Dasatinib or Nilotinib Discontinuation in Chronic Phase (CP)-Chronic Myeloid Leukemia (CML) Patients (pts) with Durably Undetectable BCR-ABL Transcripts: Interim Analysis of the STOP 2G-TKI Study with a Minimum Follow-up of 12 Months – on Behalf of the French CML Group Filmc

Abstract Background: Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL have revolutionized the prognosis of pts suffering from CML but these drugs are considered as non-definitively curative and current recommendation is to treat pts during their entire lifespan. However, prospective trials such as STIM, TWISTER and EUROSKI suggest that imatinib may be successfully stopped in pts with deep and sustained molecular responses. Here, we report on the feasibility of second generation TKIs discontinuation in the setting of the French STOP 2G-TKI study. Methods: Adult CP-CML pts on dasatinib or nilotinib first line or after imatinib without prior allogeneic transplantation or progression to advanced phase CML were proposed TKI discontinuation when presenting: (1) b2a2 or b3a2 BCR-ABL transcripts subtype, 2) TKI treatment duration for at least 36 months, (3) CMR4.5 achieved and maintained for at least 24 months. The primary objective was treatment-free survival without loss of major molecular response (MMR). After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 12 months, every 3 months during the 2ndyear and every 3 to 6 months thereafter. Molecular relapse was defined by MMR loss on a single occasion and triggered TKI reintroduction. Data as of August 1, 2014 are reported in pts with at least 12 months of follow-up (n=52) and median follow-up was 32 months (12-56). Results: Median age was 60 years (34-81) and 61.5% of pts were female. Sokal risk group was low in 58%, intermediate in 23%, high in 13% and unknown in 6%. 2G-TKIs were given after imatinib intolerance in 67% of pts, suboptimal response or resistance to imatinib in 23% and upfront in 10%. Median duration of CML, TKI treatment, 2G-TKI treatment and CMR4.5 was 83 months (36-218), 78 months (36-136), 39 months (19-72) and 28 months (24-64), respectively. Twenty four pts lost MMR after a median time of 4 months (1-38) at last follow-up. Importantly, no loss of CHR or progression to advanced phase CML was observed. The 12- and 24-month probabilities of treatment-free survival without MMR loss were 61.4% (95% CI, 48.1-74.6) and 57% (95% CI, 43.3-70.6), respectively. The majority of relapses occurred within 6 months and in a landmark analysis, pts who were still in MMR without therapy at 6 months had 12- and 24-month probabilities of treatment-free survival without MMR loss of 91.2% (95% CI, 81.6-100) and 84.7% (95% CI, 72.2-97.1), respectively. All pts but 1 who lost MMR restarted 2G-TKI treatment and regained MMR after a median time of 3 months (1-8). Pts in MMR without any therapy (n=28) displayed varying patterns of spontaneous molecular response including stable CMR4.5 in 7 and fluctuations between CMR4.5 and MR4.5, CMR4.5 and MR4, CMR4.5 and MMR in 9, 4 and 4 pts, respectively. Gender, age, prior interferon exposure, 2G-TKI type, treatment duration and duration of CMR4.5 were not found to have any impact on outcome. By contrast, prior history of suboptimal response or resistance to imatinib was associated with a significantly lower chance of successful treatment discontinuation, with a 12-month probability of treatment-free survival without MMR loss of 41.7% (95% CI; 13.8%-69.6%), compared to 67.3% (95% CI, 52.6%-81.8%) in other patients (p=0.04). Conclusions: 2G-TKI could be safely and successfully discontinued in CP-CML pts with long-lasting undetectable BCR-ABL transcripts, especially in those without prior history of suboptimal response or resistance. Most of molecular relapses had an early onset and all were sensitive to 2G-TKI resumption. The recurrence of low levels of detectable residual disease below MMR after 2G-TKI withdrawal did not automatically herald CML relapse and did not preclude the possibility to remain treatment-free. Disclosures Nicolini: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Rousselot:Novartis: Research Funding. Gardembas:BMS: Honoraria. Legros:Novartis, BMS: Honoraria. Etienne:Novartis, BMS,Pfizer, ARIAD Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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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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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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Cessation of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response: Results of the Euro-Ski Trial

Blood ◽

10.1182/blood.v128.22.787.787 ◽

2016 ◽

Vol 128 (22) ◽

pp. 787-787 ◽

Cited By ~ 32

Author(s):

Francois-xavier Mahon ◽

Johan Richter ◽

Joelle Guilhot ◽

Henrik Hjorth-Hansen ◽

Antonio Almeida ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Treatment Duration ◽

Research Funding ◽

Kinase Inhibitors ◽

P Value ◽

Molecular Response ◽

Free Survival ◽

Tki Treatment

Abstract Background: Tyrosine kinase inhibitors (TKI) have dramatically improved survival in chronic myeloid leukemia (CML) with a high proportion of patients reaching deep molecular responses (DMR). The effectiveness of stopping TKI treatment is a key question regarding the management of CML. Actually, in several studies, it has been proven that a substantial part of patients in DMR can safely and successfully stop TKI therapy. However, the exact preconditions for stopping CML treatments are not yet defined. This is the aim of the European stop TKI (EURO-SKI) trial (ClinicalTrials.gov numbers: NCT01596114). Methods: Chronic phase CML patients without prior TKI failure, treated with either imatinib, nilotinib or dasatinib, in DMR (BCR-ABL <0.01% on the international scale, MR4) for the duration of at least one year were proposed to stop TKI treatment. Molecular recurrence (MR) was defined by the loss of the major molecular response (MMR, BCR-ABL <0.1% IS) at any one point. We estimated molecular recurrence-free survival (MRFS) with the Kaplan-Meier method. The potential prognostic values for MR were tested by univariate and multivariable analyses and the cut-off was identified with the minimal p-value approach. Results: From June 2012 to December 2014, 821 CP CML patients were included in 11 European countries belonging to the European Leukemia Net (ELN). 750 patients had assessable molecular data (European standardization according to Cross et al, Leukemia 2012) for the estimation of MRFS. Of these patients, 348 lost MMR and 5 died in remission ; MRFS was 62% (95% confidence interval (CI): 59% - 67%) at 6 months (m), 56% (CI: 52% - 59%) at 12 m and 52% (CI: 48% - 56%) at 24 m on an "Intention to Treat Basis ". At the time of evaluation most patients regained DMR, and importantly, no progression to advanced disease phase was noted. A prognostic modelling was performed based on 448 patients treated with imatinib. Univariate analysis showed no significant association between age, gender, depth of molecular response (MR4.5 vs. no MR4.5) or any variable part of the Sokal, EURO, EUTOS, or ELTS scores and MMR status at 6 months after treatment stop. Treatment duration with imatinib and MR4duration prior to the stop were significantly (p<0.001) correlated with MMR status at 6 months. The odds ratio for treatment duration was 1.16 (95%-CI: 1.08-1.25), meaning that one additional year of treatment increases the odds to stay in MMR at 6 months by 16%. Molecular relapse-free survival at 6 months was 65.5% for imatinib treatment > 5.8 years and 42.6% for treatment ≤ 5.8 years. This cut-off was identified with the minimal p-value approach. A true pharmaco-economic study will be necessary but taking into account the number of months without treatment in 603 patients, Imatinib front line (with a median observation time of 24 m for patients still off treatment) and the cost of imatinib in each of the 11 European countries (range: 1.734-3.370 Euro per month) the total estimated savings amounted to 27.85 million Euro. Conclusion: Using standardized molecular monitoring, stopping TKI therapy in a very large cohort of CML-patients appears feasible and safe and high MRFS rates are achievable. Longer duration of imatinib-therapy (optimal ≥ 5.8 years) prior to TKI-stop is associated with a higher probability of MRFS. Taking into account the long follow-up without molecular relapse in the historical studies such as STIM1 (Etienne et al; JCO 2016) the "operational" cure of CML with oral TKI is an up-to-date issue. Disclosures Mahon: NOVARTIS PHARMA: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; PFIZER: Honoraria; ARIAD: Honoraria. Richter:Ariad: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Almeida:BMS: Speakers Bureau; Shire: Speakers Bureau; Alexion: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Berger:NOVARTIS PHARMA: Honoraria. Machova Polakova:Bristol Myers-Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Honoraria, Research Funding. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Saussele:NOVARTIS PHARMA: Consultancy, Honoraria; BMS: Honoraria.

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FINAL Analysis of a PAN European STOP Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia : The EURO-SKI Study

Blood ◽

10.1182/blood-2021-148369 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 633-633

Author(s):

Francois-Xavier Mahon ◽

Johan Richter ◽

Andreas Hochhaus ◽

Panayiotis Panayiotidis ◽

Antonio Medina de Almeida ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Final Analysis ◽

Molecular Response ◽

Molecular Test ◽

Advisory Committees ◽

Free Survival ◽

Tki Treatment

Abstract Background: With the dramatic success of tyrosine kinase inhibitors (TKI) to treat Chronic myeloid leukemia (CML), the life expectancy of CML patients is now close to that of the general population. In addition, treatment cessation is now a realistic goal for some CML patients. This was shown by several clinical trials such as the STIM study leading to the concept of TFR (treatment free remission). Around 40-60% of patients with stable DMR [deep molecular response, corresponding to <0.01% BCR-ABL (IS)] can stop the TKI successfully, e.g. in accordance with recommendations from the European LeukemiaNet. In the interim analysis of the first 200 patients of the EURO-SKI (European Stop TKI) trial, 62% were in major molecular response (MMR: <0.1% BCR-ABL1 IS) at 6 months. DMR duration before TKI stop was most predictive for maintenance of MMR. Here we present the final analysis of the EURO-SKI trial after 3 years of follow-up. Aims: The main objectives of The EURO-SKI trial were the evaluation of molecular recurrence-free survival (MRecFS) after Stopping TKI in a large Pan-european cohort of CML patients and definition of prognostic markers to increase the rate of patients in durable deep MR after stopping TKI. Further aims are the evaluation of harmonized methods of molecular monitoring. Methods: Adult CML patients in chronic phase CML on TKI treatment in confirmed DMR for at least one year (confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. DMR confirmation was performed in standardized laboratories. Primary endpoint was maintenance of MMR after stopping TKI. According to protocol, a 36 months follow-up was planned. The null hypotheses were that MMR maintenance at 6 and 36 months was less or equal than 40% and less or equal than 35%, respectively. Results: Between May 2012 and December 2014, 868 patients were pre-registered by 61 centers from 11 countries. 140 pts were excluded (consent withdrawal n=1, protocol violation n=38, not eligible n=74, DMR not confirmed n=11, atypical/unknown transcript n=15, missing data n=1) resulting in 728 eligible patents. Of these, 46.8% were female. Median age at diagnosis was 52 years (range, 11 to 85 years). Median duration of TKI treatment was 7.5 years (range, 3.0-14.1 years) and median duration of MR4 before TKI cessation was 4.7 years (range, 1.0-13.3 years). Nine patients died without MMR loss (none CML related), 15 patients restarted TKI without MMR loss. At 6 months, 713 patients were available (without molecular test at 6 months: n=6, TKI restart without relapse: n=9). Since 434 patients (61%) [95% CI: 57-64] remained without relapse during the first 6 months, the null hypothesis was rejected (p<0.0001). At 36 months, 678 patients could be analyzed (TKI restart without relapse: n=17, no molecular test at 36 months: n=33). With 309 patients in MMR, corresponding to 46% [95% CI: 42-49], the null hypothesis of 35% or less was rejected (p<0.0001). MRecFS at 36 months resulted in 48% (CI: 44-52%) and molecular recurrence- and treatment-free survival (MRecTFS) in 46% (CI: 43-50%) (Fig 1). No blast crisis occurred. Regarding prognostic factors, we confirmed that TKI treatment duration and DMR duration were still the most important factors to predict MMR loss at 6 months. For the late recurrence, i.e., between 6 and 36 months (57 patients), TKI treatment duration before stop was the only relevant variable in a preliminary univariate logistic analysis. Summary/Conclusion: With this final analysis of the largest TFR trial, we confirm the MRecFS and MRecTFS rates at 6 months previously obtained from the interim analysis. However, late molecular recurrence (15% between 6 and 36 months) occurred and the underlying mechanisms need to be discussed. Nevertheless, 46% of the patients, were still in MRecTFS at 3 years. Figure 1 Figure 1. Disclosures Hochhaus: Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Hjorth-Hansen: AOP: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Mustjoki: Novartis: Research Funding; BMS: Research Funding; Janpix: Research Funding; Pfizer: Research Funding. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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Efficacy and Safety of a FLAG-Sequential Regimen Followed By Hematopoietic Stem Cell Transplantation for Myelodysplasia or Acute Leukemia in Fanconi Anemia: A Franco-Brazilian Report

Blood ◽

10.1182/blood-2019-122007 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2498-2498

Author(s):

Pierre-Edouard Debureaux ◽

Flore Sicre de Fontbrune ◽

Carmem M. S. Bonfim ◽

Jean-Hugues Dalle ◽

Nimrod Buchbinder ◽

...

Keyword(s):

Cumulative Incidence ◽

Research Funding ◽

Bone Marrow Failure ◽

Clonal Evolution ◽

Infectious Complications ◽

Hematopoietic Stem ◽

Free Survival ◽

History Of ◽

Syncytial Virus

Background: Fanconi anemia (FA) is the most frequent genetic cause of bone marrow failure (BMF) due to a DNA repair mechanism defect. The natural history of FA is marked by progressive BMF during early childhood. Throughout life, the hematopoietic situation may change by clonal evolution toward myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure in FA patients. The role of HSCT for FA patients with AML or advanced MDS is less defined. Currently, HSCT first line result offers 50% Overall Survival (OS) for patients with cytogenetic abnormalities only and 30% OS for patients with advanced MDS or AML in FA (Ayas et al., JCO 2013; Mitchell et al., BJH 2014). We previously reported a FLAG-sequential approach in 6 patients with FA (5 AML and 1 advanced MDS), all alive at a median follow-up of 28 months (Talbot et al., Hematologica 2014). We update here those patients and report 12 more patients treated by FLAG-sequential since then. Materials & Methods: This retrospective study (2006-2019) was conducted in 7 centers in France and Brazil on behalf of the French Reference Center for Aplastic Anemia to evaluate FLAG-sequential in FA patients with morphological clonal evolution (no patients with cytogenetic abnormalities only). The study was conducted in accordance with the Declaration of Helsinki. Anonymous data collection was declared to the appropriate authorities. The FLAG-sequential treatment consisted of FLAG, Fludarabine 30 mg/m²/d for five days and Cytarabine 1 g/m²x2/d with G-CSF for five days, which was followed three weeks later by Cyclophosphamide 10 mg/kg/d for four days, Fludarabine 30 mg/m²/d for four days and TBI 2 Gy (Fig 1A). In a haploidentical setting, Cyclophosphamide at 30 mg/kg/d was performed only in post-transplantation, at Days +4 and +5 (Fig 1B). Results: Eighteen patients were included with 14 AML, 1 acute lymphoblastic leukemia (ALL), and 3 RAEB-2 (Table 1). The median age at the time of HSCT was 22 years (4-37 years). Fifteen patients (83%) were older than 10 years at the time of HSCT. The median follow-up was 31 months (3- 153 months). Eight patients (44%) had complex karyotype. None of the included patients had a history of solid malignancies before HSCT. All patients engrafted. The cumulative incidence of neutrophil engraftment at Day 60 was 94% (95% CI 63-100%) with a median of 18 days (12-343 days). The cumulative incidence of platelet engraftment at Day 60 was 83% (95% CI 50%-96%) with a median of 25 days (17-245 days). The donor chimerism was complete at Day +100 for 15 patients. The three patients without full donor chimerism at Day +100 either had a relapse (n=1) and 2 early deaths before Day+100 from steroid-refractory aGVHD (n=1) or septic shock (n=1). None of the patients received a second HSCT. Non-relapse mortality (NRM) at 3 years was 32% (95% CI 6-58%) (Fig 2). Cumulative incidence of grades II to IV aGVHD was 56% (35% grades III to IV). Cumulative incidence of extensive cGVHD was 16%. Infectious complications during HSCT include the following: CMV (n=8), EBV (n=2), adenovirus (n=4), BK virus (n=7), respiratory syncytial virus (n=1), candidaemias (n=2) and invasive aspergillosis (n=3). Progression free survival (PFS) and OS at 3 years were 53% (95%CI 32-89%) and 53% (95%CI 32-89%), respectively (Fig 2). Cumulative incidence of relapse at 3 years was 13% (95%CI 0-31%) (Fig 2). Seven patients died during the study. Causes of death were relapse (n=2), aGVHD (n=2), cGVHD (n=1), septic shock (n=1), and respiratory syncytial virus associated with invasive aspergillosis (n=1). GVHD-relapse free survival (GRFS) at 3 years was 48% (95%CI 29-78%). One patient had anal epidermoid carcinoma at 4 years after HSCT, which required multiple surgical ablations. Conclusion: With almost 3 years follow-up, which is long enough for our results to be considered robust, we report an OS and PFS of 53%, which compares favorably to historical controls since all of our 18 patients were treated with florid disease at time of HSCT (and not with cytogenetic abnormality only, known to be associated with a better prognosis). Toxicity is still a concern in this particular population of FA patients with notably a high rate of infectious complications. Future well designed prospective clinical trials will refine this sequential strategy, which appears promising in this particular difficult clinical situation. Disclosures Socie: Alexion: Consultancy. Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

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ENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Blood ◽

10.1182/blood.v116.21.207.207 ◽

2010 ◽

Vol 116 (21) ◽

pp. 207-207 ◽

Cited By ~ 18

Author(s):

Timothy P. Hughes ◽

Andreas Hochhaus ◽

Giuseppe Saglio ◽

Dong-Wook Kim ◽

Saengsuree Jootar ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clonal Evolution ◽

Molecular Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Free Survival ◽

Superior Efficacy ◽

Rate Of Progression

Abstract Abstract 207 Background: Results from the phase 3, international, randomized ENESTnd trial have demonstrated the superior efficacy of nilotinib over imatinib with significantly higher rates of major molecular response (MMR), complete cytogenetic response (CCyR), and with significantly lower rates of progression to AP/BC on treatment. Here, we present data with a median follow-up of 18 months. Methods: 846 CML-CP patients were randomized to nilotinib 300 mg twice daily (bid) (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg once daily (n=283). Primary endpoint was MMR (≤ 0.1% BCR-ABLIS) rate “at” 12 months, as previously presented. Key secondary endpoint was durable MMR at 24 months. Other endpoints assessed at 24 months include progression to AP/BC (with and without clonal evolution), event-free survival, progression-free survival, and overall survival (OS). Results: With a median follow-up of 18 months, the overall best MMR rate was superior for nilotinib 300 mg bid (66%, P < .0001) and nilotinib 400 mg bid (62%, P < .0001) compared with imatinib (40%). Superior rates of MMR were observed in both nilotinib arms compared with the imatinib arm across all Sokal risk groups (Table). The overall best rate of BCR-ABLIS ≤ 0.0032% (equivalent to complete molecular response, CMR) was superior for nilotinib 300 mg bid (21%, P < .0001) and nilotinib 400 mg bid (17%, P < .0001) compared with imatinib (6%). The overall best CCyR rate was superior for nilotinib 300 mg bid (85%, P < .001) and nilotinib 400 mg bid (82%, P=.017) compared with imatinib (74%). The superior efficacy of nilotinib was further demonstrated using the 2009 European LeukemiaNet (ELN) 12-month milestone in which fewer patients had suboptimal response or treatment failure on nilotinib 300 mg bid (2%, 3%) and nilotinib 400 mg bid (2%, 2%) vs imatinib (11%, 8%). Rates of progression to AP/BC on treatment were significantly lower for nilotinib 300 mg bid (0.7%, P=.006) and nilotinib 400 mg bid (0.4%, P=.003) compared with imatinib (4.2%). The rate of progression on treatment was also significantly lower for nilotinib when including clonal evolution as a criteria for progression (Table). There were fewer CML-related deaths on nilotinib 300 mg bid (n=2), and 400 mg bid (n=1) vs imatinib (n=8). Estimated OS rate (including data from follow-up after discontinuation) at 18 months was higher for nilotinib 300 mg bid (98.5%, P=.28) and nilotinib 400 mg bid (99.3%, P=.03) vs imatinib (96.9%). Both drugs were well-tolerated. Discontinuations due to adverse events or laboratory abnormalities were lowest for nilotinib 300 mg bid (7%) compared with nilotinib 400 mg bid (12%) and imatinib (9%). With longer follow up there has been minimal change in the occurrence of AEs. Minimum 24-month follow-up data for all patients will be presented. Conclusions: With longer follow-up, nilotinib was associated with a significantly lower rate of progression to AP/BC on treatment and lower rates of suboptimal response or treatment failure vs imatinib. Nilotinib resulted in fewer CML-related deaths and a higher OS rate vs imatinib. Nilotinib induced superior rates of MMR, CMR, and CCyR vs imatinib in patients with newly diagnosed CML-CP. Taken together, these data support nilotinib as a new standard of care for patients with newly diagnosed CML. Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Meyers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Hochhaus:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. le Coutre:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Clark:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Honoraria, Research Funding. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp:Novartis Pharma AG: Employment. Haque:Novartis: Employment. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

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Seven-Year Follow-up Data on Sequential Prospective Trials of Imatinib 400mg Vs 800mg Daily Schedule for Front-Line Treatment of Chronic Myeloid Leukemia (CML).

Blood ◽

10.1182/blood.v116.21.3438.3438 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3438-3438

Author(s):

Naveen Pemmaraju ◽

Hagop Kantarjian ◽

Susan O'Brien ◽

Srdan Verstovsek ◽

Elias Jabbour ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Chronic Phase ◽

Annual Rate ◽

Molecular Response ◽

Free Survival ◽

Cumulative Rate ◽

Prospective Trials

Abstract Abstract 3438 Background: The standard of care for most patients (pts) with CML has been imatinib mesylate at a dose of 400mg by mouth daily. Earlier studies have suggested that there may be a benefit to pts to start treatment at a higher dose as this may result in faster and more durable responses to imatinib. It is not yet known whether long-term event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) will be impacted by the higher dosing schedule. Objectives: To determine the long term responses and clinical benefit of imatinib 800mg daily versus 400mg daily dosing when used as upfront treatment strategy in CML. Methods: We conducted sequential prospective trials using imatinib 400mg or 800mg daily as initial therapy for patients with previously untreated chronic phase CML. Results: A total of 281 pts were included in these trials: 208 treated with 800mg and 73 with 400mg. The median follow-up for each group was 79 months (range: 3–107) and 110 months (range: 2–116). The overall, cumulative rate of complete cytogenetic response (CCyR) was 91% and 87%, respectively (p=0.49) for those treated with high- and standard-dose, and the cumulative rate of major molecular response (MMR) was 87% and 78%, respectively (p=0.06). Rates of CCyR at 12 months were 90% and 66%, respectively (p < 0.001), and MMR at 18 months 82% and 68%, respectively (p=0.04). A significantly better EFS (definition per IRIS criteria) was observed for the 800 mg group compared to that in the 400mg group (log-rank test, p=0.049; estimated 7-year EFS 86% vs 76% by Kaplan-Meier method). No significant differences were seen for survival free from transformation to accelerated and blast phase (p = 0.46) and overall survival (p = 0.27). For OS, thus far 19 pts in the 800mg group have died (2 probable CML-related, 3 unknown causes, 14 non CML related) compared to 13 pts (10 probable CML-related, 3 non CML-related) in the 400mg group. The table below shows the annual rate of events and transformation for each dose group. Treatment discontinuation for toxicity occurred in 16 (8%) pts treated with 800mg and 6 (8%) pts treated with 400mg. Conclusions: At 7-year follow up, pts treated with 800mg demonstrated a significantly better EFS (by IRIS criteria) compared to those treated with 400mg. There is a trend for a lower annual rate of events and transformation with the higher dose, particualry in the earlier years, but no difference in OS. These results suggest a modest benefit for patients treated with higher dose imatinib. Disclosures: Off Label Use: imatinib at dose of 800mg po daily for CML. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Verstovsek:Incyte Corporation: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; BMS: Honoraria, Research Funding; Novarits: Honoraria, Research Funding.

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Detailed Investigation On Characteristics of Japanese Patients with Chronic Phase CML Who Achieved a Durable CMR After Discontinuation of Imatinib – an Updated Result of the Keio STIM Study.

Blood ◽

10.1182/blood.v120.21.2788.2788 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2788-2788 ◽

Cited By ~ 4

Author(s):

Eri Matsuki ◽

Yukako Ono ◽

Koharu Tonegawa ◽

Masatoshi Sakurai ◽

Hiroyoshi Kunimoto ◽

...

Keyword(s):

Peripheral Blood ◽

Copy Number ◽

Treatment Duration ◽

Japanese Patients ◽

The Other ◽

Molecular Response ◽

Imatinib Treatment ◽

Free Survival ◽

Number Of Patients

Abstract Abstract 2788 Background and Purpose: Tyrosine kinase inhibitor (TKI) therapy has become the standard treatment for patients with chronic myelogenous leukemia (CML). It can induce durable hematologic, cytogenetic and molecular response, leading to a marked improvement of progression-free survival (PFS). On the other hand, long-term discontinuation of TKIs has recently been investigated by many groups. Our study was designed to confirm whether TKI could be safely discontinued in Japanese patients who have maintained complete molecular response (CMR) for at least 2 years, and to identify possible factors associated with prolonged drug-free survival (DFS), including immunologic profile. The effect of imatinib discontinuation in terms of quality of life (QOL) was also assessed. Method: Adult patients with CML who have sustained CMR (defined as negative quantitative and qualitative PCR of bcr-abl in the bone marrow) for more than 2 years were enrolled in the study. Treatment with imatinib or one of the other TKIs was initiated if the peripheral blood quantitative PCR (TMA method) value exceeded 100 copies. Lymphocyte subset analysis was performed before discontinuation of the drug, and at 6 months after discontinuation or re-induction of the drug in case of relapse. In 6 patients, WT-1 specific cytotoxic T lymphocyte (CTL) frequency was also assessed before, 3 and 6 months after drug discontinuation. QOL analysis was performed using SF-36 questionnaire before, 2 months and 1 year after discontinuation of imatinib. Patients: 41 patients were enrolled in the study, among which 40 patients were analyzed. The median age of the patients was 54 (range 28 – 83) years old. The Sokal risk score was low in 24 (60%), intermediate in 10 (25%) and high in 3 (7.5%) patients. The median time on imatinib treatment was 98 (range 24–126) months and the median duration of CMR was 49.5 months (range 24–106). Results: The median follow-up of the patients at the time of this analysis was 15.5 months (range 2–18). Treatment was restarted in 18 patients (45%), and the estimated DFS rate at 12 months was 55.4% (Fig 1). In 5 patients, imatinib was commenced again, whereas 13 patients were re-treated with dasatinib. All but one patient restored CMR after commencing TKIs. Among various factors including age, previous interferon treatment, duration of imatinib treatment, duration of CMR, time until CMR, sex, cytomegalovirus serology and Sokal risk score, duration of CMR was identified as a significant factor associated with prolonged DFS on univariate analysis (p=0.027), the difference which was also significant upon multivariate analysis (p=0.014). Regarding lymphocyte subsets in the peripheral blood, no significant changes were observed in CD4, 19, 56, ab TCR, gd TCR, CD4/CD25 positive cell population, but, there was a significant increase in the proportion of CD8 positive T cells among those who relapsed and those who did not (2.4% vs −2.4%, p=0.04). There was a trend for increased proportion of WT-1 specific CTL in patients who were restarted on TKI therapy. QOL scores of both physical and mental domains did not differ significantly with the discontinuation of imatinib or re-initiation of treatment, although symptoms such as facial puffiness or muscle cramping were markedly decreased with discontinuation. There was also no difference in the patients' QOL according to the choice of drug used for re-treatment. Altogether 6 patients had fluctuating PCR copy number during follow-up, of which 2 were restarted on treatment. Others have maintained low copy number or have returned to negative during follow-up. Due to the small number of patients, no specific clinical factors or immunophenotypes associated with sustained low count PCR were identified. Conclusion: Sustained CMR was achieved in a substantial proportion of patients who had been in CMR for over 2 years. All patients restarted on TKI treatment remained sensitive to treatment. Longer time in CMR was identified as a significant factor related to sustained CMR in our patient population. Increase in CTL may also correlate with the necessity to restart treatment. Longer observation period and increased number of patients is necessary to draw a concrete conclusion, and to identify the role of immunologic profiles relative to persistence of CMR. Disclosures: No relevant conflicts of interest to declare.

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Skin Cancers Among Chronic Lymphocytic Leukemia (CLL) Patients - the Effect of UV Radiation and CLL Clinical Characteristics

Blood ◽

10.1182/blood.v128.22.4772.4772 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4772-4772 ◽

Cited By ~ 4

Author(s):

Geffen Kleinstern ◽

Abdul Rishi ◽

Sara J Achenbach ◽

Kari Rabe Chaffee ◽

Neil E. Kay ◽

...

Keyword(s):

Skin Cancer ◽

Uv Radiation ◽

Mayo Clinic ◽

Research Funding ◽

Sun Exposure ◽

Prior History ◽

Skin Cancers ◽

History Of ◽

Very High

Abstract Background: It is well established that the incidence of skin cancers in patients with CLL are significantly elevated compared to age- and sex- matched controls. However, little is known about the characteristics of CLL patients who develop skin cancer. Herein, we evaluate the associations of CLL clinical and prognostic characteristics, along with UV radiation exposure, with risk of first skin cancer following CLL diagnosis. Methods: Newly diagnosed CLL patients from Minnesota, Iowa, and Wisconsin were enrolled in the Mayo Clinic case-control study from 2002-2015 and systematically followed in the Iowa/Mayo Lymphoma SPORE. Clinical and prognostic CLL data were obtained from the Mayo Clinic CLL database, and skin cancer clinical data were abstracted from medical records using a standard protocol. The CLL international prognostic index (CLL-IPI) was computed using a weighted average of five independent CLL prognostic factors (IGHV mutational status, serum b2-microglobulin, Rai stage, age, and FISH 17p deletion/TP53 status). Self-reported history of midday sun exposure at various ages (birth to age 12; 13 to 21 years; 22 to 40 years, and 41+ years) was obtained from a risk factor questionnaire. For each age, we asked the extent of mid-day sun as: practically no exposure (under 3 hours per week), little exposure (4-7 hours per week), moderate exposure (8 to 14 hours per week) and extensive exposure (15+ hours per week). Midday sun exposure was modeled as an ordinal covariate. To evaluate associations with risk of skin cancer following CLL diagnosis, we calculated time from date of CLL diagnosis to date of first skin cancer, death, or last known follow-up. We used Cox regression analysis to estimate hazard ratios (HRs) and 95% CIs. CLL treatment was considered a time-dependent covariate. Results: Among 846 CLL patients enrolled, the median age at diagnosis was 63 years (range 28-91), 68% were male, 7% had Rai stage III-IV at diagnosis. Based on the CLL-IPI, 42% were categorized as low risk, 33% as intermediate risk, and 25% as high or very-high risk. 109 CLL cases (13%) had one or more reported skin cancers at or prior to CLL diagnosis. Melanoma was observed in 19 (2%) cases and non-melanoma was in 90 (11%) cases. At a median follow-up of 7 years from CLL diagnosis, 165 patients (20%) had one or more skin cancers after CLL diagnosis. Among these patients, 49 had skin cancer before CLL diagnosis. The most frequent skin cancer was squamous cell carcinoma (59%), followed by basal cell (31%), melanoma (5%), and Merkel cell (1%). 552 (65%) of the 846 patients returned a questionnaire. Significant associations of clinical and prognostic characteristics with risk of first skin cancer were observed for age (HR=1.35 per 10 year increase, 95% CI=1.17-1.56, P<0.001), male sex (HR=1.38, 95% CI 0.98-1.96, p=0.07), prior history of skin cancer (HR=4.19, 95% CI=2.98-5.88, P<0.001), and CLL-IPI (HR=1.26, 95% CI= 1.03-1.54, P=0.026, after adjusting for age, sex, and prior skin cancer). Of note, the risk of first skin cancer in those CLL patients categorized as very high via CLL-IPI had 2.28 fold risk (95% CI 1.02-5.11). Midday sun exposures for each of the ages considered showed no evidence of association with risk of first skin cancer (all P>0.05). 50 CLL patients were treated prior to first skin cancer following CLL diagnosis; we observed no evidence of association between treatment and risk of first skin cancer (HR=1.44, 95% CI= 0.93-1.92, P=0.12). Conclusion: CLL patients who are at an increased risk of skin cancer following CLL diagnosis are those who either have had a prior history of skin cancer or a more aggressive CLL disease at diagnosis, according to CLL IPI. Routine skin cancer screening is currently recommended for CLL patients. Our data suggest that more frequent screening would be particularly important among patients with aggressive CLL and who have a prior history of skin cancer. Unexpectedly, we found no evidence of association of skin cancer risk with UV radiation following CLL diagnosis or with CLL treatment. Further investigation is needed to determine whether other factors increase the risk of skin cancer following CLL diagnosis. Disclosures Shanafelt: Genentech: Research Funding; GlaxoSmithkKine: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding.

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Safety and Efficacy of Venetoclax-Based Treatment in Elderly CLL Patients: A Retrospective Study from the Filo Group

Blood ◽

10.1182/blood-2021-149640 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3747-3747

Author(s):

Charlotte Doublet ◽

Marie-Sarah Dilhuydy ◽

Emmanuelle Ferrant ◽

Pierre Feugier ◽

Alexandra Fayault ◽

...

Keyword(s):

Retrospective Study ◽

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Oncology Nurses ◽

Advisory Committees ◽

Free Survival ◽

Daily Dose ◽

History Of

Abstract Median age at diagnosis of chronic lymphocytic leukemia is 72 years. However, only few patients over 80 years of age are included in clinical trials, even in those devoted to unfit patients. In order to evaluate both efficiency and safety of venetoclax in this category of patients, we conducted a multicentric retrospective study and collected data from 77 CLL patients from 19 FILO centers who started venetoclax after 80 years of age. Median age at venetoclax initiation was 86 years old (81-97). 63% of patients had a history of heart disease, 62% had renal failure (moderate 59% and severe 3%) and 29% had a history of severe infections. Despite their comorbidities and a CIRS greater than 6 in 70% of cases, their autonomy was preserved with a median performans status of 1 (0-4). In this comorbid geriatric population, pretherapeutic geriatric assessment was only performed in a single patient. The median number of prior therapies was 2 (0-6) with an exposure to a BCR inhibitor in 56% of cases. 11q and 17p deletion were found in 39% and 30% of cases respectively, 39% of patients had a complex karyotype and 30% harbored a TP53 mutation. However, in this real life population, these prognostic factors were only performed in half of patients. IGHV mutational status was only available in 11 patients, and 83% of them had unmutated IGHV. At the time of venetoclax initiation, the tumor lysis syndrome (TLS) risk was moderate in 57% of cases and high in 8% of cases. Venetoclax was administered as a single agent (42%) or in association with rituximab (58%). In total, half of the patients were hospitalized at each dose ramp-up, and only 3 patients were treated on outpatient basis. 82% of the cohort was able to reach the daily dose of 400mg. Half of the patients were included in a phone call monitoring program with oncology nurses to pre-emptively manage side effects and foster therapy adherence. The safety study reported 14% of TLS, with 2 discontinuations of treatment within the first month: one of which led to dialysis and the other to death. As in the previously published studies, 25% of patients had infectious complications, and grade 3 haematological and digestive toxicities were reported in 42% and 22% of cases, respectively. The reduction of the daily dose of venetoclax was necessary for 33%. Permanent discontinuation of venetoclax occurred in 40% of subjects, including 29% of early withdrawal (within the first 3 months). Main reasons for discontinuation were intolerance (21%), CLL progression (21%), death (21%) and scheduled treatment discontinuation (10%). The overall response rate was 86%, consisting of 49% of complete response (unconfirmed by bone marrow biopsy) and 37% of partial response. With a median follow-up of 21months, estimated progression free survival and overall survival were 29 and 38 months respectively. Prior exposure to a BCR inhibitor had no impact on progression free survival. To conclude, venetoclax has a manageable safety profile in elderly patients with comorbidities and can induce prolonged responses. Finally, if additional follow-up by oncology nurses seems to be more and more implemented, the pre-therapeutic onco-geriatric evaluation remains underexploited in this population. Disclosures Ferrant: AstraZeneca: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Other: Travel, Accommodations, Expenses. Feugier: Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria. Laribi: AstraZeneca: Other: Personal Fees; Le Mans Hospital: Research Funding; AbbVie: Other: Personal Fees, Research Funding; Jansen: Research Funding; Novartis: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding. Tchernonog: JANSSEN: Consultancy; ABBVIE: Consultancy; ASTRAZENECA: Consultancy. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Quinquenel: Abbvie: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria.

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