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1.
Blood ; 143(11): 983-995, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-37979133

ABSTRACT

ABSTRACT: Older patients with classical Hodgkin lymphoma (cHL) require more effective and less toxic therapies than younger patients. In this multicenter, prospective, phase 2 study, we investigated a new firstline therapy regimen comprising 6 cycles of prednisone (40 mg/m2, days 1-5), vinblastine (6 mg/m2, day 1), doxorubicin (40 mg/m2, day 1), and bendamustine (120 mg/m2, day 1) (PVAB regimen) every 21 days for patients with newly diagnosed cHL aged ≥61 years with an advanced Ann Arbor stage. A Mini Nutritional Assessment score ≥17 was the cutoff value for patients aged ≥70 years. The primary end point was the complete metabolic response (CMR) rate after 6 cycles. The median age of the 89 included patients was 68 years (range, 61-88 years), with 35 patients (39%) aged ≥70 years. Seventy-eight patients (88%) completed the 6 cycles. The toxicity rate was acceptable, with a 20% rate of related serious adverse events. CMR was achieved by 69 patients (77.5%; 95% confidence interval [CI], 67-86). After a median follow-up of 42 months, 31 patients progressed or relapsed (35%), and 24 died (27%) from HL (n = 11), toxicity during treatment (n = 4), secondary cancers (n = 6), or other causes (n = 3). The 4-year progression-free survival (PFS) and overall survival rates were 50% and 69%, respectively. Multivariate analysis showed that liver involvement (P = .001), lymphopenia (P = .001), CRP (P = .0005), and comedications (P = .003) were independently associated with PFS. The PVAB regimen yielded a high CMR rate with acceptable toxicity. Over long-term follow-up, survival end points were influenced by unrelated lymphoma events. This trial was registered at www.clinicaltrials.gov as #NCT02414568 and at EudraCT as 2014-001002-17.


Subject(s)
Hodgkin Disease , Humans , Aged , Middle Aged , Aged, 80 and over , Hodgkin Disease/pathology , Vinblastine/adverse effects , Prednisone/adverse effects , Bendamustine Hydrochloride/adverse effects , Prospective Studies , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Doxorubicin/adverse effects , Cyclophosphamide , Vincristine
2.
Br J Haematol ; 204(6): 2233-2236, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38504454

ABSTRACT

The bendamustine-rituximab (BR) schedule is an efficient first-line therapy in Waldenström macroglobulinaemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high response rate and good progression-free (PFS) and overall survival (OS). With a median follow-up of 76.1 months (95% confidence interval [CI] 69.9-80.6), 5-year outcome is still excellent at 66.63% (95% CI 56.09-79.17) for PFS and 80.01% (95% CI 70.82-90.41) for OS. The rate of secondary cancers is 17.66% (IQR 7.99-27.64) at 66 months. Relapsed patients who received ibrutinib as second-line clearly benefited from this schedule. This confirms current recommendations suggesting BR long-term efficacy as first-line option in WM.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bendamustine Hydrochloride , Rituximab , Waldenstrom Macroglobulinemia , Humans , Bendamustine Hydrochloride/administration & dosage , Bendamustine Hydrochloride/therapeutic use , Waldenstrom Macroglobulinemia/drug therapy , Waldenstrom Macroglobulinemia/mortality , Rituximab/administration & dosage , Rituximab/therapeutic use , Male , Female , Aged , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aged, 80 and over , France , Follow-Up Studies , Treatment Outcome
3.
Blood ; 140(17): 1845-1857, 2022 10 27.
Article in English | MEDLINE | ID: mdl-35917453

ABSTRACT

Treatment results for patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive chemotherapy are disappointing. This multicenter, open-label, phase 3 trial randomized (2:1) untreated adults with FLT3mut+ AML ineligible for intensive induction chemotherapy to receive gilteritinib (120 mg/d orally) and azacitidine (GIL + AZA) or azacitidine (AZA) alone. The primary end point was overall survival (OS). At the interim analysis (August 26, 2020), a total of 123 patients were randomized to treatment (GIL + AZA, n = 74; AZA, n = 49). Subsequent AML therapy, including FLT3 inhibitors, was received by 20.3% (GIL + AZA) and 44.9% (AZA) of patients. Median OS was 9.82 (GIL + AZA) and 8.87 (AZA) months (hazard ratio, 0.916; 95% CI, 0.529-1.585; P = .753). The study was closed based on the protocol-specified boundary for futility. Median event-free survival was 0.03 month in both arms. Event-free survival defined by using composite complete remission (CRc) was 4.53 months for GIL + AZA and 0.03 month for AZA (hazard ratio, 0.686; 95% CI, 0.433-1.087; P = .156). CRc rates were 58.1% (GIL + AZA) and 26.5% (AZA) (difference, 31.4%; 95% CI, 13.1-49.7; P < .001). Adverse event (AE) rates were similar for GIL + AZA (100%) and AZA (95.7%); grade ≥3 AEs were 95.9% and 89.4%, respectively. Common AEs with GIL + AZA included pyrexia (47.9%) and diarrhea (38.4%). Gilteritinib steady-state trough concentrations did not differ between GIL + AZA and gilteritinib. GIL + AZA resulted in significantly higher CRc rates, although similar OS compared with AZA. Results support the safety/tolerability and clinical activity of upfront therapy with GIL + AZA in older/unfit patients with FLT3mut+ AML. This trial was registered at www.clinicaltrials.gov as #NCT02752035.


Subject(s)
Azacitidine , Leukemia, Myeloid, Acute , Adult , Humans , Aged , Azacitidine/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/diagnosis , Pyrazines/adverse effects
4.
Am J Hematol ; 99(10): 1870-1876, 2024 Oct.
Article in English | MEDLINE | ID: mdl-38899566

ABSTRACT

Venetoclax-azacitidine is the standard of treatment for unfit acute myeloid leukemia patients. In the VIALE-A study, treatment was given until progression but there are no data on its optimal duration for responding patients who do not tolerate indefinite therapy. We retrospectively analyzed the outcome of patients who discontinued venetoclax or venetoclax-azacitidine due to poor tolerance. Sixty-two newly diagnosed (ND) AML patients and 22 patients with morphological relapse or refractory AML were included. In the ND cohort (n = 62), 28 patients stopped venetoclax and azacitidine and 34 patients continued azacitidine monotherapy. With a median follow-up of 23 months (IQR, 20-32), median overall survival and treatment-free survival were 44 (IQR, 16-NR) and 16 (IQR, 8-27) months, respectively. Patients who stopped both treatments and those who continued azacitidine monotherapy had the same outcomes. Negative minimal residual disease was associated with a 2-year treatment-free survival of 80%. In the RR cohort (n = 22), median overall survival and treatment-free survival were 19 (IQR, 17-31) and 10 (IQR, 5-NR) months, respectively. Prior number of venetoclax-azacitidine cycles and IDH mutations were associated with increased overall survival. The only factor significantly impacting treatment-free survival was the number of prior cycles. This study suggests that patients who discontinued treatment in remission have favorable outcomes supporting the rationale for prospective controlled trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Azacitidine , Bridged Bicyclo Compounds, Heterocyclic , Leukemia, Myeloid, Acute , Sulfonamides , Humans , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Azacitidine/therapeutic use , Azacitidine/administration & dosage , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Male , Female , Middle Aged , Aged , Retrospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Treatment Outcome , Adult , Mutation , Aged, 80 and over , Disease-Free Survival , Isocitrate Dehydrogenase/genetics , Withholding Treatment/statistics & numerical data
6.
Blood ; 137(25): 3495-3506, 2021 06 24.
Article in English | MEDLINE | ID: mdl-33598678

ABSTRACT

Conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL), such as cytotoxic chemotherapy and alemtuzumab, have limited efficacy and considerable toxicity. Several novel agent classes have demonstrated preclinical activity in T-PLL, including inhibitors of the JAK/STAT and T-cell receptor pathways, as well as histone deacetylase (HDAC) inhibitors. Recently, the BCL-2 inhibitor venetoclax also showed some clinical activity in T-PLL. We sought to characterize functional apoptotic dependencies in T-PLL to identify a novel combination therapy in this disease. Twenty-four samples from patients with primary T-PLL were studied by using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis (priming) and the relative dependence of a cell on different antiapoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis and predominantly depended on BCL-2 and MCL-1 proteins for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting the JAK/STAT pathway with the JAK1/2 inhibitor ruxolitinib or HDAC with belinostat both independently increased dependence on BCL-2 but not MCL-1, thereby sensitizing T-PLL cells to venetoclax. Based on these results, we treated 2 patients with refractory T-PLL with a combination of venetoclax and ruxolitinib. We observed a deep response in JAK3-mutated T-PLL and a stabilization of the nonmutated disease. Our functional, precision-medicine-based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting a clinical exploration of such combinations in T-PLL.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Leukemia, Prolymphocytic, T-Cell/drug therapy , MAP Kinase Signaling System/drug effects , Neoplasm Proteins , Aged , Aged, 80 and over , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Female , Humans , Leukemia, Prolymphocytic, T-Cell/metabolism , Leukemia, Prolymphocytic, T-Cell/pathology , Male , Middle Aged , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Nitriles/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Sulfonamides/pharmacology
7.
Blood ; 137(8): 1019-1023, 2021 02 25.
Article in English | MEDLINE | ID: mdl-33167024

ABSTRACT

Trials assessing first-line, fixed-duration approaches in chronic lymphocytic leukemia (CLL) are yielding promising activity, but few long-term data are available. We report follow-up data from a phase 2 trial (ICLL07 FILO) in previously untreated, medically fit patients (N = 135). Patients underwent obinutuzumab-ibrutinib induction for 9 months; then, following evaluation (N = 130 evaluable), those in complete remission and with bone marrow measurable residual disease (BM MRD) <0.01% (n = 10) received ibrutinib for 6 additional months; those in partial remission and/or with BM MRD ≥0.01%, the majority (n = 120), also received 4 cycles of immunochemotherapy (fludarabine/cyclophosphamide-obinutuzumab). Beyond end of treatment, responses were assessed every 3 month and peripheral blood MRD every 6 months. At median follow-up 36.7 months from treatment start, progression-free and overall survival rates (95% confidence interval) at 3 years were 95.7% (92.0% to 99.5%) and 98% (95.1% to 100%), respectively. Peripheral blood MRD <0.01% rates were 97%, 96%, 90%, 84%, and 89% at months 16, 22, 28, 34, and 40, respectively. No new treatment-related or serious adverse event occurred beyond end of treatment. Thus, in previously untreated, medically fit patients with CLL, a fixed-duration (15 months), MRD-guided approach achieved high survival rates, a persistent MRD benefit beyond the end of treatment, and low long-term toxicity. This trial was registered at www.clinicaltrials.gov as #NCT02666898.


Subject(s)
Adenine/analogs & derivatives , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Piperidines/therapeutic use , Adenine/administration & dosage , Adenine/adverse effects , Adenine/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Cyclophosphamide/therapeutic use , Follow-Up Studies , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Neoplasm, Residual/diagnosis , Neoplasm, Residual/drug therapy , Piperidines/administration & dosage , Piperidines/adverse effects , Remission Induction , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/adverse effects , Vidarabine/therapeutic use
8.
Haematologica ; 108(1): 181-195, 2023 01 01.
Article in English | MEDLINE | ID: mdl-35708139

ABSTRACT

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma most reported in Asia. We performed a comprehensive clinical, pathological and genomic study of 71 European MEITL patients (36 males, 35 females, median age 67 years). The majority presented with gastrointestinal involvement and had emergency surgery, and 40% had stage IV disease. The tumors were morphologically classified into two groups: typical (58%) and atypical (i.e., non-monomorphic or with necrosis, angiotropism or starry-sky pattern) (42%), sharing a homogeneous immunophenotypic profile (CD3+ [98%] CD4- [94%] CD5- [97%] CD7+ [97%] CD8+ [90%] CD56+ [86%] CD103+ [80%] cytotoxic marker+ [98%]) with more frequent expression of TCRgd (50%) than TCRab (32%). MYC expression (30% of cases) partly reflecting MYC gene locus alterations, correlated with non-monomorphic cytology. Almost all cases (97%) harbored deleterious mutation(s) and/or deletion of the SETD2 gene and 90% had defective H3K36 trimethylation. Other frequently mutated genes were STAT5B (57%), JAK3 (50%), TP53 (35%), JAK1 (12.5%), BCOR and ATM (11%). Both TP53 mutations and MYC expression correlated with atypical morphology. The median overall survival (OS) of 63 patients (43/63 only received chemotherapy after initial surgery) was 7.8 months. Multivariate analysis found a strong negative impact on outcome of MYC expression, TP53 mutation, STAT5B mutation and poor performance status while aberrant B-cell marker expression (20% of cases) correlated with better survival. In conclusion, MEITL is an aggressive disease with resistance to conventional therapy, predominantly characterized by driver gene alterations deregulating histone methylation and JAK/STAT signaling and encompasses genetic and morphologic variants associated with very high clinical risk.


Subject(s)
Enteropathy-Associated T-Cell Lymphoma , Male , Female , Humans , Aged , Enteropathy-Associated T-Cell Lymphoma/genetics , Enteropathy-Associated T-Cell Lymphoma/metabolism , Enteropathy-Associated T-Cell Lymphoma/pathology , Genomics , Mutation , Signal Transduction
9.
Haematologica ; 108(10): 2774-2782, 2023 10 01.
Article in English | MEDLINE | ID: mdl-37078253

ABSTRACT

Belantamab mafodotin (BM) is an anti-BCMA antibody-drug conjugate (GSK2857916) that represents an alternative option in multiple myeloma. We sought to assess the efficacy and safety of BM in a real-world setting in patients who benefited from an early access program. We conducted an observational, retrospective, multicenter study. Eligibility criteria were treatment of relapsed or refractory multiple myeloma (RRMM) in monotherapy in adult patients who have received at least three lines of therapy previously, including at least one immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, and whose disease progressed during the last treatment period. The primary endpoint of the study is to assess the overall survival (OS). Between November 2019 and December 2020, 106 patients were treated with BM; 97 were eligible for the efficacy evaluation and 104 for safety. The median age was 66 (range, 37-82) years. High-risk cytogenetics were identified in 40.9% of patients. Fifty-five (56.7%) patients were triple-class refractory and 11 (11.3%) were penta-class refractory. The median number of prior lines of treatment was five (range, 3-12). The median number of BM cycles administered was three (range, 1-22). The overall response rate at best response was 38.1% (37/97). The median OS was 9.3 months (95% confidence interval [CI]: 5.9-15.3), and median progression-free survival was 3.5 months (95% CI: 1.9-4.7). The median duration of response was 9 months (range, 4.65-10.4). Treatment was delayed for 55 (52.9%) patients including 36.5% for treatment-related toxicity. Ophthalmic adverse events, mainly grade ≤2, were the most common toxicity (48%). The occurrence of keratopathy was 37.5%. Overall, our data are concordant with the results from DREAMM-2 in terms of efficacy and safety on a non-biased population.


Subject(s)
Multiple Myeloma , Adult , Humans , Aged , Multiple Myeloma/drug therapy , Treatment Outcome , Retrospective Studies , France
10.
Br J Haematol ; 198(3): 535-544, 2022 08.
Article in English | MEDLINE | ID: mdl-35438802

ABSTRACT

In order to improve the outcome observed with azacitidine (AZA) in higher-risk Myelodysplastic syndrome (MDS), its combination with other drugs in MDS must be evaluated. So far, no combination has not been shown to be more effective than AZA alone. AZA-PLUS was a phase II trial that, in a "pick a winner" approach, randomly assigned patients with higher-risk MDS, CMML and low blast count AML to: AZA; AZA plus lenalidomide; AZA plus Valproic Acid or AZA plus Idarubicin. 322 patients were included. After six cycles, 69 (21.4%) CR + PR were observed with no benefit from any combination. Median EFS and OS were 17.2 and 19.7 months in the whole cohort, respectively, with no difference across randomised arms. Infection and rates of hospitalisation during the first six cycles were higher in the AZA-LEN And AZA-IDA arm, related to increased myelosuppression. Factors associated with better response were IPSS, favourable or intermediate karyotype, haemoglobin, lower circulating blast count, fibrinogen level and lower LDH, while poorer survival was seen in therapy-related MDS and, in the case of TP53, PTPN11 or CSF3R mutation. The combinations used did not improve the outcome obtained with AZA alone. However, our "pick a winner" randomised strategy may remain useful with potentially more active drugs to be tested in combination with AZA.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Azacitidine , Leukemia, Myeloid, Acute , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azacitidine/therapeutic use , Humans , Idarubicin/therapeutic use , Lenalidomide/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mutation , Treatment Outcome , Valproic Acid/therapeutic use
11.
Blood ; 135(24): 2137-2145, 2020 06 11.
Article in English | MEDLINE | ID: mdl-32219442

ABSTRACT

Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Cytarabine/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Sulfonamides/administration & dosage , Adult , Aged , Aged, 80 and over , Female , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Mutation , Remission Induction , Treatment Outcome
12.
Oncology ; 100(10): 519-528, 2022.
Article in English | MEDLINE | ID: mdl-35051930

ABSTRACT

INTRODUCTION: The aim of the study was to evaluate in real-life conditions the effectiveness and safety of a biosimilar of epoetin alfa (Retacrit®) in chemotherapy-induced anemia and the impact of iron supplementation. METHODS: This was a longitudinal, observational, prospective study of 12-16 weeks conducted in 195 French centers. The primary endpoint was the achievement of target Hb (with an increase of Hb ≥1 g/dL) or an increase of Hb ≥2 g/dL, in the absence of transfusion in the previous 3 weeks. RESULTS: 2,076 patients (women, 50.6%; mean age, 67.0 years) with malignant diseases (solid tumors, 79.8%; lymphomas, 12.7%; multiple myeloma, 6.6%) were analyzed. A total of 655 patients received oral iron (40.5%), intravenous iron (58.9%), or both (0.6%). At inclusion, 10.0% and 18.2% of patients without and with iron supplementation had serum ferritin <100 µg/L, respectively. Transferrin saturation (TSAT) ≤20% was more frequent in patients with supplementation (76.6%) than without supplementation (33.9%). The mean weekly doses of epoetin alfa biosimilar and planned duration of treatment were comparable regardless of iron supplementation. The primary endpoint was achieved in 70.5% and 70.2% of patients without and with iron supplementation, respectively. Three (0.1%) serious thromboembolic events related to treatment with epoetin alfa biosimilar were reported. CONCLUSION: Epoetin alfa biosimilar was effective and well tolerated for treating chemotherapy-induced anemia. Patients in subgroup with iron supplementation had lower TSAT at inclusion compared to subgroup without supplementation. Comparable mean Hb levels were achieved in both subgroups. The rate of patients with iron supplementation through the intravenous route was however insufficient.


Subject(s)
Anemia , Antineoplastic Agents , Biosimilar Pharmaceuticals , Hematinics , Neoplasms , Aged , Anemia/chemically induced , Antineoplastic Agents/adverse effects , Biosimilar Pharmaceuticals/adverse effects , Dietary Supplements , Epoetin Alfa/therapeutic use , Female , Ferritins/adverse effects , Hematinics/adverse effects , Humans , Iron , Neoplasms/drug therapy , Prospective Studies , Recombinant Proteins/adverse effects , Transferrins/therapeutic use
13.
Hematol Oncol ; 40(3): 400-408, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35385885

ABSTRACT

In symptomatic Waldenström macroglobulinemia (sWM) patients, prognosis is assessed with the international prognostic scoring system (IPSSWM). In follicular lymphoma and other B-cell and T-cell lymphomas, disease progression within 24 months (POD24) or (in patients without POD24) after 24 months has been proposed as the start date for stratifying subsequent survival. In the present report, we assessed in a large series of 472 sWM patients, the prognostic value of this new dynamic endpoint already reported in many other lymphomas subtypes. The 3 year subsequent survival for patients with POD24 was 75% and 93% for patients without POD24. In sWM patients, departure from the proportional hazards assumption complicated this analysis. In patients without POD24, the median subsequent progression-free survival time of 43 months accounted for favorable outcome, whereas survival after progression was not influenced by the time to progression. In addition, sensitivity analysis showed that the baseline IPSSWM score also influenced survival after POD24. In sWM patients, we conclude that the apparent difference in survival after POD24 or the 24 months time-point (in patients without POD24) is mainly explained by the prolonged subsequent progression free survival of latter patients. Indeed, the mortality after progression is not influenced by the time to this event.


Subject(s)
Disease Progression , Waldenstrom Macroglobulinemia , Humans , Prognosis , Progression-Free Survival , Waldenstrom Macroglobulinemia/pathology , Waldenstrom Macroglobulinemia/therapy
14.
Hematol Oncol ; 40(5): 976-986, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35789106

ABSTRACT

Most relapses of primary central nervous system lymphoma (PCNSL) occur in the brain and are associated with a poor prognosis. Isolated intraocular relapses (IIORs) are rare and poorly described. We retrospectively selected from the French Lymphome Oculo-Cérébral database PCNSL patients who initially presented with cerebral localization and who experienced IIOR during the course of the disease. Of the 1472 patients included in the database, 55 patients presented an IIOR. Their median age was 68 years, and median Karnofsky Performance Status 80. IL-10 levels in the aqueous humor and/or in the vitreous were increased in 42/46 patients. 45/55 patients received systemic chemotherapy, and 11/55 received high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) as consolidation treatment. After a median follow-up of 69 months, 42/55 patients had relapsed, including 90% of the patients who did not receive HCT-ASCT at IIOR and 40% of the patients who received HCT-ASCT at IIOR (p < 0.001). The first relapse after the initial IIOR was exclusively in the eye in 23/42 patients, and 29/42 patients had a subsequent brain relapse during the course of the disease. The median progression-free survival, brain-free survival and overall survival from IIOR were 12.2, 48.6 and 57.1 months, respectively. Isolated intraocular relapse is not exceptional in the course of PCNSL and deserves systematic ophthalmological follow-up. Its prognosis is much better than the prognosis of brain relapse, with an evolution close to that of primary vitreoretinal lymphoma. With the exception of patients who received HCT-ASCT at IIOR, almost all patients subsequently relapsed, often with other IIORs.


Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma , Retinal Neoplasms , Humans , Aged , Transplantation, Autologous , Retrospective Studies , Vitreous Body
15.
Clin Exp Rheumatol ; 40(7): 1336-1342, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35579092

ABSTRACT

OBJECTIVES: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE. METHODS: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders. RESULTS: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83). CONCLUSIONS: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.


Subject(s)
Autoimmune Diseases , Leukemia, Myelomonocytic, Chronic , Myelodysplastic Syndromes , Venous Thromboembolism , Autoimmune Diseases/complications , Autoimmune Diseases/epidemiology , Case-Control Studies , Humans , Leukemia, Myelomonocytic, Chronic/complications , Leukemia, Myelomonocytic, Chronic/epidemiology , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/epidemiology , Retrospective Studies , Venous Thromboembolism/diagnosis , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiology
16.
Dermatol Ther ; 35(8): e15620, 2022 08.
Article in English | MEDLINE | ID: mdl-35669995

ABSTRACT

Primary focal hyperhidrosis (PFH) is a frequent condition which can seriously affect the quality of life. Intradermal injections of botulinum toxin A (BTA) is a safe temporary treatment. The objective was to assess the factors associated with the efficacy of the axillary injections of abobotulinumtoxinA in PFH. Among a cohort of 236 patients followed for axillary injections of BTA between 2001 and 2020 for severe PFH, we included patients treated with 150 units per armpit of abobotulinumtoxinA with a minimum follow-up of three years. We described the characteristics of the patients and then searched for association between variables (sex, age, multifocal PFH and duration of efficacy of the first injection [<6 or ≥6 months]) and the number of injections received in three years, counted at the second injection date, by univariate and multivariate logistic regression. Ninety patients were included (62 women, median age of 29 years and 12.2% of multifocal PFH). The median duration of efficacy of the first injection was six months (interquartile range 3-9). The duration of efficacy of the first injection ≥6 months was significantly associated with less injections during the 3-year follow-up in univariate (odds ratio [OR]: -1.18 [95% confidence interval (CI): -1.80 to -0.55]; p < 0.01) and multivariate (OR: -1.16 [95% CI: -1.79 to -0.53]; p < 0.01) logistic regression. There was no significant difference with female sex, age, or multifocal PFH. A duration of efficacy of the first injection greater than six months seems to indicate a better response profile to BTA.


Subject(s)
Botulinum Toxins, Type A , Hyperhidrosis , Adult , Axilla , Botulinum Toxins, Type A/therapeutic use , Female , Humans , Hyperhidrosis/diagnosis , Hyperhidrosis/drug therapy , Injections, Intradermal , Male , Quality of Life , Retrospective Studies , Treatment Outcome
17.
Br J Haematol ; 194(2): 336-343, 2021 07.
Article in English | MEDLINE | ID: mdl-34151423

ABSTRACT

Despite a moderate prevalence in low-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), thrombocytopenia remains a risk of severe bleeding and therapeutic options are still limited. There are only a few studies with eltrombopag (ELT), a thrombopoietin receptor agonist, in those patients. In this retrospective multicentre study, ELT was used in 50 patients with MDS and 11 with CMML, with no excess of marrow blasts and platelet counts of <50 × 109 /l in a 'real-life' situation. Platelet response occurred in 47 (77%) patients. The median (range) duration of response was 8 (0-69) months. None of the eight still responders who discontinued ELT had relapsed, at a median (range) of 16 (6-23) months after ELT discontinuation. Although 36% of the patients were anti-coagulated or anti-aggregated only 10% of patients had Grade ≥3 bleeding events. Thrombotic events were observed in six (10%) patients, who all but one had a medical history of arterial or venous thrombosis. Progression to acute myeloid leukaemia occurred in four (7%) patients. In this first 'real-life' study, ELT was effective and generally well tolerated in patients with MDS/CMML without excess blasts.


Subject(s)
Benzoates/therapeutic use , Hydrazines/therapeutic use , Leukemia, Myelomonocytic, Chronic/drug therapy , Myelodysplastic Syndromes/drug therapy , Pyrazoles/therapeutic use , Receptors, Thrombopoietin/agonists , Thrombocytopenia/drug therapy , Aged , Aged, 80 and over , Blood Platelets/drug effects , Female , France/epidemiology , Humans , Leukemia, Myelomonocytic, Chronic/epidemiology , Male , Myelodysplastic Syndromes/epidemiology , Retrospective Studies , Thrombocytopenia/epidemiology
18.
Haematologica ; 106(5): 1414-1422, 2021 05 01.
Article in English | MEDLINE | ID: mdl-33626866

ABSTRACT

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with systemic inflammatory or autoimmune diseases in 10-20 % of cases. Among them, immune thrombocytopenia (ITP) has been reported but large studies assessing this association are missing. Whether such patients have a particular phenotype and require particular management is unclear. This study analyzes the clinical spectrum, outcome and therapeutic management of patients with ITP associated with MDS or CMML, in comparison (i) to patients with primary ITP without MDS/CMML and (ii) to patients with MDS/CMML without ITP. Forty-one MDS/CMML-associated ITP patients were included, with chronic ITP in 26 (63%) patients, low-risk myelodysplasia in 30 (73%) patients and CMML in 24 (59%) patients. An associated autoimmune disease was noted in 10 (24%) patients. In comparison to primary ITP patients, MDS/CMML-associated ITP patients had a higher occurrence of severe bleeding despite similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulin (IVIg) (56%). Response achievement with IVIg was more frequent in primary ITP than in MDS/CMML-associated ITP patients. Response rates to second-line therapies were not statistically different between primary ITP and MDS/CMMLassociated ITP patients. Ten percent (n=4) of patients with MDS/CMML-associated ITP had multirefractory ITP versus none in primary ITP controls. After a median follow-up of 60 months, there was no difference in overall survival between MDS/CMML-associated ITP and primary ITP patients. Leukemia-free-survival was significantly better in MDS/CMMLassociated ITP patients than in MDS/CMML without ITP MDS/CMML-associated ITP have a particular outcome with more severe bleeding and multirefractory profile than primary ITP, similar response profile to primary ITP therapy except for IVIg, and less progression toward acute myeloid leukemia than MDS/CMML without ITP.


Subject(s)
Leukemia, Myeloid, Acute , Leukemia, Myelomonocytic, Chronic , Myelodysplastic Syndromes , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Humans , Leukemia, Myelomonocytic, Chronic/complications , Leukemia, Myelomonocytic, Chronic/diagnosis , Leukemia, Myelomonocytic, Chronic/therapy , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/therapy , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Purpura, Thrombocytopenic, Idiopathic/etiology , Purpura, Thrombocytopenic, Idiopathic/therapy
19.
Ann Hematol ; 100(6): 1359-1376, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33796898

ABSTRACT

The incidence of acute myeloid leukemia increases with age, and more than half of AML patients are over 60 years old. Treating elderly AML patients presents several challenges and uncertainties, linked partly to disease characteristics and partly to the difficulty of establishing which patients could benefit from the best treatment. Although some elderly fit patients can receive intensive therapy, many of them are not treated and not enrolled in clinical trials. Yet supportive care is associated with significantly lower survival rates compared to intensive therapy or lower intensive therapy. A poorer prognosis in elderly patients is related to age, functional status, and comorbidities, combined with leukemia characteristics. Chronological age is not the best surrogate factor for selecting patients eligible for intensive chemotherapy. Scoring systems-including patient characteristics (ECOG, comorbidities) and disease characteristics (cytogenetics and molecular parameters)-designed to evaluate probabilities of response to treatment, morbidity, and survival may be used to balance the risk-benefit ratio for intensive therapy. A geriatric assessment (GA) to evaluate physical function, comorbidities, nutritional status, cognitive function, and social support could help identify the most vulnerable patients so that they can receive intensive therapy. A GA would also help take the necessary steps to improve tolerance to treatment. Evaluating markers of fitness and quality of life as part of clinical trials should be favored.


Subject(s)
Leukemia, Myeloid, Acute/epidemiology , Age Factors , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Comorbidity , Functional Status , Geriatric Assessment , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Prognosis , Quality of Life
20.
Ann Hematol ; 100(4): 987-993, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33495922

ABSTRACT

The BCL2 inhibitor venetoclax is transforming the management of patients with chronic lymphocytic leukemia (CLL), given its high efficacy in relapsed/refractory CLL as observed in both early-phase and randomized clinical trials. The present study aimed to determine whether venetoclax is effective and well tolerated in patients with CLL or Richter's syndrome (RS) in a real-world setting and to highlight factors impacting survival. Data from a venetoclax French compassionate use program were collected for 67 patients (60 with CLL and 7 with RS). Most patients presented adverse genetic features, such as TP53 disruption (74%) or complex karyotype (58%). Tumor lysis syndrome was observed in 14 (22%) patients, and 16 (24%) patients were hospitalized for grade III/IV infection. In the CLL cohort, ORR was 75 %, 1-year PFS was 61% (95% CI = 47-72%) and 1-year OS 70% (95% CI = 56-80%). No impact of TP53 disruption was noted while complex karyotype was identified as a predictor of both inferior PFS (HR = 3.46; 95% CI = 1-12; log-rank p = 0.03) and OS (HR = 3.2; 95% CI = 0.9-11.4, log-rank p = 0.047). Among the seven patients with RS, two achieved an objective response to venetoclax; however, the median OS was only 1.1 month. The well-balanced safety/efficacy profile of venetoclax is confirmed in this real-world setting. Complex karyotype should be evaluated as a predictive factor of survival for patients treated by venetoclax.


Subject(s)
Antineoplastic Agents/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Sulfonamides/therapeutic use , Abnormal Karyotype , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Compassionate Use Trials , Drug Evaluation , Female , France , Genes, p53 , Hematopoietic Stem Cell Transplantation , Humans , Infections/etiology , Kaplan-Meier Estimate , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Lymphoma, Large B-Cell, Diffuse/etiology , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/therapy , Male , Middle Aged , Progression-Free Survival , Retrospective Studies , Sulfonamides/adverse effects , Treatment Outcome , Tumor Lysis Syndrome/etiology
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