Event-Free Survival According to Age in Patients with Chronic Myeloid Leukemia Receiving Imatinib Frontline: The Younger, the Later, the Worse?

Abstract Differences in baseline features and follow-up among patients with chronic myeloid leukemia (CML) according to age at diagnosis have been recently reported in cohorts from clinical controlled trials (Castagnetti F et al, 2015). To evaluate this issue in a real-life setting, we revised 207 consecutive CML patients treated at our Institution with imatinib frontline from 6/2002 to 6/2013, dividing them in young adults (>20 <45 years) (YA), middle-aged adults (≥45 <65 years) (MA) and elderly (≥65 years) (EL). The main features at baseline of the whole cohort and of the 3 age groups are reported in the Table. Table.ALLYAMAELpN° of patients207617274M/F108/8930/3140/3238/360.752Median WBC (x 109/l)IQR66.1 (32.7 - 119.0)109.8 (65.9 - 148.0)59.5 (31.3 - 126.6)40.1 (26.5 - 81.4)<0.001Median Hb (g/dl)(IQR)12.5 (11.0 - 13.5)11.7 (9.8 - 12.7)12.7 (11.0 - 14.2)12.8 (11.3 - 13.7)0.002Median PLT (x 109/l)IQR414 (275 - 616)445 (291 - 597)378 (262 - 546)457 (271 - 732)0.287Spleen enlargement (>5cm) N° (%)17 (8.3)11 (18.3)4 (5.6)2 (2.7)0.003Sokal score (N°)Low/Int/High89/93/2047/9/338/27/54/57/12<0.001Comorbidities ≥ 2, N° (%)77 (37.2)5 (8.1)26 (36.1)46 (62.1)<0.001 The rates of complete cytogenetic response (CCyR) were similar (86.4% in YA, 95.5% in MA and 91.0% in EL, p=0.227) while the rate of major molecular response was higher in the MA group (89.7% vs 63.8% in YA and 75.8% in EL, p=0.001). The number of events (permanent discontinuation due to toxicity, primary or secondary resistance, any death for CML related or unrelated causes) was lower in the MA group [8 (11.1%) vs 21 (34.4%) in YA and 28 (37.8%) in EL, p=0.001]: no difference was observed in the rate of evolution to blastic phase [3 (4.9%) in YA, 1 (1.4%) in MA and 2 (2.7%) in EL, p=0.478]. The number of deaths was higher in the EL group [12 (16.2%) vs 2 (3.2%) in YA and 0 in MA, p<0.001]: it is worth of note, however, that 11/12 deaths in the EL group were not related to CML progression. The 4-year event-free survival (EFS) for the whole cohort was 73.5% (95%CI 67.0 - 80.0): the 4-year EFS in the MA group [92.0% (95%CI 85.1 - 98.9)] was significantly higher than in YA group [67.3% (95%CI 55.1 - 79.5)] and in EL group [61.1% (95%CI 49.5 - 73.7)] (p=0.001). The 4-year overall survival (OS) for the whole cohort was 94.4% (95%CI 90.9 - 97.9): the 4-year OS in the EL group [72.4.% (95%CI 56.9 - 87.9)] was significantly lower than in YA group [96.3% (95%CI 91.2 - 100)] and in MA group (100%) (p<0.001). In conclusion, age at diagnosis influences significantly the course of CML patients treated with imatinib: the MA group has the best follow-up with an excellent OS and EFS, while the relatively lower OS and EFS in the EL group are clearly related to the incidence of unrelated deaths like in the general aged population. A possible explanation of the counterintuitive worse course of YA group is the delayed diagnosis in these patients (higher WBC counts, lower Hb levels, higher rate of spleen enlargement > 5 cm) compared to aged patients, who have often concomitant diseases and make routinely blood analyses: however, a more aggressive biology of CML in YA could not be excluded and warrants further investigations. Disclosures No relevant conflicts of interest to declare.

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Generic Imatinib in Chronic Myeloid Leukemia: Survival of the Cheapest

Blood ◽

10.1182/blood.v128.22.630.630 ◽

2016 ◽

Vol 128 (22) ◽

pp. 630-630 ◽

Cited By ~ 6

Author(s):

Danthala Madhav

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Imatinib Mesylate ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Quantitative Polymerase Chain Reaction ◽

Comparable Efficacy ◽

Molecular Response ◽

Free Survival

Abstract Introduction: The patent expiration of Imatinib mesylate (Glivec, ®Novaritis) on February 1, 2016, has brought the focus back on generic versions of the drug, and an opportunity to provide a safe and cost effective alternative. India has witnessed a mushrooming of home grown pharmaceutical companies, that have drawn on Darwinian theory to promote the concept of "survival of the cheapest", in pursuit of a deeper penetrance into the cash strapped population. The launch of Veenat (®NATCO pharma) at a fraction of the price of the innovator drug is a case in point. Objectives: To determine the molecular and cytogenetic responses, survival endpoints (event free survival (EFS), failure free survival (FFS), transformation free survival (TFS), overall survival (OS), and safety of innovator and generic brands of imatinib. Materials and Methods: In this retrospective analysis, data from 1,812 patients with chronic myeloid leukemia (CML) treated with frontline Imatinib mesylate (Innovator/Generic) at a single institution between 2008 and 2014 is included. Of these 1,812 patients, 445 were excluded due to inadequate data and follow up. Thus, data from 1,193 patients who were treated with Glivec (®Novartis), and 174 patients with Veenat (®NATCO) was available. Observations: A higher percentage of patients in the generic arm compared to the innovator arm, were in accelerated phase (9.7% vs 6.7%) and blast crisis (7.4% vs 3.7%), respectively.After a median follow up of 1,347 days, 805 (67.4%) patients achieved complete cytogenetic response (CCgR), 259 (21.7%) achieved major molecular response (MR3), and 205 (17.1%) achieved 4 log reduction in BCR ABL transcripts (MR4) in the innovator arm. After a median follow up of 1,220 days, 112 (64.3%), 24 (13.7%), and 42(24.1%) patients achieved a CCgR, MR3 and MR4 respectively, in the generic arm.Follow up assessments using real-time quantitative polymerase chain reaction (q-PCR) and/ or cytogenetic tests were not available in 230 (19.2%) and 40 (22.9%) patients, in the innovator and generic groups respectively, despite inclusion in a sponsorship program.Adherence to treatment was poor in 192 (16%) and 30 (17.2%) patients in the innovator and generic arms respectively. Results: In a fairly homogenous population of lower economic strata, on a free drug access program, the prime factors influencing adherence were low educational level, assumptions of "cure", recent bereavement, stigma of cancer diagnosis and repeated hospital visits. Transformation to accelerated/blast phase occurred in 7.7% and 7.4% of patients in the innovator and generic arms respectively. Testing for BCR-ABL1 mutations was done in 31 (17.8%) patients in the generic arm and 132(11%) patients in the innovator arm, after failure of treatment or suboptimal response. Mutations were identified in 14 (8%) patients in the generic arm and 52 (4.3%) patients in the innovator arm.The most common subsequent treatments chosen were, dose escalation (249 [20.8%] vs 30 [17.2%]), Nilotinib (26 [2.1%] vs 8 [4.5%]), Dasatinib (11 [0.9%] vs 9 [5.1%]) and hydroxyurea (11 [0.9%] and 4 [2.2%]) in the innovator and generic arms respectively. There was no difference in EFS (p=0.46), FFS (p=0.16), TFS (p=0.9), or OS (p=0.13) between the two groups. The frequency of reported grade 1, or 2 non-hematological adverse events which included musculoskeletal pain, muscle cramps, and peripheral edema, and hematological adverse events was comparable between the study groups. However, the incidence of grade 3 skin rash was higher in the generic group (2.8%) in comparison to the innovator group (0.2%). Conclusion: The findings of the present study showed comparable efficacy and safety of the generic and innovator versions of imatinib in the treatment of patients with chronic myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

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Five-Year Outcome of 215 Newly Diagnosed Chronic Myeloid Leukemia Patients Treated Frontline with Nilotinib-Based Regimens: A Gimema CML Working Party Analysis

Blood ◽

10.1182/blood.v124.21.3141.3141 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3141-3141

Author(s):

Gabriele Gugliotta ◽

Fausto Castagnetti ◽

Massimo Breccia ◽

Luciano Levato ◽

Giovanna Rege-Cambrin ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Cytogenetic Response ◽

Molecular Response ◽

Newly Diagnosed ◽

Secondary Resistance ◽

Long Term Outcome ◽

Free Survival

Abstract Background. Nilotinib (NIL) is a potent and selective BCR-ABL inhibitor approved for the frontline treatment of chronic myeloid leukemia (CML) based on the results of the ENESTnd study. The sustained superiority of NIL vs. imatinib (IM) was confirmed after 5 years of follow-up (Hughes et al, abs. 677, EHA 2014). However, few data are available on patients (pts) treated frontline with NIL outside of Company-initiated trials. Objectives. To analyze the long-term outcome in a large, independent cohort of newly diagnosed CML pts treated frontline with NIL-based regimens. Methods. We analyzed 215 pts, enrolled in 2 multicenter phase II studies conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00481052 and NCT00769327) or treated at the Bologna University Hospital, with NIL 300 mg or 400 mg BID as initial treatment; 123 pts received a sequential treatment with NIL and IM (NIL-IM), with a 3-months (mos) rotation period (all patients received NIL in the first 3 mos). The median age was 53 years (range 18–86). Ten out of 215 pts (5%) had a high EUTOS score. The median follow-up was 57 mos (range 36–81 mos). We assessed: the rates of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR); the rates of optimal responders at each milestone according to ELN 2013 recommendations; the overall survival (OS; any death included), progression-free survival (PFS; progression to accelerated/blast phase [AP/BP] and deaths for any cause), failure-free survival (FFS; failures according to ELN 2013 recommendations and deaths for any cause), and event-free survival (EFS; events: failures, permanent discontinuation of NIL for any cause, including deaths). All analysis was made according to the intention-to-treat principle. Results. The cumulative rates of CCyR and MMR were 93% and 88%, respectively. At 3 mos, 82% of the pts were in Partial Cytogenetic Response and 90% had a BCR-ABL/ABL (IS) < 10%; at 6 mos, 86% were in CCyR and 83% had a BCR-ABL/ABL (IS) < 1%; at 12 mos, 72% were in MMR; all these pts were optimal responders according to ELN 2013 recommendations. Overall, 80 (37%) pts permanently discontinued NIL: 45 (21%) for adverse events or intolerance; 25 (12%) for failures; 7 (3%) while in stable MR4; 3 (1%) for other reasons. Cardiovascular adverse events (CVAE) were cause of permanent NIL discontinuation, after a median time of 37 mos, in 13 (6%) pts, and included 4 peripheral arterial occlusive diseases and 3 ischemic coronary diseases; only one pt died for CVAE. Nine (4.1%) pts progressed to AP/BP, 8/9 during the 1st year of therapy and one after 25 mos; all pts subsequently died (after a median of 13 mos, range 1-34 mos). NIL-resistant mutations were identified in 6 of these pts (4 T315I; 1 Y253H; 1 F359V); 7/9 progressions occurred in patients receiving NIL-IM. In addition, 6 pts were classified as failures at 3,6, or 12 mos according to ELN 2013 recommendations; afterwards, 10 pts developed a secondary resistance (3 loss of CHR, 3 loss of CCyR, and 4 confirmed loss of MMR). Overall, 17 (8%) pts died, in 7 cases for reasons unrelated to CML progression. The estimated 6-year OS, PFS, FFS, and EFS were 91%, 91%, 83%, and 59%, respectively. Conclusions. Our National experience showed that most pts treated frontline with NIL-based regimens were optimal responders according to ELN recommendations and that 91% of the patients were estimated to be alive and progression-free at 6 years. In particular, NIL alone was highly effective in the prevention of AP/BP. Considering that AP/BP had in most cases an early onset and an extremely poor prognosis, its prevention should be the priority of CML treatment, especially in the firsts 2-3 years. However, afterwards, the relatively high number of CVAE observed, suggests to focus, at least in selected patients, on strategies aimed at the prevention of CVAE (NIL dose reduction? switch to IM?). Acknowledgments. European LeukemiaNet, COFIN, Bologna University, BolognAIL Disclosures Gugliotta: Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy. Castagnetti:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Abruzzese:Novartis: Consultancy. Martinelli:ARIAD: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other. Baccarani:Novartis, BMS, Pfizer, Ariad: Consultancy, Honoraria, Speakers Bureau. Rosti:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy; Ariad: Consultancy; Pfizer: Consultancy.

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Sustained Responses and Resistance to Imatinib Mesylate in the First 173 Chronic Myeloid Leukemia Patients Accrued by the SCREEN Multicenter Study: First Interim Report.

Blood ◽

10.1182/blood.v114.22.4276.4276 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4276-4276

Author(s):

Paolo Vigneri ◽

Fabio Stagno ◽

Stefania Stella ◽

Alessandra Cupri ◽

Michele Massimino ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Imatinib Mesylate ◽

Myeloid Leukemia ◽

Chromosomal Abnormalities ◽

Conflicts Of Interest ◽

Chronic Phase ◽

Molecular Response ◽

Primary Resistance ◽

Secondary Resistance

Abstract Abstract 4276 Introduction Imatinib mesylate (IM) has shown unprecedented effectiveness in the treatment of Chronic Myeloid Leukemia (CML) patients (pts) in the chronic phase of the disease. As most of the data concerning the efficacy of the drug derive either from a single sponsored trial or from single institution reports, we decided to accrue all CML pts diagnosed in the Italian region of Sicily to the observational SCREEN (Siciliy CML Regional Enterprise) study, to evaluate the hematological, cytogenetic and molecular responses of this unselected population to IM. Patients and Methods Although the study is still ongoing, 173 consecutive CML pts have been enrolled between January 2005 and June 2009 (cutoff time for the first interim analysis) by one of the 12 institutions involved. Each center was responsible for the diagnosis, treatment (IM 400 mg qd) and follow-up of the pts accrued, while all molecular analyses were centralized in Catania. Median follow-up time was 31 months. Eleven pts (6.3%) are currently off study. Results Pts characteristics were as follows: 95 males (54.9%) and 78 females (45.1%) were enrolled with a median age of 53 years (range 24-90). Eighty-nine pts (51.4%) were low Sokal risk, 62 (35.8%) were intermediate risk and 22 (12.8%) were high risk. Nine pts (5.2%) displayed additional chromosomal abnormalities. Median leukocyte counts (1×109L) were 67.6 (range 3.4-718), median hemoglobin (g/L) was 122 (range 75-170) while median platelet counts (1×109L) were 317 (range 67-2620). Cumulative incidences of complete hematologic response (CHR) and complete cytogenetic response (CCyR) were 98.3% and 85% respectively, while 59.2% of pts obtained a major molecular response (MMR). At 54 months, estimated overall survival was 95.6%. Estimated progression free survival (accounting for all pts that failed IM according to the European Leukemia Net criteria) was 75.1%. Thirty pts (17.3%) presented resistance to IM, either because of failure to obtain a satisfactory response (primary resistance, 21 pts) or because of loss of previously obtained responses (secondary resistance, 9 pts). Thirty-three pts (19%) presented a suboptimal response, 8 because of failure to achieve a CCyR by 12 months of therapy and the remaining 25 because of lack of a MMR after 18 months of IM. Only 3 pts (1.7%) were intolerant to IM. Interestingly, the median amount of BCR-ABL transcript at diagnosis (measured according to the International standardized Scale) displayed by pts that failed IM or achieved a suboptimal response (106.5IS) was significantly higher than that of pts obtaining an optimal response (61.9 IS p=0.0031). Conclusions IM is a highly effective and well-tolerated treatment for most chronic phase CML pts, producing high rates of CHR and CCyR. Approximately 60% of cases will also achieve a MMR. 35-40% of pts will either fail IM or obtain only partially satisfying results (suboptimal response). High levels of BCR-ABL transcript at diagnosis might allow a rapid identification of this less responsive pt population. Disclosures: No relevant conflicts of interest to declare.

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The Impact of Early Molecular Response in Event Free Survival in Patients with Chronic Myeloid Leukemia Treated with Imatinib

Blood ◽

10.1182/blood.v124.21.5536.5536 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5536-5536

Author(s):

Laura Fogliatto ◽

Marcelo Eduardo Zanella Capra ◽

Mariza Shaan ◽

Tito Vanelli Costa ◽

Mayde Seadi Torriani ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Significant Proportion ◽

Chronic Phase ◽

Molecular Response ◽

Event Free Survival ◽

Durable Response ◽

Free Survival ◽

The Impact

Abstract Background Monitoring response to TKI therapy is one of the key management strategies of chronic myeloid leukemia (CML). Early molecular response to first-line TKI therapy is emerging as an effective prognostic factor indicator of long-term durable response and survival. Objectives We conducted a study to evaluate the importance of the early molecular response (EMR) at 3, 6 and 12 months (mo), and 3-year event free survival (EFS). Methods This is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) enrolled in 14 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. EFS was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Results We analyzed data from 517 pts with CML-CP diagnosed since 1990. After a median observation time of 46 months, 5-year overall survival (OS) was 86% and 5-year event-free-survival was 53%. At 3 mo, EFS was 72,5% for 46 pts with BCR-ABLIS ≤10% compared to 58% for 14 pts with BCR-ABLIS >10% (p<0,07). Similarly, when EMR was analysed at 6 mo, the EFS was 81% for 75 pts with BCR-ABLIS ≤1%, while 31% of EFS was achieved for 38 pts with BCR-ABLIS >1% (p<0,001). At 12 mo, the 3-year EFS was 86% for 65 pts with with BCR-ABLIS ≤0,1% compared to 54% for pts with BCR-ABLIS>0,1% (p<0,001). Conclusions A significant proportion of pts achieve ERM after 3,6 and 12 mo of imatinib therapy with better 3-year EFS. ERM may could identify those pts more likely to have a favorable outcome. Disclosures No relevant conflicts of interest to declare.

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Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽

10.1182/blood.v114.22.3302.3302 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3302-3302

Author(s):

Massimo Breccia ◽

Fabio Stagno ◽

Roberto Latagliata ◽

Paolo Vigneri ◽

Laura Cannella ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Standard Dose ◽

Acquired Resistance ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

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Initial Molecular Response at 3 Months May Predict Both Response and Event-Free Survival at 24 Months in Imatinib-Resistant or -Intolerant Patients With Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase Treated With Nilotinib

Journal of Clinical Oncology ◽

10.1200/jco.2011.40.5217 ◽

2012 ◽

Vol 30 (35) ◽

pp. 4323-4329 ◽

Cited By ~ 65

Author(s):

Susan Branford ◽

Dong-Wook Kim ◽

Simona Soverini ◽

Ariful Haque ◽

Yaping Shou ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Cumulative Incidence ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Molecular Response ◽

Close Monitoring ◽

Event Free Survival ◽

Free Survival ◽

Transcript Levels ◽

Imatinib Resistant

Purpose The association between initial molecular response and longer-term outcomes with nilotinib was examined. Patients and Methods Patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase from the phase II nilotinib registration study with available postbaseline BCR-ABL1 transcript assessments were included (N = 237). Results BCR-ABL1 transcript levels (International Scale [IS]) at 3 months correlated with complete cytogenetic response (CCyR) by 24 months. Patients with BCR-ABL1 (IS) of > 1% to ≤ 10% at 3 months with nilotinib had higher cumulative incidence of CCyR by 24 months than patients with BCR-ABL1 (IS) of > 10% (53% v 16%). BCR-ABL1 (IS) at 3 months predicted major molecular response (MMR) by 24 months. Cumulative incidence of MMR by 24 months for patients with BCR-ABL1 (IS) of > 0.1% to ≤ 1%, > 1% to ≤ 10%, and > 10% was 65%, 27%, and 9%, respectively. These differences were observed for patients with or without baseline BCR–ABL1 mutations and for those with imatinib resistance or intolerance. Estimated event-free survival (EFS) rates at 24 months decreased with higher transcript levels at 3 months; patients with BCR-ABL1 (IS) of ≤ 1% had an estimated 24-month EFS rate of 82%, compared with 70% for patients with BCR-ABL1 (IS) of > 1% to ≤ 10% and 48% for patients with BCR-ABL1 (IS) of > 10%. Conclusion Patients with BCR-ABL1 (IS) of > 10% at 3 months had a lower cumulative incidence of CCyR and MMR and lower rates of EFS versus patients with BCR-ABL1 (IS) of ≤ 10%. Prospective studies may determine whether close monitoring or alternative therapies are warranted for patients with minimal initial molecular response.

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TKI Treatment Discontinuation: How Many Patients Could Stop Tyrosine Kinase Treatment According to Discontinuation Trials Criteria? Incidence and Prognostic Impact of Deep Molecular Response in a Cohort of Chronic Myeloid Leukemia Patients of South Brazil's Hematology Centers

Blood ◽

10.1182/blood.v124.21.5542.5542 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5542-5542

Author(s):

Laura Fogliatto ◽

Marcelo Eduardo Zanella Capra ◽

Mariza Shaan ◽

Tito Vanelli Costa ◽

Luis Carlos Zanandrea Contin ◽

...

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Molecular Response ◽

Imatinib Treatment ◽

Event Free Survival ◽

Free Survival ◽

The Future ◽

Tki Discontinuation

Abstract Sustained deep molecular response (MR4.5) after imatinib treatment defines a subgroup of patients with chronic myeloid leukemia (CML) with better outcome and that probably would be able to stop treatment in the future, according to results of clinical TKI discontinuation trials. Most of these trials showed that patients with a long-term imatinib treatment and low Sokal risk have a higher probability of maintain a deep molecular remission after stopping treatment. OBJECTIVES The main objective is to review the molecular responses, overall survival and event free survival of CP CML patients that have been treated with imatinib in 14 hematology centers in South Brazil. Using our data basis we also would like to see how many of them present long-term imatinib treatment, sustained deep molecular remission and correlate these findings with the Sokal risk groups. These data would allow us to predict patient profile that could be able to discontinue the treatment in the future in a prospective clinical trial. PATIENTS AND METHODS This is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) that have been treated in 14 hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. MR(4.5) was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction. All tests were performed at a central standardized according to ELN. Event-free-survival (EFS) was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Overall survival (OS) was measured from the start of imatinib until death of any cause or to the date patient was last known to be alive. RESULTS Data from 474 patients was analyzed. After a median observation time of 46 months, 5-year overall survival (OS) was 86%, 5-year event-free-survival was 53%. Of the 474 patients, 258 had adequate PCR evaluations during treatment. 118 of 258 (45,7%) patients achieved MR(4.5) and 69 of 258 (27%) had sustained response for at least two years after a minimum time of treatment of 3 years. The cumulative incidence of MR(4.5) after 9 years was 76% (median, 3 years). In the group that achieved MR(4.5), there was only 1 (0,8%) death and 1 (1,1%) progression compared to 8 deaths (5,7%) and 8 progressions (7,5%) in the group without MR(4.5); these differences were significant with p=0,03 and 0,02 respectively. In the subgroup of 69 patients that had had been treated with imatinib for 3 year or more and sustained deep response (RM4,5) for at least two years, 21 pts had low Sokal risk, 7 pts intermediate Sokal risk and only 4 pts a high Sokal risk. Unfortunately, in 37 pts the Sokal risk could not be accessed due to missing information. CONCLUSION In our series MR(4.5) is reached in the majority of patients with long-term imatinib treatment. MR(4.5) is a predictor of outcome with only one disease progression and one death due to CML in this group of patients. Unfortunatly PCR are not available for all patients in our clinical practice, but this situation are improving. Regarding the 69 patients with TKI discontinuation trial criteria, we find out that 21 patients fulfill such criteria. In the future, according to the results of current stop trials it could be possible include this selected group of CP CML patients in a prospective clinical trial. Disclosures No relevant conflicts of interest to declare.

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Duration of Major Molecular Response and Discontinuation in Deep Molecular Response (MR4.5) Were Associated with Longer Treatment-Free Survival after Imatinib Discontinuation - Results from Two Prospective Brazilian Trials

Blood ◽

10.1182/blood-2019-125368 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1655-1655

Author(s):

Katia B Pagnano ◽

Fernanda S Seguro ◽

Eliana C Miranda ◽

Ana Beatriz Pascoal Lopes ◽

Andre Abdo ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Cox Regression ◽

Chronic Phase ◽

Molecular Response ◽

Free Survival ◽

Deep Molecular Response ◽

Treatment Free Remission

Several trials have demonstrated the feasibility of discontinuation of tyrosine kinase inhibitors (TKI) treatment in chronic myeloid leukemia (CML) patients (pts) with deep molecular response. Aims: to report the results of two Brazilian imatinib (IM) discontinuation trials and to evaluate factors impacting in treatment-free remission (TFR) and treatment-free survival (TFS) after IM discontinuation. Methods:Between September 2016 and January 2019, 60 CML pts were included in two ongoing phase II, single arm, prospective Brazilian discontinuation trials: Pilot Study of Discontinuation in Patients With Chronic Myeloid Leukemia With Deep Molecular Response - Evaluation of Pioglitazone in Treatment-free Remission (TFR) (EDI-PIO UNICAMP)(NCT02852486)and Imatinib Discontinuation in Patients With Chronic Myeloid Leukemia Chronic Phase With Sustained MR4log(USP) (NCT03239886). Inclusion criteria: age >18 years, chronic phase, minimum of 3 years of IM therapy, deep molecular response for ≥ 2 years (confirmed by 4 tests in the last 2 years, defined as MR4.0 in USP trial and MR4.5 in EDI-PIO). Patients participating in EDI-PIO trial used pioglitazone 30 mg/day plus IM for 3 months before IM discontinuation (n=30). After discontinuation, pts were monitored by quantitative RQ-PCR monthly in the first year, every 2 months in the second year and every 3 months in the third year. Criteria for IM re-initiation: loss of MMR (in one test), loss of cytogenetic response, loss of hematologic response, disease progression or confirmed loss of MR4.0 (this criteria used only in EDI-PIO trial). TFR was calculated from the date of discontinuation until first event (loss of MMR; IM reintroduction; death any cause or last follow-up); TFS was calculated from the date of IM discontinuation until reintroduction or last follow-up (censoring deaths not related to CML). Adverse events after IM discontinuation were reported according to CTCAE. Results:Data cut-off for analysis was February 2019. In the 1stanalysis 48 pts who discontinued IM in MR4.5 were analyzed. Patient's characteristics from EDIPIO (n=30) and USP (n=18) trials were: 57% vs. 67% male, median age of 55 (29-77) and 56 (33-95) years (29-95) at discontinuation; 16% and 33% had used previously Interferon; median duration of IM treatment of 10 (3-16) vs. 10 (5-15) years; median duration of MMR 95 (30-149) vs. 93 (57-130) months; MR4.0 was 90 (26-135) vs. 89 (30-123) months; and MR4.5 was 76 (23-135) vs. 75 (30-102) months; none variable had statistical difference.One patient died in MMR due to cardiac failure. TFR was 61% (95% CI 47-75) at 20 months. Sixteen (33%) out 48 re-initiated IM (2 with confirmed loss of MR4.0 and 14 with loss of MMR) in a median time of 20 (1-26) months. All relapsed pts recovered MMR after IM reintroduction, in a median time of 2 months (0-4). There was no transformation to advanced phases. No serious adverse events were reported during pioglitazone treatment. In the Cox regression the duration of MMR was associated with a longer TFR HR: 0.96 (beta-) (CI 95%:0.94-0.99, P= 0.006). Gender, age at diagnosis, age at discontinuation, treatment with pioglitazone, Sokal and EUTOS scores, BCR-ABL transcripts type, duration of IM therapy, duration of MR4.0 and MR4.5 and previous use of Interferon did not affect TFR.In the second analysis all 60 pts were included. TFS was 56% and was higher in pts who discontinued IM in sustained MR4.5 vs. MR4.0 (63% vs. 33%, P=0.04)(Figure). The independent factors for TFR in the multivariate analysis by Cox-regression were the duration of MMR [HR: 0.97 (beta-), 95%CI: 0.95-0.98, P=0.001] and intermediate/high risk Sokal [HR 3.14 95%CI: 1.08-9.11, P= 0.035]. Twenty-four out of 60 pts (40%) re-initiated IM (2 with confirmed loss of MR4.0 and 22 with loss of MMR).Adverse events occurred in 38 (63%) pts, 30% attributed to withdrawal syndrome. Some pts presented more than one event. Grade 1-2: arthralgia or muscular pain (17), hyperglycemia (4), hypertriglyceridemia (2), polycythemia (2), hypertension (3), and others (11). Four pts had grade 3-4 event: arthralgia (1), death for cardiac failure (1), abortion and hypertriglyceridemia (1). Conclusions:both trials demonstrated the feasibility and safety of IM discontinuation in pts in sustained deep molecular response. The duration of MMR was associated with a higher TFR and TFS rate. Imatinib discontinuation was more successful in pts in stable MR4.5. Figure Disclosures Pagnano: Pint Pharma: Consultancy; Abbvie: Consultancy; Sandoz: Consultancy. Delamain:Novartis: Honoraria.

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Discontinuation of Imatinib in Children with Chronic Myeloid Leukemia: An International Registry of Childhood Chronic Myeloid Leukemia (I-CML-Ped) Study

Blood ◽

10.1182/blood-2020-135844 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 53-54

Author(s):

Frédéric Millot ◽

Meinolf Suttorp ◽

Stéphanie Ragot ◽

Guy Leverger ◽

Jean-Hugues Dalle ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Age At Diagnosis ◽

Molecular Response ◽

Imatinib Treatment ◽

Advisory Committees ◽

Treatment Free Remission ◽

Tki Discontinuation

Background: Imatinib, a tyrosine kinase inhibitor (TKI) is currently proposed as first line therapy in children with chronic myeloid leukemia (CML) in chronic phase (CP). Studies in adults with CML demonstrated that 40 to 50% of patients with prolonged deep molecular response under TKI could discontinue TKI permanently without molecular relapse. However, data regarding TKI discontinuation in children with CML are limited. Methods: Using the ELN criteria we identified in the International Registry of Childhood Chronic Myeloid Leukemia 18 patients less than 18 years of age at diagnosis with CML in CP exhibiting under imatinib treatment sustained deep molecular response >MR4.0 (DMR) for ≥ 2 years and then discontinued the TKI. We retrospectively analyzed outcome of these patients and treatment-free remission rate (TFR) at various time points. Treatment with imatinib was resumed in case of molecular relapse defined as loss of major molecular response (MMR). Results: There were 11 boys and 7 girls. From diagnosis in CP until TKI discontinuation the 18 children showed no progression, resistance, warning or suboptimal response or switch to another TKI before discontinuation. Median age at diagnosis of CML was 11.9 years (range, 2.3 to 15.8 years) and median age at discontinuation of TKI was 16 years (range, 9 to 24 years). Median overall follow-up from diagnosis of CML was 107 months (range, 67-209 months). DMR was achieved after a median time of 12 months (range, 3 - 50 months) on imatinib. Before discontinuation median treatment duration of imatinib was 73.25 months (range, 32 to 109 months) and median duration of MR4.0 was 46.2 months (range, 23.9 to 98.6 months). Seven patients experienced molecular relapse 4.1 months (range, 1.9-6.4 months) after stopping and restarted imatinib. Two patient resumed imatinib 3.6 and 3.4 months after discontinuation because of increased in transcript level (from 0.001% to 0.01 and 0.012, respectively) but without loss of MMR. The median molecular follow up after discontinuation was 116 months (range, 71 to 209 months) for the patients without molecular relapse. The proportion of patients maintaining molecular free remission was 61% (95% CI, 38%-83%), 56% (95% CI, 33%-79%) and 56% (95% CI, 33%-79%) at 6, 12, and 36 months, respectively (Figure 1). Six of the 7 children who experienced molecular relapse after discontinuation again achieved MR4.0 at median of 4.7 months (range, 2.5-18 months) after restart of imatinib; the remaining patient achieved MMR but not DMR and was switched to Dasatinib. No withdrawal syndrome was observed in this cohort of 18 patients. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment duration before discontinuation and duration of DMR until imatinib discontinuation had no influence on treatment free remission. Conclusion: These data indicate that imatinib could be safely discontinued in children younger than 18 years of age at diagnosis of CML with sustained MR4.0 for at least 2 years under imatinib. Larger studies of TKI discontinuation in children with CML are needed in order to identify factors predicting treatment free remission. Disclosures Dalle: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Orchard: Consultancy, Honoraria; Bellicum: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

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Restrospective Multicenter Study Evaluating Efficacy and Safety of Dasatinib and Nilotinib in Patients with Imatinib-Resistant or –intolerant Chronic Myeloid Leukemia in Chronic Phase: Korean CML Working Party

Blood ◽

10.1182/blood.v120.21.1691.1691 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1691-1691

Author(s):

Jeong-Ok Lee ◽

Inho Kim ◽

Joo-Seop Chung ◽

Yeo-Kyeoung Kim ◽

Ho-Young Yhim ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Progression Free Survival ◽

Cytogenetic Response ◽

Molecular Response ◽

Efficacy And Safety ◽

Event Free Survival ◽

Free Survival ◽

Imatinib Resistant

Abstract Abstract 1691 Dasatinib and nilotinib have been founded to be effective and well-tolerated in patients who develop resistance or intolerance to imatinib. Not enough data are currently available to recommend one over the other as the preferred second-line therapy based on efficacy data. Therefore we planned a multicenter retrospective study to analyze the efficacy and safety of dasatinib and nilotinib in patients with imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. In this Korean multicenter study, 126 patients imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase were treated with dasatinib (n=76) or nilotinib (n=50) The purpose of this study was to compare rates of cytogenetic and molecular response rate, event-free survival (EFS), progression-free survival (PFS) and overall survival (OS), and toxicities of nilotinib and dasatinib treatment of imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. PFS was defined as the time from the start of treatment to the earliest date of any of following event: loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR), progression to accelerated phase (AP) or blastic phase (BP), discontinuation due to treatment failure as assessed by the clinician, and death from any cause on therapy. Event was defined by any one of the following: loss of CHR, loss of MCyR, progression to AP or BP, discontinuation due to treatment failure as assessed by the clinician, treatment discontinuation due to toxicity, and death from any cause on therapy. For dasatinib and nilotinib group, median ages (51 years old vs. 53), median durations of CML (23.7 months vs. 19.8 ) before receiving dasatinib or nilotinib and duration of prior imatinib treatment (21.7 months vs 17.7) were comparable. Nilotinib group had a higher proportion of intermediate and high sokal scores at the time of diagnosis than dasatinib group (41.5 vs 29.3% (high), 41.5% vs 32.5%(intermediate), 17.1% vs 37.9(low), p= 0.04). After median follow-up durations of 20.2 months of dasatinib group and 25.3 months of nilotinib group, the rates of major molecular response were 50.0% for dasatinib group and 59.6% for nilotinib group (p=NS) and the rates of MCyR (complete and partial cytogenetic response) were 78.4% for dasatinib group and 74.5% for nilotinib group (p=NS). The estimated EFS at 24 months was 67% and 48% in dasatinib and nilotinib group, respectively. (p<0.05). The estimated PFS at 24 months was 85% and 56% in dasatinib and nilotinib group, respectively. (p<0.05) Overall survival rates were comparable in both treatment groups (24-months OS; dasatinib 91%, nilotinib 94%; p=0.65). Both were generally well tolerated. Hematologic toxicities were more frequent among patients receiving dasatinib. 10 patients (13%) had pleural effusion in dasatinib; 9 events were grade 1 or 2. Elevated liver enzyme were more frequent among patients receiving dasatinib. In conclusion, In this study population, nilotinib and dasatinib showed similar cytogenetic and molecular response rates and survival. Toxicity profiles of two drugs were different and both drugs showed tolerable toxicities. In terms of event-free survival and progression-free survival, dasatinib was superior to nilotinib, but caution is warranted in interpretation because baseline characteristics including hematologic and cytogenetic response at the time of start with dasatinib and nilotinib and sokal scores at the time of diagnosis were different. Disclosures: No relevant conflicts of interest to declare.

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