Outcome of patients of CML in AP and BC with imatinib: A retrospective analysis of patients from India

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17531-17531
Author(s):  
H. Menon ◽  
S. S. Hingmire ◽  
R. Bharath ◽  
K. Jain ◽  
N. Ghadyalpatil ◽  
...  
Keyword(s):  
Median Survival ◽  
Median Duration ◽  
Single Agent ◽  
Active Agent ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Imatinib Treatment ◽  
Advanced Phase ◽  
The Impact

17531 Background: Imatinib is a very active agent in advanced phase CML. The present study assesses the impact of Imatinib therapy on the outcome of Indian patients with CML in Accelerated Phase (AP) and Blast Crisis (BC). Methods: Patients of CML in AP or BC who were treated with Imatinib based therapy between 2001 and 2006 were analyzed retrospectively. Results: A total of 65 patients who received Imatinib based treatment for CML in AP or BC were analyzed. Thirty eight (58.46 %) patients diagnosed in chronic phase (CP) were initiated on Imatinib based treatment at time of progression to AP or BC. The remaining 27 (41.53 %) patients had AP or BC of CML at initial diagnosis. At the time of start of Imatinib treatment 36 (55.38 %) patients had AP and 29 (44.61 %) were in BC. Imatinib as a single agent was used in 41 (63.07 %) patients (27 in AP and 14 in BC) and in combination with oral 6-MP and Etoposide was used in 24 (36.92 %) patients (14 in AP and 10 in BC). Hematological response (HR) was seen in 64.61% (42 out of 65) patients, complete HR in 32 (49.23 %) and partial HR in 10 (15.38 %). Cytogenetic response (CR) was noted in 21 (32.31%) patients (Complete -10, Partial -9, and Minor - 2). Twenty eight (43.07%) patients remained progression free (HR+CR in 16 and only HR in 12 patients) till the last date of follow up (median duration of follow-up was 17 months).For the whole group (n=65) the overall survival from the diagnosis of AP or BC after commencing Imatinib treatment was 65.3%, 51.6% and 34.4% at 1, 2 and 3 years respectively. The median survival was 25 months. The median survival and OS at 1 year, as expected, was significantly better for patients in AP (36 months, 77.4 %) as compared to those in BC (11 months, 48.2%)(p=0.004) and both were much longer than previously reported with non-Imatinib therapy. Outcome in patients with AP or BC was not significantly improved by addition of 6-MP and Etoposide. Temporary discontinuation of Imatinb for grade III/IV toxicity was done in 27 (41.53 %) patients for a median duration of 28 days. Conclusions: Imatinib has improved the outcome of patients with advanced phase CML. Our data also documents this in patients from India. However, Imatinib needs to be studied with newer combinations to achieve long term disease control in patients with CML, particularly those in BC. No significant financial relationships to disclose.

Improved Survival in Chronic Myeloid Leukemia (CML) Since the Introductin of Imatinib Therapy - A Single Institution Historical Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2750-2750
Author(s):  
Hun Lee ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Blastic Phase ◽  
Group A ◽  
The Impact ◽  
Over Time

Abstract Abstract 2750 Background: Outcome of CML since introduction of imatinib therapy has improved. Aims: analyze improvement of CML outcome in different phases. Study Group: A total of 1,569 patients with CML referred since 1965, within 1 month from diagnosis, were reviewed and used to identify phase-specific prognostic factors: 1,148 chronic, 175 accelerated, 246 blastic. Results: The median survival was 8.9 years in chronic, 4.8 years in accelerated, and 6 months in blastic phase. In chronic phase, the 8-year survival was ≤ 15% before 1983, 42–65% from 1983 to 2000, and 87% since 2001 (Figure 1). Survival was worse in older patients (p=0.004), but less significant since 2001 (p=0.07). Survival by Sokal risk was significantly different before 2001 (p<0.001), but not since 2001 (p=0.4). In accelerated phase, survival improved over time (p<0.001); the 8-year survival in patients treated since 2001 was 75% (Figure 2). Survival by age was not different in years < 2001 (p=0.09), but was better since 2001 in patients ≤ 70 years (p=0.004). Multivariate analysis derived adverse factors since 2001: older age (p=0.049), increased marrow blasts (p=0.03). In blastic phase, the median survival improved over time (p<0.001), although it is only 7 months since 2001. Conclusions: Survival in CML significantly improved significantly since 2001, particularly so in chronic and accelerated phases. Imatinib therapy minimized the impact of known prognostic factors and Sokal risk in chronic phase, and accentuated the impact of age in accelerated and blastic phases. Disclosures: Cortes: Novartis: Consultancy; Novartis: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

scholarly journals Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 1981-1987 ◽  
Author(s):  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
Guillermo Garcia-Manero ◽  
Alfonso Quintas-Cardama ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Single Institution ◽  
Historical Experience ◽  
Blastic Phase ◽  
The Impact ◽  
Over Time

Abstract A total of 1569 patients with chronic myeloid leukemia (CML) referred to our institution within 1 month of diagnosis since 1965 were reviewed: 1148 chronic phase (CP), 175 accelerated phase (AP), and 246 blastic phase (BP). The median survival was 8.9 years in CP, 4.8 years in AP, and 6 months in BP. In CP, the 8-year survival was ≤ 15% before 1983, 42%-65% from 1983-2000, and 87% since 2001. Survival was worse in older patients (P = .004), but this was less significant since 2001 (P = .07). Survival by Sokal risk was significantly different before 2001 (P < .001), but not since 2001 (P = .4). In AP, survival improved over time (P < .001); the 8-year survival in patients treated since 2001 was 75%. Survival by age was not different in years < 2001 (P = .09), but was better since 2001 in patients ≤ 70 years of age (P = .004). In BP, the median survival improved over time (P < .001), although it has been only 7 months since 2001. In summary, survival in CML has significantly improved since 2001, particularly so in CP-AML and AP-CML. Imatinib therapy minimized the impact of known prognostic factors and Sokal risk in CP-CML and accentuated the impact of age in AP- and BP-CML.

scholarly journals Imatinib Suspension and Validation (ISAV) Study: Final Results at 79 Months

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 461-461 ◽  
Author(s):  
Silvia Mori ◽  
Philipp le Coutre ◽  
Elisabetta Abruzzese ◽  
Bruno Martino ◽  
Ester Pungolino ◽  
...  
Keyword(s):  
Relapse Rate ◽  
Median Duration ◽  
Research Funding ◽  
Well Being ◽  
Imatinib Treatment ◽  
Rt Pcr ◽  
Molecular Remission ◽  
The Impact ◽  
Risk Of Relapse

Abstract Introduction. It is known that imatinib can be safely discontinued in patients (pts) with Chronic Myeloid Leukemia (CML) with minimal residual disease. Here we report an update of the Imatinib Suspension And Validation (ISAV) study at 79 months (mts) from study initiation to provide long term follow up data. Aims. The ISAV study aims to validate the capability of digital PCR (dPCR) to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR and to evaluate relapse rate, time to recurrence, survival and the impact of imatinib treatment on Quality of Life (QoL). Methods. This study involves 15 sites, 10 in Italy and 1 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. CML pts (chronic or accelerated phase) treated with imatinib for more than 2 years and in complete molecular remission (CMR) were eligible. Patients had to be in CMR for at least 18 mts, with a minimum of 3 Q-RT-PCR performed at their own sites. After discontinuation of imatinib therapy, Q-RT-PCR was performed monthly (mts 1-6), bimonthly for 36 mts and then every 6 mts for additional 2 years, to assess the maintenance of the molecular remission. The loss of molecular remission was defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resumed imatinib treatment at the same dosage used before interruption. dPCR was performed at screening and at 36 mts for those pts who were still in remission. Patients' QoL during imatinib discontinuation/resumption was evaluated through the EORTC QLQ-C30 questionnaire. Results. The ISAV study enrolled 112 pts with a median follow-up time of 60.0 mts [95% CI: 59.6-60.6] for pts who do not relapsed; 66.1% of them completed the study as per protocol. The 58.9% of pts were male and 37.4% were aged 65 or older; median duration of imatinib treatment was 103.2 mts with median duration of CMR of 25.6 mts before imatinib discontinuation. At 79 mts from imatinib discontinuation, 56 pts of the 107 eligible ones relapsed and resumed imatinib with a relapse rate of 52.3% [95%CI: 20.4-32.6]; 69.6% of them relapsed in the first 9 mts. Of the 52 not-relapsed pts, 40 (76.9%) regained Q-RT-PCR positivity without losing MMR. In this latter group 2 pts experienced late relapses, at 30.6 and 45.5 mts respectively. A loss of CCyR occurred in 13 pts (23.6%): 10/13 CCyR losses were recovered, the remaining 3 were not assessed for response. No case of CML progression or resistance to imatinib was observed. After the resumption of imatinib the median time to MMR/CMR was 1.8 [95% CI: 1.0-2.0] mts. No significant correlation between relapse and previous duration of imatinib treatment, use of interferon, time to CCyR, Sokal score or duration of CMR was identified, while an inverse relationship between pts age and risk of relapse was evident. dPCR results before imatinib discontinuation showed that 23.4% of pts were positive and 76.6% negative at the time of discontinuation, with a Negative Predictive Value ratio (dPCR/Q-RT-PCR) of 1.1 [95%CI: 0.99-1.22]. At 36 mts from imatinib discontinuation 80.4% [95%CI: 30.6-50.4] of the pts tested were positive in dPCR. Moreover, the results of dPCR performed at imatinib discontinuation and age together can predict the risk of relapse: pts with less than 45 years and with a positive dPCR had the highest risk of relapse (100%) as opposed to pts ≥45 years and with negative dPCR (36.1%). The analysis of QoL evidenced a statistically significant improvement in the general well-being and symptoms scales at 1 month after imatinib discontinuation, particularly with regard to nausea, diarrhea, fatigue and insomnia (p<0.05). An inverse and transient trend toward increased pain emerged at mts 1 and 3. Conclusions. At 79 mts from the beginning of the study, 52.3% of pts relapsed, with 24% loosing CCyR. The majority of relapses occurred in the first 9 mts after discontinuation however late relapses were also observed, up to the 4th year. Therefore, pts who discontinue imatinib should be monitored for a long period of time, especially if they show positive PCR values after discontinuation. All relapsed pts including those who lost CCyR regained their original response after restarting TKI. Age <45 years and dPCR positivity are significantly associated with relapses. QoL analysis showed a significant decrease in symptoms after imatinib discontinuation. Funded by Regione Lombardia. Disclosures le Coutre: Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Abruzzese:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Ariad: Consultancy. Assouline:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding. Kim:Pfizer: Research Funding; BMS: Research Funding; Ilyang: Research Funding; Novartis: Research Funding. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy.

BCR-ABL RNA Levels at the Time of a Complete Cytogenetic Response (CCR) Predict the Duration of CCR in Imatinib-Treated Chronic Myeloid Leukemia Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1098-1098
Author(s):  
Richard D. Press ◽  
Zac Love ◽  
Ashlie A. Tronnes ◽  
Gwen Kurilik ◽  
Michael J. Mauro ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Log P ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Log Reduction ◽  
Complete Cytogenetic Response ◽  
Rna Levels

Abstract Background : Imatinib induces a complete cytogenetic response (CCR) in the majority of patients with chronic phase CML. CCR is durable in the majority of patients, but relapse occurs in a subset. To determine the potential of quantitative RT-PCR (qPCR) of BCR-ABL to predict cytogenetic relapse, we serially monitored residual disease in 90 CML patients with an imatinib-induced CCR. Methods and patients : mRNA was prepared from total nucleated cells from blood or bone marrow, and cDNA was synthesized using random hexamer primers. Relative BCR-ABL expression was then measured by real-time fluorescent PCR normalized for G6PDH expression. This assay has a detection limit of 1 CML cell in 100,000 and an analytical precision of 6% (CV). At the start of imatinib therapy, 85% of patients were in chronic phase, at a median 9.5 months after diagnosis. Patients were treated with imatinib alone (64%) or in combination with interferon or cytarabine (32%). One patient each was treated with imatinib in combination with either the farnesyltransferase inhibitor tipifarnib, donor leukocytes (after allogeneic BMT), or an experimental heat shock protein (hsp70) vaccine. During the imatinib follow-up time of 28 months (median), disease monitoring occurred by cytogenetics and qPCR (median 6 samples per patient). The CCR was achieved after 9.7 months (median) of imatinib therapy. Results : At the time of first achieving CCR, BCR-ABL RNA levels had decreased by a median of 1.8 logs below the median baseline level. During further follow-up, 26 patients (29%) experienced cytogenetic relapse (defined as any Ph-positive metaphase cell) at a median 6.0 months after CCR and a median 20 months after starting imatinib. There was no difference in the imatinib treatment time, the time to achieve CCR, or the post-CCR follow-up period between the patients with and without subsequent cytogenetic progression. qPCR data at the time of first CCR were available for 78 patients, including 25 of 26 with a subsequent cytogenetic relapse. The reduction of BCR-ABL RNA at the time of first achieving CCR was significantly less in those patients with a subsequent cytogenetic relapse (median 1.4 log) compared to those with a sustained CCR (median 2.0 log) (P=0.002). In the 64 patients with a sustained CCR, the molecular response progressively improved over time to reach a median reduction of 4.0 log at 15 months after CCR. Of the 29 patients achieving at least a 2 log reduction of BCR-ABL RNA at the time of first reaching CCR, only 3 (10%) had a subsequent cytogenetic relapse. In comparison, 22 of 49 patients (45%) with a less than 2 log reduction at the time of achieving CCR had a subsequent cytogenetic relapse (odds ratio = 7.1; 95% CI 1.9–26). At the time of first achieving CCR, a reduction in BCR-ABL RNA of less than 2 logs thus had a diagnostic sensitivity of 88% and a diagnostic specificity of 49% for predicting subsequent cytogenetic relapse. Conclusions : We conclude that, in the majority of imatinib-treated CML patients reaching CCR, the level of BCR-ABL RNA at the time that the CCR is first achieved is a sensitive predictor of the durability of the CCR. The availability of a laboratory marker capable of stratifying the subsequent risk of disease progression (early in remission) will be useful in targeting additional (or alternative) therapies to those patients with the highest risk.

Significant Reduction of BCR-ABL Transcripts after Switching to Imatinib Therapy in Patients with CML and Complete or Near-Complete Cytogenetic Responses to Interferon-Alpha (IFN).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2142-2142
Author(s):  
Susan Branford ◽  
Timothy Hughes ◽  
Steven Stylian ◽  
Anthony P. Schwarer ◽  
Chris Arthur ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Primary Objective ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Log Reduction ◽  
Advanced Phase ◽  
Molecular Assessment

Abstract IFN confers a survival advantage for the minority of patients with CML who achieve a complete cytogenetic response. The 10-year survival rate was reported as 72%. In the IRIS trial only 3% of patients remained on IFN after randomization and 65% crossed-over to imatinib. Imatinib offered superior compliance and toxicity profiles and clear quality of life advantages. Furthermore, patients on first line imatinib with a major molecular response (MMR) by 12 months had a 100% progression free survival to advanced phase. An important clinical question of whether IFN-responsive patients can experience further improvements with imatinib has not been answered. We studied 23 chronic phase patients treated with IFN for a median of 4.5 years (r1.6–14.3) who had achieved a complete (n=15) or near-complete (n=8) cytogenetic response. IFN was ceased and 400mg imatinib commenced in a clinical trial with the primary objective of determining if switching to imatinib in IFN-responsive patients improves response when assessed at the molecular level. Molecular assessment was undertaken for the first 12 months of imatinib therapy by measurement of peripheral blood BCR-ABL levels by quantitative PCR at 3 month intervals. A subset of 10 patients had follow-up molecular assessment for 3.8 to 4.5 years after commencing imatinib. Prior to IFN cessation all patients had detectable BCR-ABL and 16 of 23 had not achieved a MMR, which is a 3 log reduction of BCR-ABL from a standardized baseline value for untreated patients. At a median of 3 months of imatinib (r3–12) these 16 patients achieved MMR. A significant reduction of BCR-ABL over the 12 month assessment was considered >50% and this occurred in 15 of these 16 patients (median 98.4% reduction, r94.4–99.8). In the sole patient without a significant reduction, BCR-ABL returned to the pre imatinib level after repeated dose interruptions of 93 days and decrease to 200mg imatinib due to thrombocytopenia. Of the 7 patients with a MMR prior to IFN cessation, all 7 maintained this level of response after switching to imatinib. Therefore, over the 12 month assessment all patients either achieved MMR (n=16) or maintained MMR (n=7). One patient withdrew consent after 83 days. The 10 patients with longer molecular follow-up of up to 4.5 years of imatinib all maintained MMR. The typical molecular response is illustrated in the figure, which plots the log reduction of BCR-ABL from the standardized baseline for 3 patients assessed at regular time-points before and after switching to imatinib. In conclusion, the data suggest that switching to imatinib leads to rapid and significant improvement in IFN-responsive patients in terms of achieving MMR, a response with established prognostic value with imatinib therapy. The study should help patients and their physicians make evidence-based decisions about the potential benefits and risks of switching to imatinib with prior response to IFN. Figure Figure

The Impact of Cytogenetic Response At 6 Months of Therapy in Global Survival of Patients with Chronic Myeloid Leukemia Treated with Imatinib in the South of Brazil

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4453-4453
Author(s):  
Laura Fogliatto ◽  
Marcelo Capra ◽  
Mariza Schaan ◽  
Mario Sérgio Fernandes ◽  
Tito Vanelli Costa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Major Molecular Response ◽  
Global Survival ◽  
The Impact

Abstract Abstract 4453 Background Treatment of chronic myeloid leukemia with imatinib leads to disease remission in a majority of patient, but in some patients (pts) controlling the disease remains a challenge. One of the proposed prognostic factors for identifying this subset of pts is the treatment response in the first months of therapy. Objectives We conducted a study to evaluate the importance of the early complete cytogenetic response (CCyR) and the factors associated with its achievement. Methods This is a retrospective study in a cohort of pts with chronic-phase chronic myeloid leukemia (CP-CML) enrolled in 3 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Early-imatinib treatment was considered when imatinib started before 12 months (mo) from diagnosis. Patient evaluation and response criteria followed the ELN recommendations. The ACE-27 (Adult Comorbidity Evaluation-27) is a 27 item comorbidity index for patients with cancer and assign weights from 1 to 3 based on the dysfunction grade of each condition (mild, moderate and severe, respectively). An ACE-27 score was applied to each patient. Imatinib suspensions were considered if superior to 20 days at any point during therapy. Global survival (GS) was measured from the start of imatinib to the date of death from any cause. Results We analyzed data from 181 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 yr (4 – 85) and 55% were male. The median time from diagnosis to imatinib was 7 mo (0 – 178) and 71% pts were early-imatinib treated. Prior therapy with interferon was used in 60% pts. The median of follow-up was 47 mo. With 6 months of imatinib therapy, 123 pts (68%) achieved CCyR, in this group the four year global survival was 97%. 58 (32%) were not in CCyR at 6 months of therapy, in this group the four year GS was 87%. This difference was significant (P=.024; Figure 1). The chance of achieving major molecular response (MMR) during follow up was 79% for the pts with CCyR at 6 months compared to 53% for the group with no CCyR at 6 months (P<0,001). Some factors were associated with reduced chance of CCyR at 6 months. In a multivariate analysis, the pts with late-onset imatinib treatment (more than 12 mo from diagnosis) had a CCyR rate of 31%, in contrast, the pts who started imatinib before 12 mo had a rate of 50% (P=0,02). The pts with good adherence to treatment had greater CCyR rate than those with poor adherence (interruption greater than 20 days), 51,4% and 35%, respectively (P=0,04). Comorbidity measured by ACE-27 score also influenced the CCyR rates at 6 months: 54% of score 0 (no comorbidity) patients achieved CCyR, compared to 30% of pts with score 1 (mild comorbidity), 33% of pts with score 2 (moderate) and 47% of pts with score 3 (severe) (P=0,009). The greater CCyR rate in the severe comorbidity group probably lacks significance due to the reduced number of pts in this group (22). Conclusions A great proportion of pts achieve CCyR after 6 months of imatinib therapy, nevertheless, the pts who achieve CCyR by 6 months of therapy have greater proportion of major molecular response and global survival. Imatinib therapy should be started as soon as possible and additional efforts must be taken to avoid nonadherence. Finally, special attention should be given to pts with comorbidities as their results tend to be worse. Disclosures: No relevant conflicts of interest to declare.

The Majority of Chronic Myeloid Leukaemia Patients Who Cease Imatinib after Achieving a Sustained Complete Molecular Response (CMR) Remain in CMR, and Any Relapses Occur Early.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1102-1102 ◽  
Author(s):  
Davi D M Ross ◽  
Andrew Grigg ◽  
Anthony Schwarer ◽  
Christopher Arthur ◽  
Kerryn Loftus ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Median Duration ◽  
Genomic Dna ◽  
Chronic Phase ◽  
Patient Specific ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Complete Molecular Response

Abstract After 5 years of imatinib treatment 40–50% of chronic myeloid leukaemia (CML) patients will have stable undetectable BCR-ABL by real-time quantitative RT-PCR (RQ-PCR) using strict sensitivity criteria (‘complete molecular response’, CMR). Many patients who stop imatinib in CMR will relapse, but small numbers have been reported with sustained CMR after imatinib withdrawal. We designed a non-randomised prospective Phase 2 study of imatinib withdrawal in adult chronic phase CML patients in CMR for ≥2 years (ACTRN012606000118505). Patients were treated in multiple centres around Australia, and RQ-PCR for BCR-ABL was performed centrally: monthly for the first year after imatinib withdrawal, and 2-monthly in the second year. Molecular relapse was defined as a single PCR result above the level of major molecular response (MMR) or any two consecutive positive results. Molecular relapse was treated with imatinib and patients were monitored monthly for 12 months to assess response to retreatment. Patients were enrolled in two cohorts: imatinib de novo (IM only, n=5) and imatinib after prior interferon therapy (IFN-IM, n=13). The median duration of prior IFN was 39 months. Both cohorts continue to accrue. For all 18 patients the median age at study entry was 58 years; 44% were male. The median duration of imatinib treatment was 60 months (R40-89). The Kaplan-Meier estimate of the rate of sustained CMR after 12 months off treatment was 67% (95% confidence interval 40–85%, see Figure). Ten of 13 IFN-IM patients (77%) remain in CMR, and 7 of these have been in CMR for at least 12 months without treatment (maximum 23 months). The median follow-up in the IM only patients is currently only 7 months (R1-15), and 3/5 remain in CMR. All molecular relapses in both groups have occurred within 5 months of stopping imatinib. The median duration of prior imatinib treatment was not different in the 5 patients with loss of CMR (76 months) versus those in stable CMR (60 months; p=0.59). Among the 5 patients with loss of CMR the median time to molecular relapse was 3 months (range 2–5 months). Two relapsing patients lost MMR, and 3 had detectable BCR-ABL mRNA below this level. No patient has experienced haematological relapse or developed a kinase domain mutation. At last follow-up all 5 relapsing patients had regained CMR after a median of 5 months of re-treatment with imatinib. Patient-specific DNA Q-PCR assays were developed to test whether minimal residual disease (MRD) was detectable in genomic DNA in patients in CMR defined by RQ-PCR for BCR-ABL mRNA. Results are available for 6 patients, 3 of whom have relapsed. One relapsing patient had BCR-ABL DNA detected prior to imatinib withdrawal. In the remaining 2 relapsing patients BCR-ABL DNA was detected after imatinib withdrawal, but 2–3 months prior to the detection of BCR-ABL mRNA by RQ-PCR. BCR-ABL DNA increased by at least 1-log between the time of the first positive result and the detection of molecular relapse by RQ-PCR. The 3 patients in stable CMR had no detectable BCR-ABL DNA. In conclusion, with close molecular monitoring imatinib withdrawal in stable CMR appears to be safe: currently all patients are either in stable CMR off treatment or back in CMR after re-treatment. Withdrawal of effective treatment outside the setting of a clinical trial is not recommended. Monitoring of MRD by genomic DNA Q-PCR was able to detect molecular relapse prior to mRNA RQ-PCR, and shows promise for the prospective identification of patients at high risk of relapse. There is an apparent dichotomy of response between early molecular relapse and durable CMR, at least in patients treated with imatinib after IFN. It is too early to identify clinical or laboratory factors (such as prior IFN treatment) that may influence the probability of sustained CMR without treatment. Figure Figure

Discontinuation of Second Generation (2G) Tyrosine Kinase Inhibitors (TKI) in Chronic Phase (CP)-Chronic Myeloid Leukemia (CML) Patients with Stable Undetectable BCR-ABL Transcripts

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 916-916 ◽  
Author(s):  
Delphine Rea ◽  
Philippe Rousselot ◽  
François Guilhot ◽  
Michel Tulliez ◽  
Franck E. Nicolini ◽  
...  
Keyword(s):  
Median Time ◽  
Median Duration ◽  
Treatment Duration ◽  
Research Funding ◽  
Residual Disease ◽  
Chronic Phase ◽  
Molecular Response ◽  
First Line ◽  
Advanced Phase

Abstract Abstract 916 Background: TKI have proven remarkably successful against CML. Despite this progress, current recommendation is to never stop therapy. However, prospective trials such as STIM and CML8 suggest that imatinib may be stopped in patients with deep and sustained molecular responses (Mahon et al, Lancet Oncol. 2010; Ross et al, Haematologica 2012). Here, we report on the feasibility of 2G-TKI discontinuation. Methods: Adult CP-CML patients on dasatinib or nilotinib without previous allogeneic transplantation or progression to advanced phase CML were proposed treatment discontinuation provided that (1) TKI treatment duration was at least 36 months (2) BCR-ABL transcripts were undetectable for at least 24 months, with at least 20 000 amplified copies of the control gene. The primary objective was treatment-free stable major molecular response (MMR: BCR-ABL/ABL internationally standardized (IS) ratio ≤ 0.1% IS). BCR-ABL transcripts were quantified in local laboratories monthly during the first 12 months, every 2–3 months during the 2nd year and every 3–6 months thereafter. Molecular relapse was defined by the loss of MMR and triggered therapy resumption. The study is ongoing and 42 patients currently agreed to stop dasatinib (53%) or nilotinib (47%). Data as of August 1, 2012 are reported, focusing on the subgroup of 34 patients with a minimum follow-up of 6 months (median 14, range 7–33). Results: Median age was 58 (34-81), 56% of patients were females (n=19). Sokal risk group was low in 56% (n=19), intermediate in 24% (n=8), high in 11% (n=4) and unknown in 9% (n=3). Twelve patients (35%) received interferon prior to TKI therapy, 25 (74%) were treated with 2G-TKI upfront (n=2) or after imatinib intolerance (n=25) and 9 (26%) received 2G-TKI due to suboptimal response/resistance. The median time since diagnosis was 87 months (31-218), the median time since TKI initiation was 79 months (30-133), the median duration of 2G-TKI therapy was 35 months (21-72) and the median duration of undetectable BCR-ABL transcripts was 27 months (21-64). At last follow-up, the 12-month probability to remain in stable MMR was 58.3% (95% CI, 41.5%-75%). The median time to MMR loss was 4 months (1-25). Importantly, no hematologic relapse was observed and none of the patients progressed to advanced phase CML. Since in imatinib discontinuation trials, different definitions for molecular relapse were used, we also calculated the rate of relapse according to STIM (detectable BCR-ABL on 2 consecutive tests with at least 1 log increase between the 2) and CML8 (detectable BCR-ABL on 2 consecutive tests at any level). The corresponding 12-month probabilities were 55.8% (95% CI, 39.2%-72.6%) according to STIM and 44.1% (95%CI, 27.4%-60.8%) according to CML8. We searched for factors possibly associated with treatment-free stable MMR. Patients treated with 2G-TKI first line or after imatinib intolerance had a significantly higher probability of stable MMR than those who were switched to 2G-TKI because of suboptimal response/resistance (12-month rate 67.3% (95% CI, 48.6%-86%) versus 33% (95% CI; 2.5%-64.1%), p=0.02). Gender, age, prior IFN exposure, 2G-TKI type and treatment duration were not found to have any impact but caution is needed due to the small size and heterogeneity of this series. Treatment was resumed in 15 patients after a median time of 5 months (2-29). The same 2G-TKI used prior to discontinuation was reintroduced in all but 1 patient, due to tolerance issues. The median follow-up since treatment resumption was 9 months (0-27). At last follow-up, MMR was regained in all 13/15 evaluable patients and undetectable BCR-ABL in 10/13. Eighteen patients with stable MMR remained off-therapy at last follow-up (median 16 months, range: 7–33), among which 7 with stable undetectable BCR-ABL and 11 with weakly detectable BCR-ABL on 1 or more occasions. Conclusions: 2G-TKI may be safely discontinued in CP-CML patients with long-lasting undetectable BCR-ABL under strict molecular monitoring conditions, especially in patients with prior imatinib intolerance or treated with 2G-TKI as first line therapy. In patients with prior imatinib suboptimal response/resistance, strategies to improve outcome are needed. The recurrence of a low level of detectable residual disease below the MMR threshold after 2G-TKI withdrawal may not automatically herald CML relapse and may not preclude the possibility to remain treatment-free. Disclosures: Rea: BMS, Novartis, Teva: Honoraria. Rousselot:BMS, Novartis: Research Funding. Guilhot:Novartis, Ariad, and BMS: Consultancy, Speakers Bureau. Tulliez:BMS, Novartis: Honoraria. Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Guerci-Bresler:Novartis, BMS: Speakers Bureau. Legros:BMS, Novartis: Honoraria. Gardembas:Novartis: Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Mahon:Novartis, BMS: Consultancy, Research Funding.

Post hoc analysis of the CLEAR study in advanced renal cell carcinoma (RCC): Effect of subsequent therapy on survival outcomes in the lenvatinib (LEN) + everolimus (EVE) versus sunitinib (SUN) treatment arms.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4562-4562
Author(s):  
Thomas E. Hutson ◽  
Toni K. Choueiri ◽  
Robert J. Motzer ◽  
Sun Young Rha ◽  
Anna Alyasova ◽  
...  
Keyword(s):  
Median Duration ◽  
Proportional Hazards Model ◽  
Objective Response ◽  
Anticancer Therapy ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
The Sun ◽  
Post Hoc ◽  
The Impact

4562 Background: The multicenter, open-label, randomized, phase 3 CLEAR study showed that LEN + EVE had a significant PFS benefit (HR 0.65, 95% CI 0.53-0.80, P<0.001) and improved objective response rate (relative risk 1.48, 95% CI 1.26-1.74) vs SUN in the first-line treatment of patients (pts) with advanced RCC. The difference in overall survival (OS) for LEN + EVE vs SUN was not statistically significant (HR 1.15, 95% CI 0.88-1.50) (Motzer R et al. NEJM. 2021). Post hoc subgroup analyses were performed to assess the impact of subsequent therapy on OS. Methods: Pts in the CLEAR study were randomly assigned (1:1:1) to 1 of 3 treatment arms, including LEN 18 mg + EVE 5 mg once daily (QD) and SUN 50 mg QD (4 weeks on then 2 weeks off). These post hoc analyses examined OS by subsequent systemic anticancer medication in the LEN + EVE and SUN arms. Hazard ratios (HR; LEN + EVE vs SUN) were based on stratified (geographic region and MSKCC prognostic risk groups) Cox proportional hazards model. Results: Among 1069 pts with advanced RCC randomized in the CLEAR study, 714 pts were randomly assigned to the LEN + EVE and SUN arms (N=357/each). The median duration of survival follow-up was 27 months in the LEN + EVE arm and 26 months in the SUN arm. Given the shorter median duration of study treatment with SUN (7.8 months) vs LEN + EVE (11.0 months), more pts in the SUN arm received subsequent anticancer therapy during survival follow-up (LEN + EVE, n=167; SUN, n=206). Among pts who received subsequent therapy, pts in the LEN + EVE arm had a longer median time from randomization to initiation of subsequent therapy vs those in the SUN arm (8.0 vs 6.6 months, respectively). OS for the overall population, for pts with no subsequent anticancer therapy, and for pts with no subsequent immunotherapy is shown in the table. In the US population subgroup (LEN + EVE, n=62; SUN, n=61) of the CLEAR study, in which a similar number of pts received subsequent systemic anticancer therapies in the LEN + EVE vs SUN arms (62.9% vs 65.6%, respectively), OS was comparable among the 2 arms (HR 0.95, 95% CI 0.51-1.76). Overall, the safety profile was consistent with the known safety profiles of LEN + EVE and SUN. In both arms, most treatment-emergent deaths were due to progressive disease; there were few treatment-related deaths (<1%, per arm) and no clustering of events. Conclusions: In the CLEAR study, LEN + EVE met the primary endpoint of a significant benefit in PFS vs SUN. The results of these exploratory analyses suggest that subsequent systemic anticancer therapy affected the OS outcome results for LEN + EVE vs SUN in the CLEAR study. Clinical trial information: NCT02811861. [Table: see text]

Four Years of Follow-Up of 1027 Patients with Late Chronic Phase (L-CP), Accelerated Phase (AP), or Blast Crisis (BC) Chronic Myeloid Leukemia (CML) Treated with Imatinib in Three Large Phase II Trials.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 23-23 ◽  
Author(s):  
Richard T. Silver ◽  
Moshe Talpaz ◽  
Charles L. Sawyers ◽  
Brian J. Druker ◽  
Andreas Hochhaus ◽  
...  
Keyword(s):  
Phase Ii ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Imatinib Treatment ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Phase Ii Studies ◽  
Large Phase

Abstract Background This report updates the results of 3 large phase II studies of the orally available BCR-ABL tyrosine kinase inhibitor imatinib for patients (pts) in AP, BC and late chronic phase (L-CP) CML failing prior interferon therapy (Kantarjan et al, ASH 2003; Talpaz et al, ASH 2003). Methods Between August 1999 and June 2000, 1027 pts were enrolled in phase II trials for CML in L-CP (n=532), AP (n=235) or BC (n=260). Pts in L-CP were treated with 400 mg/day and pts in AP or BC with either 400 or 600 mg/day. Dose escalation up to 800 mg/d was allowed in the late-chronic phase study. Pts with a confirmed diagnosis of AP (n=181), BC (n=229) and late-chronic phase (n=454) were evaluated for efficacy. All pts were evaluated for safety. The median time from initial diagnosis to study entry was 32 months for L-CP pts. Results As of 31-Jul-03, 5% patients with BC, 25% of CML-AP and 64% of L-CP patients still remain on treatment. At the recommended dose of 600 mg, an estimated 40% (AP) and 7% (BC) of patients remained progression-free at 36 months, and an estimated 55% (AP) and 14% (BC) patients were alive at 36 months after initiation of imatinib. The 3-year survival rates for pts with AP with a major cytogenetic response at 3 months were 85% vs. 52% for pts with no response (p<0.001). In L-CP patients with a median follow-up of 40 months, 65% of patients achieved a major cytogenetic response, which was complete in 52%. The cytogenetic responses were durable with an estimated 82% of the pts in continuos major cytogenetic response at 3 years. The estimated rates of progression-free survival and overall survival at 3 years were 80% and 88%. Pts with at least a minor cytogenetic response at 6 months ≤65% Ph+ cells) had an estimated 3-year survival rate of 96% vs. 86% for pts with a ( minimal response and 81% for pts with no cytogenetic response (p<0.001). Conclusion In large phase II studies, continuous imatinib treatment is safe and has improved progression-free survival of patients at all stages of CML. Responses to imatinib are durable and are predictive of long-term outcomes. These results will be further updated at the meeting using a data base lock planned for 20-Sept-04 (using data collected up to 31-July-04, i.e. more than 4 years after the last pts enrollment).

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