Genotype-phenotype correlations in chronic granulomatous disease: insights from a large national cohort.

ABSTRACT: Neutrophils are the first line of defense against invading pathogens. Neutrophils execute and modulate immune responses by generating reactive oxygen species (ROS). Chronic granulomatous disease (CGD) is a primary immune deficiency disorder of phagocytes, caused by inherited mutations in the genes of the nicotinamide adenine dinucleotide phosphate reduced oxidase enzyme. These mutations lead to failure of ROS generation followed by recurrent bacterial and fungal infections, frequently associated with hyperinflammatory manifestations. We report a multicenter cumulative experience in diagnosing and treating patients with CGD. From 1986 to 2021, 2918 patients experiencing frequent infections were referred for neutrophil evaluation. Among them, 110 patients were diagnosed with CGD: 56 of Jewish ancestry, 48 of Arabic ancestry, and 6 of non-Jewish/non-Arabic ancestry. As opposed to other Western countries, the autosomal recessive (AR) CGD subtypes were predominant in Israel (71/110 patients). Thirty-nine patients had X-linked CGD, in most patients associated with severe infections (clinical severity score ≥3) and poor outcomes, presenting at a significantly earlier age than AR-CGD subtypes. The full spectrum of infections and hyperinflammatory manifestations is described. Six patients had hypomorphic mutations with significantly milder phenotype, clinical severity score ≤2, and better outcomes. Hematopoietic stem cell transplantation was implemented in 39 of 110 patients (35.5%). Successful engraftment was achieved in 92%, with 82% long-term survival and 71% full clinical recovery. CGD is a complex disorder requiring a multiprofessional team. Early identification of the genetic mutation is essential for prompt diagnosis, suitable management, and prevention.

Gilteritinib with or without venetoclax for relapsed/refractory FLT3-mutated acute myeloid leukaemia.

Patients with FLT3-mutated acute myeloid leukaemia (AML) that relapse or are refractory (R/R) to intensive induction have poor outcomes. Gilteritinib has recently become standard-of-care for patients with R/R FLT3-mutated AML. We investigated whether adding venetoclax to gilteritinib (gilt-ven) improves outcomes as compared with gilteritinib monotherapy. We included patients treated with gilteritinib (n = 19) and gilt-ven (n = 17) for R/R AML after intensive chemotherapy. Gilteritinib and gilt-ven groups did not differ in terms of mCRc rates (53% and 65%, p = 0.51) and realization of allogeneic haematopoietic stem-cell transplantation (HSCT, 47% and 35%, p = 0.5). Overall survival (OS) was comparable between groups, although a trend towards better OS was seen with gilt-ven (12-month OS 58.8% [95% CI 39.5%-87.6%]) versus gilteritinib (42.1% [95% CI 24.9%-71.3%] for gilteritinib). Early salvage with gilt-ven versus any other gilteritinib-based approach was associated with the best outcome (p = 0.031). Combination therapy was associated with increased haematological toxicity. In summary, gilt-ven did not improve remissions or HSCT-realization rates in patients with R/R FLT3-mutated AML as compared with gilteritinib and was associated with increased haematological toxicity. Although OS did not differ, a trend towards better survival was suggested with gilt-ven and a survival benefit was shown for gilt-ven approach when sequenced early for salvage.

Genetic backgrounds and clinical characteristics of congenital neutropenias in Israel.

BACKGROUND: Congenital neutropenias are characterized by severe infections and a high risk of myeloid transformation; the causative genes vary across ethnicities. The Israeli population is characterized by an ethnically diverse population with a high rate of consanguinity. OBJECTIVE: To evaluate the clinical and genetic spectrum of congenital neutropenias in Israel. METHODS: We included individuals with congenital neutropenias listed in the Israeli Inherited Bone Marrow Failure Registry. Sanger sequencing was performed for ELANE or G6PC3, and patients with wild-type ELANE/G6PC3 were referred for next-generation sequencing. RESULTS: Sixty-five patients with neutropenia were included. Of 51 patients with severe congenital neutropenia, 34 were genetically diagnosed, most commonly with variants in ELANE (15 patients). Nine patients had biallelic variants in G6PC3, all of consanguineous Muslim Arab origin. Other genes involved were SRP54, JAGN1, TAZ, and SLC37A4. Seven patients had cyclic neutropenia, all with pathogenic variants in ELANE, and seven had Shwachman-Diamond syndrome caused by biallelic SBDS variants. Eight patients (12%) developed myeloid transformation, including six patients with an unknown underlying genetic cause. Nineteen (29%) patients underwent hematopoietic stem cell transplantation, mostly due to insufficient response to treatment with granulocyte-colony stimulating factor or due to myeloid transformation. CONCLUSIONS: The genetic spectrum of congenital neutropenias in Israel is characterized by a high prevalence of G6PC3 variants and an absence of HAX1 mutations. Similar to other registries, for 26% of the patients, a molecular diagnosis was not achieved. However, myeloid transformation was common in this group, emphasizing the need for close follow-up.

Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia.

Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.

Non-Immunotherapy Approaches for Relapsed or Refractory AML: An Update for 2024.

BACKGROUND: Relapsed or refractory (R/R) acute myeloid leukemia (AML) is a challenging, high-risk, clinical scenario with a dismal outcome. Recent insights on the genetic, epigenetic, and metabolic events that drive clonal progression and the advent of novel therapies resulted in the incorporation of several new targeted therapies, alone or in combination, in the R/R setting with the aim of improving response rates and survival. Herein, we review current challenges and future opportunities with non-immunotherapeutic approaches to treat R/R AML. SUMMARY: Inhibitors of FLT3 and IDH 1/2 are now FDA approved for patients with R/R disease and corresponding mutations. These agents are also used in combination with intensive and low-intensity platforms in an attempt to improve response and survival. Several targeted agents are currently being tested alone or in combination in early-phase trials. These include drugs that target apoptotic pathways, drugs that interfere with key survival pathways of the R/R leukemic cell as well as therapies aimed toward the leukemia marrow microenvironment. Menin inhibitors are a promising class of active drugs in NPM1 and KMT2A-rearranged AML. KEY MESSAGES: Several new targeted therapies are being studied and are moving through pre-clinical and clinical pipelines. Significant remaining challenges include the development of synergistic combination therapies tailored to the specific biology and clinical context of the patient, and re-defining the role and timing of allogeneic transplantation in patients with R/R disease.

Utility of echocardiogram in neutropenic patients with gram positive bacteremia - a retrospective study.

INTRODUCTION: Hemato-oncology patients are vulnerable to bloodstream infections due to immunocompromised state and use of intravascular catheters. Data regarding risk of infective endocarditis (IE) among those with gram positive bacteremia is limited. We aimed to evaluate the incidence of IE among neutropenic hemato-oncology patients, and to explore the yield of echocardiogram in this population. METHODS: we conducted a single retrospective study of all hospitalized hemato-oncology neutropenic patients with gram positive blood cultures between 2007 and 2021. Data regarding Patients' characteristics, blood cultures and echocardiogram was collected. RESULTS: Study included 241 patients, with 283 isolates. Coagulase negative staphylococcus (CONS) were the most commonly isolates found, followed by streptococcus viridans. Trans thoracic echocardiography (TTE) was performed in 45% of patients overall, of which 5.8% had additional Trans esophageal echocardiogram (TEE). Only a single case of IE was identified; 47 y/o multiple myeloma patient with neutropenic fever, streptococcus viridans bacteremia, and stroke caused by septic emboli. TTE and TEE failed to demonstrate valvular pathology consistent with IE. Conclusion In our experience, the yield of echocardiogram in hemato-oncological neutropenic patients with bacteremia is extremely low, owing to reduced probability of IE in this population, and thus could be avoided in most cases.

A phase 2 study of ibrutinib maintenance following first-line high-dose methotrexate-based chemotherapy for elderly patients with primary central nervous system lymphoma.

BACKGROUND: Elderly patients account for nearly 70% of all primary central nervous system lymphoma (PCNSL) cases. They cannot tolerate aggressive treatment and have poor prognosis with a median overall survival (OS) of less than 2 years and progression-free survival (PFS) of 6-16 months. Ibrutinib penetrates the blood-brain barrier and has shown activity in PCNSL. METHODS: This prospective study investigated whether ibrutinib maintenance is feasible, and whether it can benefit elderly PCNSL patients in terms of expected 2-year PFS. It is an open label, phase 2 study in newly diagnosed PCNSL patients 60-85 years old who responded to first-line high-dose methotrexate (HDMTX)-based treatment with partial or complete response. Ibrutinib maintenance (560 mg/d) was continued until disease progression or intolerable toxicity. RESULTS: Twenty patients were enrolled, with a median age of 72 years (range, 61-80). Median time on ibrutinib maintenance was 12.5 (range, 2-46) months. Twelve patients stopped treatment: five due to central nervous system relapse and seven due to adverse events that were mainly grade 2. Five patients died (25%) all due to relapse. The 1- and 2-year PFS are 90% and 72.6%, respectively, and the 2-year OS is 89%. CONCLUSIONS: The study reached its primary end points and also showed that ibrutinib maintenance is tolerated reasonably well by the elderly. Therefore, this study supports the concept that ibrutinib maintenance should be further evaluated as an optional consolidation measure in the elderly.

Venetoclax-based salvage therapy for adult patients with relapsed/refractory acute lymphoblastic leukemia.

OBJECTIVES: Dysregulation of BCL-2 family members has been reported in acute lymphocytic leukemia (ALL), with various BH3-dependencies of the leukemic clone. We conducted a multicenter retrospective cohort of patients with relapsed/refractory B or T ALL, with ven-chemotherapy or ven-navitoclax combinations, to assess efficacy and safety. METHODS: Seventeen patients were included in the analysis, median age was 32 years, with 6 B-ALL and 11 T-ALL patients. Nine patients received venetoclax combined with chemotherapy, and 13 patients received venetoclax in combination with navitoclax, vincristine and asparaginase, of which 5 were already exposed to venetoclax in previous lines. RESULTS: ORR was 55% and 46% among the ven-chemotherapy and the ven-navitoclax-chemotherapy, respectively. Most of the responders proceeded to an allogenic bone marrow transplant in both cohorts. The most common adverse effects of the ven-navitoclax combination were infectious complications and hepatotoxicity. CONCLUSIONS: Our data demonstrated the possible efficacy of ven-chemotherapy and ven-navitoclax in r/r ALL with moderate toxicity.

Extracorporeal photopheresis induces NETosis in neutrophils derived from patients with chronic graft-vs-host disease.

INTRODUCTION: Extracorporeal photopheresis (ECP) is considered an effective treatment for patients with chronic graft vs host disease (cGVHD) and demonstrates efficacy in ameliorating GVHD. The mechanism by which ECP acts against cGVHD is not fully understood. Preliminary observations have hinted at the potential involvement of neutrophil extracellular traps (NETs) formation in the pathogenesis of cGVHD. We aimed to assess the influence of ECP on the formation of NETs in patients with cGVHD as a potential mechanism in this setting. METHODS: Patients treated with ECP for cGVHD at the Rabin Medical Center were included in this study. Blood samples were obtained at three different time points: before starting an ECP cycle, at the end of the first day of treatment, and 24 h following the initiation of the ECP treatment cycle. Neutrophils were harvested from all blood samples. NET formation was assessed by measurement of NET-bound specific neutrophil elastase activity and by immunofluorescence staining. RESULTS: Six patients (two females and four males) with cGVHD were included in the study. We observed a significant increase in NET formation among all six patients following ECP. Net-bound specific neutrophil elastase activity was elevated from a median value of 2.23 mU/mL (interquartile range [IQR] 2.06-2.47 mU/mL) at baseline to a median value of 13.06 mU/mL (IQR 10.27-15.97 mU/mL) immediately after the treatment and to a peak median value of 14.73 mU/mL (IQR 9.6-22.38 mU/mL) 24 h following the initiation of the ECP cycle. A qualitative assessment of NET formation using immunofluorescence staining has demonstrated markedly increased expression of citrullinated histone H3, a marker of NET formation, following ECP treatment. CONCLUSIONS: Our preliminary data indicate that ECP induces NET formation among patients with cGVHD. The contribution of increased NET formation to the therapeutic effect of cGVHD should be further investigated.

Casting a NET on cancer: the multiple roles for neutrophil extracellular traps in cancer.

PURPOSE OF REVIEW: The role of the innate immune system has become widely appreciated in cancer and cancer-associated disorders. Neutrophils, the most abundant circulating leukocytes, have prognostic value in determining cancer progression and survival. One of the ways by which neutrophils negatively impact outcome is by formation of neutrophil extracellular traps (NETs) which result in release of nuclear chromatin and bioactive proteins into the extracellular space. Here, we review the evidence for NETs contributions to cancer progression, metastasis, and cancer-associated thrombosis (CAT). RECENT FINDINGS: NETs are increased across several cancer types and predict progression and adverse outcome. Several preclinical and clinical observations implicate NETs in promoting tumor growth, angiogenesis and metastasis via distinct pathways. Furthermore, NETs are shown to contribute to resistance to immunotherapy. NETs also emerge as key players in the prothrombotic phenotype associated with cancer that can result in potentially life-threatening arterial and venous thrombosis. Recent mechanistic insights expose several potential targets to inhibit NET formation and disrupt the interaction between NETs and tumor cells. SUMMARY: Clinical and translational insights highlight the central role of NETs in cancer progression and metastasis, disease resistance and CAT. Targeting NETs and NET-associated pathways may represent a novel approach to treat cancer.

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission after 5-azacitidine and venetoclax: a multicenter retrospective study.

The combination of hypomethylating agents and venetoclax has revolutionized the therapeutic landscape of acute myeloid leukemia (AML), especially for patients previously deemed unfit for curative-intent treatment. Some of these patients undergo allogeneic hematopoietic cell transplant (alloHCT); yet, there are scarce data regarding transplantation outcomes. We conducted a multicenter nationwide retrospective cohort study, including patients with AML who underwent alloHCT in CR1 after frontline treatment with azacitidine plus venetoclax only (aza-ven group). We collected a historical control group of patients who achieved CR1 after first-line intensive chemotherapy only, followed by alloHCT (intensive group). Patients in the aza-ven group (n = 24) were transplanted between 2019 and 2021. Compared to the intensive group, patients in the aza-ven group were older (median age 71.7 vs. 58.4 years), had higher incidence of therapy-related AML and AML with antecedent hematologic disorder and had more often adverse cytogenetics. They had a higher percentage of allografts from matched-unrelated donors, and reduced intensity conditioning was more commonly used. The estimated 12 months non relapse mortality was 19.1% in the aza-ven group and 11.8% in the intensive group. The estimated 12 months relapse-free survival and overall survival were 58% and 63% in the aza-ven group and 54% and 70% in the intensive group, respectively. The cumulative incidence of acute GVHD at 6 months and of chronic GVHD at 12 months were 58% and 40% in the aza-ven group and 62% and 42% in the intensive group, respectively. Analysis of the aza-ven group revealed that HCT-CI score and ELN risk category were predictive of RFS in both univariate analysis as well as multivariate analysis. Our data suggests that alloHCT for AML patients achieving first CR with aza-ven appears feasible, with short-term post-transplant outcomes similar to those expected after traditional intensive chemotherapy.

Venetoclax in combination with FLAG-IDA-based protocol for patients with acute myeloid leukemia: a real-world analysis.

Venetoclax in combination with intensive therapies is explored in both the upfront and relapse/refractory (R/R) setting, and available data suggest that such regimens are effective albeit with added hematological and infectious toxicity. We conducted a multicenter retrospective cohort study of patients with acute myeloid leukemia (AML) treated with venetoclax in combination with FLAG-IDA protocol. Twenty-five patients were included in this analysis (median age 53.4 years). Most patients were treated for R/R AML (n = 24, 96%) with a median of one (range 0-3) previous lines of therapy and 44% of patients (n = 11) having prior allogeneic hematopoietic cell transplantation (HCT). Median follow-up was 10 (range, 4-26) months. Platelet and neutrophil recovery were observed at a median of 31 (95% CI 17.6-38.3) and 23 (95% CI 20-28) days, respectively. The most common adverse events were infectious (blood stream infections, 48% and invasive fungal infections, 32%). Thirty-day mortality was 12%. Composite complete remission (CRc) was 72% for the entire cohort and 91% in patients treated for post-HCT relapse. Incidences of relapse-free and overall survival at 12 months were 67% (95% CI 58-76%) and 50% (95% CI 31-69%), respectively. Real-world data show that the addition of venetoclax to FLAG-IDA protocol is effective in patients with high-risk AML, most notably in the post-HCT relapse setting. Prophylaxis and surveillance for infections are crucial.

Thrombopoietin receptor agonist for treating bone marrow aplasia following anti-CD19 CAR-T cells-single-center experience.

Anti CD-19 chimeric antigen receptor T (CAR-T) cells demonstrate effective early anti-tumor response; however, impaired hematopoietic recovery is observed in about 30% of patients with prolonged cytopenia appearing as an unmet need for optimal treatment. All adult patients given commercially available anti CD-19 CAR-T for diffuse large B cell lymphoma (DLBCL) were screened at 21-28 days after CAR-T infusion for cytopenia. In case of severe persistent cytopenia, patients were given TPO receptor agonists. Initial dose of eltrombopag was 50 mg/day and gradually increased to a maximal dose of 150 mg/day. Romiplostim was given as subcutaneous injection once a week for 2 doses (125 mcg). Response was defined as transfusion independency along with resolution of severe neutropenia (ANC > 500 /microL) and/or platelets > 20,000/microL for three consecutive values on different days. TPO receptor agonists were tapered down when response was met. From May 2019 to December 2021, 93 patients were eligible (74%, tisagenlecleucel and 26%, axicabtagene ciloleucel). The median age was 69 (range, 19-85) years. Six patients (6.5%) (tisagenlecleucel, n = 4 or axicabtagene ciloleucel, n = 2) demonstrated prolonged severe cytopenia and were treated with TPO receptor agonists (eltrombopag, n = 4; romiplastim, n = 1, both drugs, n = 1). Median time from CAR-T infusion to initiation of TPO receptor agonist was 43 (range, 21-55) days. All patients were transfusion-dependent and were given daily GCSF prior to TPO receptor agonist administration. Response to TPO receptor agonists was seen in all 6 patients. Median time from TPO receptor agonist initiation to resolution of cytopenia was 22 (range, 8-124) days for Hb, 27 (range, 6-38) days for platelets, and 29 (range, 7-61) days for neutrophils. A complete resolution of all blood counts (ANC > 500 /microL and platelets > 20,000/microL and hemoglobin > 8 gr/dL) was seen in 5/6 patients. No toxicity was observed during the therapy course. This paper supports further investigation of TPO receptor agonists in the treatment of persistent cytopenia following CAR-T cell therapy.

Gilteritinib monotherapy for relapsed/refractory FLT3 mutated acute myeloid leukemia: a real-world, multi-center, matched analysis.

Patients with FLT3-mutated relapsed or refractory (R/R) acute myeloid leukemia (AML) have a dismal prognosis. Gilteritinib is a FLT3 tyrosine kinase inhibitor (TKI) recently approved for patients with R/R AML. We aimed to characterize real-world data regarding gilteritinib treatment in FLT3-mutated R/R AML and to compare outcomes with matched FLT3-mutated R/R AML patients treated with chemotherapy-based salvage regimens. Twenty-five patients from six academic centers were treated with gilteritinib for FLT3-mutated R/R AML. Eighty percent were treated with a prior intensive induction regimen and 40% of them received prior TKI therapy. Twelve patients (48%) achieved complete response (CR) with gilteritinib. The estimated median overall survival (OS) of the entire cohort was eight (CI 95% 0-16.2) months and was significantly higher in patients who achieved CR compared to those who did not (16.3 months, CI 95% 0-36.2 vs. 2.6 months, CI 95% 1.47-3.7; p value = 0.046). In a multivariate cox regression analysis, achievement of CR was the only predictor for longer OS (HR 0.33 95% CI 0.11-0.97, p = 0.044). Prior TKI exposure did not affect OS but was associated with better event-free survival (HR 0.15 95% CI 0.03-0.71, p = 0.016). An age and ELN-risk matched comparison between patients treated with gilteritinib and intensive salvage revealed similar response rates (50% in both groups); median OS was 9.6 months (CI 95% 2.3-16.8) vs. 7 months (CI 95% 5.1-8.9) in gilteritinib and matched controls, respectively (p = 0.869). In conclusion, in the real-world setting, gilteritinib is effective, including in heavily pre-treated, TKI exposed patients.

Evaluating outcomes of adult patients with acute lymphoblastic leukemia and lymphoblastic lymphoma treated on the GMALL 07/2003 protocol.

Chemotherapy-based approaches still constitute an essential feature in the treatment paradigm of adult acute lymphoblastic leukemia (ALL). The German Multicenter Study Group (GMALL) is a well-established protocol for ALL. In this study, we assessed our recent experience with the GMALL 07/2003 protocol reviewing all adult ALL patients who were treated with GMALL in three major centers in Israel during 2007-2020. The analysis comprised 127 patients with a median age of 41 years (range 17-83). Sixty-two were B-ALL (49%), 20 (16%) patients were Philadelphia chromosome positive ALL, and 45 (35%) were T-ALL. The 2-year and 5-year overall survival rates were 71% and 57%, respectively. The 2-year relapse rate was 30% with 2-year and 5-year leukemia-free survival rates of 59% and 50%, respectively. Adolescents and young adults experienced significantly longer overall survival (84 months versus 51 months; p=0.047) as well as leukemia-free survival compared with older patients (66 months versus 54 months, p=0.003; hazard ratio=0.39, 95% confidence interval, 0.19-0.79; p=0.009). T-ALL patients had longer survival compared to B-ALL patients while survival was comparable among Philadelphia chromosome positive patients and Philadelphia chromosome negative patients. An increased number of cytogenetic clones at diagnosis were tightly associated with adverse prognosis (15-month survival for ≥2 clones versus 81 months for normal karyotype; p=0.003). Positive measurable residual disease studies following consolidation were predictive for increased risk of relapse (64% versus 22%; p=0.003) and shorter leukemia-free survival (11 months versus 42 months; p=0.0003). While GMALL is an effective adult regimen, a substantial patient segment still experiences relapse.

Autoimmune and inflammatory manifestations associated with acute myeloid leukemia with Trisomy 8-Case series and review of the literature.

AML can be associated with autoimmune or inflammatory phenomena (AIP) occurring prior, concomitantly, or after its diagnosis. Trisomy 8 is one of the most common cytogenetic abnormalities associated with AML. We describe three patients with AML, trisomy 8, and associated AIP and review the known literature on this association. All of our patients had major symptomatic relief when treated with leukemia-directed therapy and corticosteroids. AIP in AML may be an underdiagnosed phenomenon, particularly in patients with trisomy 8.

T-Lymphoblastic Leukemia/Lymphoma and Thymoma: A Case Report and Review of the Literature of a Rare Association.

The co-occurrence of thymoma and T-lymphoblastic lymphoma/leukemia is an extremely rare but previously reported association that poses a diagnostic and therapeutic challenge. We describe a 67-year-old patient with long-standing untreated B1 thymoma that presented with constitutional symptoms and a painless soft tissue mass on the right chest wall. Pathological analysis of the biopsy from the mass demonstrated T-lymphoblastic leukemia/lymphoma. The patient went through a complicated course, was refractory to several lines of therapy, and eventually underwent allogeneic hematopoietic stem cell transplantation in complete remission from a matched related donor. The association between thymoma and malignant neoplasms has been described in the literature, most notably with colorectal adenocarcinoma and thyroid cancer. Thymoma-associated leukemia is, however, extremely unusual, with limited reports in the literature. Distinguishing between thymoma and leukemia can be challenging and often requires meticulous diagnostic efforts. For patients with a past history of thymoma, awareness of this particular association should be bared in mind to allow earlier diagnosis and therapy.

Identification of Cancer Cells in the Human Body by Anti-Telomerase Peptide Antibody: Towards the Isolation of Circulating Tumor Cells.

Early detection of tumor cells by identifying universal Tumor Associated Antigens (TAA) can drastically change our diagnostic, theranostic and therapeutic possibilities to cure cancer. Human Telomerase Reverse Transcriptase (hTERT), a hallmark of cancer, could act as an optimal TAA candidate. Here we report about the development of a monoclonal antibody against hTERT peptide (α-hTERT mAb) presented on the surface of cancer cells and its possible applications as a pan-cancer marker. Liquid biopsies, an innovative tool in precision oncology, comprising the noninvasive analysis of circulating tumor-derived material to counteract limitations associated with tissue biopsies. Within the tumor circulome, the US Food and Drug Administration already approved the use of circulating tumor cells (CTCs) as valid liquid biopsies. However, currently CTCs are being trapped using antibodies against specific cancer types, with anti EpCAM as the most common antibody, directed mainly against solid tumors. Moreover, the precision medicine approach is based on specific cancer type directed antibodies. Our novel mAb against the hTERT 16-mer peptide, corresponding to amino acids 611-626, is capable of detecting various types of cancer cells both in vitro and ex vivo from tumors of patients with either hematological or solid tumors. This antibody does not bind to normal lymphocytes cells. Cleavage of our antibody to F(ab')2 fragments increased its binding specificity to the tested cancer cells. Future studies may point to the use of this antibody in the procedure of capturing CTCs.

Midostaurin in combination with chemotherapy is most effective in patients with acute myeloid leukemia presenting with high FLT3-ITD allelic ratio who proceed to allogeneic stem cell transplantation while in first complete remission.

OBJECTIVES: Midostaurin, a multikinase and FLT3 inhibitor, is the first non-chemotherapy agent approved and widely adopted for the treatment of FLT3-ITD acute myeloid leukemia (AML). Yet, its role in improving survival of patients referred to allogeneic stem cell transplantation (allo-SCT) in first complete remission (CR1) needs to be defined. METHODS: This multicenter study retrospectively evaluated the outcome of 119 FLT3-ITD AML patients [59 (49.6%) males and 60 females] intensively treated between 2015 and 2019 at five Israeli centers. In our cohort, allo-SCT in CR1 was widely implemented (47%) and patient stratification was based on the current allelic ratio (AR) cutoff of 0.5. RESULTS: Ninety-eight patients (82.3%) achieved CR1/CR with incomplete count recovery (CRi). Death during induction was reported in 7 (5.9%) patients. In multivariate analysis, midostaurin use and allo-SCT in CR1 were the most significant factors affecting overall survival (OS). Midostaurin incorporation in chemotherapy regimens significantly improved CR + CRi rates (P = .002), reduced relapse rates (P = .02), and was remarkably advantageous for high-AR patients (2-year OS 82%). In low-AR patients, the midostaurin effect was much less prominent. CONCLUSIONS: Our results demonstrate benefits of midostaurin incorporation in intensive chemotherapy regimens, particularly for high-AR AML patients to whom it should be offered along with allo-SCT in CR1.

Venetoclax combinations induce high response rates in newly diagnosed acute myeloid leukemia patients ineligible for intensive chemotherapy in routine practice.

Combinations of the BCL-2 inhibitor, venetoclax, with either hypomethylating agents (HMA) or low dose cytarabine (LDAC), have shown promising results in clinical trials of AML patients unfit for intensive therapy. We report on the efficacy and safety of venetoclax combinations in AML patients treated outside of clinical trials. Complete remission (CR) + CR with incomplete count recovery (CRi) were achieved in 61% of patients, with similar CR+CRi rates in with secondary AML, and in patients who were previously treated with HMA (61% and 43%, respectively). Relapse occurred in 25% of patients, with a median event-free survival (EFS) of 11.7 months (95% CI, 10.09-13.35) in responding patients. At a median follow up of 8.7 months, the median overall survival (OS) was 9.8 months (95% CI 6.42-13.3) in the entire cohort. In multivariate analysis adverse karyotype was the only negative predictor of CR/CRi (p = .03), while both ECOG performance status (PS) and adverse karyotype were significantly associated with shorter OS (p = .023 and .038, respectively). Median OS was higher in patients achieving CR/CRi and in patients proceeding to allogeneic stem cell transplantation (allo-SCT). Treatment was well tolerated, with side effects similar to those described in the randomized clinical trials. Tumor lysis syndrome (TLS) occurred in 12% of patients. Our data support the efficacy and safety of venetoclax combinations in newly diagnosed AML patients not eligible for intensive therapy. According to our data, secondary AML patients could benefit from venetoclax combinations similarly to de-novo AML patients, and allo-SCT could be offered to selected patients achieving CR/CRi.