In total, 279 patients with hairy-cell leukemia (HCL) were analyzed, with a median follow-up of 10 years. Data were collected up to June 2018. We analyzed responses to treatment, relapses, survival, ...and the occurrence of second malignancies during follow-up. The median age was 59 years. In total, 208 patients (75%) were treated with purine analogs (PNAs), either cladribine (159) or pentosatin (49), as the first-line therapy. After a median follow-up of 127 months, the median overall survival was 27 years, and the median relapse-free survival (RFS) was 11 years. The cumulative 10-year relapse incidence was 39%. In patients receiving second-line therapy, the median RFS was 7 years. For the second-line therapy, using the same or another PNA was equivalent. We identified 68 second malignancies in 59 patients: 49 solid cancers and 19 hematological malignancies. The 10-year cumulative incidences of cancers, solid tumors, and hematological malignancies were 15%, 11%, and 5.0%, respectively, and the standardized incidence ratios were 2.22, 1.81, and 6.67, respectively. In multivariate analysis, PNA was not a risk factor for second malignancies. HCL patients have a good long-term prognosis. PNAs are the first-line treatment. HCL patients require long-term follow-up because of their relatively increased risk of second malignancies.
We conducted an observational study (FIRE) to understand the effectiveness and safety outcomes of ibrutinib in patients with chronic lymphocytic leukemia (CLL) in France, after a maximum follow-up of ...five years. Patients were included according to the French marketing authorization in 2016 (i.e. patients with relapsed or refractory CLL or to previously untreated CLL patients with deletion 17p and/or tumor protein p53 mutations unsuitable for chemoimmunotherapy) and could have initiated ibrutinib more than 30 days prior their enrolment in the study (i.e. retrospective patients) or between 30 days before and 14 days after their enrolment (i.e. prospective patients). The results showed that in the effectiveness population (N = 388), the median progression-free survival (PFS) was 53.1 (95% CI: 44.5-60.5) months for retrospective patients and 52.9 (95% CI: 40.3-60.6) months for prospective patients and no difference was shown between the PFS of patients who had at least one dose reduction versus the PFS of patients without dose reduction (p = 0.7971 for retrospective and p = 0.3163 for prospective patients). For both retrospective and prospective patients, the median overall survival was not reached. The most frequent treatment-emergent adverse event of interest was infections (57.6% retrospective; 71.4% prospective). A total of 14.6% of the retrospective patients and 22.4% of the prospective patients had an adverse event leading to death. Our findings on effectiveness were consistent with other studies and the fact that patients with dose reductions had similar PFS than patients without dose reduction is reassuring. No additional safety concerns than those already mentioned in previous studies could be noticed.Trial registration ClinicalTrials.gov, NCT03425591. Registered 1 February 2018 - Retrospectively registered.
Introduction: Hairy-cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder with a favorable outcome thanks to treatment with purine analogues (PNA) like cladribine and pentostatin. ...Here, we updated the French national retrospective cohort of HCL after 10 years of follow-up, in order to evaluate the risk of second cancers in these patients.
Methods: Data were collected up to June 2018 through a questionnaire sent to the members of the Société Française d'Hématologie, and centralized in the cohort database. We described the second malignancies observed during the follow-up, distinguishing second ‘solid’ cancers from second hematological malignancies. Then, using a Fine and Gray model, we performed a multivariate analysis in order to identify second cancer risk factors. Finally, to evaluate the excess of cancers in our cohort in comparison with the French general population, we calculated the standardized incidence ratio (SIR).
Results: 279 patients (pts) from 19 centers were included in our retrospective cohort. The median age was 59 years old (range 29-88). 21% had an infectious disease at diagnosis, 23% had a familial history of cancer and 11% a personal history of cancer before HCL diagnosis. The median number of lines of treatments was 1 (0-7). PNA (cladribine or pentostatin) were the first therapeutic choice in frontline (75% of pts) and at relapse (69%). With a median follow-up of 127 months (2-413), the median overall survival for the overall study population was 328 months (95% CI 299-357) and the median relapse-free survival (RFS) was 136 months (95% CI 109-163). Pts treated with cladribine or pentostatin in first line had a statistically significant better RFS than pts treated with ‘other’ treatments (log rank test, p < 0.001). The 10-year cumulative incidence of relapse was 39% (95% CI 33-46). Pts who received treatments other than PNA in first line had a higher risk of relapse (Gray's test, p < 0.001). For pts receiving PNA in first and second lines, there was no difference in outcomes between those who switched PNA and those who did not. In this cohort, we observed 68 second malignancies during the follow-up: 49 solid cancers (most prevalent: prostate and non-melanoma skin cancers) and 19 hematological malignancies (most prevalent: monoclonal gammopathy of undetermined significance (MGUS) and myelodysplastic syndromes (MDS)). The median onset of second cancer, second solid cancer and second hematological malignancy from HCL diagnosis was 81 months, 99 months and 78 months, respectively. The median age at diagnosis of cancer, solid cancer and hematological malignancy was 70, 69 and 77 years old, respectively. Considering death as a competing risk, the 10-year cumulative incidence of cancer, solid cancer and hematological malignancy was 15% (95% CI 11-19), 11% (95% CI 7.2-15), and 5.0% (95% CI 2.8-8.2), respectively. In multivariate analyses, IFN treatment was associated with a decreased risk for all cancers (Fine and Gray regression model, subdistribution Hazard Ratio (sdHR) 0.53 (95% CI 0.29-0.97); p = 0.038), a familial history of cancer was a risk factor for solid cancers (sdHR 2.12 (95% CI 1.15-3.91); p = 0.017), a personal history of cancer was a risk factor for hematological malignancies (sdHR 3.47 (95% CI 1.14-10.55); p = 0.028). Even after excluding non-melanoma skin cancers and MGUS, there was an excess of cancers (SIR = 2.22), solid cancers (SIR = 1.81) and hematological malignancies (SIR = 6.67).
Conclusions: In this updated real-world retrospective cohort with a long follow-up and most pts treated with PNA, we highlighted the importance and the excess of second cancers in HCL patients, in particular hematological malignancies.
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Paillassa:Janssen: Other: Bibliography board with young hematologists. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Hermine:AB Science: Membership on an entity's Board of Directors or advisory committees. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau. Troussard:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Research Support; Sysmex: Other: Research Support.
Background: Azacitidine (AZA) is the first line for myelodysplastic syndromes (MDS) and acute myeloid leukemia with less than 30% of blasts (Fenaux et al., Lancet Oncology 2009). This is also the ...treatment of AML with more than 30% of blasts uneligible for intensive chemotherapy (Dombret et al., Blood 2015). Expected response rate is around 50-60%. 50% and more than 80% of AZA responses were observed after 3 cycles and 6 cycles, respectively. Therefore, the FDA/EMEA approved schedule is 75mg/m²/day subcutaneously for seven days every 28 days for at least 6 cycles to evaluate the efficiency of the drug. Unfortunately, a proportion of patients can not achieved 3 or 6 cycles and is not evaluated. The aim of this study was to define prognostic factors predicting unachievement of 3 AZA cycles.
Methods: We analyzed retrospectively MDS and AML patients treated by AZA in 5 centers. All patients receiving at least one cycle were included. Patients were treated with conventional regimen (75mg/m²/day subcutaneously for seven days every 28 days). Responses were scored according to IWG 2006 criteria for MDS and Cheson et al. (JCO 2003) for AML. Non continuous variables were compared used khi square test. Mann Whithney test was used for continuous variables.
Results: The study population included 290 patients: F/M: 159/131; median age 71 years (range 27-94). Diagnosis at AZA onset was MDS in 208 patients (RAEB-1 = 22, RAEB-2=95, RAEB-t=87) and AML with more than 30% of blasts in 55 patients. In MDS/RAEB-t, cytogenetic according to IPSS was good in 100, intermediate in 35, poor in 56 and unknown in 17 patients; and cytogenetic according to IPSS-R was very good in 1, good in 103, intermediate in 38, poor in 18 and very poor in 28 patients. IPSS was low in 5, intermediate 1 in 32, intermediate 2 in 69 and high in 101. IPSS-R was very low in 1, low in 12, intermediate in 46, high in 86 and very high in 60 patients. Median number of cycles was 6 (range 1-69) in MDS/RAEB-t and 5 (range 1-34) in AML. Overall response rate was 42% and 44%; and median overall survival (OS) was 13.4 months (range 10.7-16.0) and 7.8 months (range 2.7-12.8) in MDS/RAEB-t and AML, respectively.
In MDS/RAEB-t and AML, we did not observe a significant difference for age, sex, WHO classification, neutrophil count, platelet count, blast count. In MDS/RAEB-t only, we did not observe a significant difference for IPSS cytogenetic, IPSS-R cytogenetic, IPSS scoring and IPSS-R scoring between patients receiving less and more than 3 AZA cycles. Nevertheless, only hemoglobin (hb) level inferior to 9g/dl is significantly associated to unachievement of 3 AZA cycles. 61% versus 24% of patients did not achieve 3 AZA cycles if hb is inferior or superior to 9g/dl respectively (p=0.001). In AML, we also did not observe a significant difference for age, sex, WHO classification, neutrophil count, platelet count, blast count between patients receiving less and more than 3 AZA cycles. 50% vs 28% of patients did not achieve 3 AZA cycles if hb is inferior or superior to 9g/dl respectively (p=0.08). As expected, median OS was significantly lower in patients with less than 3 AZA cycles in MDS/RAEB-t patients (1.7 vs 13.4 months, p<0.0001) and in AML (3.8 vs 17.6 months, p<0.0001).
Conclusion: We identified hb level less than 9g/dl as a prognostic factor of unachievement of 3 AZA cycles in MDS/RAEB-t and AML. Like in AML with hyperleukocytosis, we could discuss to treat preferentially these patients with intensive chemotherapy instead of AZA in first line. Interestingly, IPSS and IPSS-R did not predict unachievement of 3 AZA cycles and were not good tools to predict short outcome.
No relevant conflicts of interest to declare.
Management of Acute Myeloid Leukemia (AML) in the elderly is particularly difficult as life expectancy is highly variable and the benefit-risk ratio of treatment depends on comorbidities and ...age-related pharmacological specificities.
Objective:
To define the prognostic factors for overall survival (OS) and complete remission (CR) and establish a feasible and efficient new prognostic scoring system to assist clinicians in an age-adapted treatment strategy.
Methods:
From January 2000 to December 2014, 163 patients (pts) presenting an AML in a French regional cancer center in Nice were retrospectively analyzed. According to functional status, patients were treated with induction chemotherapy, azacitidine or palliative care. Complete remission rate (CR) and early-death rate were calculated. Six-month, 1-year and 2-year overall survival (OS) were analyzed with the Kaplan-Meier method and log-rank test. Univariate and multivariate logistic regression analyses were done and a p-value <0.1 and 0.05, respectively, were considered statistically significant.
Population:
From January 2000 to December 2014, 163 pts ³ 65 years were included; median age was 73.3 years (65-94.6), with 94 men (57.7%). PS was 0, 1, 2, 3 or 4 for 33 pts (20.3%), 77 pts (47.2%), 22 pts (13.5%), 20 pts (12.3%) and 6 pts (3.7%), respectively. Modified Charlson Score (calculated without considering age and leukemia criteria) was 0-1 and ³2 for 83 pts (50.9%) and 77 pts (47.2%), respectively. Secondary AML represented 44.2% of this elderly population. Induction chemotherapy was either full-dose cytarabin-daunorubicin 3+7, or cytarabin-idarubicin or cytarabin-clofarabine. Palliative care consisted of hydroxyurea and etoposid chemotherapy and best supportive care. Then, 112 pts (68.7%), 21 pts (12.9%) and 30 pts (18.4%) were treated with induction chemotherapy, azacitidine and palliative care, respectively. Among the 112 pts (68.7%) induced, 56 pts (35.9%) reached CR, 42 pts (25.8%) with a first induction and 14 pts (10.1%) with salvage chemotherapy. Otherwise, 39 pts (23.9%) ended up relapsing. Taking into account the entire treatment, 42 pts (25.8%) received azacitidine.
Results:
The 6-month, 1-year and 2-year OS for the entire cohort of 163 patients were 64.3%, 46.7% and 24.4%, respectively. Administration of induction chemotherapy was significantly predictive of CR (50% vs 2.0%, p<0.001) and almost predictive of 2-year OS (29% vs 12.5%, p=0.07). With or without induction chemotherapy, early-death rate (<8 weeks) was 12.5% and 37.3%, respectively. Thus, induction remained the best treatment for physically-fit elderly patients. Using azacitidine at any time of the treatment was a predictive factor of longer survival (1-year OS: 67.8% vs 36.9%, p=0.004). Otherwise, no impact was found on 2-year OS (25.6% vs 25.9%, NS). We tried to define a prognostic score to select elderly patients likely to benefit from induction chemotherapy. In univariate analysis, the significant prognostic factors of OS in the elderly population treated with induction chemotherapy was: age³ 75, unfavorable karyotype, creatinine clearance using the MDRD equation< 60ml/min/1.73m2, Modified Charlson Score ³2 and PS³2. In a multivariate analysis, only Charlson score and PS remained significant in terms of OS. Patients with Charlson Score ²1 and PS ²1 (0 unfavorable factor, n=60) or Charlson Score ³2 or PS ³2 (1 unfavorable factor, n=69) were considered to be at low risk (fit) for induction chemotherapy whereas patients with Charlson Score ³2 and PS³2 (2 unfavorable factors, 29 pts) were considered to be at high risk (frail). In the entire cohort (n=158 pts, data missing for 5 pts), Fit patients and Frail patients had an early-death rate of 10.8% vs 30.8% (p=0.048), a CR rate of 40.3% vs 3.8% (p<0.001), six-month OS 69.7% vs 39%, 1-year OS 53.7% vs 0% and 2-year OS 28.8% vs 0% (p<0.001), respectively. No survivors were observed in the frail group after one year of follow-up. Sub-group analysis found the same results for patients initially treated with induction chemotherapy or palliative treatment.
Conclusion:
We present a prognostic model composed of two easy-to-operate parameters that stratify patients into Fit or Frail groups. Patients with a Modified Charlson Score ³2 and a PS ³2 did not benefit from induction chemotherapy and had a high risk of death. In such cases, treatment should be azacitidine or palliative treatment. External validation is needed.
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Nicolini:Novartis: Honoraria, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting or Advisory Role, Speakers Bureau; ARIAD: Honoraria, Research Funding, Speakers Bureau; BMS: Other: Travel/Accommodations/Expenses; Novartis: Other: Travel, Accommodations, Expenses.
Autologous stem cell transplant (ASCT) after high-dose chemotherapy (HDT) increases overall survival when used in relapsed non-Hodgkin lymphoma (NHL) in patients under 65 years old. Limited ...experience is available for older patients. We present a retrospective analysis of 73 consecutive patients aged over 65 years treated for aggressive or relapsed lymphoma by HDT with carmustine, etoposide, cytarabine and melphalan (BEAM) at full dosage followed by ASCT. Patient data were obtained from medical charts from two institutions. Median age was 67 years (65-74). Significant comorbidities were present in 24.7% of patients. The median number of days for grade 4 neutropenia was 9 (5-18). The early treatment-related mortality rate (< 100 days) was 2.7%. The estimated 2-year progression-free survival and overall survival rates were 67.2% and 78.5%, respectively. In conclusion, the full-dose HDT-ASCT regimen is feasible, safe and efficient in selected patients over 65 years old.
Abstract 2813
Myelodysplastic syndroms (MDS) are an heterogenous diseases. In order to define prognosis of differents subgroups, several scoring are elaborated. The most used was IPSS score including ...pourcentage of blasts, number of cytopenia and cytogenetics. Recently, IPSS was revised. IPSS-R includes new cytogenetics subgroups, anemia, thrombocytopenia, neutropenia and pourcentage of blasts. These score were defined in untreated MDS and Acute Myeloid Leukemia (AML) with less 30% of blasts patients. IPSS-R score was evaluated in MDS untreated population included AML with 20–29% of blasts. Only 16% of patients were higher-risk IPSS MDS in this study (Greenberg et al., Blood 2012). Azacitidine (AZA) prolongs survival when used as first line treatment of higher-risk MDS and AML with 20–29% bone marrow (BM) blasts (Fenaux et al., Lancet Oncology 2009). The aim of this study is to evaluate efficacy of AZA in higher IPSS-R MDS and AML with 20–99% BM blasts.
We analyzed retrospectively MDS and AML patients treated by AZA in 6 centers. Patients having received ≥ 1 cycle of AZA and who had BM evaluation after ≥ 4 cycles, or who died or progressed before completion of 4 cycles were considered évaluable (the last 2 groups were considered as treatment failures). Responses were scored according to IWG 2006 criteria for MDS and to Cheson et al. (JCO 2003) for AML.
The study population included 149 patients: F/M: 65/84; median age 70 (range 35–88). Median number of cycle of AZA treatment was 6 (range 1–42). Diagnosis at AZA was (RAEB-1 n=1, RAEB-2 n=69, AML n=79). Median overall survival (OS) was 11 months. For MDS population excluding AML with 20–29% of blasts, IPSS score was intermediate-1 in 16 patients, intermediate-2 in 29 patients and high in 25 patients. In using IPSS-R score, we observed IPSS-R good in 2 patients, IPSS-R intermediate in 20 patients, IPSS-R poor in 29 patients and IPSS-R very poor in 19 patients. If we applied IPSS-R score in WHO-AML population, we observed IPSS-R intermediate in 11 patients, IPSS-R poor in 39 patients and IPSS-R very poor in 29 patients. In all cohort population, we observed a significant difference in median OS between « intermediate + poor » group versus very poor group (12 months vs 9 months respectively, p=0.01). In MDS sub group analysis excluding AML with 20–30% of blasts, we observed no significant difference in median OS between these 2 groups (13 months vs 9 mois respectively, p=0.39). Nevertheless, we still observed a significant difference in median OS between these 2 groups in AML population (12 months vs 6 months respectively, p=0.02).
Our results suggest that AZA cancels prognostic impact of IPSS-R score in MDS patients treated by AZA. IPSS-R score could be applied in AML population and keep his prognostic impact in AML patients treated by AZA. IPSS-R score should be evaluated in larger cohort of MDS and AML patients treated by AZA in order to confirm these results.
No relevant conflicts of interest to declare.
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