Long-Term Follow-up after Treatment Discontinuation in Patients with Chronic Myeloid Leukemia: The Korean Imatinib Discontinuation (KID) Study

Abstract Background With first-line imatinib (IM) therapy, approximately 50% of CP CML patients achieve undetectable molecular residual disease (UMRD). The recent several discontinuation clinical trials have demonstrated that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and UMRD durations prior to IM discontinuation. In our previous report, we have reported that of 90 patients with follow-up ≥12 months, the probability of sustained major molecular response (MMR) at 12 months and 24 months was 62.2% and 58.5%, respectively. However, currently, the issue on the occurrence of late relapse with a long-term follow-up after IM discontinuation is important. Therefore, here we analyzed the long-term follow-up results of the KID study. Methods CP CML patients who were treated with IM for more than 3 years and had undetectable levels of BCR-ABL1 transcripts determined by quantitative reverse transcriptase polymerase chain reaction for at least 2 years were eligible for KID study. After IM discontinuation, the molecular response was monitored using the following schedule: every month for the first 6 months, every 2 months up to 12 months, and every 3 months thereafter. In cases of MMR loss after 2 consecutive assessments (molecular relapse), IM treatment was re-introduced. Results Between October 2010 and June 2015, a total of 126 patients (70 females, 56 males) were enrolled on KID Study, with a median age of 47 years (range, 18 - 82), the percentages of patients with low, intermediate and high Sokal risk scores were 33%, 25% and 15%, respectively with unknown Sokal risk scores in 27%. And the median time on IM therapy and the median duration of sustained UMRD prior to discontinuation were 83 months (range, 32 - 141) and 41 months (range, 22 - 131), respectively. After a median follow-up of 43 months (range, 4.9 - 93.6) after IM discontinuation, 55 patients lost MMR in 2 consecutive analyses at a median time of 3 months (range, 0.9 - 53.2 months). The 12-month and overall probability of sustained MMR was 61.9 ± 4.3% and 55.1 ± 4.6%, respectively. UMRD (P = 0.001) and IM duration on treatment (P = 0.003) were associated with the probability of sustained MMR. Out of 55 patients with molecular relapse, 53 patients (except 2 patients with follow-up loss) were re-treated with IM for a median of 31.7 months (range, 5.8 - 82.9 months), 51 patients re-achieved MMR at a median of 1.9 months (range, 0.0 - 5.4 months) after resuming IM therapy and 48 of these patients re-achieved UMRD at a median of 5.8 months (range, 0.9 - 19.7 months). 2 patients who re-achieving of MMR after resuming IM therapy lost MMR again; One patient with 45.8 and 40.3 months of IM therapy duration and sustained UMRD duration prior to discontinuation, respectively lost MMR at 7.4 months after IM discontinuation and re-achieved MMR 1.7 later after IM restarting, but MMR was lost again on the assessment 8 months later. Another patient with 122.2 and 30.4 months of IM therapy duration and sustained UMRD duration prior to discontinuation, respectively relapsed at 53.2 months after IM discontinuation. Despite re-achieving MMR 1.4 later after IM restarting, the patient suddenly progressed to blast crisis at 6 months after restarting IM. Conclusions Our results showed that IM discontinuation can be applied with approximately 55% of probability of sustained MMR in the long term. Although sudden blast crisis occurring in responding patients with CML has already been reported in IM therapy, event of progression to BC in a clinical trial of IM discontinuation deserves to be followed-up with caution. Overall, both UMRD and IM duration on treatment were the most important predictors for successful IM-off. Disclosures Kim: Pfizer: Research Funding; Ilyang: Research Funding; Novartis: Research Funding; BMS: Research Funding.

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Long-Term Outcomes of Chronic Myeloid Leukemia Patients Who Lost Undetectable Molecular Residual Disease (UMRD) after Imatinib Discontinuation: Korean Imatinib Discontinuation Study (KIDS)

Blood ◽

10.1182/blood-2019-126376 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1643-1643 ◽

Cited By ~ 1

Author(s):

Sung-Eun Lee ◽

Joon Seong Park ◽

Hyeoung-Joon Kim ◽

Sung-Hyun Kim ◽

Dae Young Zang ◽

...

Keyword(s):

Median Time ◽

Research Funding ◽

Residual Disease ◽

The Other ◽

Risk Scores ◽

Late Relapse ◽

Molecular Response ◽

Long Term Follow Up

Background The recent discontinuation clinical trials have demonstrated that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and undetectable molecular residual disease (UMRD) durations prior to IM discontinuation. Moreover, treatment rechallenge in patients with molecular recurrence lead a second deep molecular response, suggesting that IM discontinuation is safe. However, the issues on the definition of molecular relapse requiring treatment resumption and the occurrence of late relapse with a long-term follow-up after IM discontinuation are important. Therefore, here we analyzed the long-term follow-up results of the patients who lost UMRD after IM discontinuation Methods CP CML patients who were treated with IM for more than 3 years and had undetectable levels of BCR-ABL1 transcripts determined by quantitative reverse transcriptase polymerase chain reaction (PCR) for at least 2 years were eligible for KID study and in cases of MMR loss after 2 consecutive assessments, IM treatment was re-introduced. After IM resumption for MMR loss, the molecular response was evaluated every month until MMR was re-achieved and every 3 months thereafter. The second stop was permitted in the patients who were in second UMRD for at least 2 years. Results Between October 2010 and June 2015, a total of 126 patients (70 females, 56 males) were enrolled on KID Study, with a median age of 47 years (range, 18-82), the percentages of patients with low, intermediate and high Sokal risk scores were 33%, 25% and 15%, respectively with unknown Sokal risk scores in 27%. And the median time on IM therapy and the median duration of sustained UMRD prior to discontinuation were 83 months (range, 32-141) and 41 months (range, 22-131), respectively. After a median follow-up of 62.6 months (range, 4.9-100.8 months) after IM discontinuation, 83 patients (65.9%) lost UMRD. Among them, 56 (67.5%) patients lost MMR in 2 consecutive analyses. The other 27 (32.5%) patients who lost UMRD but not MMR exhibited different patterns of BCR-ABL1 kinetics: 8 patients spontaneously re-achieved UMRD after a median time of 2.8 months (range, 0.9-3.0 months), and 19 patient showed fluctuation of BCR-ABL1 transcript under the level of 0.1% on IS for a median 19 months (range, 3-34), and then spontaneously returned and maintained UMRD for a median 31 months (range, 2-64). Of 73 patients who lost MR4.0, the rate of MMR loss was 76.7%. Out of 56 patients with molecular relapse, 54 patients (except two patients who restart radotinib) were re-treated with IM, all patients (except one patient lost follow-up) re-achieved MMR at a median of 1.9 months (range, 0.0 - 5.4 months) after resuming treatment. Among them, two patients who re-achieving of MMR after resuming IM therapy lost MMR again; One patient who relapsed at 53.2 months after IM discontinuation, despite re-achieving MMR 1.4 later after IM restarting, suddenly progressed to blast crisis at 6 months after restarting IM and in spite of switching to dasatinib and ponatinib, she died. Another patient lost MMR at 7.4 months after IM discontinuation and re-achieved MMR 1.7 later after IM restarting, but progressed to AP on the assessment 32 months later. The patient switched to dasatinib and lost follow-up. Among the patients who maintained a second UMRD for at least 2 years after IM resumption, 23 patients entered into a second IM stop. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusions Our results showed that 67.5% and 76.7% of patients who lost UMRD and MR4.0, respectively resulted in MMR loss, and the other patients were below MMR without re-treatment, suggesting loss of MMR can be chosen for treatment re-challenge. Overall, IM discontinuation could be applied with approximately 55% of probability of sustained MMR in the long term. In addition, we demonstrated that a second attempt might be possible. Further studies on the predictors to select patients for a trial of second stop are warranted. Disclosures Kim: Il-Yang co.: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; BMS: Research Funding; Novartis: Research Funding.

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Molecular Long-Term Surveillance of CML Patients on Imatinib Therapy. Follow-Up of German Patients Treated within the IRIS Trial.

Blood ◽

10.1182/blood.v104.11.1003.1003 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1003-1003

Author(s):

Martin C. Mueller ◽

P. Paschka ◽

T. Lahaye ◽

Ch. Lorentz ◽

N. Gattermann ◽

...

Keyword(s):

Median Time ◽

Nested Pcr ◽

Residual Disease ◽

Response To Therapy ◽

Imatinib Therapy ◽

Interferon Α ◽

Tyrosine Kinase Domain ◽

Molecular Response

Abstract High rates of complete cytogenetic response (CCR), the availability of sensitive methods to detect residual disease, and direct therapeutic consequences are leading motives to integrate regular molecular monitoring into the standards for the management of patients (pts) with chronic myeloid leukemia (CML). We sought to determine long-term dynamics of BCR-ABL mRNA expression levels in 132 CML pts (75 m, 57 f, median age 51, range 20–71 yrs) recruited into the IRIS study in 17 German centers. Pts were randomized to receive imatinib (n=69) or interferon α+Ara-C (IFN, n=63). Due to intolerance or lack of response 41 pts crossed over from IFN to imatinib. Response to therapy was sequentially monitored by conventional cytogenetics from bone marrow metaphases (n=806). BCR-ABL transcripts were determined in 1414 peripheral blood samples by quantitative real time RT-PCR (RQ-PCR) using the LightCycler technology. In case of low level (<10 transcripts/2μl cDNA) or neg RQ-PCR, nested PCR was performed. Total ABL transcripts were quantified as internal controls. A single series of BCR-ABL plasmid dilutions served as standard for both BCR-ABL and ABL transcripts. In pts on 1st-line imatinib therapy median ratios BCR-ABL/ABL gradually decreased: 4.8% at mo 3, 0.88% at mo 6, 0.22% at mo 12, 0.17% at mo 18, 0.058% at mo 24, 0.066% at mo 30, and 0.023% at mo 36. After crossover to imatinib results were not significantly different: 15.5% at mo 3, 1.6% at mo 6, 0.28% at mo 12, 0.068% at mo 18, 0.045% at mo 24, and 0.041% at mo 30. After a median follow-up of 40 mo (1–47) 31/69 pts (45%) on 1st-line imatinib were still RQ-PCR pos, 20 pts (29%) were RQ-PCR neg and nested PCR pos, and in 4 pts (5.8%) BCR-ABL became undetectable by RQ- and nested PCR. After a median time of 25 mo (3–43) on 2nd-line imatinib therapy 19/41 pts (46%) were RQ-PCR pos, 9 pts (22%) were RQ-PCR neg and nested PCR pos, and in 5 pts (12%) BCR-ABL was undetectable by RQ- and nested PCR. Considering adequate RNA quality BCR-ABL became repeatedly undetectable in 4 pts after 18–33 mo of 1st-line imatinib therapy and in 5 pts 9–33 mo after crossover from IFN to imatinib. In one patient, BCR-ABL remained undetectable after a treatment free interval of 4 weeks. After achieving CCR, 5 pts (7.2%) on 1st-line and 2 pts (4.9%) on 2nd-line imatinib therapy experienced cytogenetic relapse after a median time of 10 mo (4–21). In none of these pts mutations of the tyrosine kinase domain of BCR-ABL were detected. BCR-ABL/ABL ratios after 12 mo of imatinib therapy were significantly lower in pts in continuous CCR vs pts with subsequent relapse (0.18 vs 0.60%, respectively, p=0.04). None of the relapsing patients had achieved a ratio BCR-ABL/ABL <0.12% after 12 mo, which represents a 3-log reduction from baseline. During total follow-up ratios BCR-ABL/ABL <0.12% have been achieved in 51 pts (74%) on 1st-line and in 21 pts (51%) on 2nd-line imatinib therapy. We conclude that (i) treatment with imatinib in newly diagnosed CML pts is associated with a rapid and steady decrease of BCR-ABL transcript levels, (ii) a short trial of IFN does not jeopardize molecular response to subsequent imatinib therapy, (iii) an increasing minority of pts achieve complete molecular remission, and (iv) ratios of BCR-ABL/ABL <0.12% after 12 mo of therapy predict for long-term response.

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Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2016.68.2914 ◽

2017 ◽

Vol 35 (3) ◽

pp. 298-305 ◽

Cited By ~ 187

Author(s):

Gabriel Etienne ◽

Joëlle Guilhot ◽

Delphine Rea ◽

Françoise Rigal-Huguet ◽

Franck Nicolini ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Residual Disease ◽

Treatment Discontinuation ◽

Molecular Response ◽

Long Term Follow Up ◽

Study Population ◽

Analysis Point

Purpose Imatinib (IM) can safely be discontinued in patients with chronic myeloid leukemia (CML) who have had undetectable minimal residual disease (UMRD) for at least 2 years. We report the final results of the Stop Imatinib (STIM1) study with a long follow-up. Patients and Methods IM was prospectively discontinued in 100 patients with CML with UMRD sustained for at least 2 years. Molecular recurrence (MR) was defined as positivity of BCR-ABL transcript in a quantitative reverse transcriptase polymerase chain reaction assay confirmed by a second analysis point that indicated an increase of one log in relation to the first analysis point at two successive assessments or loss of major molecular response at one point. Results The median molecular follow-up after treatment discontinuation was 77 months (range, 9 to 95 months). Sixty-one patients lost UMRD after a median of 2.5 months (range, 1 to 22 months), and one patient died with UMRD at 10 months. Molecular recurrence-free survival was 43% (95% CI, 33% to 52%) at 6 months and 38% (95% CI, 29% to 47%) at 60 months. Treatment was restarted in 57 of 61 patients with MR, and 55 patients achieved a second UMRD with a median time of 4 months (range, 1 to 16 months). None of the patients experienced a CML progression. Analyses of the characteristics of the study population identified that the Sokal risk score and duration of IM treatment were significantly associated with the probability of MR. Conclusion With a median follow-up of more than 6 years after treatment discontinuation, the STIM1 study demonstrates that IM can safely be discontinued in patients with a sustained deep molecular response with no late MR.

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A Report on 114 Patients Who Experienced Treatment Free Remission in a Single Institution during a 15 Years Period: Long Term Follow-up, Late Molecular Relapses and Second Attempts

Blood ◽

10.1182/blood-2019-129919 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 27-27 ◽

Cited By ~ 3

Author(s):

Philippe Rousselot ◽

Clémence Loiseau ◽

Marc Delord ◽

Caroline Besson ◽

Jean-Michel Cayuela ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Median Duration ◽

Research Funding ◽

Kinase Inhibitors ◽

Molecular Response ◽

Single Institution ◽

Long Term Follow Up

Background. The A-STIM (According to Stop IMatinib, NCT1038732) observational study established the loss of major molecular response (loss of MMR, BCR-ABL1 IS >0.1%) as a practical and safe criterion for restarting therapy in patients with CML who had stopped tyrosine kinase inhibitors after a prolonged (≥2 years) and sustained deep molecular response (J Clin Oncol. 2014;32(5):424-30). We focus now on the long-term prospective follow-up of a cohort of 114 patients from a single institution included in the A-STIM observatory in order to describe late events (late molecular relapses after 2 years or more in TFR and second TFR attempts). Methods: Adult chronic phase CML patients treated with tyrosine kinase inhibitors and in sustained (≥2 years) MR4.5 (BCR-ABL1 IS ≤0.0032%) were eligible. Patients with a previous history of resistance or mutations of the BCR-ABL tyrosine kinase domain were excluded. Molecular relapses were defined by loss of MMR. After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 12 months, every 2-3 months during the 2nd year and every 3-6 months thereafter. Median follow-up from diagnosis of CML was 15.9 years. Results. Over a 15 years period, 114 patients followed at the Centre Hospitalier de Versailles were registered. Median age at diagnosis was 48.2 years, sex ratio was 0.5 and Sokal score distribution was 54%, 26% and 20% for the Low, intermediate and high-risk categories respectively. Median duration of TKIs before the first TFR attempt was 7.4 years. Thirty-six patients (31%) were previously treated with interferon, 62 (54%) received imatinib only and 52 (46%) were on 2G-TKIs at the time of discontinuation (13 as first line therapy and 39 after a switch for sub-optimal response or intolerance). Median follow-up in TFR1 was 5.4 years. TFR1 rates were 57.6% at 1 year, 53.8% at 3 years, 51.6% at 5 years and 44.5% after 7 years. The longest duration of ongoing TFR1 is 14.9 years. The duration of TKIs and the duration of MR4.5 were associated with a higher TFR1 rate; a trend was observed for previous exposure to interferon. Patients on 2G-TKIs (first or second line) had similar TFR1 rates as compared to patients on imatinib. Fifty-seven patients relapsed including 8 patients (14%) experiencing late molecular relapses. Of those, 4 patients relapsed after 5 years. The latest molecular relapse was observed after 6.4 years. In late relapsing patients, MR4.5 was lost after 10 months in median and MR4 after 22 months with a long-lasting period of fluctuations of the BCR-ABL1 ratio in-between MR4 and MR3 (a focus on patients with fluctuations of the BCR-ABL1 ratio will be presented at the congress). Out of the 57 patients who restarted a TKI, 31 patients (54%) experienced a second attempt. Median duration of TKIs between TFR1 and TFR2 was 2.9 years and total exposure to TKIs before TFR2 was 9 years. Fifteen patients (48%) were on imatinib before TFR2 whereas 16 where on 2G-TKI (52%). Median follow-up in TFR2 was 3.4 years. TFR2 rates were 53.9% at 1 year, 45.6% at 3 years and 39.9% after 5 years. The longest TFR2 is 9 years. No factor was associated with TFR2 duration, a switch to 2G-TKIs did not provide any advantage. Seventeen patients relapsed including 3 patient (17%) experiencing late molecular relapses. Anecdotally, 5 patients went to a third TFR attempt and 1 is in TFR3 for 5.2 years. Conclusion. Based on a 15 years' experience we were able to report on long term follow-up in TFR1 and in TFR2. Among patients experiencing molecular relapses, we observed 14% and 17% late relapses after more than 2 years after TFR1 and TFR2 respectively, suggesting that a long-term molecular follow-up is mandatory for CML patients in TFR. Figure Disclosures Rousselot: Incyte: Research Funding; Pfizer: Research Funding. Cayuela:Incyte: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

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Long-Term Evaluation of Efficacy and Safety of Ofatumumab Added to Fludarabine & Cyclophosphamide in Subjects with Relapsed Chronic Lymphocytic Leukemia: Final Analysis of Complement 2 Trial

Blood ◽

10.1182/blood-2018-99-112139 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3151-3151

Author(s):

Sebastian Grosicki ◽

Ewa Lech-Maranda ◽

K Govind Babu ◽

Justyna Rybka ◽

Elena Litvinskaya ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Median Time ◽

Research Funding ◽

Final Analysis ◽

Lymphocytic Leukemia ◽

Primary Analysis ◽

Long Term Follow Up ◽

Secondary Endpoints

Abstract Introduction: COMPLEMENT 2 is a phase III, randomized, open-label study, which compared the efficacy of ofatumumab (OFA) in combination with fludarabine and cyclophosphamide (FC) vs FC therapy alone in patients (pts) with relapsed chronic lymphocytic leukemia (CLL). In a previous interim analysis (2015) performed based on 194 progression-free survival (PFS) events, OFA+FC showed significant improvement of PFS and was well tolerated compared to FC in pts with relapsed CLL. Here, we report the 5-year follow-up of overall survival (OS) and safety profile of the drugs evaluated in this study. Methods: Based on stratification factors (number of prior CLL therapies and Binet stage), pts with relapsed CLL were randomized 1:1 to Arm A (OFA+FC) and Arm B (FC alone). Arm A received OFA intravenously (IV) (300 mg on day 1, cycle [c] 1; 1000 mg on day 8, c1; and 1000 mg on day 1, c2-6) in addition to FC (F [IV]: 25 mg/m2 and C [IV]: 250 mg/m2 on days 1-3, c1-6). Arm B received FC only. Pts who had achieved a complete response or partial response following at least 1 prior CLL therapy, but whose disease had progressed after >6 months (mo) were included in the present study. The primary endpoint was PFS. Key secondary endpoints were OS, time to next treatment (TTNT), and safety. During the primary analysis for PFS, all the type 1 error (1-sided alpha 0.025) was spent, resulting in no alpha remaining for inferential interpretation of the final analysis for OS. The final analysis results will be used for descriptive and supportive purposes only. Results: A total of 365 pts were randomly assigned to receive OFA+FC (n=183) or FC (n=182) in the final analysis. Overall, 119 (65%) and 102 (56%) pts completed the scheduled OFA+FC and FC treatments, respectively. Adverse events (AEs) were the main reason for treatment discontinuation in both treatment arms (50 [27%] pts in the OFA+FC arm and 52 [29%] in the FC arm). A total of 332 (91%) pts entered the follow-up phase, 172 (94%) from the OFA+FC arm and 160 (88%) from the FC arm. The follow-up phase for the OFA+FC and FC arms was approximately 41 mo and 23 mo, respectively. Baseline characteristics were similar in both arms. Median PFS was not assessed for the final analysis because the final results for the primary endpoint of PFS were reported as part of the primary analysis. PFS was 28.9 mo for OFA+FC and 18.8 mo for FC (hazard ratio [HR]=0.67, 95% confidence interval [CI]: 0.51, 0.88; p=0.0032). The final OS analysis was performed based on 82 events in the OFA+FC arm and 83 events in the FC arm. Median OS was 62.6 mo (95% CI: 44.58, NA) and 46.2 mo (95% CI: 37.72, 56.57) for the OFA+FC and FC arms, respectively (HR=0.80, 95% CI: 0.59, 1.09; p=0.143) (Figure 1). Median TTNT in the OFA+FC and FC arms was 53 mo and 40.1 mo, respectively (HR=0.77, 95% CI: 0.55, 1.08; p=0.114). As per the primary analysis, the overall response rate (95% CI) by independent review committee assessment (IRC) was 84% (77%, 89%) for OFA+FC and 68% (60%, 74%) for FC (p=0.0003). Other secondary endpoints (in mo) for OFA+FC vs FC were IRC-assessed median time to response (1 vs 1; HR=1.08, 95% CI: 0.85, 1.37; p=0.45), median duration of response (29.6 vs 24.9; HR=0.77, 95% CI: 0.56, 1.05; p=0.09), and median time to progression (42.1 vs 26.8; HR=0.63, 95% CI: 0.45, 0.87; p=0.004). All AEs and AEs of grade 3, 4, and 5 by preferred term (≥10%) are presented in Table 1. Serious drug-related AEs (≥2%) in the OFA+FC arm were pneumonia (8%), neutropenia and febrile neutropenia (7% each), and thrombocytopenia, pancytopenia, and pyrexia (2% each). Myelodysplastic syndrome was the most frequently reported secondary malignancy observed in ≥1% of pts (OFA+FC, 3 [2%]; FC, 2 [1%]). A total of 82 (45%) and 83 (47%) pts died during the study in the OFA+FC and FC arms, respectively; 2 (1%) and 6 (3%) died up to 60 days after the end of treatment, and 74 (41%) and 69 (39%) after >60 days. Three (2%) on-treatment deaths were reported in the OFA+FC arm and 4 (2%) in the FC arm. Conclusion: This final analysis confirmed the results of the primary analysis that addition of OFA to FC resulted in improvement of OS and TTNT by approximately 16 mo and 13 mo, respectively, compared to FC alone. Of note, the trend in the OS improvement seems to be maintained in the present long-term follow-up at 5 years. No new safety concerns have emerged in the long-term follow-up after treatment with OFA+FC, and the treatment was well tolerated. Disclosures Grosicki: Affimed: Research Funding. Lech-Maranda:Roche: Consultancy; Jansen-Cilag: Consultancy; Novartis: Consultancy; BMS: Consultancy; Amgen: Consultancy. Loscertales:Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Homenda:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Acerta: Consultancy, Honoraria. Blonski:Novartis: Consultancy. Stefanelli:Novartis: Employment, Equity Ownership. Vincent:Novartis: Employment. Banerjee:Novartis: Employment. Robak:AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy.

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Clinical implications of loss of minimal residual disease (MRD) negativity in multiple myeloma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.8514 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 8514-8514

Author(s):

Meera Mohan ◽

naveen kumar yarlagadda ◽

Dinesh Atwal ◽

Yadav Pandey ◽

Arya Roy ◽

...

Keyword(s):

Multiple Myeloma ◽

Median Time ◽

Plasma Cells ◽

Residual Disease ◽

Significant Proportion ◽

Clinical Relapse ◽

Long Term Follow Up ◽

Highly Correlated

8514 Background: Attainment of MRD negativity in multiple myeloma (MM) patients is increasingly considered an optimal therapeutic endpoint, but little is known about the MRD evolution in those who achieve this milestone. We investigated the clinical implication of loss of MRD negativity or MRD conversion in patients with ≥VGPR. Methods: We identified and followed 606 patients achieving a sustained ≥VGPR with bone marrow MRD negativity(≥ 2 consecutive reading) following treatment on a total therapy protocol and with a median follow-up of 10 y. All patient had negative PET and MRI DWIBS at enrollment. Serial BM aspirate MRD was determined by 8-color next generation flow (NGF, EuroFlow) with a minimal sensitivity of 10−5 cells. Results: Most MM patients were considered low risk with a UAMS GEP70 score of ≤ 0.66 (92%; 495/538) . While 60% (364/606) of patients had sustained MRD negativity, the remaining 40% (242/606) experienced MRD conversion with a 5.7 y median time from ASCT and 6.3 y from diagnosis. The risk of clinical relapse was significantly elevated in patients with MRD conversion compared to sustained MRD negativity (73%, 177/242 vs. 5%, 18/364; R.R. = 3.5; P< 0.0001). The median level of MRD positivity (> 0.2 ratio of MM cells to normal plasma cells) also highly correlated with relapse ( P< 0.0001). Loss of MRD negativity preceded clinical relapse by a median time of 1.1 years. Loss of MRD negativity without clinical relapse was seen in 27% (65/242). MRD conversion was associated with an inferior PFS and OS (PFS: 10.2 y vs. NR; P < 0.0001, H.R. 18.7; 95% CI 13.3 - 26.3 and OS: 26.1 y vs. NR; P= 0.01, H.R. 1.7; 95% CI 1.1 - 2.6). Furthermore, when MRD conversion was within 5 y of diagnosis compared > 5 y, patients had a worse OS ( P < 0.0001, H.R. 17.2; 95% CI 7.8 – 37.8). We also observed that MRD conversion later than 5 years from diagnosis did not affect the OS. In a subset of patients (n = 144) the timing of first MRD negativity following treatment was available. Attainment of MRD negativity within 6 months of diagnosis compared to any time after 6 months was predictive of future MRD conversion (65%, 17/26 vs.42%, 49/118; P = 0.03) and clinical relapse (54%, 14/26 vs.28%, 33/118; P = 0.02). Conclusions: MRD conversion occurs in a significant proportion of MM patients (40%) on long-term follow-up and predicts future clinical relapse. Significance of MRD conversion has a temporal relationship from diagnosis and portray inferior clinical outcome particularly within 5 years of diagnosis.

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Prognostication of Molecular Relapses after Dasatinib or Nilotinib Discontinuation in Chronic Myeloid Leukemia (CML): A FI-LMC STOP 2G-TKI Study Update

Blood ◽

10.1182/blood-2019-124408 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 30-30 ◽

Cited By ~ 6

Author(s):

Delphine Rea ◽

Franck E Nicolini ◽

Michel Tulliez ◽

Philippe Rousselot ◽

Martine Gardembas ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Blast Crisis ◽

Molecular Response ◽

Advisory Committees ◽

History Of ◽

Time To Relapse ◽

Tki Discontinuation

Background : Providing achievement and sustainability of deep molecular responses (DMR), patients (pts) taking tyrosine kinase inhibitors (TKI) against CML may discontinue therapy. The STOP 2G-TKI observational study showed that dasatinib and nilotinib could be safely stopped and prior suboptimal response or resistance to imatinib was an adverse prognostic factor for treatment-free remission (TFR). We present updated results with a specific focus on the risk of relapse using post-baseline information during follow-up. Methods : Adult CML pts treated with dasatinib or nilotinib without a history of allogeneic stem cell transplantation (ASCT) or progression to advanced phase stopped TKI provided that: (1) BCR-ABL transcripts were of the major type, (2) total TKI treatment duration was ≥36 months, (3) uMR4.5 had been achieved and maintained for ≥24 months (undetectable BCR-ABL with ≥32000 copies of ABL). Relapse was defined by loss of major molecular response (MMR: BCR-ABL IS >0.1%) on a single occasion and triggered TKI reintroduction. The primary objective was TFR at 12 months. After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 6-12 months, every 3 months during the 2nd year and then every 3-6 months. Data as of July 1, 2019 are reported in 104 pts (median follow-up 55 months (range: 6-70)). Results: Median age at inclusion was 56 years (range: 21-82) and 65.4% of pts were female. Sokal risk score was low in 49%, intermediate in 31%, high in 16% and unknown in 4%. 2G-TKIs were given after imatinib intolerance in 47% of pts, suboptimal response or resistance to imatinib in 22%, lack of DMR on imatinib in 3% and as 1st line treatment in 28%. Median duration of TKI, 2G-TKI and uMR4.5 was 74 months (range: 36-163), 49 months (range: 19-112) and 31 months (range: 24-72), respectively. Overall, 43 pts (41%) lost MMR within a median time of 5 months (range: 1-59). Overall 60-month TFR was 56% (95% CI, 45.8-66.3) but TFR probabilities increased up to 64% (95% CI: 53.3-74.8), 76.7% (95% CI, 65.9-87.5), 86.2% (95% CI; 76.3-96.2), and 92.1% (95% CI: 83.4-100) for pts still in MMR at 3, 6, 12 and 18 months, respectively (Figure 1). Prior suboptimal response or resistance to TKI was confirmed as the strongest adverse baseline prognostic factor with a 60-month TFR rate of 29.8% (95% CI; 10.8-48.7) (median TFR 12 months) versus 63.6% (95% CI; 52.1-75.2) (median not reached) in pts without such history (logrank p=0.0012). This was explained by significantly higher risk of early relapses (within 6 months but not later) in pts with prior suboptimal response or resistance to TKI (cumulative incidence of relapses by 6 months 47.8% (95% CI; 31.2-73.2) versus 20.9 (95% CI; 13.7-32) in other pts (p=0.00879)). Landmark analyses at specific time points were performed to study the prognostic value of molecular responses categories after TKI discontinuation. All pts in MMR but not deeper at 3 months relapsed by month 9 (median time to relapse 4 months) while pts in ≥MR4 (BCR-ABL IS ≤0.01%) had 12- and 60-months probabilities of 86.8% (95% CI; 79.1-94.4) and 74.9% (95% CI: 64-85.7), respectively (logrank p<10-4). All pts but 1 in MMR but not deeper at 6 months relapsed (median time to relapse 12 months) while pts in ≥MR4 had 12- and 60-months probabilities of 95% (95% CI; 89.6-100) and 87.5% (95% CI: 78.7-96.2), respectively (logrank p<10-4). Forty three pts restarted treatment including 1 who lost MR4.5 but not MMR and 42 who lost MMR. When treatment was reintroduced, 42 pts were in CHR and all regained MMR after a median time of 3 months (range: 1-11). The remaining pt lost MMR but not CHR 5 month after 1st line nilotinib cessation and was found in sudden myeloid blast crisis at the month 6 TKI reintroduction visit. No BCR-ABL mutation was found but an inversion of chromosome 3 at karyotyping analysis. The pt underwent ASCT after chemotherapy + ponatinib and is alive in remission 29 months later. Conclusion: 2G-TKI may be successfully stopped in CML pts with long-lasting MR4.5. Those without a history of suboptimal response or resistance have greatest chances of success. Sudden blast crisis is rare but unpredictable. Post-TKI discontinuation estimates of TFR change overtime. Together with that of molecular response type at specific time points, they represent important dynamic prognostic measures of outcome. They may also help individualizing molecular monitoring programs after TKI cessation. Disclosures Rea: Incyte Biosciences: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini:Sun Pharma Ltd: Consultancy; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Etienne:Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Guerci:INCYTE: Consultancy, Honoraria. Legros:Pfizer: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria, Research Funding. Coiteux:Pfizer: Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mahon:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau.

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Serial Minimal Residual Disease Evaluation in Patients with Chronic Lymphocytic Leukemia Under Long-Term Venetoclax Treatment

Blood ◽

10.1182/blood-2018-99-114048 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1876-1876

Author(s):

Thomas Lew ◽

Mary Ann Anderson ◽

Constantine S. Tam ◽

Sasanka Handunnetti ◽

Dennis Carney ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Residual Disease ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Minimal Residual

Abstract Background The selective BCL2 inhibitor venetoclax (Ven) achieves an overall response rate of approximately 75-80% as a single agent in relapsed and refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL)1. At one year ~75% of patients (pts) are progression-free at the approved monotherapy dose of 400 mg/day1,2 and Ven is the only novel agent with a significant rate of minimal residual disease (MRD) negativity (MRD-neg)3. The temporal pattern of MRD levels and systematic long term follow up of pts stratified by their MRD status on Ven have not been reported. We report the long term outcomes according to MRD status for 59 pts with RR-CLL/SLL who attained objective disease response to Ven, and the temporal patterns of change in MRD. Methods We reviewed the clinical outcomes to July 2018 of 67 pts with RR-CLL/SLL enrolled since June 2011 on early phase clinical studies of Ven at our two hospitals. Analysis was restricted to the 59 pts who achieved a partial response or complete response by iwCLL criteria. Pts initially received 150-1200mg Ven/day (45 ≥400mg/day) on one of three ongoing trials: Phase 1 Ven monotherapy (NCT01328626) (n=36), Phase 1b Ven plus rituximab (NCT01682616) (n=14), or Phase 2 Ven monotherapy in del(17p) CLL/SLL (NCT01889186) (n=9). For this analysis MRD-negativity was defined as <1 cell in 10-4 leukocytes by ERIC criteria, or no cells with a CLL phenotype when <400,000 cells were analyzed in an assay with a minimum sensitivity of 0.1%. Of those pts reported as MRD-neg this was confirmed at a level of 10-4 in 71%4. Unless otherwise specified, MRD-neg refers to status in the bone marrow (BM) and pts who were not tested were considered to be MRD-pos (n=2 pts). Landmark analyses of time to progression (TTP) by MRD status used the median time to achievement of MRD-neg. Fisher exact test was used to assess the association of clinical, biological and treatment variables with achievement of MRD-neg. TTP and time to MRD-neg were estimated using the method of Kaplan-Meier, and comparisons among groups used the log-rank (Mantel-Cox) test. Results Of the 59 pts who achieved an objective response to Ven, 21 (36%) achieved MRD-neg in the BM and 26 (44%) in the PB. Of the 38 pts who did not achieve BM MRD-neg, 36 (95%) had at least one BM assessment on treatment; the two remaining pts did not clear MRD in the PB. The strongest positive predictor for the achievement of BM MRD-neg was treatment with Ven plus rituximab (9 of 14 [64%]) achieved vs 13 of 45 [27%] on Ven monotherapy (p=0.02)). Complex karyotype was a negative predictor in pts receiving ≥400mg/day. TP53 aberrant state (mutation and/or del(17p)), bulky adenopathy >5cm and fludarabine-refractoriness were not significantly associated with achievement of MRD-neg, irrespective of dose (table 1). The median time to MRD-neg was 8.2 (range 2 - 46) mths for BM (fig 1A) and 5 (range <1 - 50) mths for PB, with 22/26 (85%) pts who achieved PB MRD-neg doing so within 12 mths of starting Ven. 25/26 had a contemporaneous or subsequent BM aspirate and 20 (80%) achieved BM MRD-neg after a median of 3 (<1 - 17) further mths. After a median follow up of 25 (range 2 - 55) mths since attainment of BM MRD-neg, 8/21 (38%) pts have developed confirmed re-emergence of BM MRD, and a further 2 pts have re-developed PB MRD-pos. Median time to reemergence of BM MRD has not been reached (59% BM MRD relapse free at 2 years post attainment). In a landmark analysis from median time to BM MRD-neg (8.2 mths), TTP by iwCLL criteria was significantly longer among BM MRD-neg pts (n = 21; median TTP 65 mths [95% CI 47 - undefined]) than BM MRD-pos pts (n = 31; median 22 mths [95% CI 14 - 39]; Hazard Ratio (HR) 0.11; p<0.0001) (figure 1B). Similar patterns held for the equivalent landmark analysis according to PB MRD (HR 0.21; p = 0.0002). Conclusions Venetoclax frequently induces BM MRD-neg, and pts achieving BM MRD-neg have very durable responses. Combined Ven plus rituximab increases the rate of BM MRD-neg. With Ven therapy, PB MRD status appears to be a reasonable surrogate for BM MRD status, but further validation is required. Achievement of BM MRD-neg should be the aim of therapy with Ven and Ven-based combination approaches may be the most effective way to achieve this.Roberts; N Engl J Med; 2016;374:311-22.Stilgenbauer; Lancet Oncol; 2016;17:768-78.Seymour; Lancet Oncol; 2017;18:230-40.Rawstron; Leukemia; 2016;30:929-36. Disclosures Lew: Walter and Eliza Hall: Employment, Patents & Royalties. Anderson:Genentech: Research Funding; AbbVie, Inc: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties. Tam:Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Beigene: Honoraria, Other: Travel funding; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria, Travel funding; Gilead: Honoraria; Pharmacyclics: Honoraria; Roche: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria; Roche: Honoraria. Roberts:AbbVie: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax; Genentech: Research Funding; Janssen: Research Funding. Seymour:Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding.

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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 ◽

10.1182/blood.v120.21.916.916 ◽

2012 ◽

Vol 120 (21) ◽

pp. 916-916 ◽

Cited By ~ 16

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.

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Updating Long-Term Outcome of Intermittent Imatinib (INTERIM) Treatment in Elderly Patients with Ph+-CML

Blood ◽

10.1182/blood.v124.21.1794.1794 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1794-1794 ◽

Cited By ~ 1

Author(s):

Domenico Russo ◽

Giovanni Martinelli ◽

Michele Malagola ◽

Valeria Cancelli ◽

Cristina Skert ◽

...

Keyword(s):

Research Funding ◽

Chromosomal Abnormalities ◽

Residual Disease ◽

Chronic Obstructive ◽

Molecular Response ◽

Imatinib Treatment ◽

Term Outcome ◽

Long Term Outcome

Abstract BACKGROUND: The INTERIM study (ClinicalTrials.gov NCT 00858806) showed that in elderly (> 65 years) Ph+ CML patients selected for a stable complete cytogenetic response (CCgR) lasting > 2 years, the policy of intermittent imatinib treatment (one month on/one month off) may affect the markers of residual disease (CCgR and major molecular response, MMR or MR3.0), but not the clinical outcomes (overall survival and progression-free survival) (Russo D et al, Blood 2013; 121(26):5138-44). AIMS: To update the results of the INTERIM Study, with a follow up ≥ 5 years. METHODS: After 4 years of follow up, patients continouing INTERIM treatment were monitored with peripheral blood RT-Q-PCR every 3 months according to the ELN-2013 guidelines. RESULTS: At 48thmonth, out of 76 patients enrolled in the INTERIM study, 13 (17%) had lost CCgR and MMR, 14 (18%) had lost MMR only and 50 patients (75%) continued INTERIM. The patients who had lost CCgR and/or MMR resumed imatinib continuously and all of them regained the CCgR and the MMR, within 3 to 12 months. No patient progressed to accelerated or blastic phase, or developed clonal chromosomal abnormalities in Ph+ cells, or BCR-ABL mutations. No patient complained of new or more severe side effects during the months “on”. After a follow up ≥ 5 years, 45/76 (59%) enrolled patients are on INTERIM, with a probability of maintaining intermittent administration of 59% (95% CI: 46-69). No patient lost the CCgR and only 9 additional patients lost the MMR while on intermittent treatment. All these patients resumed continuous imatinib treatment and regained the MMR. Thus, at ≥ 5 years, the probability of maintaing CCgR is 80% (95% CI 68-87) and the probability of maintaining the MMR is 61% (95% CI: 48-71). From start of INTERIM, 6 patients died but no deaths were related to CML progression (3 cases of other non haematological neoplasms, 1 stroke, 1 myocardial infarction, 1 chronic obstructive pulmonary disease).The PFS at ≥ 5 years is 94% (95% CI: 89-100) CONCLUSIONS: In summary, with a follow up ≥ 5 years, intermittent imatinib administration (INTERIM) confirmed to be safe, to produce a reversible increase of residual molecular disease in about one third of patients, but not to affect the long-term outcome. Aknowledgments: This work was supported in part by EuropeanLeukemiaNet (contract LSHC-CT-2004-503216) through the European Treatment and Outcome Study (EUTOS), supported by Novartis Oncology Europe, and COFIN 2009 Disclosures Russo: Celgene: Research Funding; Gilead: Research Funding; Novartis: Consultancy. Martinelli:Novartis: Speakers Bureau; Bristol-Meyers and Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Soverini:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Speakers Bureau. Turri:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Abruzzese:Novartis: Consultancy. Tiribelli:Novartis: Consultancy, Honoraria; Bristol-Meyers and Squibb: Consultancy, Honoraria. Rosti:Consultant: Consultancy, Speakers Bureau; Bristol-Meiers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau.

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