Factors Predicting Intentional Non-Adherence In Chronic Myeloid Leukemia: A Multivariate Analysis On 2546 Patients By The CML Advocates Network

Abstract Background Adherence to the prescribed dose of tyrosine kinase inhibitors (TKIs) is critical to maximize treatment effectiveness in chronic myeloid leukemia (CML). While patient-centered outcome studies are lacking in this area, literature has shown that a significant proportion of patients report both intentional and unintentional non-adherence. Objective The main objective of this multivariate analysis was to identify risk factors that might predict intentional non-adherence to TKIs in CML. Methods The CML Advocates Network, connecting 79 CML patient groups from 63 countries, conducted an international project investigating patterns of medication-taking behaviors of CML patients, supported by CML investigator groups in Germany, Italy and France. We sought to demonstrate the relationship between 16 factors and adherence in this multinational cohort. A web-based survey was launched in 12 languages, enrolling CML patients from Sept 2012 to Jan 2013. The identical questionnaire was provided to a cohort of patients recruited in clinics in France, Germany and Italy, returned by patients in a pre-stamped envelope to an independent data center. Questions included potential factors associated with non-adherence as well as on patients' perception of disease and treatment burden. Based on previous literature and on clinical relevance, a pool of 16 candidate factors, potentially predicting intentional non-adherence, was selected for analysis. These included: frequency of CML medication, co-payment for CML treatment, and current TKI therapy. Patients who reported having skipped intentionally one or more doses over the last year were considered as “intentional non-adherers”. Univariate logistic regression analysis was performed to examine the impact of pre-selected candidate factors on the probability of intentional non-adherence. Two multivariate models were fitted based on line of therapy received by patients (i.e. first line and second or greater lines of therapy). Results This patient-led study is the largest study conducted to date on the influencers of non-adherence in CML. Overall, 2546 adult CML patients (47.6% female) under TKI treatment from 79 countries responded to the survey. 2151 patients responded online, 395 questionnaires were returned on paper. No significant difference on intentional non-adherence was observed between paper or online responses. Median age of patients was 51 years (range 18-96) and median time from diagnosis was 4 years (0-27). Overall, 51.6% of all respondents reported having missed at least one dose unintentionally over the last year, and 19.5% did so intentionally. This analysis regards the intentional non-adherent population (n=490). Of those, 60% were on imatinib, 20% on nilotinib, 14% on dasatinib, 6% on other TKIs. Several factors predicted intentional non-adherence in univariate analysis, including education level (P=0.016) and co-payment for TKIs (P=0.005). For patients on first line TKI (n=1551), the following factors independently predicted a higher likelihood of being intentional non-adherers: younger age (P=0.015), longer time since diagnosis (P<0.001), lower satisfaction with information received from healthcare providers (P=0.002), higher burden on social life (P<0.001) and not being fully informed on the importance of adherence (P=0.042). Non-adherence was lower when patients were told every dose was important to make the treatment work (P=0.042). Overall, intentional non-adherers intended to avoid fatigue (13%), diarrhea and GI issues (11%), nausea (10%) and muscle pain (9%). For patients in second or greater lines of therapy (n=985) all of the above factors were still statistically significant except for satisfaction with information received. Being female (P<0.001) also increased the likelihood of intentional non-adherence in this group. Discussion Despite there is clear evidence that survival is close to that of the general population when CML is treated effectively in chronic phase with current therapies, every fifth CML patient deliberately skips doses. Key factors predicting intentional non-adherence can potentially help physicians and patient organisations to identify patients early who should be monitored more closely and informed about the importance of adherence. Managing side effects proactively also reduces reasons for intentional non-adherence. Disclosures: Geissler: Novartis: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Efficace:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy. Bombaci:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. de Jong:Novartis: Membership on an entity’s Board of Directors or advisory committees. Gavin:Celgene: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Daban:Ariad: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Pelouchová:Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Sharf:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees.

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A New Cytokine-Based Stratification Is Highly Predictive of Survivals in AML Patients

Blood ◽

10.1182/blood-2019-125774 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1412-1412

Author(s):

Pierre Peterlin ◽

Joelle Gaschet ◽

Thierry Guillaume ◽

Alice Garnier ◽

Marion Eveillard ◽

...

Keyword(s):

Multivariate Analysis ◽

Risk Stratification ◽

Univariate Analysis ◽

Standard Of Care ◽

Healthy Controls ◽

First Line ◽

Serum Samples ◽

Gm Csf ◽

Significant Difference ◽

The Impact

Introduction: Recently, a significant impact of the kinetics of Fms-like tyrosine kinase 3 ligand concentration (FLc) during induction (day[D]1 to D22) has been reported on survivals in first-line acute myeloid leukemia (AML) patients (pts) (Peterlin et al, 2019). Three different FLc profiles were disclosed i) sustained increase of FLc (FLI group, good-risk), ii) increase from D1 to D15, then decrease at D22 (FLD group, intermediate-risk) and iii) stagnation of low levels (<1000 pg/mL, FLL group, high-risk). An update of this prospective monocentric study (www.ClinicalTrials.gov NCT02693899) is presented here evaluating also retrospectively the impact on outcomes of 6 other cytokine level profiles during induction. Methods: Between 05/2016 and 01/2018, 62 AML pts at diagnosis (median age 59 yo [29-71], <60 yo n=33) eligible for first intensive induction were included and provided informed consent. They received standard of care first-line chemotherapy. Serum samples collected on D1, 8, 15 & 22 of induction were frozen-stored until performing ELISA for FL, TNFa, SCF, IL-1b, IL-6, IL-10, GM-CSF. Normal values were assessed in 5 healthy controls. Pts outcomes considered were relapse/leukemia-free (LFS) and overall (OS) survivals. Results: FLI, FLD and FLL profiles were observed for 26, 22 and 14 pts respectively. A total of 372 samples were assayed for the 6 other cytokines. Median concentrations at D1, D8, D15, D22 for these 6 cytokines were as follows, considering the whole cohort (and healthy donors): TNFa: 0.53, 0, 0, 0 (0); SCF: 5.91, 0, 0, 0 (3); IL-1b : 0, 0, 0, 0 (0); IL-6: 4.85, 16.28, 10.11, 7.1 (0), IL-10: 0, 0, 0, 0 (0) and GM-CSF:1.63, 1.8, 0.67, 1.34 (9.98). Median IL-6 and GM-CSF levels, compared to healthy controls, were respectively higher and lower during induction. No significant difference was observed in terms of median cytokine concentrations at any time when comparing the three FL sub-groups or FLI vs FLD pts. With a median follow-up of 28 months (range: 17-37), FLI and FLD pts show now similar 2-y LFS (62.9% vs 59%, p=0.63) and OS (69.2% vs 63.6%, p=0.70). FLL pts have a significantly higher rate of relapse (85,7% vs FLI 19,2% vs FLD 32%, p=0,0001). Comparing FLL vs FLI+FLD pts disclosed significantly different LFS (7.1% vs 61.1%, p<0.001) but not OS (36.7% vs 66.6%, p=0.11). In univariate analysis, 2y LFS and OS were not affected by the concentration (< or > median) of the 7 cytokines studied except for LFS and GM-CSFc at D8 (p=0,04) and D15 (p=0,08), for LFS and FLc at D1 (p=0.06), D8 (p=0,03), D15 (p=0,04) and D22 (p=0,03) and for OS and GM-CSF at D15 (p=0.08). A significant association between LFS was observed with ELN 2017 risk stratification (2-y LFS: favorable: 68,1% vs intermediate: 48,1% vs unfavorable: 30,7%, p=0.03) but not OS (2 y: 77% vs 55,5% vs 46,1%, p=0.09). Multivariate analysis showed that no factor was independently associated with OS while LFS remained significantly associated with the FLc profile (FLL vs others, HR: 5.79. 95%CI: 2.48-13.53, p<0.0001) and GM-CSF at D15 (HR: 0.45; 95%CI: 0.20-0.98, p=0.04) but not with ELN 2017 risk stratification (p=0.06). Cytokine levels were then assessed to try to better discriminate FLI and FLD pts. A significant higher IL-6 level at D22 was found in relapsed or deceased FLI/FLD pts (median:15,34 vs 5,42 pg/mL, p=0,04). FLI/FLD pts with low IL-6 at D22 (< median, 15.5 pg/mL, n=35 vs n=14 with high level) had significant better 2y LFS and OS (74,2% vs 38,4%, p=0,005 and 77,1% vs 38,4%, p=0,009, respectively). A new prognostic risk-stratification could thus be proposed, i.e. FLI/FLD with IL-6 <15.5 pg/mL (favorable), FLI/FLD with IL-6 >15.5 pg/mL (intermediate) and FLL (unfavorable). This new classification was considered for a second multivariate analysis, showing that it is the strongest factor associated with OS (p=0.006, ELN p=0.03, FL profile p=0.04) and LFS (p<0.0001, ELN p=0.005, GM-CSFc D15 p=0.03) (figure 1). Conclusion: This study confirms stagnation of low FLc during AML induction as a strong poor prognosis factor. Moreover, IL-6 levels at D22 further discriminate FLI/FLD pts. Thus, a new cytokine-based risk-stratification integrating FL kinetics and IL-6 levels during induction may help to better predict outcomes in first-line AML patients. These results need to be validated on a larger cohort of AML patients while anti-IL-6 therapy should be tested in combination with standard 3+7 chemotherapy. Figure 1 Disclosures Peterlin: AbbVie Inc: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy; Astellas: Consultancy. Moreau:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria.

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Predictive Value Of Early Molecular Responses In Outcomes Of Patients With Chronic Myeloid Leukemia Treated With Imatinib In First-Line Therapy

Blood ◽

10.1182/blood.v122.21.4941.4941 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4941-4941

Author(s):

Katia B. Pagnano ◽

Bruna Vergilio ◽

Eliana C M Miranda ◽

Marcia Torresan Delamain ◽

Maria Helena De Almeida ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cytogenetic Response ◽

Molecular Response ◽

First Line ◽

Molecular Responses ◽

Advanced Phase ◽

Significant Difference ◽

The Impact

Abstract Several studies demonstrated the prognostic significance of an early molecular response in chronic myeloid leukemia (CML) patients (pts) treated with imatinib in first line or other tyrosine kinase inhibitors. Aims: The aim of this study was to evaluate the impact of early molecular responses, at 3 and 6 months after treatment with imatinib in CML pts and correlate these responses with CCR, MMR, overall survival (OS) and event free survival (EFS). Patients and Methods Between February 2006 and June 2012, 95 adult pts with newly diagnosed CML in chronic phase (CP) received imatinib 400mg/daily. CP was defined using WHO 2008 criteria. All pts received a short course of hydroxiurea until imatinib was available. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1% (IS). Statistical analysis: OS was measured from imatinib start until date of death or last visit. An event was defined as death from any cause. EFS was measured from imatinib start until the first event (loss of complete hematological response (CHR); complete cytogenetic response (CCR), progression to advanced phase, death or imatinib discontinuation) or last visit. OS and EFS rates were calculated using Kaplan-Meier method and log-rank test to compare its curves. The MMR probabilities according to molecular responses at 3 and 6 months were calculated by c2 method and cumulative incidence, considering as competitive event death or progression, before the event. Results 95 pts were analyzed, 57 (60%) male, with a median age of 47 years (17-79); Sokal score: high, intermediate and low was 30, 38.6 and 31.4% respectively; EUTOS scores was 81.5% low and 18.5% high. The median time from diagnosis until imatinib therapy was 1 month (0-5) and the follow-up was 39 month (3-89). Responses: 88% achieved CHR; 50% CCR and 53% MMR. One patient progressed to advanced phase during follow-up, while on imatinib treatment. 21 (22%) pts discontinued imatinib due to intolerance (47.6%); resistance (42.9%), death (4.8%) and Allo-HSCT (4.8%). At 3 months from the start of therapy, 30/64 (46.8%) achieved CCR, 15/64 (23.4%) partial cytogenetic response and 20/64 (31.2%) less than partial; by RQ-PCR, 72.3% (68/94) achieved at 3 months BCR-ABL transcripts ≤10% and 27.7% (26/94) > 10%. At 6 months 55.2% (48/87) had BCR-ABL transcripts ≤ 1% and 44.8% (39/87) >1%. The OS was 97% (95%CI: 95-99%) and EFS 63% (95%CI: 52-75%).There was no significant difference in OS and EFS in pts with RQ-PCR > 10% vs ≤ 10% at 3 months (figure 1), but pts with BCR-ABL transcripts > 10 and >1-10% at 6 months had an inferior EFS in comparison with pts with BCR-ABL transcripts ≤ 1% (41%,50%,89% respectively - p= 0.005), (figure 2). The CI showed that CCR pts at 3 months reached MMR earlier at 24 month (54% vs 18%, p=0.03), as well as CCR pts at 6 months, albeit no significance statistically (52% vs 37%, p= 0.16). For RQ-PCR at 3 months, pts with BCR-ABL transcripts 0-1% had a probability of 88% to achieve MMR, 1-10% had 52% and >10% 42%, p< 0.0001 (figure 3). In conclusion, our results show that early molecular responses are predictive of achieving MMR and BCR-ABL transcripts <1% at 6 months is predictive of EFS in CP-CML treated with imatinib. Disclosures: No relevant conflicts of interest to declare.

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Impact of Day 28 Absolute Lymphocyte Count on Outcome of Adult Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.5256.5256 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5256-5256

Author(s):

Naresh Bumma ◽

Jing Ai ◽

Xuefei Jia ◽

Sean Hobson ◽

Donna Abounader ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Lymphocyte Count ◽

Myeloid Leukemia ◽

Univariate Analysis ◽

Absolute Lymphocyte Count ◽

Advisory Committees ◽

The Impact ◽

Acute Myeloid

Abstract Introduction: Lymphocyte recovery after induction chemotherapy (IC) predicts outcome in adult patients (pts) with acute myeloid leukemia (AML) (Behl et al. Leukemia 2006; 20: 29-34). However, it is unknown whether absolute lymphocyte count (ALC) recovery after IC predicts outcome in those pts who are then treated with allogeneic hematopoietic stem cell transplant (AHCT) in first complete remission (CR1). We hypothesized that the prognostic impact of ALC might be nullified by AHCT in CR1 due to the abrogation of normal immunologic recovery. In this study, our aims were to (1) evaluate the impact of Day 28 ALC on all AML pts receiving IC and (2) to specifically, evaluate the impact of Day 28 ALC on the subset of AML pts proceeding to AHCT in CR1. Methods: A retrospective chart review of 180 adult AML pts (≥ 18 years of age) who were treated with IC during the years 2001- 2012 at the Cleveland Clinic was performed. Institutional Review Board approval was obtained. Pts with acute promyelocytic leukemia were excluded . Ninety-four of the 180 pts received AHCT in CR1. A total of 141 AML pts receiving IC and a total of 66 pts receiving IC and then receiving AHCT in CR1 were eligible for data analysis because Day 28 ALC was missing in the remainder of the pts. Prior studies in AML identified an ALC of < 500/ µL at Day 28 of IC as predictive of overall survival. We stratified Day 28 ALC into the following categories: (a)< 250/ µL (b) < 350/ µL (c) < 500/ µL and (d) < 500/ µL for Max ALC [Max ALC was defined as the maximum ALC value between days 26 and 30 after the initiation of IC]. Other variables collected included age at diagnosis, WBC at diagnosis, and cytogenetic (CG) risk. CG risk was ascribed by CALBG criteria. The Kaplan-Meier method was used to summarize overall survival (OS) and relapse-free survival (RFS), which were measured for all pts from the time of diagnosis. The log-rank test was used for univariate analysis of categorical factors and the Cox proportional hazards model was used for measured factors and multivariate analysis. We performed two separate analyses : one for all AML pts (n=141); and a second analysis only focusing on those receiving AHCT in CR1 (n=66). Results: Pt characteristics for the entire AML cohort: The median age was 58.0 years (20.0-80.0); 46.1% female. The median WBC at diagnosis was 11.6 K / µL (range 0.7-220.7) and median Day 28 ALC was 400/ µL (0-2.4). Twenty-seven pts (19.7%) had favorable CG, 84 (61.3%) intermediate, and 26 (19.0%) unfavorable. Most pts (91%) received "7+3" IC and 93 (66%) also received at least 1 cycle of post-remission chemotherapy. On univariate analysis, age ≥60 (HR 2.72, p< 0.001), CG risk (HR 2.13, p < 0.001), Day 28 ALC < 250/ µL (HR 1.60, p=0.022), Day 28 ALC < 350/ µL (HR 1.57, p=0.029), and max ALC < 500/ µL (HR 1.54, p=0.035) were associated with a worse OS from the initiation of treatment. Low ALC was associated with both a higher incidence of refractory disease and death during induction (p=0.015). In our second analysis of pts undergoing AHCT in CR1, although not statistically significant, max ALC < 500/ µL (during IC) was associated with a trend towards decreased OS from the start of treatment on both univariate (HR 1.88,p= 0.13) and multivariate (HR 2.16, p=0.075) analysis. Conclusions: Max ALC < 500/ µL is predictive of outcome in AML pts undergoing IC, and there is a suggestion that this effect may not be abrogated by AHCT. A larger study will be needed to further confirm these findings. Therapies to improve lymphocyte recovery may be important in the treatment of AML. Disclosures Sekeres: Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees.

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First-Line Second Generation Tyrosine Kinase Inhibitors in Newly Diagnosed Accelerated Phase Chronic Myeloid Leukemia Patients.

Blood ◽

10.1182/blood-2018-99-113058 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 48-48 ◽

Cited By ~ 2

Author(s):

Marie Balsat ◽

Vincent Alcazer ◽

Gabriel Etienne ◽

Gaelle Fossard ◽

Francoise Huguet ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Board Of Directors ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Newly Diagnosed ◽

First Line ◽

Advisory Committees ◽

Free Survival

Abstract Introduction Up to 10% of patients (pts) with chronic myeloid leukemia (CML) are already in accelerated phase (AP) at diagnosis and despite treatment advances in the field of tyrosine kinase inhibitors (TKIs), management of these pts is challenging. This study aims to examine the benefit of second generation BCR-ABL tyrosine kinase inhibitors (TKI2) as first-line treatment for newly diagnosed AP-CML. Methods Pts meeting criteria for AP-CML at diagnosis and treated with first-line TKI2 (i. e. Nilotinib or Dasatinib) were included in this retrospective multicenter observational national study. AP-CML were defined according to the ELN (Baccarani, Blood 2013) as hematological acceleration (HEM-AP, any of the following features: blasts in PB or marrow 15-29%, or blasts+promyelocytes in PB or marrow >30% with blasts <30%, basophils in PB ≥20%, or persistent thrombocytopenia <100×109/L (unrelated to therapy) and/or chromosomal abnormalities in addition to the Ph at diagnosis (ACA-AP). Pts initiated nilotinib at 6-800 mg BID or dasatinib at 100-140 mg QD with further dose adaptations according to toxicities or response. Overall survival (OS), progression-free survival (PFS) and failure-free survival [FFS= progression to blast crisis, death, loss of any previous response (CHR, CCyR, or MMR) discontinuation of TKI2 for toxicity], were analysed since TKI2 initiation in intention-to-treat. Results Sixty-six pts were analysed: 45 males (68%) and 21 females (32%) with a median age at diagnosis of 49 (15-78.5) years. The median follow-up of the cohort was 43.5 (1.7-117) months. We segregated the pts in HEM-AP (n=33) and ACA-AP (n=33) for further analyses. Nine pts with HEM-AP harboured ACA and were analysed in the HEM-AP group. Fusion transcripts were of the Major BCR in 57 pts, 6 pts had atypical BCR-ABL transcripts (2 e19a2, and 1 e1a2 in the HEM-AP group and 2 e19a2 and 1 Ma3 in the ACA-AP group), and 3 transcripts unknown. Not surprisingly, spleen enlargement was significantly greater in the HEM-AP group [10 (5-14.75) vs. 3 (0-10)cm, p=0.014]. PB basophils [median 10 (6-16) vs. 3 (2-5)%, p <0.001], PB blasts [median: 12.05 (7.5-15) vs. 1.5 (0-4)%, p<.001], as well as PB blasts+promyelocytes [median 14 (11-20) vs. 4 (1-7)%, p<.001]. Hemoglobin levels were significantly lower in the HEM-AP group [median 93 (6-113.5) vs 120 (100-134) g/L, p<0.001]. Neither WBC counts, platelets counts, nor BCR-ABL/ABL load differed significantly between the 2 groups. In the ACA-AP group, 10 (30%) pts harbored major route ACA and 23 (70%) pts harbored minor route ACA of whom 3 pts with i(17q) and 1 with 7q abnormalities. In the ACA-AP group, Sokal score was low in 42%, intermediate in 32% and high in 26% of pts (2 pts unknown). Dasatinib was initiated in 19/33 pts (57.5%) in the HEM-AP group and in 8/33 pts (24%) in the ACA-AP group. Treatment responses did not significantly differ between ACA-AP and HEM-AP group, regardless of the TKI2 administered, with 33/33 (100%) vs 31/33 (94%) pts achieving a CHR, 2/33 (6%) pts vs 0/33 (0%) pts achieving a MCyR, 5/33 (15%) pts vs 5/33 (15%) pts achieving CCyR, 9/33 (27%) pts vs 4/33 (12%) pts achieving a MMR respectively. However, 11/33 (33%) HEM-AP vs 22/33 (66%) ACA-AP pts achieved a deep molecular response (p=0.013, Fisher test). Median times to CHR and MMR were not significantly different between ACA-AP group and HEM-AP group with 1.05 vs 1.25 months (p=0.088) for CHR and 6 vs 7 months (p=0.156) for MMR, respectively. Overall, the estimated 7-yr FFS rate was 56.92% (95%CI: 40-81), 7-yr PFS was 83.42% (95% CI: 69.6-100%) and 7-yr OS was 87.14% (95%CI: 73.5-100%) (Figure 1.) with no significant differences between ACA-AP vs HEM-AP pts [7-yr FFS: 57.7 vs. 62%, p=0.739; 7-yr PFS: 84.7% vs. 84%, p=0.185; 7-yr OS: 88.9% vs 86.6%, p=0.132] respectively. There was also no difference in FFS, PFS and OS according to the type of TKI2. The only factors influencing negatively OS were the % of BM blasts (HR=1.17, 95%CI: 1.1-1.28, p<0.001) and the % of BM blasts+promyelocytes (HR=1.14, 95%CI: 1.06-1.22, p<0.001). We identified too few significant factors in univariate analysis to perform a multivariate analysis. Conclusion The initiation of a TKI2 in newly diagnosed AP-CML pts induces excellent response and survival rates, probably superior to that of Imatinib first-line, and counterbalances the negative impact of this advanced disease, particularly in HEM AP subgroup. Disclosures Etienne: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau. Berger:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mahon:Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; BMS: Speakers Bureau. Rea:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Pfizer: Honoraria. Nicolini:BMS: Consultancy, Speakers Bureau; Incyte Biosciences: Consultancy, Speakers Bureau; Sun Pharma Ltd: Consultancy.

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ELN 2013 Response Status Criteria: Relevance For De Novo imatinib Chronic Phase Chronic Myeloid Leukemia Patients?

Blood ◽

10.1182/blood.v122.21.4029.4029 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4029-4029

Author(s):

Gabriel Etienne ◽

Stephanie Dulucq ◽

Axelle Lascaux ◽

Anna Schmitt ◽

Audrey Bidet ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

De Novo ◽

Clonal Evolution ◽

Chronic Phase ◽

Risk Scores ◽

Advisory Committees ◽

Significant Difference ◽

Response Status

Abstract Purpose to evaluate the relevance of the 2013 ELN response status criteria for de novo imatinib (400 mg/d) chronic phase chronic myeloid leukemia (CP-CML) patients. Patients and Methods Response status according to the 2009 and 2013 criteria were determined in 180 unselected patients. Outcome of the subgroups of patients were then compared. Results One hundred and eighty patients were included in this study. The median age at diagnosis was 58.1 years (range, 19.8-88.9) and 112 (62.2%) were male. Sokal risk scores were low in 50 patients (27.7%), intermediate in 74 (41.1%), high in 38 (21.1%) and unknown in 18 patients (10%). Ten patients (5.5%) had clonal evolution at diagnosis. With a median follow up of 5.4 years, the 180 patients were classified as optimal responders (OR2009) (n=113, 62.7%), suboptimal responders (SOR2009) (n=47, 26.1%) and failures (FAIL2009) (n=20, 11.1%) according to the 2009 ELN criteria and optimal responders (OR2013) (n=77, 42.7%), warnings (WAR2013) (n=59, 32.7%) and failures (FAIL2013) (n=44, 24.4%) according to the 2013 ELN criteria. All the patients classified as failures according to the 2009 criteria were classified as failures by the 2013 criteria. Results are presented in table 1. No difference was observed in event-free (EFS), progression-free (PFS) and overall (OS) survivls between OR2009 and SOR2009 or between OR2013 and WAR2013. PFS and OS were not different between SOR2009 and FAIL2009 whereas a significant difference was observed between WAR2013 and FAIL2013 in PFS and OS (p=.003 and p=.024 respectively). No difference in terms of outcome was observed between OR2009 patients who became WAR2013 when compared to OR2013 patients. When compared to FAIL2009 patients, SOR2009 patients who became WAR2013 had better EFS, FFS, PFS and OS. No difference was observed in PFS or OS in SOR2009 patients who became FAIL2013. Conclusion The 2013 ELN response status criteria have improved patients classification in terms of response status. However this improvement is related to a better definition of failure rather than that of optimal response for CP-CML patients treated with IM frontline therapy. Disclosures: Etienne: Ariad Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Dulucq:Novartis: Membership on an entity’s Board of Directors or advisory committees. Nicolini:Ariad Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Teva: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Mahon:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees.

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Fms-like Tyrosine Kinase 3 Ligand Concentration Kinetic Profile during Induction Is Strongly Predictive of Survivals in AML: Results of the FLAM/Flal Study

Blood ◽

10.1182/blood-2018-99-111694 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1484-1484

Author(s):

Pierre Peterlin ◽

Joelle Gaschet ◽

Thierry Guillaume ◽

Alice Garnier ◽

Marion Eveillard ◽

...

Keyword(s):

Bone Marrow ◽

Tyrosine Kinase ◽

Board Of Directors ◽

Univariate Analysis ◽

Advisory Committees ◽

Kinetic Profile ◽

Significant Difference ◽

Low Levels ◽

The Impact ◽

Bone Marrow Blasts

Abstract The cytokine Fms-like tyrosine kinase 3 ligand (FL) is a key regulator of hematopoiesis. In a previous Phase 1 study testing a radioimmunotherapy regimen for relapsed/refractory acute lymphoblastic leukemia (ALL), responders showed increased soluble FL serum concentration (sFLc) after salvage regimen (Chevallier, Lancet Haematol., 2015). This prospective monocentric study (ClinicalTrials.gov NCT02693899) aimed to assess the impact of sFLc in ALL and acute myeloid leukemia (AML) patients treated according to standard-of-care intensive first-line chemotherapy regimens. Serum samples were collected on days 1, 8, 15, 22 of induction, at days 1, 8, 15 of each intensive consolidation or day 1 of each non intensive consolidation when appropriate, frozen-stored then tested by ELISA (DY308, R&D Systems, Minneapolis, MN). The following outcomes were considered to assess the impact of sFLc: refractory status after induction (≥5% bone marrow blasts or persistent aplasia >45 days), morphologic, immunophenotypic, cytogenetic or molecular relapses, event-free (EFS) and overall survival (OS). All patients provided informed consent. Between May 2016 and January 2018, 80 patients were included. Data were ultimately available for 16 ALL and 62 AML patients. A total of 579 samples were assayed. Analysis of the results disclosed 3 sFLc kinetic profiles during induction i) sustained increase from days 1 to 22 (FLI group), ii) increase from days 1 to 15, then decrease at day 22 (FLD group) and iii) stagnation of low levels all along (<1000 pg/mL from days 1 to 22, FLL group). The 16 evaluable ALL patients were classified as FLI (n=2), FLD (n=7) and FLL (n=7). All reached a cytologic complete remission after induction and only 2 relapses have been documented so far in this group. No impact of sFLc kinetic profile was seen in this context. Conversely, a significant impact of sFLc during induction (but not during consolidation) was observed in AML patients. The median age in this group was 59 years old (range: 29-71, <60 years n=33). The median follow-up for alive patients was 541 days (range: 154-787). sFLc levels were assayed in 244 samples. Twenty-six patients were classified as FLI (42%), 22 as FLD (35%) and 14 as FLL (23%). Median sFLc at days 1, 8, 15, 22 were as follows for the three groups: FLI: 2, 724, 3673, 5753 pg/mL; FLD: 6, 1229, 6019, 684 pg/mL; and FLL: 0, 60, 124, 81 pg/mL. There was no significant difference between the 3 groups regarding age, ELN 2010 risk-stratification (ELNrs), OMS classification, WBC and bone marrow blasts percentages at diagnosis. When comparing the 3 sFLc groups, almost all refractory patients (n=6) were found in the FLL group (n=5, FLD n=1, FLI n=0, p=0.0007). Three cytologic relapses occurred in the FLI group, 7 in the FLD group (cytologic n=4, molecular n=2, immunophenotypic n=1) and 7 in the FLL group (cytologic n=4, molecular n=2, immunophenotypic n=1). There were more relapses in the FLL group (n=7/9 [78%] vs FLD n=7/21 [33%] vs FLI n=3/26 [11.5%], p=0.0009). In univariate analysis, 2-year EFS and OS were significantly better for the FLI group (79.1+-8 vs FLD 54.9%+-11 vs FLL 11.4%+-10,p<0.001; and 80.4%+-8 vs FLD 58.6%+-11 vs FLL 18.6%+-10, p=0.09,respectively). There was a trend for the association of 2-year EFS (but not OS) with ELNrs (favorable:70.9%+-11, vs Int-1+Int-2:57.1%+-10 vs adverse 33%+-13,p=0.06). Stratification of the patients according to the median sFLc level at day +15 (2952pg/mL) also showed significantly different 2 year EFS at 38.2%+-9 for low levels vs 71.8%+-8 for high levels (p=0.02). The same was true for day +22 median sFLc level (1390pg/mL) at 38.9%+-9 vs 73.6%+-8 (p=0.02). Age had no impact on EFS nor OS. In multivariate analysis considering age, ELNrs, sFLc at days 15 and 22 levels, and sFLc kinetic profile during induction, the latter remained the most powerful factor independently associated with EFS (HR: 3.62; 95%CI: 1,65-7,94, p=0,001; ELNrs: HR: 1.74; 95%CI: 0,98-3.10, p=0.05; sFLc at day+15 p=0,37; sFLc at day+22, p=0.24, age p=NS). sFLc kinetic profile was the sole factor that was also independently associated with OS (HR: 2.60; 95%CI: 1.12-6,07, p=0.02). In conclusion, sFLc kinetic profile during induction appears to be a new powerful early prognostic parameter in AML patients. These results need to be validated on a larger cohort of patients and the mechanism by which induction sFLc levels may impact AML outcome remains to be elucidated. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Jak-2 and Nfkbia Gene Expression Play a Strategic Role in Chronic Myeloid Leukemia (CML) Molecular Response during Early Nilotinib Treatment: The PhilosoPhi34 Data

Blood ◽

10.1182/blood-2018-99-113273 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5118-5118

Author(s):

Ester Pungolino ◽

Mariella D'adda ◽

Alessandra Trojani ◽

Alessandra Perego ◽

Chiara Elena ◽

...

Keyword(s):

Gene Expression ◽

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Biological Data ◽

Molecular Response ◽

First Line ◽

Down Regulation ◽

Advisory Committees

Abstract Background Targeted therapy with Tyrosine-Kinase-Inhibitors (TKIs) totally modified the course of treatment of Chronic Myeloid Leukemia (CML). The objectives and the needs of treatment have been modified during the last years and the discontinuation of therapy is now a feasible aim. However, a lot of biological data acquired in the last twenty years, showed that degree and mechanisms of Leukemic Stem Cells (LSCs) clearance during TKI treatment are not clearly established as well as the predictive criteria for a stable and prolonged Treatment Free Remission (TFR). The multicentre, prospective, single-arm PhilosoPhi34 study (EudraCT: 2012-005062-34) was designed by the Rete Ematologica Lombarda (REL), to verify the in-vivo activity and time-course of first-line Nilotinib (NIL) therapy on Bone Marrow (BM) CD34+/lin-Ph+ cells clearance. An exploratory Gene Expression Profiling (GEP) study of CD34+/lin- cells at diagnosis and at 12 months (mos) of treatment, for the first 30 evaluable pts, was included. Preliminary GEP data suggested a correlation between different NFKBIA expression at diagnosis and at 12 mos and the achievement of a deeper Molecular Response (MR) (Pungolino et al, AJH 2018). We report here some results of GEP analysis on all enrolled evaluable pts and their possible correlation with clinical data. Methods BM cells were collected and stored at diagnosis and at 12 mos of treatment. CD34+/lin- cells were purified with a Diamond CD34 Isolation Kit Miltenyi (97% of purity). For GEP analysis we used Affymetrix HG-U133 Plus 2.0 microarray and Genechip platform (Affymetrix) and the Affymetrix GeneChip Scanner 3000. Data was pre-processed and normalized using the Robust Multi-array Average (RMA) algorithm. The Significant Analysis of Microarrays (SAM) was used to identify genes with statistically significant changes in expression. P-values were corrected for multiple testing using false discovery rate, for differentially expressed genes confirmation. We chose to analyse different expression of NFKBIA (the inhibitor of NF-kB onco-gene) in order to confirm the preliminary data reported on the first 30 analysed pts. Pts were monitored according to ELN-recommendation. Biological data were correlated with MR at 3, 12 and 36 mos of therapy. We use Fishers test to compare unbalanced group. Results Out of the 87 enrolled pts, 80 completed the first 12 mos of treatment and 78 (1 failure and 77 CCyR) were evaluable for GEP analysis. We observed 2726 genes symbol differentially expressed of which 1868 are coding genes. Among these, JAK-2 showed a down regulation at 12 mos (p: .024). JAK-2 expression ranged from 2.62 to 4.95 at diagnosis and from 1.48 to 5.58 at 12 mos. Only 26/78 pts increased JAK-2 expression that was > 4 in 1/26 pts, at diagnosis; 2/26 (7.69%) pts showed a H Sokal. Other 52/78 pts decreased JAK-2 expression that was ≥ 4 in 21/52 pts, at diagnosis; 10/52 (19.23%) pts and 6/21 (28,57%) pts showed a H Sokal. Similarly, when we compared low JAK-2 expression (< 3.5) vs vary high expression (≥ 4) 2/21 vs 6/22 pts had H Sokal (9.52% vs 27.27%; p: .0057). Considering the role of JAK-2 and NFKBIA in cell regulation and survival, we evaluated how the combination of their different expression impact on MR (i.e. NFKBIA increased expression/JAK-2 decreased expression vs NFKBIA decreased expression/JAK-2 increased expression). Data are reported in Table 1 and 2. Conclusion GEP analysis showed a down regulation of JAK-2 expression after 12 mos of first line NIL treatment, in 78 early chronic phase CML pts. Data suggest that high expression of JAK-2, at diagnosis, correlate with H Sokal score. However, H Sokal pts with a JAK-2 down regulation, obtain during treatment similar MR compared to L Sokal pts. Additionally, the study confirms our preliminary observation on 30 pts , concerning the role of NKBIA up - regulation in increasing percentage of earlier and deeper MR . The better condition of NFKBIA and JAK-2 expression (up regulation of NFKBIA and down regulation of JAK-2) is associated with a higher percentage of early MR3 and optimal responses over time, despite the higher number of H Sokal pts in this group. A study with NIL as first line treatment combined with low dose of JAK-2 inhibitor and a natural inhibitor of NF-kB (such as curcuma), during the first year of treatment, to increase the deeper MR rate and the probability of TFR is warrented. Disclosures Rossi: Sandoz: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Teva: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Novartis: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Concomitant Treatment with Ruxolitinib and Deferasirox in the Management of Iron Overload in Patients with Myelofibrosis: A Multicenter Italian Experience

Blood ◽

10.1182/blood-2019-127488 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 839-839 ◽

Cited By ~ 1

Author(s):

Elena Maria Elli ◽

Ambra Di Veroli ◽

Alessandra Iurlo ◽

Ida Carmosino ◽

Giulia Benevolo ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Median Time ◽

Univariate Analysis ◽

Significant Proportion ◽

Iron Chelation ◽

Concomitant Treatment ◽

Advisory Committees ◽

Impact On Survival ◽

The Impact

Introduction: Deferasirox (DFX) is the currently available iron-chelation therapy (ICT) for the management of iron overload (IOL), mainly in myelodysplastic syndromes; recently, two retrospective independent studies (Di Veroli, 2018; Elli, 2019) demonstrated that a treatment with DFX is feasible and effective also in the setting of myelofibrosis (MF). However, no data are still available regarding the concomitant use of DFX in patients (pts) treated with Ruxolitinib (Rux). Aims and Methods: We retrospectively collected in 16 Italian Centers 59 pts (M: 37; F: 22) with primary MF (n=41) or post-Polycythemia Vera (n=9) and post-Essential Thrombocythemia (n=9) MF, treated with Rux and DFX for the management of IOL secondary to transfusion-dependent anemia. Primary endpoint of the study was to evaluate the efficacy of DFX in terms of reduction of ferritin levels and hematological improvement (HI). Additional endpoints were the safety of DFX associated to Rux treatment and the impact on survival and leukemic evolution. Results: The main features of pts at diagnosis and at baseline of DFX treatment are reported in Table 1 (column A). Pts started DFX after a median time from MF diagnosis of 26.7 months [Interquartile range (IR) 2.6-240.9] and from transfusion dependency of 13.5 months (IR 1.5 - 145.3). Forty-eight pts started DFX when already under Rux treatment, while 11 pts before Rux treatment. The median ferritin level (FL) at baseline was 1675 ng/mL (IR 646-6447). The median starting dose of DFX was 1000 mg/day (12.5 mg/kg/day). All pts were evaluable for DFX response (> 3 months of DFX), with a median time of DFX and Rux exposure of 14.5 months (IR 3.2-73.3) and 40 months (2.1-88.6), respectively; the median period of concomitant DFX-Rux treatment was 11.1 months (3.7-58.4). As to ICT efficacy, 24 pts (40.7%) obtained an iron chelation response (ICR), defined as a stable reduction of FL < 1.000 ng/mL or a reduction ≥ 50% of FL respect to baseline. The main variables analyzed in pts with ICR or no ICR were reported in Table 1 (Column B and C, respectively). At univariate analysis, pts who obtained ICR did not presented significant differences compared to pts without ICR, except for a significantly lower median FL at diagnosis (251 vs 496 mcg/l, p=0.008). As expected, ICR pts showed a progressive significant reduction of FL at 3, 6, 12 and 18 months, respect to baseline, in contrast to pts without ICR (p < 0.0001). The median time of exposure to DFX was higher in ICR vs no ICR group (22.0 vs 12.9 months, p=0.03), as well as the median time of concomitant DFX-Rux treatment (14.2 vs 9.7 months, p=0.019). The International Working Group criteria (Cheson, 2006) were applied to assess HI during ICT. Erythroid response (ER) was defined as complete (CR: achievement of transfusion independency), partial (PR: reduction in the transfusion requirement ≥ 50% and/or increase of haemoglobin levels) or no response (NR). ER was observed in 25 pts (42.4%) with ten (17%) obtaining CR, 15 (25.4%) PR and 34 (57.6%) NR. Obtainment of ICR predicted for the achievement of ER: 17 (70.8%) pts with ICR achieved CR or PR compared to 8 (22.8%) without ICR (p =0.0007). DFX-related toxicities occurred in 30 pts (50.8%) and consisted mainly in renal impairment (32.2%), liver enzymes alterations (6.7%) or epigastric pain (8.4%): however, only in one case was observed a grade 3 toxicity. Overall, a dose reduction/temporary discontinuation related to DFX-toxicity was reported in 14 (23.7%) pts; however only 5 (8.4%) pts completely discontinued ICT because of grade ≥ 2 toxicity. After a median follow-up from diagnosis of 58.6 months (IR 7.1-282.9), 19 pts (32.2%) died [13 of them (22%) for leukemic evolution or disease progression]. The 3-year cumulative overall survival (Figure 1) and the 3-year cumulative incidence of leukemic evolution (Figure 2) from DFX initiation were 75.1% (95%CI 55.6 - 94.6) and 20.2% (95%CI 2.1 - 38.3) in pts who obtained ICR compared to 54.5% (95%CI 31.9 - 77.1) and 36.1% (95%CI 13.1 - 59.1) in pts without ICR, respectively (p=0.13 and p=0.153). Conclusions: The present multicenter study showed that ICT with DFX is effective and safe also in this setting of pts receiving concomitant Rux treatment. HI with ER seems occur in a significant proportion of pts and correlates with the achievement of ICR. Further larger and prospective investigations are required in order to evaluate the impact on survival and leukemic evolution of this combination. Disclosures Elli: Novartis: Membership on an entity's Board of Directors or advisory committees. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Benevolo:Novartis Pharmaceuticals: Consultancy. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Bonifacio:Novartis: Honoraria; Amgen: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Cilloni:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Tiribelli:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Trawinska:Novartis: Consultancy, Honoraria. Breccia:BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Palumbo:Janssen: Honoraria; Celgene: Honoraria; Teva: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Hospira: Honoraria. Latagliata:Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Pfizer: Honoraria.

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Analysis of Early Events during the First Year of Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Phase - Chronic Myeloid Leukemia: A "Campus CML" Study

Blood ◽

10.1182/blood-2021-149780 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1487-1487

Author(s):

Mario Tiribelli ◽

Isabella Capodanno ◽

Maria Cristina Miggiano ◽

Cristina Bucelli ◽

Francesco Cavazzini ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Hematologic Toxicity ◽

Molecular Response ◽

Advisory Committees ◽

Primary Resistance ◽

Number Of Patients ◽

The Impact

Abstract Background Tyrosine kinase inhibitors (TKIs) revolutionized treatment of chronic myeloid leukemia (CML). However, the first months of therapy are crucial, as optimal response is defined as the achievement of molecular milestones at 3, 6 and 12 months (mo.) and as many toxicities, also causing a TKI switch, are more frequent in the 1st year. Methods To evaluate achievement of early molecular response (MR) and incidence of events leading to a TKI change during the 1st year of therapy, we retrospectively studied 1650 CP-CML patients diagnosed from 2012 and 2019 at 31 Hematology Centres and treated with frontline imatinib (IM) or second-generation (2G) TKIs dasatinib or nilotinib. Optimal MR at 3, 6 and 12 mo. were assessed according to 2020 ELN recommendations. Results Frontline TKI was IM in 926 (56.1%) and 2G-TKIs in 724 (43.9%) cases: the main clinical features at diagnosis of the entire cohort and according to frontline treatment is reported in the Table 1. Commonest comorbidities were arterial hypertension (38.7%), previous neoplasm (13.6%), diabetes (11.3%), peripheral vascular diseases (7.8%), COPD (7.5%) and ischemic heart disease (6.8%). IM-treated patients were older (p<0.001), with higher ELTS score (int/high 47.6% vs 35.6%, p<0.001) and more comorbidities (p<0.005 for all diseases). Optimal MR was achieved at 3 mo. by 1186/1430 (82.9%), at 6 mo. by 1025/1352 (75.8%) and at 12 mo. by 826/1264 patients (65.3%), respectively. Total number of patients discontinuing TKI in the 1st year was 321/1650 (19.4%), being higher with IM (237/926, 25.5%) than 2G-TKIs (84/724, 11.6%) (p<0.001). Main causes were primary resistance (8.7%, 12.3% IM vs 4.2% 2G-TKIs, p<0.001), extra-hematologic toxicity (6.4%, 8.2% IM vs 4.2% 2G-TKIs, p>0.001), hematologic toxicity (1.7%, 2.0% IM vs 1.4% 2G-TKIs, p=0.25) and progression (1.0%, 1.2% IM vs 0.8% 2G-TKIs, p=0.56). Cumulative incidence of discontinuation at 3, 6 and 12 mo. were 5.6%, 10.7% and 19.3%, respectively; values for IM and 2G-TKIs at the three timepoints were 8.1%, 15.0%, 25.5% and 2.5%, 5.3%, 11.5% (p<0.001) (Fig. 1). Conclusions This real-world study on over 1600 CML patients shows that almost 20% discontinue frontline TKI during the 1st year, mostly for primary resistance or toxicity. Discontinuation rates are higher with IM compared to 2G-TKIs, mostly at 3 mo. and are probably due to a lower attainment of early MR. The impact of older age, higher risks and heavier burden of comorbidities in IM patients should be considered and need deeper investigation. Figure 1 Figure 1. Disclosures Elena: GILEAD: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; CELGENE: Other: funding for meeting participation. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Pfizer: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Bonifacio: Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Novartis: Honoraria. Latagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria.

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R-Interferon Treatment before Imatinib Reverses the Negative Impact of e13a2 Transcript Type on Treatment Free Remission Duration after Tyrosine Kinase Inhibitors Discontinuation in Chronic Myeloid Leukemia Patients

Blood ◽

10.1182/blood-2019-125313 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4146-4146

Author(s):

Mariella D'Adda ◽

Mirko Farina ◽

Angela Passi ◽

Rosa Daffini ◽

Doriana Gramegna ◽

...

Keyword(s):

Prognostic Factors ◽

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Board Of Directors ◽

Median Time ◽

Myeloid Leukemia ◽

Prognostic Impact ◽

Advisory Committees ◽

Tki Discontinuation ◽

Transcript Type

BACKGROUND Tyrosine Kinase Inhibitor (TKIs) discontinuation has become, nowadays, under proper conditions, a feasible option for chronic myeloid leukemia (CML) also in "real life" setting. Different papers investigated which factors (age, sex, type of TKI, previous r-interferonα -r-INFα- therapy, line of therapy at stop, type of transcript, duration of TKI therapy and of sustained deep molecular response -sDMR-, Sokal risk score) could predict a successful TKIs discontinuation either within protocols or outside of clinical trials, and the results are not unique. AIM We retrospectively evaluated our CML pts who stopped TKI after sDMR in order to assess the variables that could influence the probability of a durable TFR. METHODS BCR-ABL transcripts were determined by RQ-PCR performed according to EAC protocol (Gabert et al, 2003) and to the standards of the Italian National Network Labnet. Criteria for TKI discontinuation was sustained DMR (MR4 or better) for at least 2 years. After TKI withdrawal, RQ-PCR for BCR-ABL was performed every month during the first year and every 2 months thereafter. TKI treatment was reintroduced if DMR loss occurred.TFR was assessed using the Kaplan-Meier method; potential prognostic factors were considered for multivariable analyses at a level less than .20. RESULTS Between October 2010 and January 2019, 68 patients discontinued TKIs, 18 of them after less than 5 years of treatment because of pregnancy desire (3), intolerance (6), patient's desire/non compliance (5), enrollment in study protocols (4). At discontinuation median age was 63 years (30-85), median time from TKI start 85 months (30-190), median duration of sustained DMR 48 months (24-153). Sokal distribution was 48%, 31% and 18% for low, intermediate and high risk respectively (2 patient was not evaluable). E14a2 transcript type was present in 52 pts and e13a2 in 16 pts. Thirty-eight patients stopped imatinib, 25 nilotinib (19 in 1st line, 6 in 2nd line), 5 dasatinib. Before imatinib 15 patients received r-IFNα, for a median time of 60 months (3-256). Median follow up after TKI stop was 39 months (5-105, >24 in 61, <12 in only 2 patients). Twenty-eight (41%) patients lost DMR. Median time off-therapy for these patients was 3 months (1-19), only 2 lost DMR after 6 months (at +16 and +19 months). One patient aged 87 years has not yet resumed therapy but remains in stable MR3 at 34 months after TKI discontinuation. Therapy was restarted in 27 patients (1 in MR1, 11 in MR2, 15 in MR3), 24 achieved a second DMR after a median interval of 2 months (1-18); 3/27 patients are in M3 after 2, 22 and 26 months. Neither cytogenetic relapses, nor progressions were documented. One patient died in DMR for pancreatic cancer. Univariate analysis showed no difference in relapse risk according to age, gender, type of TKI (imatinib vs 2nd generation TKIs), and Sokal score, while the e14a2 vs e13a2 transcript type (p = 0.011), duration of TKI therapy > 60 months (p = 0.025) and previous r-IFNα therapy (p=0.021) were significantly linked to better outcome after TKI discontinuation; sDMR > 72 months is very close to be a significant variable (p=0.055). At multivariate analysis only the type of BCR-ABL transcript (p=0.027) and previous r-IFNα ( p=0.016) remained independent significant prognostic factors -figure A and figure B-. CONCLUSION e14a2 transcript type was confirmed as a robust favorable prognostic factor for TFR maintenance. In our experience, 2GTKIs didn't impact favorably TFR duration after TKIs discontinuation, conversely r-IFNα treatment before TKI improved the probability of maintaining DMR after TKI withdrawal, particularly in e13a2 patients. In fact r-IFNα before imatinib reversed the negative prognostic impact on TFR maintenance of the e13a2 transcript type. Disclosures D'Adda: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Rossi:Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Daiichi-Sankyo: Consultancy.

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