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Objectives Systemic inflammatory and autoimmune diseases can be associated with myelodysplastic syndromes. Current treatments (steroids, immunosuppressive agents, biologics) are unsatisfactory because of their low response rate, dependence or adverse events. We aimed at evaluating the effects of low doses of IL-2 (ld-IL2) as a regulatory T-cell inducer in this context. Methods We treated three patients with ld-IL2 with myelodysplastic syndromes and an associated dysimmune disorder (polymyalgia rheumatic, relapsing polychondritis associated with Sweet's syndrome and vasculitis with cutaneous and joint involvement, respectively). All three patients were dependent on steroids and refractory to biologics or azacitidine. They received doses of 1–1.5 million units of proleukin/day during 5 days and then every fortnight. Results The treatment led to a clinical improvement and steroid sparing in 2/3 patients with no serious adverse events, and no progression of the disease. Conclusion Our results support the investigation of ld-IL2 in MDS associated with immune disorders in controlled clinical studies. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to a-ketoglutarate. IDH1/2 mutations define distinct subsets of cancers, including low-grade gliomas and secondary glioblastomas, chondrosarcomas, intrahepatic cholangiocarcinomas, and hematologic malignancies. Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in the accumulation and secretion in vast excess of an oncometabolite, the D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis. Indeed, high levels of D-2HG inhibit a-ketoglutarate-dependent dioxygenases, including histone and DNA demethylases, leading to histone and DNA hypermethylation and finally a block in cell differentiation. Furthermore, D-2HG is a biomarker suitable for the detection of IDH1/2 mutations at diagnosis and predictive of the clinical response. Finally, mutant-IDH1/2 enzymes inhibitors have entered clinical trials for patients with IDH1/2 mutations and represent a novel drug class for targeted therapy. [ABSTRACT FROM AUTHOR]

Introduction: Hemophagocytic lymphohistiocytosis induced by viral diseases is a well recognized entity. Severe forms of H5N1 influenza are known to be associated with symptoms very similar to a reactive hemophagocytic syndrome. We report a case of fulminant lymphohistiocytosis associated with the pandemic A (H1N1) variant.Case Presentation: A 42-year-old Caucasian woman developed a syndrome of fatal hemophagocytic lymphohistiocytosis shortly after H1N1 influenza. Initial symptoms of the viral disease were unusual, with acute abdominal involvement. Our patient's course was complicated by diffuse skin rash and ileal ischemia. Our patient died of refractory shock and multi-organ failure. Skin, ileum and colon histology was consistent with an acute apoptosis combined with an increased cellular regeneration.Conclusions: Influenza may be complicated by severe forms of hemophagocytic lymphohistiocytosis. To ensure early recognition and treatment, physicians should be aware of the possible induction of the syndrome by the novel H1N1 variant. The rapid occurrence of a multi-organ involvement with evocative biological features of macrophage activation should alert clinicians. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Patients and Methods Results Conclusion Early‐phases clinical trials (Phases 1 and 2) have evolved from a traditional assessment of toxicity to an adaptive approach based on patients' medical needs and access to effective new therapies. The global risks, benefits, and relevance of early‐phases clinical trials participation for patients with hematological malignancies remain poorly evaluated.All early‐phases clinical trials participations for patients with hematological malignancies, from 2008 to 2023, in a tertiary academic center in Europe, were reviewed. Patient's demographics, tumor type categories, therapeutic responses, mortality, overall survival (OS), and investigational product (IP) were assessed.Over the period 2008–2023, 736 patients participating in 92 different early‐phases clinical trials, were analyzed. The most common tumor categories were diffuse large B‐cell lymphoma (n = 253; 34.4%), acute myeloid leukemia/myelodysplastic syndrome (n = 164; 22.3%) and multiple myeloma (n = 100; 13.6%). The median OS was 14.8 (95% CI: 12.4–17.9) months and response rate 31.9%, including complete responses in 13.5% of patients. By tumor categories, the highest and lowest median duration of OS were observed for patients with Hodgkin lymphoma (99.8; [95% CI: 47.0‐not reached] months) and peripheral T‐cell lymphoma (8.9 [95% CI: 5.3–12.0] months), respectively. The on‐protocol and treatment‐related mortality rates were 5.43% and 0.54%, respectively. Overall response rate was 29.1% including 13.5% of complete response. Overall, 202 (27.5%) patients received an IP later approved by the health authorities, and those patients had better OS (18.2 months vs. 12.1 months HR: 1.160 [95% CI; 0.6977–1.391], p = 0.0283).In conclusion, patients with hematologic malignancies who have participated in early‐phases clinical trials over the past 15 years have achieved variable therapeutic response rates, acceptable risk/benefit ratio and potentially significant therapeutic advantages. This study provides framework material for hematologists to further discuss clinical trial participation with their patients. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 71-year-old man hospitalized for septic shock due to Streptococcus gallolyticus and was diagnosed with bone marrow necrosis and secondary bone marrow infection caused by septicemia, and died without taking specific treatment except for antibiotherapy.

The SARS-CoV-2 pandemic still represents a threat for immunosuppressed and hematological malignancy (HM) bearing patients, causing increased morbidity and mortality. Given the low anti-SARSCoV-2 IgG titers post-vaccination, the COVID-19 threat prompted the prophylactic use of engineered anti-SARS-CoV-2 monoclonal antibodies. In addition, potential clinical significance of T cell responses has been overlooked during the first waves of the pandemic, calling for additional in-depth studies. We reported that the polarity and the repertoire of T cell immune responses govern the susceptibility to SARS-CoV-2 infection in health care workers and solid cancer patients. Here, we longitudinally analyzed humoral and cellular immune responses at each BNT162b2 mRNA vaccine injection in 47 HM patients under therapy. Only one-third of HM, mostly multiple myeloma (MM) bearing patients, could mount S1-RBD-specific IgG responses following BNT162b2 mRNA vaccines. This vaccine elicited a S1-RBD-specific Th1 immune response in about 20% patients, mostly in MM and Hodgkin lymphoma, while exacerbating Th2 responses in the 10% cases that presented this recognition pattern at baseline (mostly rituximab-treated patients). Performing a third booster barely improved the percentage of patients developing an S1-RBD-specific Th1 immunity and failed to seroconvert additional HM patients. Finally, 16 patients were infected with SARS-CoV-2, of whom 6 developed a severe infection. Only S1-RBD-specific Th1 responses were associated with protection against SARS-CoV2 infection, while Th2 responses or anti-S1-RBD IgG titers failed to correlate with protection. These findings herald the paramount relevance of vaccine-induced Th1 immune responses in hematological malignancies. [ABSTRACT FROM AUTHOR]

A 37-year-old man presented a slight debility. The hemogram showed a phenotype of β-thalassemia minor: Hb (13.1 g/dL), mean corpuscular volume (MCV) (62 fL) with low mean corpuscular hemoglobin (MCH) (20.8 pg), associated with a high level of Hb A2 of 5.3%. The serum ferritin level was 1,072 ng/mL. The sequencing of the mutated fragment revealed a duplication of four bases of codons 7/8 involving a shift in the open reading frame starting from codon 9 with a TGA stop codon at codon 23: codons 7/8/9 (+AGAA); GAG.AAG.TCT(Gly-Lys-Ser)>GAG.AA AGAAG. The human hemoglobin (Hb) instability tests were negative. The patient did not present the high iron Fe (HFE) mutation (C282Y, H63D). The same mutation was found in five other unrelated families (representing a total of 23 patients). All of their ancestors came from the north of France. This mutation has not been described before and could have its origins in the native populations of Northern France. [ABSTRACT FROM AUTHOR]

Germline mutations in adult AML patients are uncommon and often associated with organ dysfunction (i.e. I GATA2 i deficiency [[6]]) or a preexisting hematologic disorders (i.e. thrombocytopenia in I RUNX1 i mutated patients [[7]]), but could also found in de "novo" patients (i.e. I CEBPA i [[8]] and I DDX41 i [[9]]). Three patients (50%) had extramedullary localization (nodal involvement, hepatosplenomegaly and skin lesion in 3, 2, and 1 patients respectively), compared to 11/72 (15%) for other AML patients. As we treated patients from this geographic area with familial history of AML but no personal history of MPN, we wondered if CNVdup14 could arise in " I de novo i AML" patients. Genetic predisposition to acute myeloid leukemia (AML) concerns a minority of adult patients. [Extracted from the article]

Objectives: To evaluate the efficacy and tolerability of an attenuated immunochemotherapy regimen based on cytarabine, etoposide and dexamethasone plus rituximab (R‐mini‐CYVE) in patients with relapsed or refractory B‐cell non–Hodgkin's lymphoma (NHL). Methods: We included pretreated adult patients with B‐cell NHL who were ineligible for high‐dose immunochemotherapy (HDT). Cytarabine and etoposide were given at four different dose levels, depending on the patient's frailty. Up to 8 cycles were administered. Results: Between 2013 and 2019, 56 patients with diffuse large B‐cell lymphoma (n = 45, 80%) and indolent B‐cell lymphoma (n = 11, 20%) were included. Median age was 75 (range: 36‐88). Nineteen patients (35%) had a performance status ≥2. Patients received a median of 4 cycles of R‐mini‐CYVE. The objective response and the complete response rates were 50% and 33%, respectively. Median progression‐free survival and overall survival times were 5.7 (95% CI: 0.5‐10.9) and 14.7 (95% CI: 3.5‐25.9) months, respectively. Grade ≥3 anaemia, thrombocytopenia and neutropenia occurred in 44%, 55% and 60% of the patients, respectively. The most frequent non‐haematological grade ≥3 adverse events were sepsis (21%), fatigue (13%) and cytarabine‐related neurotoxicity (5%). Conclusion: R‐mini‐CYVE demonstrated a meaningful antitumour efficacy and an acceptable safety profile in patients with relapsed/refractory B‐cell NHL who were ineligible for HDT. [ABSTRACT FROM AUTHOR]

Background: High‐dose cyclophosphamide to treat solid refractory tumors demonstrated meaningful activity, while data to treat lymphoma remain scarce. This study aims to assess high‐dose cyclophosphamide to treat relapsed or refractory lymphoma. Methods: A phase II study included adult patients with relapsed or refractory B‐cell non‐Hodgkin's lymphoma, previously treated by ≥2 prior lines with no other available option of therapy. High‐dose cyclophosphamide was given intravenously 3 g/m2 over two consecutive days and repeated once at 28 days in responding patients. Rituximab 375 mg/m2 intravenously was added in patients not refractory to anti‐CD20 antibody. Results: Forty‐two patients with median age 65 [56‐70] years were included. Patients had previously received a median of four lines of therapies. Tumor types were diffuse large B‐cell lymphoma (n = 26; 62%), indolent B‐cell non‐Hodgkin lymphoma (n = 10; 24%), or mantle lymphoma (n = 6; 14%). Hematologic and non‐hematologic grade 3‐5 toxicities occurred in 42 (100%) and 18 (43%) of patients, respectively. The overall response rate was 45%. Conclusion: One to two cycles of high‐dose cyclophosphamide in hard‐to‐treat patients with relapsed or refractory B‐cell non‐Hodgkin lymphoma demonstrated a favorable safety and efficacy profile. This regimen could serve as a bridge to modern cellular therapy with CAR‐T cell. [ABSTRACT FROM AUTHOR]

Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 doseescalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. [ABSTRACT FROM AUTHOR]

Purpose Radiation combined with chemotherapy has recently been proposed to treat patients with localised extranodal natural killer (NK)/T lymphoma (ENKTL), nasal type. However, the modalities of the chemoradiotherapy combination and drug choices remain a matter of debate. We conducted a concurrent chemoradiotherapy (CCRT) study with the ESHAP (Etoposide, Steroid, High-dose Ara-C and Platinum) regimen. Methods An induction phase with two upfront courses of CCRT delivering a 40 Gy dose of radiation concurrently with two cycles of the ESHAP chemotherapy regimen, followed by a consolidation phase with 2–3 cycles of ESHAP chemotherapy alone. Results Thirteen patients with localised ENKTL nasal type were enrolled between January 2005 and December 2014. The median age was 62 years. Ten and three patients had Ann Arbor stage IE and IIE disease, respectively. They all completed the induction CCRT phase. A median of two consolidation ESHAP cycles were delivered. During consolidation, 8/13 (62%) patients had a reduction in the number of chemotherapy cycles or reduced chemotherapy doses, due to haematologically adverse events. The other five patients (38%) received the full number of ESHAP cycles of chemotherapy scheduled without a dose reduction. All but one patient (92%) experienced grade 3–4 haematological toxicity. The main non-haematological grade 3–4 toxicity was mucositis in 6/13 (46%) patients. All but one patient (92%) achieved a complete remission. Two-year overall survival was 72%. Conclusions With optimal management of the specific toxicities induced by this treatment modality, CCRT with the ESHAP regimen yielded high efficacy against localised ENKTL, nasal type. [ABSTRACT FROM AUTHOR]

The article focuses on determination of retroperitoneal fibrosis (RPF) as extramedullary hematopoiesis of a chronic myelomonocytic leukemia (CMML). It mentions that CMML-associated RPF that remained unresponsive to steroids but dramatically improved upon treatment with the demethylating drug azacytidine. It states that the occurrence of an autoimmune or inflammatory disorder, mostly a vasculitis, an arthritis or a relapsing polychondritis is a well-known feature in CMML.

Outcome of patients with high risk MDS and CMML who failed treatment with azacitidine remains poor with a median survival of 6 months, without established therapy available except allogeneic hematopoietic stem cell transplantation. The objective of our study was to evaluate efficacy of decitabine after azacitidine failure in a relatively large patient cohort based on conflicting results with 0–28% response rates (RR) in this setting in small patient series. Thirty-six consecutive high risk MDS and CMML patients who received decitabine after azacitidine failure were retrospectively reviewed. Response was based on IWG 2006 criteria for MDS and CMML with WBC <13 G/l and also included for proliferative CMML the evolution of WBC, splenomegaly (SMG) and extramedullary disease (EMD). Patients received a median number of 3 (range 1–27) cycles of decitabine and 12 patients received at least 6 cycles. Seven (19.4%) patients were responders including 3 marrow CR (mCR), 2 stable disease (SD) with HI-E, 1 SD with HI-N and HI-P and 1 SD with HI-N. In a CMML patient with SD, specific skin lesions resolved with decitabine. Responses were generally short lived (2–5 months) except 1 responder currently ongoing with +11 months follow up. Two non-responders had prolonged SD (without HI) of 21 and 27 months duration respectively. Median OS from onset of decitabine was 7.3 months, without significant difference between responders and non-responders. Treatment with decitabine after azacitidine failure yielded modest ORR (19.4%) with short response duration and poor OS. Thus, use of decitabine in such patients who failed or progressed after azacitidine cannot be recommended, underscoring the need for novel strategies in this setting. [ABSTRACT FROM AUTHOR]

Megakaryopoiesis is a 2-step differentiation process, regulated by thrombopoietin (TPO), on binding to its cognate receptor myeloproliferative leukemia (MPL). This receptor associates with intracytoplasmic tyrosine kinases, essentially janus kinase 2 (JAK2), which regulates MPL stability and cell-surface expression, and mediates TPO-induced signal transduction. We demonstrate that JAK2 and MPL mediate TPO-induced proliferation arrest and megakaryocyte differentiation of the human megakaryoblastic leukemia cell line UT7-MPL. A decrease in JAK2 or MPL protein expression, and JAK2 chemical inhibition, suppress this antiproliferative action of TPO. The expression of JAK2 and MPL, which progressively increases along normal human megakaryopoiesis, is decreased in platelets of patients diagnosed with JAK2- or MPL-mutated essential thrombocytemia and primary myelofibrosis, 2 myeloproliferative neoplasms in which megakaryocytes (MKs) proliferate excessively. Finally, low doses of JAK2 chemical inhibitors are shown to induce a paradoxical increase in MK production, both in vitro and in vivo. We propose that JAK2 and MPL expression levels regulate megakaryocyte proliferation vs differentiation in both normal and pathological conditions, and that JAK2 chemical inhibitors could promote s paradoxical thrombocytosis when used at suboptimal doses. [ABSTRACT FROM AUTHOR]

Background: The Prognostic Inflammatory and Nutritional Index (PINI) is a simple scoring system that aggregates two blood markers of inflammatory [C-reactive protein (CRP) and orosomucoid] and of nutritional (albumin and prealbumin) states. It is used in routine practice in geriatric medicine, especially in hospitalized elderly patients. This study was undertaken to evaluate the usefulness of PINI index in multiple myeloma (MM), a malignancy of the elderly. Method: The PINI score was determined in 231 previously untreated patients with MM, of whom 112 were ≥65 yrs old. The serum albumin, prealbumin, orosomucoid (human α1-acid glycoprotein), and hsCRP are measured routinely by immunonephelometry. Results: In the overall population and the elderly subset, PINI ≥ 4 ('high PINI') was correlated with a shorter median survival, 26 vs. 65 months in the high and low PINI groups, respectively. The prognostic impact of PINI index was dramatic in the elderly MM subgroup, 6 and 45 months, respectively. The high PINI index also predicted for shorter survival in various groups with good prognostic, such as low International Staging System (ISS) stages, low b2m, and absence of del17p and t(4;14), further demonstrating its prognostic impact on overall survival. In multivariate analysis, PINI index provided additional survival prognostic information to b2m in a b2m/PINI model. Conclusion: PINI index appears to be a useful and easy-to-perform marker in routine to determine the prognosis of patients with MM, especially in the elderly population. PINI might represent an alternative to ISS score, especially in elderly patients, in the future. [ABSTRACT FROM AUTHOR]

Summary The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors. [ABSTRACT FROM AUTHOR]