Dexamethasone treatment for COVID-19 is related to increased mortality in hematologic malignancy patients: results from the EPICOVIDEHA Registry.

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Pharmaceutical cancer care for haematology patients on oral anticancer drugs: Findings from an economic, clinical and organisational analysis.

OBJECTIVE: The clinical benefit of pharmaceutical cares in improving the quality-of-care outcomes is well demonstrated. Clinical pharmacy services are not systematically deployed in cancer units in the absence of economic data. The aim of this prospective, observational 1-year study was to evaluate the clinical, economic and organisational impacts of pharmaceutical care into a multidisciplinary day hospital for patients treated with oral cancer drugs. METHODS: All pharmacists' interventions (PI) were documented and their impact and the probability of adverse drug events were assessed using the clinical, economic and organisational tool. RESULTS: Among 360 admissions, an average of 1.81 PI per admission was accepted. Among 452 PI leading to a clinical benefit on the patient, 16.9% had a major impact, and 1.9% had an impact on survival. The large majority of PIs (87%) increased the quality-of-care organisation. The budget impact model showed a total cost savings and cost avoidance of €539,047 per year and a cost-benefit ratio of 7.07:1. The direct cost-benefit was €201,741, and the cost avoidance was €337,306. CONCLUSION: Multidisciplinary care and pharmaceutical care are key elements to improve cancer patients' outcomes and avoid evitable healthcare costs.

Prolonged in-hospital stay and higher mortality after Covid-19 among patients with non-Hodgkin lymphoma treated with B-cell depleting immunotherapy.

Prolonged Covid-19 is an emerging issue for patients with lymphoma or immune deficiency. We aimed to examine prolonged length of in-hospital stay (LOS) due to Covid-19 among patients with lymphoma and assess its determinants and outcomes. Adult patients with lymphoma admitted for Covid-19 to 16 French hospitals in March and April, 2020 were included. Length of in-hospital stay was analyzed as a competitor vs death. The study included 111 patients. The median age was 65 years (range, 19-92). Ninety-four patients (85%) had B-cell non-Hodgkin lymphoma. Within the 12 months prior to hospitalization for Covid-19, 79 patients (71%) were treated for their lymphoma. Among them, 63 (57%) received an anti-CD20 therapy. Fourteen patients (12%) had relapsed/refractory disease. The median LOS was 14 days (range, 1-235). After a median follow-up of 191 days (3-260), the 6-month overall survival was 69%. In multivariable analyses, recent administration of anti-CD20 therapy was associated with prolonged LOS (subdistribution hazard ratio 2.26, 95% confidence interval 1.42-3.6, p < 0.001) and higher risk of death (hazard ratio 2.17, 95% confidence interval 1.04-4.52, p = 0.039). An age ≥ 70 years and relapsed/refractory lymphoma were also associated with prolonged LOS and decreased overall survival. In conclusion, an age ≥ 70 years, a relapsed/refractory lymphoma and recent administration of anti-CD20 therapy are risk factors for prolonged LOS and death for lymphoma patients hospitalized for Covid-19. These findings may contribute to guide the management of lymphoma during the pandemic, support evaluating specific therapeutic approaches, and raise questions on the efficacy and timing of vaccination of this particular population.

Serotonin, hematopoiesis and stem cells.

A large number of studies have focused on the role of serotonin as a neurotransmitter in the central nervous system, although only a small percentage of the body's serotonin (∼5%) can be found in the mature brain of mammals. In the gut, the enterochromaffin cells are scattered in the enteric epithelium from the stomach through the colon and produce over 95% of the body's serotonin. Since the generation of tryptophan hydroxylase (Tph1 and Tph2) knockout mice, unsuspected roles have been identified for serotonin synthesized outside the brain. Moreover, the murine model deficient in peripheral serotonin (Tph1-/-) is a unique experimental tool for exploring the molecular and cellular mechanisms involving serotonin's local effects through microserotonergic systems. In this review, we focus on peripheral serotonin and its role on progenitor or stem cells as well as on hematopoietic progenitors. We discuss the possible role of serotonin in hematopoietic diseases, and whether targeting the serotonergic system could be of therapeutic value for the regulation of normal and pathological hematopoiesis.

Salvage therapy post pomalidomide-based regimen in relapsed/refractory myeloma.

The combination of pomalidomide and low-dose dexamethasone (Pom-Dex) has proved effective and safe in patients with end-stage relapsed/refractory multiple myeloma (RRMM), otherwise characterized by a very poor outcome. MM remains an incurable disease with unavoidable relapses, and the outcome after pomalidomide is still dismal. However, some patients demonstrate prolonged survival even beyond pomalidomide therapy.We sought to analyze the treatment of RRMM patients following Pom-Dex therapy and the response and survival after this next treatment line.We studied 134 patients treated with Pom-Dex until progression across two IFM studies. Seventy percent of these patients received further therapy after Pom-Dex. Among the treated patients, one third responded and one third maintained stable disease. The median OS for treated patients was 12 months (6.5;17), with 22 and 12.5% of patients surviving beyond 2 and 3 years, respectively. The factors associated with a better outcome were exposure to a triplet-based regimen containing a novel agent, response to therapy, absence of adverse cytogenetic, and a longer time from diagnosis to post pomalidomide therapy.This study suggests that patients relapsing after Pom-Dex therapy can still benefit from a further line of treatment. A subset of these treated patients even displayed a prolonged OS, while the prognosis remained very poor without treatment. An active approach could therefore be recommended even in this adverse situation, however guided by the patients' prognosis factors.

Treatment of Newly Diagnosed Elderly Multiple Myeloma.

Multiple myeloma (MM) is a disease of the elderly, with a median age at diagnosis of approximately 70 years old, and more than 30 % of patients aged >75 years. This latter and very elderly population is going to significantly rise in the near future given the increase in life expectancy in Western countries, and, most importantly, global health status of elderly patients is improving, justifying appropriate treatments. Changes in treatment paradigm from the old melphalan-prednisone regimen used since the 1970s to its use as a backbone in a nontransplant setting since the late 1990s have highlighted different subgroups in elderly MM. Some "elderly" patients could be treated like transplant eligible patients, more likely those aged between 65 and the early 70; while a second group would rather be referred to current approved treatment regimens for the non-transplant setting. A dose-intensity approach seems reasonable for this group, aiming for the best response, eventually the complete response (CR) or even minimal residual disease (MRD). The advent of novel agents such as thalidomide, bortezomib, and most recently lenalidomide have allowed a major improvement in outcome as compared to historical combinations, and soon the novel class of monoclonal antibodies should help to further improve these patients' survival. Nonetheless, elderly patients are more susceptible to side effects and are often unable to tolerate full drug doses, and thus require lower dose intensity regimens, or novel drugs or combinations with more favourable safety profile. Recent developments in MM have focused on identifying these vulnerable patients through geriatric assessment and novel myeloma scoring system, including the notions of frailty, disability and comorbidities. Eventually, we have reached an era in which we should be able to provide individualized treatment strategies and drug doses-"tailored therapy"-to improve tolerability and optimize efficacy and ultimately survival for most elderly MM patients.

Lenalidomide is safe and active in Waldenström macroglobulinemia.

Lenalidomide is manageable and effective in multiple myeloma, particularly in elderly patients. Surprisingly, the combination of lenalidomide with rituximab produced clinically significant anemia at 25 mg/day for 21/28 days, the highest possible dose, in Waldenström's Macroglobulinemia (WM). We aimed to determine the maximum tolerated dose (MTD) of single agent lenalidomide and determine its impact on WM. RV-WM-0426 is a multicenter dose escalation open label phase 1/2 study of lenalidomide in relapsed/refractory WM (RRWM). Lenalidomide was given orally 21/28 days per cycle for 1 year, at escalated dose of 15 to 20 mg during phase 1 to determine the MTD; the phase 2 part was conducted at the MTD. Seventeen RRWM patients were included. The MTD was established at 15 mg/day 21/28. By ITT analysis, the overall response rate was 29%. With a median follow-up of 36 months, median TTP was 16 months (95% CI 5.5-26), the 5-year OS was 91%. The most frequent adverse events ≥ grade 3 at 15 mg were 14% anemia and 43% neutropenia. The MTD of lenalidomide is 15 mg/day 21/28 days in RRWM. Lenalidomide is active in the treatment of RRWM and the safety profile appears manageable. Future studies may look into combinations of lenalidomide and continuous dosing.

IgA kappa/IgA lambda heavy/light chain assessment in the management of patients with IgA myeloma.

BACKGROUND: Accurate quantification of immunoglobulin A (IgA) monoclonal immunoglobulins by serum protein electrophoresis (SPEP) can be difficult and can impact the assessment of response among patients with multiple myeloma (MM). Therefore, there is a need to identify new assays that better reflect disease burden and response to treatment, and correlate with patient outcome. IgA Hevylite (HLC) measures IgA kappa and IgA lambda separately and provides precise quantitative measurements of the monoclonal IgA expression and polyclonal-isotype matched suppression. In the current study, the authors assessed the usefulness of these assays in the diagnosis of IgA MM and sought to comment on the prognostic value of the assays. METHODS: A study of 157 patients with IgA MM for whom diagnostic samples were available was performed. HLC measurements were performed on a nephelometer and the results were compared with those of electrophoresis. RESULTS: All presentation sera (100 IgA kappa specimens and 57 IgA lambda specimens) were found to have abnormal IgA HLC ratios (IgA kappa median ratio: 336.2 [range, 8.2-7353] and IgA lambda ratio: 0.011 [range, 0.0003-0.45]). In comparison, SPEP bands were quantifiable in only 105 of 157 samples (67%) (median, 28.5 g/L [range, 2.2 g/L-98 g/L]). Of the total of 157 patients, 12 patients (8%) presented with oligosecretory myeloma (<10 g/L; including 4 patients with nonquantifiable SPEP bands). HLC uniquely allows for the measurement of isotype paired suppression, which was found to be associated with shortened overall survival in the current study. CONCLUSIONS: In the current study, IgA HLC ratios were found to be abnormal in all patients and the assay was able to produce quantifiable results in more MM sera than either SPEP or total IgA, potentially representing a solution to the issue of comigration and oligosecretory MM. These preliminary data require confirmation in larger prospective trials to validate the usefulness of IgA HLC.

Posterior reversible encephalopathy syndrome (PRES) and myeloma.

Posterior reversible encephalopathy syndrome (PRES) has rarely been described in myeloma, but chemotherapy is a known risk factor. We report 3 patients with myeloma who developed PRES, and analyzed them with 13 published cases, mostly women. The most frequent causative agents were proteasome inhibitors and autologous stem cell transplantation. Risk factors were frequently associated: hypertension, infection or renal failure. Symptoms included headache, blurred vision, altered mental status, seizures. Most patients experienced rapid clinical recovery, without relapse even after resuming treatment. Although rare, we must remain vigilant about PRES in myeloma patients. Stricter control of blood pressure could limit its occurrence.

Efficacy and safety profile of long-term exposure to lenalidomide in patients with recurrent multiple myeloma.

BACKGROUND: Lenalidomide in combination with dexamethasone (Len/Dex) is indicated for patients with recurrent/refractory multiple myeloma (RRMM) who were treated with 1 prior therapy until evidence of disease progression. The objective of the current study was to determine the efficacy and safety profile of long-term exposure to Len/Dex. METHODS: A total of 50 patients with RRMM who were treated with long-term Len for ≥ 2 years from 2 Intergroupe Francophone du Myélome (IFM) centers (Lille and Nancy) were included in the current study. RESULTS: The median age of the patients was 58 years, with 30% of the patients aged >65 years, 49% having an International Staging System stage of 2 and 3, 12% having severe renal insufficiency, and 8% demonstrating an adverse result on fluorescence in situ hybridization. Approximately 56% of the patients received treatment with Len/Dex for ≥ 3 years. The median duration of treatment with Len/Dex was 3 years (range, 2 years-7 years). The response rates for partial response or better and very good partial response or better for the overall cohort were 96% and 74%, respectively, which is similar to patients exposed to Len for ≥ 3 years. With a median follow-up of 4 years, 19 (38%) patients had stopped treatment with Len/Dex. The time to disease progression rate at 37 months was 78% and 91%, respectively, in patients exposed to Len for 2 years to <3 years and for ≥ 3 years (P=025). The safety profile was manageable, similar to that of Len when administered for a shorter period of time; 16% of patients had grade 3 to 4 neutropenia, 6% had thrombopenia, 6% had anemia, and 20% experienced thromboembolic events, all of venous type. The annual incidence rate of second primary malignancy was 1.96% in the current series. CONCLUSIONS: The results of the current study confirmed that the Len/Dex combination is feasible for long-term use in patients with RRMM, with a significant benefit noted in terms of time to disease progression for prolonged treatment with Len/Dex.

A deep dive into future therapies for microcytic anemias and clinical considerations.

INTRODUCTION: Microcytic anemias (MA) have frequent or rare etiologies. New discoveries in understanding and treatment of microcytic anemias need to be reviewed. AREAS COVERED: Microcytic anemias with a focus on the most frequent causes and on monogenic diseases that are relevant for understanding biocellular mechanisms of MA. All treatments except gene therapy, with a focus on recent advances. PubMed search with references selected by expert opinion. EXPERT OPINION: As the genetic and cellular backgrounds of dyserythropoiesis will continue to be clarified, collaboration with bioengineering of treatments acting specifically at the protein domain level will continue to provide new therapies in hematology as well as oncology and neurology.

Molnupiravir compared to nirmatrelvir/ritonavir for COVID-19 in high-risk patients with haematological malignancy in Europe. A matched-paired analysis from the EPICOVIDEHA registry.

INTRODUCTION: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections and decrease hospitalisation and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, whereas molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir because it is associated with fewer drug-drug interactions and contraindications. A caveat for molnupiravir is the mode of action induces viral mutations. Mortality rate reduction with molnupiravir was less pronounced than that with nirmatrelvir/ritonavir in patients without haematological malignancy. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, molnupiravir and nirmatrelvir/ritonavir were compared in a cohort of patients with haematological malignancies. METHODS: Clinical data from patients treated with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and severity of baseline haematological malignancy to controls treated with nirmatrelvir/ritonavir. RESULTS: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (interquartile range [IQR] 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 56.9% (n=66) of the patients had controlled baseline haematological malignancy, 12.9% (n=15) had stable disease, and 30.2% (n=35) had active disease at COVID-19 onset in each group. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of patients in the two groups were vaccinated (molnupiravir n=77, 66% vs. nirmatrelvir/ritonavir n=87, 75%), more of those treated with nirmatrelvir/ritonavir had received four vaccine doses (n=27, 23%) compared with those treated with molnupiravir (n=5, 4%) (P<0.001). No differences were detected in COVID-19 severity (P=0.39) or hospitalisation (P=1.0). No statistically significant differences were identified in overall mortality rate (P=0.78) or survival probability (d30 P=0.19, d60 P=0.67, d90 P=0.68, last day of follow up P=0.68). Deaths were either attributed to COVID-19, or the infection was judged by the treating physician to have contributed to death. CONCLUSIONS: Hospitalisation and mortality rates with molnupiravir were comparable to those with nirmatrelvir/ritonavir in high-risk patients with haematological malignancies and COVID-19. Molnupiravir is a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy.

Targeting Serotonin With Common Antidepressants Induces Rapid Recovery From Cytopenia.

The hematopoietic system uses several, yet undiscovered, factors to adapt to stresses such as chemotherapy, infections, or bleeding. Serotonin is commonly known as a neurotransmitter but is also produced and used in peripheral organs. In particular, we have shown that serotonin synthesized in the bone marrow is necessary for erythroid progenitors' survival and proliferation. Serotonin levels can be increased by FDA approved antidepressants called selective serotonin reuptake inhibitors (SSRI). In this work, we report a previously unknown role of SSRI in the recovery of cytopenia, after autologous hematopoietic stem cell transplantation in patients and after sub-lethal irradiation in mice. We also observed an unexpected cooperation between SSRI and G-CSF on the improvement of the 3 hematopoietic lineages. Of note, SSRI do not seem to affect blood cells production in the absence of stress-induced hematopoiesis. We propose that the serotonergic system could be a valuable therapeutic target in stress-induced cytopenia, especially as a rescue after radiation or chemotherapy.

Enhancing Erythropoiesis by a Phytoestrogen Diarylheptanoid from Curcuma comosa.

Erythropoietin (Epo) is widely used for the treatment of anemia; however, non-hematopoietic effects and cancer risk limit its clinical applications. Therefore, alternative molecules to improve erythropoiesis in anemia patients are urgently needed. Here, we investigated the potential effects of a phytoestrogen diarylheptanoid (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol, (ASPP 049) isolated from Curcuma comosa on promoting erythropoiesis. Treatment with C. comosa extract improved anemia symptoms demonstrated by increasing red blood cell numbers, hematocrit, and hemoglobin content in anemic mice. In addition, ASPP 049, the major compound isolated from C. comosa, enhanced the suboptimal Epo dosages to improve erythroid cell differentiation from hematopoietic stem cells, which was inhibited by the estrogen receptor (ER) antagonist, ICI 182,780. Moreover, the ASPP 049-activated Epo-Epo receptor (EpoR) complex subsequently induced phosphorylation of EpoR-mediated erythropoiesis pathways: STAT5, MAPK/ERK, and PI3K/AKT in Epo-sensitive UT-7 cells. Taken together, these results suggest that C. comosa extract and ASPP 049 increased erythropoiesis through ER- and EpoR-mediated signaling cascades. Our findings provide insight into the specific interaction between a phytoestrogen diarylheptanoid and Epo-EpoR in a hematopoietic system for the potential treatment of anemia.

BLNK mutation associated with T-cell LGL leukemia and autoimmune diseases: Case report in hematology.

We present the case of a female patient with a heterozygous somatic BLNK mutation, a T-cell LGL (large granular lymphocyte) leukemia, and multiple autoimmune diseases. Although this mutation seems uncommon especially in this kind of clinical observation, it could represent a new mechanism for autoimmune diseases associated with LGL leukemia. The patient developed several autoimmune diseases: pure red blood cell apalsia, thyroiditis, oophoritis, and alopecia areata. She also presented a T-cell LGL leukemia which required treatment with corticosteroids and cyclophosphamide, with good efficacy. Interestingly, she had no notable infectious history. The erythroblastopenia also resolved, the alopecia evolves by flare-ups, and the patient is still under hormonal supplementation for thyroiditis and oophoritis. We wanted to try to understand the unusual clinical picture presented by this patient. We therefore performed whole-genome sequencing, identifying a heterozygous somatic BLNK mutation. Her total gamma globulin level was slightly decreased. Regarding the lymphocyte subpopulations, she presented a B-cell deficiency with increased autoreactive B-cells and a CD4+ and Treg deficiency. This B-cell deficiency persisted after complete remission of erythroblastopenia and LGL leukemia. We propose that the persistent B-cell deficiency linked to the BLNK mutation can explain her clinical phenotype.

Erythrocytosis associated with IgA nephropathy.

BACKGROUND: Erythrocytosis is a hematological disorder usually related to hematopoietic stem cell somatic mutations. However, unexplained erythrocytosis remains frequent. In this study, we evaluated the involvement of IgA1, a regulator of erythropoiesis also implicated in IgA nephropathy (IgAN) pathophysiology, in unexplained polycythemia/erythrocytosis (PE) of IgAN patients. METHODS: IgAN-PE patients' serum was collected, analyzed and used to study IgA1 effect on proliferation and differentiation of erythroid progenitors. Hematological parameters of transgenic mice for human alpha1 heavy chain were studied. Multicentric observational cohorts of chronic kidney disease (CKD) patients, including both native kidney diseases and renal transplants, were studied to analyze patient hemoglobin levels. FINDINGS: We retrospectively identified 6 patients with IgAN and unexplained PE. In large CKD cohorts, IgAN was associated with PE in 3.5% of patients (p<0.001 compared to other nephropathies). IgAN was an independent factor associated with higher hemoglobin levels (13.1g/dL vs 12.2 g/dL, p=0.01). During post-transplant anemia, anemia recovery was faster in IgAN patients. Elevated polymeric/monomeric IgA1 ratio as well as high Gd-IgA1 rate were observed in circulating IgA1 of the 6 IgAN-PE patients as compared with control or IgAN patients without PE. IgA1 from these patients increased the sensitivity of erythroid progenitors to Epo. In mice, we also observed an elevation of hematocrit in alpha1 knock-in mice compared to wild type controls. INTERPRETATION: These data identify a new etiology of erythrocytosis and demonstrate the role of pIgA1 in human erythropoiesis. This syndrome of IgA-related erythrocytosis should be investigated in case of unexplained erythrocytosis and renal disease. FUNDING: This work was supported by INSERM (French national institute for health and medical research), Labex GRex and Imagine Institute (Paris, France).

Neuropilin-1 cooperates with PD-1 in CD8+ T cells predicting outcomes in melanoma patients treated with anti-PD1.

Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.