5.7, 7, 8.3 and 16.4 months, respectively, for NILO pts; 5.7, 8.8, 17.4 and 27.2 months, respectively, for DASA pts. To analyze the relationship between the degree of MR and clinical outcome we excluded pts not achieving a CCyR as their best response since the clinical significance of CCyR is well known. For the remaining 438 pts, the depth of molecular remission was inversely correlated with the risk of losing CCyR (19%, 16%, 11%, 7%, 2% in pts with <MMR, MMR, MR4, MR4.5 and UND, respectively) or losing MMR (31%, 42%, 24%, 2%, respectively), as well as the risk of events (22%, 20%, 15%, 12%, 3%, respectively), transformation (3%, 5%, 0%, 1%, 0%, respectively), or death (25%, 11%, 8%, 6%, 4%, respectively). The 6-year OS for pts with <MMR, MMR, MR4, MR4.5 and UND is 74%, 84%, 95%, 96% and 99%, respectively (p<.0001); transformation-free survival (TFS) is 95%, 93%, 100%, 99% and 100%, respectively (p<.014); event-free survival (EFS) is 74%, 74%, 86%, 89% and 99%, respectively (p<.0001). To adjust for the lead-time to achieve deeper responses, we then calculated OS, TFS and EFS rates at 6 years according to the depth of molecular response at 18 or 24 months. Results are summarized in table 1. Conclusion: Most patients treated with TKI as initial therapy for early CP CML achieve a MR during the course of treatment. BCR-ABL transcripts become undetectable in a significant fraction of them. Achieving a MMR or better at 18 months or 24 months is associated with significantly superior 6-years OS, TFS and EFS. These result suggest that deeper molecular responses (MMR and beyond) are associated with clinical benefit, with a particularly good outcome for those achieving undetectable transcript levels. Disclosures: Off Label Use: Imatinib, dasatinib and nilotinib frontline for chronic phase chronic myeloid leukemia on clinical trial. Kantarjian:Bristol-Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Jabbour:Pfizer: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Ravandi:Bristol-Myers-Squibb: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

scholarly journals Factors associated with achievement and durability of cytogenetic response in patients with chronic myeloid leukemia treated with imatinib

2011 ◽  
Vol 68 (11) ◽  
pp. 911-916 ◽  
Author(s):  
Irena Cojbasic ◽  
Lana Macukanovic-Golubovic
Keyword(s):  
Relative Risk ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Risk Groups ◽  
Cytogenetic Response ◽  
Complete Cytogenetic Response

Background/Aim. Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor, has revolutionized the treatment of Bcr-Abl positive chronic myeloid leukemia and become the standard of care for this disease. The aim of this study was evaluation and analysis of cytogenetic response in different intervals and risk groups as well as finding association between pre-treatment characteristics and later probability of achievement of major cytogenetic response. Methods. We analyzed a total of 22 adult patients with newly diagnosed Philadelphia positive early chronic phase chronic myeloid leukemia treated at our institution from June 2006 to December 2009. Results. The median follow-up time for patients during treatment with imatinib was 25.7 months (range, 12-42 months). A complete hematologic response was achieved in all of the analyzed patients within 6 months from the start of the treatment. The major cytogenetic response rate was 81.8%, and the complete cytogenetic response rate was 72.7%. The patients with low or moderate relative risk had the rate of complementary achieving major and complete cytogenetic response of 75-90%. A multivariate analysis identified the following independent prognostic factors for achieving major cytogenetic response: the absence of splenomegaly, white blood cell count less than 10 ? 109/L, the platelet count less than 450 ? 109/L, the presence of less than 5% of bone marrow blasts and basophils, the absence of blasts in peripheral blood, the presence of less than 7% of basophils in peripheral blood. Conclusion. Patients who early achieve complete and major cytogenetic response as well as those with low and moderate relative risk have a higher rate of achieving and maintaining complete cytogenetic response. There are also characteristics of patients before treatment that may indicate the treatment outcome.

Infectious Events In Patients with Chronic Myeloid Leukemia Treated with Nilotinib as a Front Line Therapy and After Imatinib Failure

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1233-1233 ◽  
Author(s):  
Ali M Al-Ameri ◽  
Jorge E. Cortes ◽  
Hagop Kantarjian ◽  
Elizabeth Burton ◽  
Alfonso Quintas-Cardama ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Fungal Infections ◽  
Therapy Group ◽  
Chronic Phase ◽  
Infectious Complications ◽  
Front Line ◽  
Line Therapy ◽  
Group 6

Abstract Abstract 1233 Background: Different tyrosine kinase inhibitors have different effect on various kinases. Dasatinib and bosutinib inhibt Src, an effect that has been suggested could have an immunosuppressive effect. Others, such as imatinib and nilotinib, have no discernible effect on Src. All agents however can cause myelosuppression. Because of these effects, and in view of long-term us of these agent, infectious complications may occur during therapy. The risk of infectious complications with nilotinib therapy has not been reported. Aim: To investigate the frequency and characteristics of infectious events in patients (pts) with chronic myeloid leukemia (CML) treated with Nilotinib as a front line therapy (FL) or after Imatinib failure (IF). Methods: Retrospective review of medical records of patients who received Nilotinib between Jun 2004 and Jun 2010, either as FL therapy or as salvage therapy after IF. Results: The total number of pts treated were 169, including 90 FL pts and 79 IF pts. Overall, 132 pts (78%) were in chronic phase and 37 pts (22%) were in accelerated phase. The median age was 53 (20 - 87) years and 57% of the pts were male. Median follow up for all patients was 30 months. Among the FL therapy group, 9 (10%) pts developed any infection, whereas 29 of 79 (37%) pts treated with nilotinib after IF developed any infection. Table 1 shows the types of infections for both groups. Of the 43 infections in the IF group, 26 (60%) were clinically documented infections (CDI), 8 FUO (19%), 3 bacterial (7%), 5 viral (12%) [Zoster (2), influenza (2), RSV (1)] and 1 (2%) fungal infections. Nine (21%) of these infectious episodes occurred with neutropenia and 24/43 episodes (56%) required hospitalization. In the FL group, 6 (60%) of the events were CDI, 2 (20%) were FUO, 1 (10%) was bacterial and 1 (10%) was viral [zoster]. None of the FL group events were associated with neutropenia and only 2/10 episodes required hospitalization. We also studied the relationship of infectious events according to the nilotinib doses at the moment of the infection. In IF group, 46% of the events occurred at 800mg/day, 30% at 400mg/day, 14% at 1200 mg/day and 10% at 200mg/day or less. In the FL group, 6 (60%) events occurred at 800mg/day and 40% at 400mg/day. There was no statistically significant association between infectious event rate and the nilotinib starting dose. Overall mortality at 30 months was 22% (29/169), 35 (44%) of the IF group died and 2 (2%) of the FL died. Three of the deaths in the IF group and none in the FT group were due to infection. Conclusions: Although several patients developed infectious complications during nilotinib therapy, particularly when used after imatinib failure, these episodes were common infections that responded rapidly to adequate intervention. Atypical infections were not seen. Further research is needed to determine predisposing factor and measures to prevent infections. Disclosures: Cortes: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Pfizer: Consultancy. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. O'Brien:Novartis: Research Funding; BMS: Research Funding.

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.

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