Poor prognosis of SRSF2 gene mutations in patients treated with VEN-AZA for newly diagnosed acute myeloid leukemia.

Mutations in spliceosome genes (SRSF2, SF3B1, U2AF1, ZRSR2) correlate with inferior outcomes in patients treated with intensive chemotherapy for Acute Myeloid Leukemia. However, their prognostic impact in patients treated with less intensive protocols is not well known. This study aimed to evaluate the impact of Spliceosome mutations in patients treated with Venetoclax and Azacitidine for newly diagnosed AML. 117 patients treated in 3 different hospitals were included in the analysis. 34 harbored a mutation in at least one of the spliceosome genes (splice-mut cohort). K/NRAS mutations were more frequent in the splice-mut cohort (47% vs 19%, p=0.0022). Response rates did not differ between splice-mut and splice-wt cohorts. With a median follow-up of 15 months, splice mutations were associated with a lower 18-month LFS (p=0.0045). When analyzing splice mutations separately, we found SRSF2 mutations to be associated with poorer outcomes (p=0.034 and p=0.037 for OS and LFS respectively). This negative prognostic impact remained true in our multivariate analysis. We believe this finding should warrant further studies aimed at overcoming this negative impact.

Efficacy and safety of bosutinib in patients treated with prior imatinib and/or dasatinib and/or nilotinib: Subgroup analyses from the phase 4 BYOND study.

The BYOND study evaluated the efficacy and safety of bosutinib 500 mg once daily in patients with chronic myeloid leukemia (CML) resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). These post-hoc analyses assessed the efficacy and safety of bosutinib by resistance or intolerance to prior TKIs (imatinib-resistant vs dasatinib/nilotinib-resistant vs TKI-intolerant), and cross-intolerance between bosutinib and prior TKIs (imatinib, dasatinib, nilotinib), in patients with Philadelphia chromosome-positive chronic phase CML. Data are reported after ≥3 years' follow-up. Of 156 patients with Philadelphia chromosome-positive chronic phase CML, 53 were imatinib-resistant, 29 dasatinib/nilotinib-resistant, and 74 intolerant to all prior TKIs; cumulative complete cytogenetic response rates at any time were 83.7%, 61.5%, and 86.8%, and cumulative major molecular response rates at any time were 72.9%, 40.7%, and 82.4%, respectively. Of 141, 95, and 79 patients who received prior imatinib, dasatinib, and nilotinib, 64 (45.4%), 71 (74.7%), and 60 (75.9%) discontinued the respective TKI due to intolerance; of these, 2 (3.1%), 5 (7.0%), and 0 had cross-intolerance with bosutinib. The response rates observed in TKI-resistant and TKI-intolerant patients, and low cross-intolerance between bosutinib and prior TKIs, further support bosutinib use for patients with Philadelphia chromosome-positive chronic phase CML resistant/intolerant to prior TKIs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02228382.

[Optimizing the use of bosutinib in patients with chronic-phase chronic myeloid leukemia: Recommendations of a panel of experts from the Fi-LMC (French CML working group)]. / Optimisation du bosutinib dans la leucémie myéloïde chronique : recommandations du Fi-LMC (France Intergroupe des leucémies myéloïdes chroniques).

The treatment of chronic myeloid leukemia relies on orally available tyrosine kinase inhibitors targeting the BCR::ABL1 oncoprotein. Bosutinib is a second generation adenosine triphosphate-competitive inhibitor approved for use in frontline adult chronic phase-chronic myeloid leukemia and all phases-chronic myeloid leukemia in the second line setting or beyond. Its efficacy was demonstrated in several pivotal clinical trials at 400mg once daily in the first line context and at 500mg once daily beyond first line. Bosutinib-related adverse events frequently occur early after treatment initiation and include gastro-intestinal symptoms and cytolytic hepatitis. These drug-related adverse events must be properly managed in order to preserve safety, efficacy and treatment acceptability. The French chronic myeloid leukemia study group gathered a panel of experts in hematology, pharmacology and hepatology in order to elaborate practical recommendations on the management of bosutinib treatment. These recommendations aim at optimizing the short and long-term tolerance and benefit/risk balance of bosutinib, mainly focusing at gastro-intestinal and liver toxicities.

First-line second generation tyrosine kinase inhibitors in patients with newly diagnosed accelerated phase chronic myeloid leukemia.

Accelerated phase (AP) CML at onset and have poorer prognosis than CP-CML. We hypothesize that off-license use of second generation TKI (TKI2) as front-line therapy might counterbalance this poor prognosis, with limited toxicity. In "real-life" conditions, newly diagnosed patients meeting the ELN cytological criteria for AP-CML or harboring ACA and treated with first-line TKI2 were included in this retrospective multicenter observational study. We enrolled 69 patients [69.5 % male, median age 49.5 years, median follow-up 43.5 months], segregated into hematologic AP [HEM-AP (n = 32)] and cytogenetically defined AP [ACA-AP (n = 37)]. Hematologic parameters were worse in HEM-AP [spleen size (p = 0.014), PB basophils (p < .001), PB blasts (p < .001), PB blasts+promyelocytes (p < .001), low hemoglobin levels (p < .001)]. Dasatinib was initiated in 56 % patients in HEM-AP and in 27 % in ACA-AP, nilotinib in 44 % and 73 % respectively. Response and survival do not differ, regardless of the TKI2: 81 % vs 84.3 % patients achieved CHR, 88 % vs 84 % CCyR, 73 % vs 75 % MMR respectively. The estimated 5-year PFS 91.5 % (95%CI: 84.51-99.06 %) and 5-year OS 96.84 % (95%CI: 92.61-100 %). Only BM blasts (p < 0.001) and BM blasts+promyelocytes (p < 0.001) at diagnosis negatively influenced OS. TKI2 as front-line therapy in newly diagnosed AP-CML induce excellent responses and survival, and counterbalance the negative impact of advanced disease phase.

Late relapse after hematopoietic stem cell transplantation for acute leukemia: a retrospective study by SFGM-TC.

Late relapse (LR) after allogeneic hematopoietic stem cell transplantation (AHSCT) for acute leukemia is a rare event (nearly 4.5%) and raises the questions of prognosis and outcome after salvage therapy. We performed a retrospective multicentric study between January 1, 2010, and December 31, 2016, using data from the French national retrospective register ProMISe provided by the SFGM-TC (French Society for Bone Marrow Transplantation and Cellular Therapy). We included patients presenting with LR, defined as a relapse occurring at least 2 years after AHSCT. We used the Cox model to identify prognosis factors associated with LR. During the study period, a total of 7582 AHSCTs were performed in 29 centers, and 33.8% of patients relapsed. Among them, 319 (12.4%) were considered to have LR, representing an incidence of 4.2% for the entire cohort. The full dataset was available for 290 patients, including 250 (86.2%) with acute myeloid leukemia and 40 (13.8%) with acute lymphoid leukemia. The median interval from AHSCT to LR was 38.2 months (interquartile range [IQR], 29.2 to 49.7 months), and 27.2% of the patients had extramedullary involvement at LR (17.2% exclusively and 10% associated with medullary involvement). One-third of the patients had persistent full donor chimerism at LR. Median overall survival (OS) after LR was 19.9 months (IQR, 5.6 to 46.4 months). The most common salvage therapy was induction regimen (55.5%), with complete remission (CR) obtained in 50.7% of cases. Ninety-four patients (38.5%) underwent a second AHSCT, with a median OS of 20.4 months (IQR, 7.1 to 49.1 months). Nonrelapse mortality after second AHSCT was 18.2%. The Cox model identified the following factors as associated with delay of LR: disease status not in first CR at first HSCT (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.04 to 1.64; P = .02) and the use of post-transplantation cyclophosphamide (OR, 2.23; 95% CI, 1.21 to 4.14; P = .01). Chronic GVHD appeared to be a protective factor (OR, .64; 95% CI, .42 to .96; P = .04). The prognosis of LR is better than in early relapse, with a median OS after LR of 19.9 months. Salvage therapy associated with a second AHSCT improves outcome and is feasible, without creating excess toxicity.

Dasatinib plus Peg-Interferon alpha 2b combination in newly diagnosed chronic phase chronic myeloid leukaemia: Results of a multicenter phase 2 study (DASA-PegIFN study).

Superior rates of deep molecular response (DMR) have been reported with the combination of tyrosine kinase inhibitors and pegylated-interferon-alpha (Peg-IFN) in patients with newly diagnosed chronic phase-chronic myeloid leukaemia (CP-CML). In this setting, this study investigated the efficacy and safety of dasatinib combined to Peg-IFN-α2b (Dasa-PegIFN, NCT01872442). A total of 79 patients (age ≤65 years) started dasatinib; 61 were eligible for Peg-IFNα-2b add-on therapy at month 3 for a maximum 21-months duration. Dasatinib was continued thereafter. The primary endpoint was the cumulative rate of molecular response 4.5 log (MR4.5 ) by 12 months. The results are reported for the 5-year duration of the study. Grade 3 neutropenia was frequent with the combination but did not induce severe infection (one of grade 3). Other adverse events were generally low grade (4% of grade 3-4) and expected. Seventy-nine per cent and 61% of patients continued the Peg-IFN until months 12 and 24, respectively. Overall, at these time points, MR4.5 rates were 25% and 38%, respectively. Thereafter, 32% and 46% of patients achieved a sustained (≥2 years) MR4.5 or MR4 , respectively. This work established the feasibility and high rates of achievement of early and sustained DMR (a prerequisite for treatment-free-remission) with dasatinib and Peg-IFNα-2b combination as initial therapy.

Kinetics of early and late molecular recurrences after first-line imatinib cessation in chronic myeloid leukemia: updated results from the STIM2 trial.

Discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia is feasible in clinical practice based on recently published international recommendations. Nevertheless, factors predictive of molecular recurrence have not been fully elucidated and long-term follow-up of patients enrolled in clinical studies are required in order to update knowledge on discontinuation attempts particularly in terms of the safety and durability of treatment-free remission (TFR). In the current study, we updated results from the STIM2 study in the light of the consensual criterion of molecular recurrence reported in different international recommendations. Among the 199 patients included in the perprotocol study, 108 patients lost a major molecular response. With a median follow-up of 40.8 months (5.5-111 months), the probability of treatment-free remission was 43.4% [36.3-50.4] at 5 years, 40.9% [32.8-47.3] at 7 years and 34.5% [25.6- 43.3] at 9 years. Molecular recurrence occurred between 0 to 6 months, 6 to 24 months and after 24 months in 75 patients (69%), 15 patients (14%) and 18 patients (17%), respectively. Notably, the kinetics of molecular recurrence differed significantly between these three subgroups with a median time from loss of MR4 (BCR::ABL1 IS≤0.01%) to loss of major molecular response of 1, 7 and 22 months, respectively. Predictive factors of molecular recurrence differed according to the time of occurrence of the molecular recurrence. Durations of imatinib treatment and deep molecular response as well as BCR::ABL1/ABL1 levels at cessation of tyrosine kinase inhibitor treatment, as quantified by reverse transcriptase droplet digital polymerase chain reaction, are involved in molecular recurrence occurring up to 24 months but not beyond. (ClinicalTrial. gov Identifier NCT#0134373).

Azacitidine Plus Venetoclax for the Treatment of Relapsed and Newly Diagnosed Acute Myeloid Leukemia Patients.

Venetoclax (VEN) belongs the BH3-mimetic class that selectively targets BCL-2, activating apoptosis. The combination of VEN and azacitidine (AZA) has changed the paradigm of treatment of newly diagnosed (ND) acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy. There is scarce evidence for the use of VEN-AZA for relapsed or refractory (R/R) AML. We compared the outcome of 39 R/R AML and 38 ND AML patients treated between 01/20 and 12/21. The median age was 69 (22-86) and 73 (61-81) in the R/R and ND groups, respectively. Adverse cytogenetics were found in 36% of patients in the R/R group and 59% of patients in the ND group. Overall response rate was 37% in R/R AML, including 13% CR, 8% CRi, 3% PR and 13% MLFS, and 58% in the ND AML, including 32% CR, 13% CRi and 13% MLFS. Adverse cytogenetics was associated with treatment failure in the R/R group (Relative Risk = 0.13, p = 0.005). Median overall survival (OS) was 5.9 months in the R/R group and 9.4 months in the ND group. Median OS was 2.2 months in the adverse cytogenetics group versus 8.7 months in the intermediate cytogenetics group in the R/R group (p = 0.02). Median leukemia-free survival was not different between the two groups (9.4 months and 10.3 months), indicating that VEN-AZA can be an efficient salvage treatment for selected R/R AML patients. In conclusion, VEN-AZA is a promising treatment for ND AML and for selected R/R AML patients.

Paroxysmal nocturnal hemoglobinuria and vascular liver disease: Eculizumab therapy decreases mortality and thrombotic complications.

A total of 2%-10% of patients with vascular liver disease (VLD) have paroxysmal nocturnal hemoglobinuria (PNH). Eculizumab reduces complement-mediated haemolytic activity in PNH. This study was aimed at assessing the impact of eculizumab on VLD outcome. Retrospective cohort of PNH patients, in Valdig registry, who had VLD diagnosed between 1997 and 2019 is considered. Eculizumab was the exposure of interest. Studied outcomes were death, venous thrombosis, bleeding, arterial ischemic event, infection, and liver-related complications. We compared survival and new thrombotic events from PNH/VLD cohort to Envie2 non-PNH cohort. Sixty-two patients (33 women), median age 35 years (28-48) and median follow-up VLD diagnosis 4.7 years (1.2-9.5), were included. Clone size was 80% (70-90), median hemoglobin concentration was 10.0 g/dl (8-11), and lactate dehydrogenase (LDH) was 736 IU (482-1744). Forty-two patients (68%) had eculizumab; median exposure time was 40.1 [9.3-72.6] months. Mortality was significantly lower in exposed versus nonexposed period: 2.6 versus 8.7 per 100 (PY), incidence rate ratio (IRR) was 0.29, 95% CI (0.1-0.9), p = .035. Thrombosis recurrence occurred less frequently during the exposure to eculizumab: 0.5 versus 2.8 per 100 PY, IRR 0.22 (0.07-0.64). Other secondary end points (i.e., bleeding, arterial ischemic lesions, infection, and liver complications) were less common during the exposure to eculizumab, although not reaching statistical significance. Six-year thrombosis-free survival was 70%, 95% CI [0.60-0.83] for PNH cohort and 83%, 95% CI [0.70-1.00] for non-PNH Envie 2 patients, (p < .001). In conclusion, patients with PNH and VLD are at higher risk of recurrent thrombosis than non-PNH patients. Eculizumab is significantly associated with a lower mortality and less thrombotic recurrence in patients with PNH and VLD.

The Management of a Comprehensive Cancer Center during the First Six Months of the COVID-19 Pandemic in the South of France: Lessons from the Paoli-Calmettes Institute's Experience.

During the COVID-19 pandemic, it was rapidly established that cancer patients have an increased risk of developing severe forms of the 2019 coronavirus disease (COVID-19) due to a backlog of cancer diagnostics and immunosuppressive treatments. Cancer centers had to quickly adapt to continue cancer therapies despite the high infection risks and major disruptions in the French healthcare system. We described and analyzed the impact of the pandemic in our institution: management adjustments, COVID-19 infection rates in patients and staff, and impacts on clinical activities and finances during the first wave of the pandemic from March to September 2020. We also compared the results to the clinical activity data from preceding periods. A crisis unit was rapidly created that met 27 times over 66 days, generating numerous changes in hospital protocol. While our area was devastated by the pandemic, the infection rate of our staff and patients remained low (less than 1.5% of all employees). However, the lockdown period was accompanied with a reduction of most clinical activities, leading to decreases of 43%, 36%, 36%, 1%, and 10% in surgery, endoscopy, radiotherapy, and in- and out-patient chemotherapy sessions, respectively, with substantial financial loss. Our report highlights the need for the rapid creation, implementation, and adaptation of new protocols during a pandemic's evolution to prevent disease transmission. Lessons from this situation should provide motivation to better prepare for/limit the dismantling of cancer therapies that can dramatically impact patient care and have deleterious consequences on an institution's financial situation.

Dasatinib dose optimisation based on therapeutic drug monitoring reduces pleural effusion rates in chronic myeloid leukaemia patients.

Dasatinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib-associated significant adverse events (AEs) by 12 months (primary endpoint). Eligible patients started dasatinib at 100 mg per day followed by dasatinib (C)min assessment. Patients considered overdosed [(C)min ≥ 3 nmol/l) were randomised between a dose-reduction strategy (TDM arm) and standard of care (control arm). Out of 287 evaluable patients, 80 patients were randomised. The primary endpoint was not met due to early haematological AEs occurring before effective dose reduction. However, a major reduction in the cumulative incidence of PlEff was observed in the TDM arm compared to the control arm (4% vs. 15%; 11% vs. 35% and 12% vs. 39% at one, two and three years, respectively (P = 0·0094)). Molecular responses were superimposable in all arms. Dasatinib TDM during treatment initiation was feasible and resulted in a significant reduction of the incidence of PlEff in the long run, without impairing molecular responses. (NCT01916785; https://clinicaltrials.gov).

Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial.

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.

Cardiovascular Toxicity Related to Cancer Treatment: A Pragmatic Approach to the American and European Cardio-Oncology Guidelines.

The considerable progress made in the field of cancer treatment has led to a dramatic improvement in the prognosis of patients with cancer. However, toxicities resulting from these treatments represent a cost that can be harmful to short- and long-term outcomes. Adverse events affecting the cardiovascular system are one of the greatest challenges in the overall management of patients with cancer, as they can compromise the success of the optimal treatment against the tumor. Such adverse events are associated not only with older chemotherapy drugs such as anthracyclines but also with many targeted therapies and immunotherapies. Recognizing this concern, several American and European governing societies in oncology and cardiology have published guidelines on the cardiovascular monitoring of patients receiving potentially cardiotoxic cancer therapies, as well as on the management of cardiovascular toxicities. However, the low level of evidence supporting these guidelines has led to numerous discrepancies, leaving clinicians without a consensus strategy to apply. A cardio-oncology expert panel from the French Working Group of Cardio-Oncology has undertaken an ambitious effort to analyze and harmonize the most recent American and European guidelines to propose roadmaps and decision algorithms that would be easy for clinicians to use in their daily practice. In this statement, the experts addressed the cardiovascular monitoring strategies for the cancer drugs associated with the highest risk of cardiovascular toxicities, as well as the management of such toxicities.

Socioeconomic deprivation is associated with decreased survival in patients with acute myeloid leukemia.

BACKGROUND: Socioeconomic deprivation is associated with poor prognosis in patients with solid tumors. However, few studies have assessed the association between socioeconomic parameters and prognosis in Acute Myeloid Leukemia (AML), and these report conflicting results. Our monocentric study assessed the impact of socioeconomic deprivation using the validated EPICES (Evaluation of Deprivation and Inequalities in Health Examination Centers) score in a prospective cohort of intensively treated AML patients. METHODS: EPICES questionnaires were given to patients receiving intensive chemotherapy for newly diagnosed AML at the Paoli Calmettes Institute between July 2012 and December 2014. Study participants were categorized as non-deprived (score <30.17), deprived (score 30.17-48.51), or very-deprived (score ≥ 48.52). The primary endpoint was Overall Survival (OS). The independence of EPICES score effects was analyzed via Cox regression with adjustment for confounding factors. RESULTS: 209 AML patients received the questionnaire, 149 (71.3 %) patients responded. The median EPICES score was 23.6; 26.8 % and 10.1 % of patients were deprived and very deprived, respectively. OS was 23.16 months (95 %CI [17.15-33.31]). According to multivariate analysis, a very-deprived EPICES score, European Leukemia Net categories, age, smoking, and the absence of allogeneic stem cell transplantation were independent factors associated with decreased OS. CONCLUSION: Our results underscore the importance of integrating nonbiological factors in the prognostic stratification of AML patients. The very deprived population exhibited worse OS, confirming that socioeconomic parameters play a role in patient outcomes in AML. Very deprived patients with AML should receive specific attention and adapted clinical management.

Cardiac failure in patients treated with azacitidine, a pyrimidine analogue: Case reports and disproportionality analyses in Vigibase.

AIMS: Azacitidine (AZA), a pyrimidine analogue, is validated for high-risk myelodysplastic syndrome or low-blast acute myeloid leukaemia in unfit patients for more intensive treatment. This study assessed the putative link between cardiac failure (CF) and AZA exposure. METHODS: Cases of CF in patients treated with AZA were retrospectively collected and described from several centres of the Groupe Francophone des Myélodysplasies. A description analysis and a disproportionality analysis using Vigibase, the WHO Global Individual Case Safety Reports (ICSRs) database, were conducted on ICSRs by the Standardized MedDRA Queries (SMQ broad) cardiac failure and by preferred terms cardiac failure and cardiac failure acute. The reported odds ratio (ROR) and its 95% 2-sided confidence interval was computed by comparing the proportion of CF reports with the suspected drug (AZA) and the proportion of reports of the same adverse drug reaction with all other suspected drugs in the database during the same period. RESULTS: In the 4 case reports, all patients presented a cardiovascular history. In 1 patient, CF recurred after AZA re-challenge. The pharmacovigilance analysis in Vigibase retrieved 307 ICSRs of CF (SMQ) with AZA. Significant disproportionality signals associated with AZA were identified by using the SMQ cardiac failure (ROR 1.3) and the preferred terms cardiac failure (ROR 5.1) and cardiac failure acute (ROR 23.2). CONCLUSION: This study points to the potential role of AZA in the occurrence of CF. Cardiac evaluation before AZA initiation and regular monitoring of cardiac function during AZA treatment should be performed in patients with a history of cardiovascular disease.

Alternative Effective and Safe Induction Regimens for Newly Diagnosed Acute Myeloid Leukemia in Patients With Cardiac Contraindication to Anthracyclines.

INTRODUCTION: The standard first-line treatment for acute myeloid leukemia (AML) is a combination of cytarabine and anthracyclines. To date, there is no commonly agreed-on regimen for patients who are ineligible for this therapy because of cardiac comorbidities or prior exposure to anthracyclines. We compared 3 anthracycline-free regimens currently used in France. PATIENTS AND METHODS: Two patients with newly diagnosed or relapsed/refractory AML were treated intensively in 3 French centers. All patients had at least one contraindication to the receipt of anthracyclines. Three regimen types were used: fludarabine, cytarabine, and granulocyte-colony stimulating factor (FLAG); clofarabine and cytarabine (CLARA); and topotecan plus cytarabine (TA). RESULTS: Thirty patients (58%) had de novo AML. The European LeukemiaNet 2013 risk categories were favorable, intermediate, and adverse in 4 (8%), 27 (52%), and 20 (39%) patients, respectively. Twenty-four patients received TA and 28 FLAG/CLARA regimens. Fifty percent of patients had cardiac dysfunction, and 50% had prior anthracycline exposure above the maximum tolerated dose. The rate of cardiac events was similar after TA (17%) and FLAG/CLARA (25%) (P = .78). The 5-year nonrelapse mortality was 17.9% and 12.5% in the TA and FLAG/CLARA groups, respectively (P = .59). In patients with previously untreated AML, complete response occurred in 18 (72%) of 25, but median overall survival was only 9.7 months. CONCLUSION: TA, FLAG, and CLARA regimens are efficient and are associated with acceptable toxicity in AML patients ineligible for the 3 + 7 regimen as a result of cardiac comorbidities. However, long-term outcome remains disappointing, thereby highlighting the need for the development of less toxic regimens.

Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients.

PURPOSE: Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation. PATIENTS AND METHODS: We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML. RESULTS: A total of 218 patients with de novo chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1-64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in BCR-ABL1 levels defined as molecular recurrence. The molecular recurrence-free survival was 52% [95% confidence interval (CI), 45%-59%] at 6 months, and 50% (95% CI, 43%-57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of BCR-ABL1 in 175 of 218 patients at imatinib cessation. To apply positive BCR-ABL1/ABL1 ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%IS. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified predictive factors of molecular recurrence, with P = 0.0366 (HR, 0.635; 95% CI, 0.415-0.972] and P = 0.008 (HR, 0.556; 95% CI, 0.360-0.858), respectively. CONCLUSIONS: We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with de novo chronic phase CML.See related commentary by Yan et al., p. 6561.

Thiotepa, Fludarabine, and Busulfan Conditioning Regimen before T Cell-Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia: A Bicentric Experience of 100 Patients.

Haploidentical stem cell transplantation (haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) is an alternative treatment for acute myeloid leukemia (AML) patients who lack HLA-matched donors. Relapse after haplo-SCT remains a major concern, especially after nonmyeloablative conditioning regimens. Promising results were reported for TBF-based conditioning regimens (thiotepa, busulfan, and fludarabine) in patients transplanted from different categories of donors and for various disease types but not specifically in PT-Cy haplo-SCT for AML. Here we evaluate the outcome of 100 AML patients who received haplo-SCT with PT-Cy after TBF conditioning regimens (reduced-intensity conditioning, n = 77; myeloablative conditioning, n = 23) in 2 transplant programs. Cumulative incidences of grades III to IV acute and moderate or severe chronic graft-versus-host disease (GVHD) were 7% and 14%, respectively. NRM at 2 years was 28%, significantly influenced by disease status at haplo-SCT (first complete response [CR1] versus advanced AML: 16% versus 38%, P = .016) but not by conditioning intensity or age. The cumulative incidences of relapse at 2 years were 17% and 24% in CR1 and advanced AML, respectively (not significant). Progression-free survival, overall survival, and GVHD and relapse-free survival at 2 years were 67%, 71%, and 49% in CR1 patients, respectively, whereas comparative values in patients with advanced disease were 37%, 41%, and 32%. Our study suggests that TBF conditioning for PT-Cy haplo-SCT is safe and effective for AML patients in CR1. In patients with more advanced disease, the relatively low incidence of relapse seems counterbalanced by a high nonrelapse mortality, underlining the need for alternative strategies to decrease relapse risk, without increasing the intensity of conditioning regimen.

Autoimmune diseases in myelodysplastic syndrome favors patients survival: A case control study and literature review.

BACKGROUND: We conducted a monocentric retrospective study of patients with myelodysplastic syndromes (MDS) and autoimmune or inflammatory disorders (AIMs) and a literature review. We analyzed the association with subgroups of the WHO 2016 MDS classification and patient's survival in a case control study. Risk factors associated with survival were analyzed by uni- and multivariate analysis. RESULTS: From all MDS patients 11% presented with AIMs. These were heterogeneous and the most frequent where polyarthritis (25%) and autoimmune cytopenias (17%). No difference for frequency and type of AIMs was observed for the WHO 2016 MDS subgroups (p = .3). In the case control study WHO classification, karyotype abnormalities, IPSS-R and IPSS were similar in both groups. The overall survival from MDS diagnosis was better in the group with AIMs [10.3 ±â€¯0.6 (IC95% 6.2-12.9) versus 4.8 ±â€¯1.1 years (IC95% 4.2-8.7), p = .04]. The better survival was restricted to MDS with low or intermediate-1 IPSS [11.1 ±â€¯1.5 (IC95% 9.9-NR) versus 8.7 ±â€¯1.3 years (IC95% 4.8-10.3), p = .006]. The better survival was only observed when AIMs diagnosis was timely associated or appeared after MDS diagnosis (p = .04). Factors associated with a better overall survival and survival without AML were steroid dependence [respectively HR = 0.042, p = .003, (IC95% 0.005-0.33) and HR = 0.07, p = .002, (IC95% 0.013-0.39)], a diagnosis of AIMs and MDS timely associated [respectively HR = 0.05, p = .009, (IC95% 0.006-0.478) and HR = 0.1, p = .008, (IC95% 0.018-0.54)] or a diagnosis of AIMs after MDS [respectively HR = 0.024, p = .009, (IC95% 0.001-0.39) and HR = 0.04, p = .008, (IC95% 0.003-0.43)]. CONCLUSION: Autoimmune and inflammatory diseases associated to MDS are heterogeneous. AIMs diagnosed after or concomitantly to MDS seems associated with a better survival. Prospective studies are necessary to demonstrate that autoimmunity is associated to a better control of the MDS clone.