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.

Herpesviridae in critically ill hematology patients: HHV-6 is associated with worse clinical outcome.

PURPOSE: Although viral infections are frequent among patients with hematological malignancies (HM), data about herpesviridae in critically ill hematology patients are scarce. We aimed at determining the impact of herpesviridae reactivation/infection in this population. MATERIAL AND METHODS: We performed a single center retrospective study including all consecutive adult hematology patients admitted to our comprehensive cancer center ICU on a 6-year period. Clinical characteristics, microbiological findings, especially virus detection and outcome were recorded. RESULTS: Among the 364 included patients, HHV-6 was the predominant retrieved herpesviridae (66 patients, 17.9%), followed by HSV1/2 (41 patients, 11.3%), CMV (38 patients, 10.4%), EBV (24 patients, 6.6%) and VZV (3 patients). By multivariable analysis, HHV-6 reactivation was independently associated with hospital mortality (OR, 2.35; 95% CI, 1.03-5.34; P = 0.042), whereas antiviral prophylaxis during ICU stay had a protective effect (OR, 0.41; 95% CI, 0.18-0.95; P = 0.037). HHV-6 pneumonitis was independently associated with 1-year mortality (OR, 6.87; 95% CI, 1.09-43.3; P = 0.04). CONCLUSIONS: Among critically ill hematology patients, HHV-6 reactivation and pneumonitis are independent risk factors for hospital and 1-year mortality, respectively. Impact of prevention and treatment using agents active against HHV-6 should be assessed to define a consensual diagnostic and therapeutic strategy.

Saprochaete clavata Outbreak Infecting Cancer Center through Dishwasher.

Saprochaete clavata is a pathogenic yeast responsible for rare outbreaks involving immunocompromised patients, especially those with hematologic malignancies. During February 2016-December 2017, we diagnosed S. clavata infections in 9 patients (8 with fungemia), including 3 within 1 month, at a cancer center in Marseille, France. The patients (median age 58 years), 4 of 9 of whom had acute myeloid leukemia, were hospitalized in 3 different wards. Ten environmental samples, including from 2 dishwashers and 4 pitchers, grew S. clavata, but no contaminated food was discovered. The outbreak ended after contaminated utensils and appliances were discarded. Whole-genome sequencing analysis demonstrated that all clinical and environmental isolates belonged to the same phylogenetic clade, which was unrelated to clades from previous S. clavata outbreaks in France. We identified a dishwasher with a deficient heating system as the vector of contamination.

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.

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.

HLA-Matched Sibling versus Unrelated versus Haploidentical Related Donor Allogeneic Hematopoietic Stem Cell Transplantation for Patients Aged Over 60 Years with Acute Myeloid Leukemia: A Single-Center Donor Comparison.

Haploidentical related donor (HRD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) was developed as a valid option for the treatment of acute myeloid leukemia (AML) in the absence of a matched donor. However, many investigators are reluctant to consider the use of this alternative in elderly patients, anticipating high morbidity. Here, we report a single-center comparison of HRD versus matched sibling donor (MSD) and unrelated donor (UD) allo-HSCT for patients with AML aged ≥60 years. Ninety-four patients (MSD: n = 31; UD: n = 30; HRD: n = 33) were analyzed. The median age was 65 (range, 60 to 73) years. We observed a higher cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) after UD allo-HSCT (MSD versus UD versus HRD: 3% versus 33% versus 6%, respectively; P = .006). Two-year cumulative incidence of moderate or severe chronic GVHD was 17%, 27%, and 16% in the MSD, UD, and HRD groups, respectively (P = .487). No difference was observed in the 2-year cumulative incidence of relapse or nonrelapse mortality (NRM) (relapse: MSD versus UD versus HRD: 32% versus 25% versus 25%, respectively; P = .411; NRM: MSD versus UD versus HRD: 19% versus 27% versus 24%, respectively; P = .709). At 2 years, progression-free survival, overall survival, and GVHD- and relapse-free survival were 48%, 50%, and 39%, respectively, in the MSD group; 48%, 51%, and 23%, respectively, in the UD group; and 50%, 52%, and 32%, respectively, in the HRD group, without statistically significant differences between the groups. We conclude that HRD allo-HSCT is highly feasible and no less efficient than MSD or UD allo-HSCT in patients with AML aged ≥60 years. Thus, the absence of a HLA-identical donor should not limit the consideration of allo-HSCT for the treatment of AML.

Impact of gene mutations on treatment response and prognosis of acute myeloid leukemia secondary to myeloproliferative neoplasms.

Acute myeloid leukemias secondary (sAML) to myeloproliferative neoplasms (MPN) have variable clinical courses and outcomes, but remain almost always fatal. Large cohorts of sAML to MPN are difficult to obtain and there is very little scientific literature or prospective trials for determining robust prognostic markers and efficient treatments. We analyzed event-free survival (EFS) and overall survival (OS) of 73 patients with MPN who progressed to sAML, based on their epidemiological characteristics, the preexisting MPN, the different treatments received, the different prognostic groups and the responses achieved according to the ELN, and their mutational status determined by next-generation DNA sequencing (NGS). For 24 patients, we were able to do a comparative NGS analysis at both MPN and sAML phase. After acute transformation EFS and OS were respectively of 2.9 months (range: 0-48.1) and 4.7 months (range: 0.1-58.8). No difference in EFS or OS regarding the previous MPN, the ELN2017 prognostic classification, the first-line therapy or the response was found. After univariate analysis, three genes, TP53, SRSF2 and TET2, impacted pejoratively sAML prognosis at sAML time. In multivariate analysis, TP53 (P = .0001), TET2 (P = .011) and SRSF2 (P = .018) remained independent prognostic factors. Time to sAML transformation was shorter in SRSF2-mutated patients (51.2 months, range: 14.7-98) than in SRSF2-unmutated patients (133.8 months, range: 12.6-411.2) (P < .001). Conventional clinical factors (age, karyotype, ELN2017 prognostic classification, treatments received, treatments response, Allo-SCT…) failed to predict the patients' outcome. Only the mutational status appeared relevant to predict patients' prognosis at sAML phase.

Kinetics of Cytotoxic Lymphocytes Reconstitution after Induction Chemotherapy in Elderly AML Patients Reveals Progressive Recovery of Normal Phenotypic and Functional Features in NK Cells.

NK cells are defective in acute myeloid leukemia (AML) at diagnosis. Here, we studied the kinetic of expression of the major activating and inhibitory receptors of NK, CD8 T, and γδ T cells in patients undergoing chemotherapy (CT) for the treatment of AML (n = 29). We showed that NK cells are the main affected population at diagnosis and that expression of activating receptors is partially restored within a few weeks after CT. CD8 T cells and γδ T cells are only weakly affected at diagnosis. Killer cell immunoglobulin-like receptor expression by NK cells, but not NKG2A and CD85j, was downregulated. Interestingly, the development of NK cells appeared altered as the most immature CD56bright NK cells were seriously underrepresented. Finally, we showed that NK cell functions were only partially restored 6 weeks after CT as degranulation capabilities of NK cells recovered, whereas cytokine production remained low. Our data point out NK cells as antitumor effectors peculiarly hampered by leukemic cells. This study may indicate a timeline when NK-mediated therapies or other immunotherapies could be performed, particularly for patients excluded of hematopoietic stem cell transplantation.

A conditioning platform based on fludarabine, busulfan, and 2 days of rabbit antithymocyte globulin results in promising results in patients undergoing allogeneic transplantation from both matched and mismatched unrelated donor.

Conditioning regimen including fludarabine, intravenous busulfan (Bx), and 5 mg/kg total dose of rabbit antithymocyte globulin (r-ATG) (FBx-ATG) results in low incidence of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) from HLA-matched related or unrelated donors (MUD). However, whether this platform produces similar results in the setting of one mismatch unrelated donor (MMUD) Allo-HSCT is not known. We retrospectively analyzed patients aged less than 65 years who were diagnosed with hematological malignancies and received FBx-ATG regimen prior to Allo-HSCT from MUD (N = 74) or MMUD (N = 40). We compared outcome of MUD versus MMUD patients. There was no difference in the cumulative incidence of grades II-IV acute GVHD (MUD: 34% vs. MMUD: 35%, P = 0.918), but MMUD patients developed more grade III-IV acute GVHD (MUD: 5% vs. MMUD: 15%, P = 0.016). The cumulative incidences of overall chronic GVHD (MUD: 33% vs. MMUD: 22%, P = 0.088) and extensive chronic GVHD (MUD: 20% vs. MMUD: 19%, P = 0.594) were comparable. One-year NRM was similar in both groups (MUD: 16% vs. MMUD: 14%, P = 0.292); similarly, progression-free survival (MUD: 59% vs. MMUD: 55%, P = 0.476) and overall survival (MUD: 63% vs. MMUD: 61%, P = 0.762) were not different between both groups. With a median follow up of 24 months, 35 of 74 MUD patients (47%) and 19 of 40 MMUD patients (48%) were free of both disease progression and immunosuppressive treatment. We conclude that the FBx-ATG regimen results in low incidences of NRM and GVHD in both MUD and the MMUD recipients.

Outcome of relapse after allogeneic stem cell transplant in patients with acute myeloid leukemia.

Although allogeneic stem cell transplant (Allo-SCT) is an effective treatment for high-risk acute myeloid leukemia (AML), relapses remain a major cause of treatment failure. There is currently no standard of care for post-transplant relapse of AML, but the increasing numbers of investigational agents in this setting require a better knowledge of their outcome. We retrospectively evaluated the efficacy of salvage therapies in 54 patients with AML relapsing after Allo-SCT. Twenty-four patients received intensive salvage treatment (17 non-intensive chemotherapy, 13 supportive care). Complete remissions (CRs) were seen only in the group who received intensive salvage (CR rate: 17/24 [71%]). One-year overall survival was 19% (median: 3.4 months) in the whole study group and 33% in the intensive savage group (vs. 7% for patients without intensive salvage, p = 0.004). Factors influencing overall survival (OS) were: time to relapse after Allo-SCT (hazard ratio [HR]: 3.7 [1.6-8.8]) and performance status (PS) at relapse (HR: 2.2 [1.1-4.4]) by multivariate analysis. Our results confirm the poor prognosis of AML relapse after Allo-SCT. In selected patients salvage chemotherapy produces CRs, but these are short lived. Other strategies aiming at modulating immune antileukemic activity have to be developed.

Combination of cytarabine and topotecan in patients treated for acute myeloid leukemia with persistent disease after frontline induction.

After a first course of induction chemotherapy, 30-40% of patients with acute myeloid leukemia (AML) do not achieve a complete response (CR). A second course of an anthracycline and intermediate-dose cytarabine (IDAC) allows a significant number of patients with persistent AML at day 14 to finally achieve a CR. We hypothesized that use of a topotecan and cytarabine combination in this setting might improve tolerance and efficacy. Cytarabine (1000 mg/m(2)/12 h days 1-4) was combined with topotecan (TA, 1.25 mg/m(2)/day by continuous intravenous infusion [CIV] days 1-4) in 31 consecutive patients with ≥ 5% marrow blasts by day 14 of induction. The median follow-up was 36 months. The CR rate was 81%, and the 2-year probability of overall survival and cumulative incidence of relapse were 66% and 38%, respectively. No unexpected toxicity was observed. Comparison with historical controls treated with the combination of a similar schedule of cytarabine and an anthracycline showed a better CR rate (p = 0.054), overall survival (p = 0.03) and cumulative incidence of relapse (p = 0.03). These results were confirmed in a multivariate analysis model. This work shows that the substitution of an anthracycline by topotecan is feasible and associated with significant efficacy for patients with AML with persistent leukemia at day 14 after standard-dose anthracycline induction.

Improved outcome of patients with low- and intermediate-risk cytogenetics acute myeloid leukemia (AML) in first relapse with gemtuzumab and cytarabine versus cytarabine: results of a retrospective comparative study.

BACKGROUND: Acute myeloid leukemia (AML) in first relapse is associated with a poor outcome even when treated with intermediate- to high-dose cytarabine (IHDAraC). Gemtuzumab ozogamycin (GO) used as a single agent has clinical activity in relapsed and refractory AML. Various combination regimens of GO have been developed, but few data are available regarding their efficacy compared with IHDAraC-based regimens. METHODS: The authors performed a retrospective analysis of response and survival in 90 AML patients in first relapse treated with either IHDAraC (n = 56) or IHDAraC + GO (n = 34). Patient characteristics of the two groups were comparable. RESULTS: Median follow-up was 37 months. Compared with IHDAraC, IHDAraC + GO induction was associated with a better response rate (68% vs 45%, P = .04), a better overall survival (median, 35 months vs 6 months, P = .001), and a better event-free survival (24 months vs 6 months, P = .002). This effect was limited to patients with low-risk and intermediate-risk cytogenetics. In multivariate analysis, age, cytogenetic risk, first complete remission duration, and the use of IHDAraC + GO were independently associated with better results. CONCLUSIONS: This study showed that the addition of GO to IHDAraC is associated with a better efficacy for patients in first relapse of AML with low- or intermediate-risk cytogenetics. Prospective controlled studies of GO in this population are warranted. Patients with high-risk cytogenetics should be offered investigational new drugs.