Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX.

OBJECTIVES: Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies. METHODS: Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose. RESULTS: 110 patients (median age 71 (68-79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors. CONCLUSIONS: This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.

Susceptibility to mycobacterial infection in VEXAS syndrome.

OBJECTIVES: VEXAS is a recently described acquired auto-inflammatory and hematologic syndrome caused by somatic mutations in UBA1. To date, VEXAS is not a recognized cause of acquired immunodeficiency. PATIENTS AND METHODS: Two of our 10 VEXAS patients developed a disseminated Mycobacterium avium infection. To shed light on this observation, we retrospectively studied all patients with disseminated non-tuberculous mycobacterial infections (NTMi) seen at our institution over 13 years. Inclusion criteria were a positive blood/bone marrow culture, or 2 positive cultures from distinct sites, or one positive culture with 2 involved sites. RESULTS: patient 1 presented with fever, rash, orbital cellulitis and lung infiltrates. Patient 2 presented with fever and purpura. In both cases, Mycobacterium avium was identified on bone marrow culture. Twenty cases of disseminated NTMi were reviewed. Among 11 HIV-negative patients, three had chronic immune-mediated disease; three had untreated myeloid neoplasm; two had VEXAS; one had undergone kidney transplantation; one had GATA-2 deficiency; and one had no identified aetiology. None had lymphoid neoplasia or had undergone bone marrow transplantation. HIV-negative cases had higher CD4 counts than HIV-positive patients (median CD4: 515/mm3  vs 38/mm3, p< 0.001). Monocytopenia was present in seven cases. At 2 years, six patients had died, including both VEXAS patients. DISCUSSION: VEXAS patients have an intrinsic susceptibility to disseminated NTMi, which may result from monocytic dysfunction. NTMi can mimic VEXAS flare. Clinicians should maintain a high suspicion for opportunistic infections before escalating immunosuppressive therapy. Further studies are needed to confirm and better decipher the herein reported observations.

Phase I study of zoledronic acid combined with escalated doses of interleukine-2 for early in vivo generation of Vγ9Vδ2 T-cells after haploidentical stem cell transplant with posttransplant cyclophosphamide.

The presence of donor Vγ9Vδ2 T-cells after haploidentical hematopoietic stem cell transplant (h-HSCT) has been associated with improved disease-free survival. These cells kill tumor cells in a non-MHC restricted manner, do not induce graft-versus-host disease (GVHD), and can be generated by stimulation with zoledronic acid (ZA) in combination with interleukin-2 (IL-2). This monocentric phase I, open-label, dose-escalating study (ClinicalTrials.gov: NCT03862833) aimed at evaluating the safety and possibility to generate Vγ9Vδ2 T-cells early after h-HSCT. It applied a standard 3 + 3 protocol to determine the maximum tolerated dose (MTD) of increasing low-doses of IL-2 (5 days [d] per week, 4 weeks) in combination with a single dose of ZA, starting both the first Monday after d + 15 posttransplant. Vγ9Vδ2 T-cell monitoring was performed by multiparameter flow cytometry on blood samples and compared with a control cohort of h-HSCT recipients. Twenty-six patients were included between April 2019 and September 2022, 16 of whom being ultimately treated and seven being controls who received h-HSCT only. At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. MTD was not reached. A significantly higher number of Vγ9Vδ2 T-cells was observed during IL-2 treatment compared with controls. In conclusion, early in vivo generation of Vγ9Vδ2 T-cells is feasible after h-HSCT by using a combination of ZA and repeated IL-2 infusions. This study paves the way to a future phase 2 study, with the hope to document lesser posttransplant relapse with this particular adaptive immunotherapy.

Peripheral levels of monocytic myeloid-derived suppressive cells before and after first induction predict relapse and survivals in AML patients.

Myeloid Derived Suppressive Cells (MDSC) are capable to suppress innate and adaptive immune responses, thus favouring solid cancer progression. However, little is known about the role of MDSC in acute myeloid leukaemia (AML). In this monocentric prospective study, 73 adult AML patients, eligible for first-line intensive chemotherapy, were included with the aim to study the influence on long-term outcomes of peripheral blood (PB) levels of monocytic (M) MDSC (M-MDSC) assessed by flow cytometry. A percentage of peripheral M-MDSC higher than 0.55% of leukocytes at diagnosis and a decrease of M-MDSC% after induction came out both as independent negative prognostic factors for leukaemia-free and overall survival.

Effectiveness of a third dose of BNT162b2 anti-SARS-CoV-2 mRNA vaccine over a 6-month follow-up period in allogenic hematopoietic stem cells recipients.

This study reports the effectiveness of three injections of BNT162b2 anti-SARS-CoV-2 mRNA vaccine in 141 Allo-HSCT recipients with a median follow-up of 6 months post-third shot. We demonstrate a long-term high protection of Allo-HSCT recipients since only 2 infections and one death related to COVID-19 occurred.

Red blood cell transfusion burden in myelodysplastic syndromes (MDS) with ring Sideroblasts (RS): A retrospective multicenter study by the Groupe Francophone des Myélodysplasies (GFM).

BACKGROUND: MDS-RS patients are characterized by chronic anemia and a low risk of Acute Myeloid Leukemia (AML) progression and they generally become Red Blood Cell (RBC) transfusion dependent (TD). STUDY DESIGN AND METHODS: We performed a retrospective "real-life" observational study of 6 months in 100 MDS-RS TD patients, recruited in 12 French centers, to describe transfusion characteristics, and evaluate the frequency and causes of hospitalizations, health costs, and morbidity, associated with transfusion dependency, in a French population of RBC transfusion-dependent MDS-RS patients. RESULTS: 79% of the patients had high transfusion burden (HTB) and 21% low transfusion burden (LTB). HTB patients had a longer disease duration (6 vs. 3.7 years, p = 0.0078), more frequent iron chelation (82% vs. 50%, p = 0.0052) and higher serum ferritin (p = 0.03). During the 6-month study period, 22% of the patients required inpatient hospitalization, 36% of them for symptomatic anemia requiring emergency RBC transfusion. The 6-month median transfusion costs, including the cost of the day care facility, transportation to and from the hospital, iron chelation, and lab tests, was 16,188€/patient. DISCUSSION: MDS-RS represents the archetypal type of chronically transfused lower-risk MDS. Most of those patients have a high transfusion burden and thus frequently need visits to the hospital's day care facility, and frequent hospitalizations, with an overall high median treatment cost. Those costs should be compared with costs of new treatments potentially able to avoid RBC transfusion dependence and to reduce the complications of chronic anemia in MDS-RS patients.

Posttransplant Cyclophosphamide and Antithymocyte Globulin versus Posttransplant Cyclophosphamide as Graft-versus-Host Disease Prophylaxis for Peripheral Blood Stem Cell Haploidentical Transplants: Comparison of T Cell and NK Effector Reconstitution.

A higher incidence of graft-versus-host disease (GVHD) has been observed after haploidentical hematopoietic stem cell transplantation (h-HSCT) with posttransplant cyclophosphamide (PTCY) using peripheral blood stem cells (PBSC) as a source of graft. Moreover, combining PTCY with antithymocyte globulin (ATG) may help to reduce GVHD incidence. In this study, early immune reconstitution, especially of T and NK cell compartments, was compared after both types of transplant (PTCY versus PTCY + ATG) investigate their influence on patient outcomes. This retrospective study included 58 adults who received a reduced intensity conditioning to PBSC h-HSCT with cyclosporine and mycophenolate mofetyl + PTCY (n = 32) or PTCY + ATG (n = 26) as GVHD prophylaxis. Both groups shared similar characteristics except for the median number of CD3+ T cells infused, significantly higher for PTCY + ATG patients. Blood samples from all patients were collected three times a week from day 0 until day 30 then at day 60 and day 90/100 to evaluate T and NK cells reconstitution by flow cytometry. The results show that PTCY + ATG versus PTCY alone significantly limits the occurrence of acute grade 2-4 GVHD after reduced intensity conditioning PBSC h-HSCT, perhaps because of the combined effect of T and NK cell reconstitution. Indeed, although a slower T cell reconstitution with PTCY + ATG may limit GVHD occurrence, the quicker reconstitution of some NK cell subtypes may help with avoiding relapse. Larger prospective studies are needed to better determine which NK cell subsets may influence the incidence of relapse after h-HSCT and optimize donor selection.

Dramatic Recovery after Etoposide Phosphate Infusion for Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome following Treatment with Tisagenlecleucel in a Young Patient with Relapsed Acute Lymphoblastic Leukemia: A Case Report.

The occurrence of a secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) after CAR T-cell infusion is very rare and mostly fatal. Treatment recommendations for such a complication are not yet established. Here, we report the dramatic recovery of HLH/MAS following tisagenlecleucel infusion in a young patient with relapsed acute lymphoblastic leukemia using etoposide phosphate (EP). We propose that monitoring for the occurrence of HLH/MAS should be part of surveillance after CAR T-cell infusion and that EP treatment appears to be useful to control this severe and rare complication.

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.

Grade 2 acute GVHD is a factor of good prognosis in patients receiving peripheral blood stem cells haplo-transplant with post-transplant cyclophosphamide.

BACKGROUND: The impact of acute graft versus host disease (GVHD) on survivals for patients receiving a haploidentical allogeneic stem-cell transplant (Allo-SCT) with peripheral blood stem-cells (PBSC) complemented by post-transplant cyclophosphamide (PTCY) is ill-known. MATERIAL AND METHODS: This retrospective study included 131 patients who received a PBSC haplograft in order to precise the impact of acute GVHD on outcomes. There were 78 males and 53 females and the median age for the whole cohort was 59 years (range: 20-71). Thirty-five patients were allografted for a lymphoid disease and 96 for a myeloid malignancy, including 67 patients with acute myeloid leukemia (AML). RESULTS: The cumulative incidence (CI) of day 100 grade 2-4 and 3-4 acute GVHD was 43.4 + 4.6% and 16.7 + 3.4%, respectively. The 2-year CI of moderate/severe chronic GVHD was 10.1 + 2.8%. The only factor affecting the occurrence of GVHD was GVHD prophylaxis. Indeed, CI of day 100 grade 2-4 (but not grade 3-4) acute GVHD was significantly reduced when adding anti-thymoglobulin (ATG) to PTCY. However, in multivariate analysis, grade 2 acute GVHD was significantly associated with better disease-free (HR: 0.36; 95%CI: 0.19-0.69, p = .002) and overall (HR: 0.35; 95%CI: 0.1-0.70, p = .003) survivals. The same results were observed when considering only AML patients. CONCLUSION: Acute grade 2 GVHD is a factor of good prognosis after PBSC haplotransplant with PTCY. Further and larger studies are needed to clarify the complex question of GVHD prophylaxis in the setting of haplo-transplant, especially that of combining ATG and PTCY.

Impact of KIR/HLA Incompatibilities on NK Cell Reconstitution and Clinical Outcome after T Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation with Posttransplant Cyclophosphamide.

Little is known regarding the effect of KIR/HLA incompatibilities (inc.) in the setting of T-replete haploidentical allogeneic hematopoietic stem cell transplantation using posttransplant cyclophosphamide (PTCy). In this retrospective study, the impact of KIR/HLA inc. on clinical outcomes and NK cell reconstitution was studied in a cohort of 51 consecutive patients receiving a T cell-replete haploidentical allogeneic hematopoietic stem cell transplantation after a reduced-intensity conditioning using peripheral blood stem cells as the source of the graft and PTCy as graft-versus-host disease (GvHD) prophylaxis. The NK cell repertoire reconstitution was examined by multiparameter flow cytometry in 34 of these 51 patients from day 0 to day 100 posttransplant. Genetic KIR2DL/HLA inc. were found to be significantly associated with more GvHD (81.2 versus 45.7%, p = 0.01) and less relapse (6.2 versus 42.8%, p = 0.008) in this context. GvHD is associated with increased levels of differentiated and activated NK cells. A significant loss of KIR2DL2/3+ NK cells was observed at day 30 in patients with inhibitory KIR/HLA inc., suggesting that responsive KIR NK cells are particularly targeted by the immunosuppressive PTCy treatment. Further investigations are needed from a larger cohort with an identical clinical approach to consolidate these results and to identify the NK cell subsets that may be beneficial for the graft-versus-leukemia effect observed. Because many haploidentical donors can be identified in a family, the prediction of KIR NK cell alloreactivity could be of crucial importance for donor selection and patient outcome.

Absence of influence of peripheral blood CD34+ and CD3+ graft cell counts on outcomes after reduced-intensity conditioning transplantation using post-transplant cyclophosphamide.

The influence of peripheral blood stem cell (PBSC) graft cell contents after transplant with post-transplant cyclophosphamide (PTCY) remains unclear. Here, we retrospectively report on a cohort of 77 adults who received a Baltimore-based reduced-intensity conditioning regimen either with fludarabine (n = 40) or clofarabine (n = 37) and PTCY. With a median follow-up of 29.2 months, [2-]year overall (OS), disease-free (DFS), and GVHD/relapse-free survival (GRFS) rates were 62.8%, 51%, and 36.7%, respectively. The incidence of grades [2-]4 acute GVHD was significantly higher in patients transplanted with a haplodonor (n = 56), at 57.1% vs 19% (p = 0.006). PBSC graft cell contents (CD45+, CD34+, and CD3+ cells) had no impact on any outcome. Considering immune reconstitution until 1 year, only monocytes were above the normal range (as early as day + 30) during the first year post-transplant. In multivariate analysis, an older donor (> 45 years) and a high/very high disease risk index were independently associated with lower OS. A higher monocyte count (> median) at day + 90 was also associated with better OS, DFS, and GRFS. Donor/recipient CMV status matching was independently associated with GRFS. In conclusion, our data support the fact that there is no need to manipulate the graft before infusion in the particular context of PBSC/PTCY Baltimore-based allotransplant.

Progression of disease within 2 years (POD24) is a clinically relevant endpoint to identify high-risk follicular lymphoma patients in real life.

Follicular lymphoma (FL) is an indolent non-Hodgkin's lymphoma with heterogeneous outcomes. Progression or relapse of FL within 2 years (so-called POD24) after diagnosis is associated with a poor outcome for patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) in clinical trials. POD24 needs further validation before it can be used as a relevant endpoint to assess treatment efficacy. In the present retrospective monocentric study, we investigated the predictive value of POD24 in a cohort of grade 1, 2, or 3a FL patients treated in our institution (Nantes Medical University, France) and registered in our local database. We investigated the nature of treatment lines, patients' outcomes, and the prognostic value of POD24. Between 2007 and 2016, 317 patients were included. After first-line therapy, 60 patients relapsed within 2 years (POD24-pos cohort), and 254 patients did not relapse within 2 years (PO24-neg cohort). Thirty-three patients died, and 34 patients had an aggressive transformation. The median follow-up is 59.9 months (1.6-395.5). The median PFS is 59.9 months. Overall survival (OS) at 1 year, 3 years, and 5 years is 98.4% [97.0-99.8], 95.1% [92.6-97.6], and 92.5% [89.3-95.9], respectively. The 5-year OS was statistically lower for POD24-pos patients (82% [71.9-93.5]) than for POD24-neg patients (93.3% [88.98-97.8]) (p = 10-5). In multivariate analyses, transformation was predictive of OS, and PS (≥ 1) was predictive of POD24. POD24 is predictive of a worse OS and may be recommended as a relevant endpoint in clinical trials and in real life in particular for patients with advanced disease.

Influence of Donor Type (Sibling versus Matched Unrelated Donor versus Haploidentical Donor) on Outcomes after Clofarabine-Based Reduced-Intensity Conditioning Allograft for Myeloid Malignancies.

Clofarabine-based reduced-intensity conditioning (RIC) regimens are well-established schedules for allograft in patients with myeloid malignancies. A retrospective study was conducted including all adults allografted in our department with such a regimen and disease with the aim to assess whether or not the donor type (matched sibling [MSD], matched unrelated [MUD], or haploidentical [haplo]) impacted outcomes. Between October 2009 and February 2018, 118 patients met the inclusion criteria. Thirty-six, 55, and 27 patients received a graft from an MSD, MUD, or haplo donor, respectively. Peripheral blood stem cells (PBSCs) were the source of graft for all patients. The median age of the entire cohort was 62 years (range, 20 to 73), and the median follow-up was 31 months (range, 4.5 to 106). All patients engrafted except 1 haplo recipient. Neutrophils (>.5 × 109/L) and platelets (50 × 109/L) recoveries were significantly delayed in the haplo group (P = .0003 and P < .0001) compared with MSD and MUD. Acute grades II to IV or III to IV graft-versus-host disease (GVHD) incidences were similar between the 3 groups as well as the incidence of moderate or severe chronic GVHD. Also, similar 2-year overall survival (OS; 64.7% versus 73.9% versus 60.2%, P = .39), disease-free survival (DFS; 57.7% versus 70.9% versus and 53.6%, P = .1), and GVHD relapse-free survival (37.9% versus 54.3% versus 38.9%, P = .23) were observed between MSD versus MUD versus haplo groups. The same was true when considering only acute myeloid leukemia (AML) cases. In multivariate analysis the type of donor remained independent of outcomes in this series, whereas myelodysplastic syndrome (versus AML), high disease risk index, and older donor (≥50 years) were associated with lower OS and DFS. These data suggest that haplo donors are an acceptable alternative for patients receiving a clofarabine-based RIC PBSC allograft for myeloid malignancies who lack an MSD or a MUD.

Deauville Scores 4 or 5 Assessed by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Early Post-Allotransplant Is Highly Predictive of Relapse in Lymphoma Patients.

The impact of early fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET-CT) status on survival after allogeneic transplantation for lymphoma is poorly reported. This retrospective study included all adult Hodgkin lymphoma (HL) or non-Hodgkin lymphoma(NHL) patients (>18 years old) who benefited from FDG PET-CT before (within 1 month) and/or early (+3 months and within +6 to 9 months) after allogeneic stem cell transplantation in our institution between 2005 and 2015 and who were still without documented progression or relapse at the time of the FDG PET-CT. All FDG PET-CT were reviewed by a nuclear medicine expert in hematology and restaged according to the Deauville scale. FDG-PET CT was considered positive when the uptake was higher than liver background (Deauville score ≥ 4). The primary objective was to study the impact of pre- and post-transplant FDG PET-CT on lymphoma-free survival (LFS) and overall survival (OS). Inclusion criteria were fulfilled for 103 patients (69 men; median age, 51.6 years old; range, 22 to 67). Diagnoses were high-grade NHL (n = 47), low-grade NHL (n = 6), T cell lymphoma (n = 34), and HL (n = 16). More than half of the patients were in complete remission at the time of transplant (n = 56). A reduced-intensity conditioning regimen was applied in most cases (n = 90). With a median follow-up of 49.5 months (range, 6 to 140.5) for alive patients, median 3-year OS and LFS were, respectively, 81% (range, 71% to 87%) and 65% (range, 54% to 74%) for the entire cohort. In multivariate analysis, positive FDG PET-CT at 3 months was the strongest independent factor significantly associated with poorer LFS (hazard ratio, 9.22; 95% confidence interval, 1.88 to 645.2; P = .006). FDG PET-CT positivity at 3 months appears to be highly predictive of LFS in patients after allogeneic transplantation and may help to guide strategies to prevent relapse. These results need to be validated prospectively.

FLT3 ligand plasma levels have no impact on outcomes after allotransplant in acute leukemia.

OBJECTIVE: This study was designed to assess the impact on outcomes of early soluble Fms-like tyrosine kinase 3 ligand concentrations (sFLc) in patients receiving an allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). METHODS: This was a prospective monocentric study including all allo-HSCT patients included in the previous FLAM/FLAL study (Peterlin et al., 2019). Blood samples collected before the start of conditioning then post-transplant were frozen, stored and tested by ELISA. The parameters considered were hematopoietic recoveries, Leukemia Free Survival and Overall Survival, acute and chronic GVHD, grade 3 or 4 acute and/or extensive chronic GVHD-free and relapse-free survival (GRFS). RESULTS: Forty-one patients were included, a total of 179 samples were assayed for sFLc. There was no impact of sFLc levels (<=median vs> median) on acute and chronic GVHD incidences, LFS, OS nor GRFS. CONCLUSION: At variance with induction results for AML (Peterlin et al., 2019) endogenous sFLc do not appear to be a prognostic marker at the time of or after allo-HSCT. Even though the results are negatives, this is, to the best of our knowledge, the only prospective series specifically addressing the question of sFLc impact after allo-HSCT in acute leukemias.

Pomalidomide, cyclophosphamide, and dexamethasone for relapsed/refractory multiple myeloma patients in a real-life setting: a single-center retrospective study.

Pomalidomide dexamethasone is a standard of care for relapsed multiple myeloma (MM) patients who received at least two prior lines of therapy, including both lenalidomide and proteasome inhibitors (PI). We report here a real-life single-center series of 49 consecutive patients with relapsed and refractory MM treated with the triplet pomalidomide cyclophosphamide dexamethasone (PCD) combination. The median of prior lines of therapy was 3 and all patients were previously exposed to proteasome inhibitors and lenalidomide. The overall response rate was 76%, including 27% very good partial response or better. With a median follow-up of 16 months, the median progression-free survival (PFS) was 7.3 months and the median overall survival was not reached. Regarding safety, most frequent toxicity was hematologic, including 37% grade 3-4 cytopenias. Nine patients (18%) discontinued therapy due to adverse event. Our study confirms that PCD combination is feasible and results in favorable response rate and PFS in comparison with pomalidomide dexamethasone alone.

Single-agent daratumumab in very advanced relapsed and refractory multiple myeloma patients: a real-life single-center retrospective study.

The anti-CD38 monoclonal antibody daratumumab is approved as a single agent for the treatment of patients with relapsed and refractory multiple myeloma (RRMM) who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMID), or who are double refractory to a PI and an IMID. To date, no real-life data on the efficacy and tolerance of daratumumab in this setting are available. We report here the results of a single-center series of 41 RRMM patients treated with single-agent daratumumab outside clinical trials. Patients received a median number of 4 prior therapies. All patients were previously exposed to PI and IMID and all patients were refractory to the last line of therapy. Most patients presented with high-risk characteristics, including 24% adverse cytogenetics (del17p/t(4,14)), 31% extramedullary disease and 12% circulating plasmacytosis at time of daratumumab therapy. The overall response rate was 24%, including 5% very good partial response or better. After a median follow-up of 6.5 months, all patients experienced disease relapse. The median progression-free survival was 1.9 months. At the time of disease progression, 44% of patients did not receive subsequent therapy. The median overall survival was 6.5 months. No new safety signal was identified. These real-life results revealed modest efficacy of single-agent daratumumab in advanced patients with RRMM in comparison with data from clinical trials.

Use of eltrombopag in aplastic anemia in Europe.

Eltrombopag (ELT), an oral thrombopoietin receptor agonist, has recently emerged as a promising new drug for the treatment of aplastic anemia (AA). How ELT is used outside of clinical trials in the real-world setting and results of this treatment are not known. We conducted therefore a retrospective survey on the use of ELT in AA among EBMT member centers. We analyzed the 134 patients reported in our survey together with 46 patients recently published by Lengline et al. The median follow-up from start of ELT treatment was 15.3 months, with 85.6% patients alive at last follow-up. Importantly, only 28.9% of our patients received ELT according to the FDA/EMA label as monotherapy in the relapsed/refractory setting, whereas 16.7% received ELT upfront. The overall response rate in our cohort was 62%, very similar to the results of the pivotal ELT trial. In multivariate analysis, combination therapy with ELT/cyclosporine/ATG and response to previous therapy were associated with response. Overall survival was favorable with a 1-year survival from ELT start of 87.4%. We identified age, AA severity before ELT start and response to ELT as variables significantly associated with OS. Two patients transformed to MDS; other adverse events were mostly benign. In sum, ELT is used widely in Europe to treat AA patients, mostly in the relapsed/refractory setting. Response to ELT is similar to the clinical trial data across different age groups, treatment lines, and treatment combinations and results in favorable survival.

Fungal Prophylaxis with a Gastro-Resistant Posaconazole Tablet for Patients with Hematological Malignancies in the POSANANTES Study.

Posaconazole is an antifungal drug used in both prophylaxis and treatment of invasive fungal infections. Its oral formulation requires therapeutic drug monitoring. To overcome gastric acidity, a gastro-resistant posaconazole tablet has recently been developed. POSANANTES was a prospective noninterventional study that aimed to monitor plasma concentration trough level (Cmin) of posaconazole tablets used prophylactically in patients with hematological malignancies. Fifty patients were included. Group A (n = 31) included patients receiving induction chemotherapy for myeloid malignancies, and group B (n = 19) included patients treated for graft-versus-host disease after allogeneic hematopoietic stem cells transplantation. In multivariate analysis, female sex, group B assignment, and evaluation of Cmin at day 8 (versus any other day planned by the analysis) were associated with a higher Cmin, while diarrhea was associated with a lower Cmin (P < 0.05). Thirty-four percent (n = 17) of all included patients had to prematurely stop treatment, mainly in group A. In conclusion, this real-life prospective study showed good absorption of posaconazole tablets used for prophylaxis in patients with hematological malignancies, even though this strategy was somewhat limited due to the high number of patients in group A who had to stop their treatment in an untimely fashion.