Efficacy and safety of TPO receptor agonists in treatment of ITP associated with predominantly antibody deficiencies.

Predominantly antibody deficiencies have an estimated prevalence of more than 1/25,000. Their classical phenotype entails the association of autoimmune manifestations with increased susceptibility to infections. Up to 8% of these patients ultimately develop immune thrombocytopenic purpura (ITP). Reducing the risk of infections and considering non immunosuppressive treatments, such as thrombopoietin receptor agonists (TPO-RAs), are important needs in these patients. This nationwide retrospective case series assessed outcomes and safety of TPO-RAs as treatment for ITP in adults diagnosed with predominantly antibody deficiencies. Response and complete response to treatment were defined as platelet count reaching 30 x 109/L and 100 x 109/L respectively. We analyzed data from 28 patients. The median follow-up after introduction of the first TPO-RAs was 33 months (range, 2 weeks - 10,6 years). After 6 weeks of follow up, response was achieved for 24 out of 28 patients (85.7%), among which 21 patients (75%) displayed a complete response. At the last available follow-up visit only 7 patients (25%) needed second-line therapies for ITP among which only 5 patients (17.9%) received immunosuppressants. Only 3 patients (10.7%) reported hepatobiliary laboratory adverse events of light or mild severity and 3 patients (10.7%) reported thrombotic events. In conclusion, TPO-RAs appeared as an effective and safe option of treatment in these case series. Our results suggest that Eltrombopag or Romiplostim should be considered as second line therapy of ITP related to predominantly antibody deficiencies.

[Nurturing and growing a community of department heads: Act 2 in haematology]. / Faire vivre et grandir une communauté de chefs de service : acte 2 en hématologie.

In response to the French hospital system crisis and the challenges faced by the heads of departments, we have undertaken an initiative to create a community of heads of haematology departments willing to assist each other. Our inaugural seminar, held in January 2023, established the foundational "core" group of heads of department. Throughout 2023, this emerging community has prospered, offering sustained support to peers. In January 2024, we broadened our community to include other heads of departments, following a second seminar gathering 36 participants. During this event, we took the time to exchange thoughts and reflect on our missions. Building on the experience of guest speakers and employing methods of co-development and co-construction in plenary sessions, small-group workshops, and social gathering, we were able to discover and experience the collective intelligence, creativity, strength, and support stemming from such a group. This peer community of heads of departments stands as a powerful tool for management support, whereby personal experiences nourish and enrich the experience of others. We hope that our initiative will inspire heads of departments from other specialties so that, together, we can better work towards our missions as heads of departments and collaborate on rebuilding the hospital "from the bottom up".

Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial.

CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65-79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10-5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10-5 were reported in 35 patients (26%, 95% confidence interval (CI) 19-34) in IsaRd versus 71 (53%, 95% CI 44-61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89-5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10-5 and 10-6, and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10-5, the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877 .

Long-term results of Waldenström macroglobulinaemia treatment by bendamustine and rituximab: A study on behalf of the French Innovative Leukemia Organization (FILO).

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.

Real-life effectiveness of carfilzomib in patients with relapsed multiple myeloma receiving treatment in the context of early access: The CARMYN study.

The real-life retrospective observational study CARMYN aimed at investigating the long-term efficacy and safety of carfilzomib in combination with dexamethasone and lenalidomide (KRd, 159 patients). These patients (62% in first and 38% in second relapse, median age 62 yo) were treated between 02/2014 and 02/2017. Most had been pre-exposed to bortezomib (98.2%) and to an IMID (75.4%). At the time of collection, 90% had permanently discontinued carfilzomib. Data collection was conducted from January to July 2021 in 27 participating sites, after a median of 39 months follow-up. For patients treated with KRd, an overall response rate of 78.4% translated in a median progression free survival (PFS) of 24.0 months (95% CI 18.8-27.6) and a median overall survival (OS) of 51.1 months (95% CI 41.3-not reached). Results were poorer but difficult to interpret in the small cohort of Kd recipients. The study is one of the longest real-life studies of carfilzomib treatment in patients in first or second relapse. CARMYN confirmed the real-life long-term efficacy of carfilzomib in combination with lenalidomide and dexamethasone with results similar to those of clinical trials. The KRd regimen is thus an option to consider for late relapses in the current context of MM management.

Comparison of efficacy and toxicity according to etoposide and cytarabine dosing in BEAM conditioning followed by autologous stem cell transplantation in Hodgkin lymphoma.

The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell transplantation (ASCT) is a commonly used intensification regimen for patients with Hodgkin lymphoma. As etoposide and cytarabine dosing are not defined, we conducted a retrospective, multicenter study, to compare efficacy and toxicity in 130 patients with Hodgkin lymphoma receiving etoposide and cytarabine at either 200 mg/m2/d (n = 50), 400 mg/m2/d (n = 35), or etoposide 200 mg/m2/d and cytarabine 400 mg/m2/d (n = 45). Progression-free survival and overall survival were not associated with the intensity of conditioning. Increased conditioning intensity was associated with longer duration of thrombocytopenia, a higher number of transfused RBC and platelet units and a higher frequency of mucositis, but serious adverse events or infectious complications were not increased. The intensity of BEAM regimen was not associated with survival but with the rate of cytopenia and mucositis advocating for the use of lower dosing in frail patients.

Real-world study of the efficacy and safety of belantamab mafodotin (GSK2857916) in relapsed or refractory multiple myeloma based on data from the nominative ATU in France: the IFM 2020-04 study.

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.

Salvage therapy with brentuximab-vedotin and bendamustine for patients with R/R PTCL: a retrospective study from the LYSA group.

Patients with relapsed or refractory (R/R) peripheral T-cell lymphomas (PTCL) have a poor prognosis. Bendamustine (B) and brentuximab-vedotin (Bv) have shown interesting results in this setting. However, little information is available about their efficacy in combination. This multicenter and retrospective study aimed to evaluate the efficacy and safety of the combination of BBv in patients with noncutaneous R/R PTCL among 21 LYSA centers in France and Belgium. The primary objective was the overall response rate. A total of 82 patients with R/R PTCL were included. The best overall response rate (ORR) was 68%, with 49% of patients in complete response (CR). In multivariable analysis, only the disease status after the last regimen (relapse vs refractory) was associated with the response with an ORR of 83% vs 57%. Median duration of response was 15.4 months for patients in CR. With a median follow-up of 22 months, the median progression free survival (PFS) and overall survival (OS) were 8.3 and 26.3 months respectively. Moreover, patients in CR, who underwent an allogeneic transplant, had a better outcome than patients who did not with a median PFS and OS of 19.3 vs 4.8 months and not reached vs 12.4 months, respectively. Fifty-nine percent of patients experienced grade 3/4 adverse events that were mainly hematologic. BBv is highly active in patients with R/R PTCL and should be considered as a one of the best options of immunochemotherapy salvage combination in this setting and particularly as a bridge to allogeneic transplant for eligible patients.

Ki67 Immunohistochemical Expression Level ≥70%, Bulky Presentation ≥7.5 cm, Meningeal Lymphomatosis, and Interim PET ΔSUVmax After 4 Treatment Cycles <71% as Parts of a Practical Scoring System to Predict Progression-Free Survival and Overall Survival in Diffuse Large B-Cell Lymphoma.

Currently, prognostic models in diffuse large B-cell lymphoma (DLBCL) fail to closely reflect patients' biological, clinical, and survival heterogeneity. We, therefore, assessed the impact of clinical, biological, immunohistochemical (IHC), baseline (0), and interim (after 2 and 4 treatment cycles) PET (PET0, PET2, and PET4) data not yet included in any scoring system on DLBCL outcome. The analysis was conducted on 89 previously untreated adult patients of the Finistere Observatory Cohort (O.Ly.Fin) with documented DLBCL, recruited between January 2010 and December 2017, with progression-free survival (PFS) and overall survival (OS) as primary and secondary endpoints, respectively. Seventy-eight patients were treated with rituximab, cyclophosphamide, hydroxyadriamycin, vincristine, and prednisone (R-CHOP), while 11 received R-dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and hydroxyadriamycin (EPOCH). Patients were followed up until June 20, 2020. On multivariate analysis, Ki67 ≥ 70% on IHC (K), bulky presentation ≥7.5 cm (B), meningeal lymphomatosis (M), and PET0-PET4 ΔSUVmax <71% (P4) were identified as strong independent predictors of PFS, and all variables but bulky disease also strongly and independently predicted OS. Using these 4 parameters, we designed a scoring model named KBMP4 stratifying patients into low- (0 parameter), intermediate- (1 or 2), and high-risk (≥3) subgroups by the Kaplan-Meier analysis. At a median follow-up of 43 months, PFS and OS were both 100% in the low-risk subgroup, 71.4 and 90.5%, respectively, in the intermediate-risk subgroup, and 0 and 55.5%, respectively, in the high-risk subgroup. Use of the KBMP4 model in clinical practice may improve accuracy in prognostic prediction and treatment decisions in de novo DLBCL patients.

Subcutaneous Rituximab-MiniCHOP Compared With Subcutaneous Rituximab-MiniCHOP Plus Lenalidomide in Diffuse Large B-Cell Lymphoma for Patients Age 80 Years or Older.

PURPOSE: The prognosis of elderly patients with diffuse large B-cell lymphoma (DLBCL) is worse than that of young patients. An attenuated dose of chemotherapy-cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-miniCHOP)-is a good compromise between efficacy and safety in very elderly patients. In combination with R-CHOP (R2-CHOP), lenalidomide has an acceptable level of toxicity and may mitigate the negative prognosis of the non-germinal center B-cell-like phenotype. The Lymphoma Study association conducted a multicentric, phase III, open-label, randomized trial to compare R-miniCHOP and R2-miniCHOP. PATIENTS AND METHODS: Patients of age 80 years or older with untreated DLBCL were randomly assigned into the R-miniCHOP21 group or the R2-miniCHOP21 group for six cycles and stratified according to CD10 expression and age. The first cycle of rituximab was delivered by IV on D1 after a prephase and then delivered subcutaneously on D1 of cycles 2-6. Lenalidomide was delivered at a dose of 10 mg once daily on D1-D14 of each cycle. The primary end point was overall survival (OS). RESULTS: A total of 249 patients with new DLBCL were randomly assigned (127 R-miniCHOP and 122 R2-miniCHOP). The median age was 83 years (range, 80-96), and 55% of the patients were classified as non-GCB. The delivered dose for each R-miniCHOP compound was similar in both arms. Over a median follow-up of 25.1 months, the intention-to-treat analysis revealed that R2-miniCHOP did not improve OS (2-year OS 66% in R-miniCHOP and 65.7% in R2-miniCHOP arm, P = .98) in the overall population or in the non-GCB population. Grade 3-4 adverse events occurred in 53% of patients with R-miniCHOP and in 81% of patients with R2-miniCHOP. CONCLUSION: The addition of lenalidomide to R-miniCHOP does not improve OS. Rituximab delivered subcutaneously was safe in this population.

Diagnosis and prognosis are supported by integrated assessment of next-generation sequencing in chronic myeloid malignancies. A real-life study.

Next-generation sequencing (NGS) is used to investigate the presence of somatic mutations. The utility of incorporating routine sequencing to guide diagnosis and therapeutic decisions remains unclear. We report the findings of an observational, multicenter study that aimed to assess the impact of somatic mutation testing by NGS in a reallife setting of chronic myeloid malignancies. A total of 177 patients were enrolled, partitioned into two overlapping groups. In group A (n=94), the indication was to search for clonal hematopoiesis, in a context of suspected myelodysplastic syndrome or myeloproliferative neoplasia. In group B (n=95), the theranostic impact of somatic mutations was studied. A panel of 34 genes was used on DNA extracted from blood or bone marrow samples. Within group A, the detection of clonal hematopoiesis supported the diagnosis of chronic myeloid malignancies for 31 patients while the absence of clonal hematopoiesis ruled out the suspected diagnosis in 47 patients. Within group B, NGS identified prognostically relevant somatic mutations in 32 patients, which had a therapeutic impact in 18 cases. By determining the presence or absence of somatic mutations, the application of NGS in daily practice was found to be useful for an integrated final diagnosis in 83% of the patients. Moreover, the search for somatic mutations had a prognostic impact that led to treatment modification in 19% of the cases. This study outlines the fact that adequate implementation of new investigations may have a significant positive medico-economic impact by enabling appropriate management of patients.

Blastic plasmacytoid dendritic cell neoplasms: results of an international survey on 398 adult patients.

The purpose of this study is to describe the clinical and prognostic features and to evaluate the outcome of different therapeutic approaches among patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) who have been diagnosed and treated in different institutions. A total of 398 patients from 75 centers were included in the study. Treatment consisted of non-Hodgkin lymphoma (NHL)-like regimens in 129 (32.8%) patients and acute leukemia (AL)-like regimens in 113 (23.5%) patients. In 61 (15.5%) and 16 (4.1%) patients, chemotherapy was followed by allogeneic and autologous hematopoietic stem cell transplantation (HSCT), respectively. Twenty-seven (6.9%) patients received radiotherapy, 6 (1.5%) received new agents, and 62 (15.7%) received palliative care. After a median follow-up of 12 months, median overall survival (OS) was 18 months. Patients who received NHL/AL-like regimens, followed by allogeneic HSCT, had the best outcome; median OS was not reached. OS was 65 months for patients who underwent autologous HSCT; 18 months and 14 months, respectively, for those treated with AL-like and NHL-like regimens without consolidation; and 4 months for those receiving palliative care (P < .001). In BPDCN, chemotherapy with lymphoma- or AL-like regimens, followed by transplantation, represents the therapeutic strategy associated with the best outcome. Consolidation with allogeneic HSCT, when feasible, appears superior to autologous HSCT.

Lymphomas with kidney involvement: the French multicenter retrospective LyKID study.

The LyKID study is a nationwide survey in France of lymphoma patients with renal involvement based on biopsy and/or imaging, to evaluate its impact on disease outcome and renal function. A total of 87 adult cases of B or T-cell lymphomas were retrospectively analyzed. Interstitial topography was observed in most of the kidney biopsies (54/66; 80%). Kidney failure (glomerular filtration rate <60 mL/min/1.73 m2) was present in 47% of patients and was associated with non-significantly different outcome. After lymphoma treatment, 44% of patients had persistent chronic kidney failure (CKF); kidney failure at diagnosis was the only parameter associated with CKF in multivariate analysis. DLBCL (diffuse large B-cell lymphomas) represented half of the series, with noticeably CNS (central neurological system) relapse in 17% patients, while fewer than one of two patients had received CNS prophylaxis. To our knowledge, the LyKID study represents the largest published non-autopsy lymphoma series with renal involvement.

Aquagenic pruritus in essential thrombocythemia is associated with a higher risk of thrombosis.

BACKGROUND: Thromboses and phenotypic evolutions (leukemia, myelofibrosis) are the most frequent complications in polycythemia vera (PV) and essential thrombocythemia (ET). Aquagenic pruritus (AP) is not only PV symptom, but is also present in ET. The presence of pruritus in PV is associated with a lower risk of arterial thrombosis. AIMS: To date, no equivalent study has been done to analyse the impact of AP for ET patients. MATERIALS & METHODS: We used the data from our cohort of patients with myeloproliferative neoplasms seen in our institution (OBENE database, NCT02897297). We collect information at diagnosis, presence or not of AP and all types of complications during their follow-up. To avoid masked PV, all JAK2 positive cases were tested isotopic red mass cell if appropriate. RESULTS: Among 396 ET patients, presence of AP was found in 42 (10.6%). ET patients with AP were more proliferative, more symptomatic at diagnosis and more difficult to treat. Furthermore, they presented increased risk of thromboses (30.9 versus 17%, P = .03; OR = 2.2 [1.01;4.66]) and phenotypic evolutions (33.3 versus 13.3%, P = .0007; OR = 3.2 [1.44;6.77]), during follow-up. DISCUSSION: Aquagenic pruritus is classically associated to PV. But we confirmed here that AP is also present in ET and characterizes patients with higher risk of morbidity (thrombotic events and phenotypic evolutions). CONCLUSIONS: The systematic determination of the presence of AP in ET patients should permit us to better identify these high-risk patients for better management and follow-up.

Immune-checkpoint inhibitors to treat cancers in specific immunocompromised populations: a critical review.

INTRODUCTION: Because of their efficacy against numerous cancers, immune-checkpoint inhibitors (ICIs), anti-cytotoxic T-lymphocyte antigen-4, and anti-programmed cell death monoclonal antibodies are being used ever more often in oncology. However, some patients were excluded from clinical trials because of their comorbidities despite their potentially higher cancer frequencies, as is the case for immunocompromised patients. Areas covered: We analyzed reported preclinical and clinical information and evaluated the risk/benefit ratio for four immunocompromised populations: people living with human immunodeficiency virus (PLHs), solid-organ transplant recipients, recipients of hematopoietic stem-cell allografts, and patients with autoimmune diseases. Expert commentary: Information available in the literature is fragmentary and scarce, making it difficult to evaluate the risk/benefit ratio. It can, nonetheless, be noted that ICI use in PLHs seems possible. For solid-organ transplant recipients, the risk for the graft seems elevated. For the other two populations, it is difficult to conclude at this time.