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.
Despite improvement in survival of newly diagnosed adult precursor B-acute lymphoblastic leukemia/lymphoma (B-ALL), the results of relapsed/refractory disease are poor. Blinatumomab, a bispecific ...monoclonal antibody directed against CD19/CD3 show clinical activity against relapsed/refractory B-ALL and in minimal residual disease (MRD)-positive patients.
We report our “real-world” experience with blinatumomab in patients with relapsed/refractory B-ALL.
Twenty-one patients, at a median age 52 years with median disease duration of 10 months, were included. Indications for treatment were hematological relapse (
n
= 17), MRD positivity (
n
= 2), inability to continue intensive chemotherapy (
n
= 1), and bridging to a second alloSCT (
n
= 1). Blinatumomab was given as first salvage in 11 patients and after at least one prior salvage treatment in eight.
Complete response (CR) was newly achieved in 47% and was maintained in 75% of patients with baseline CR. At a median follow-up of 12.4 months, 13 patients were alive, and 11 in CR. Median leukemia-free survival was 8.7 months, and median overall survival was 15.2 months. Median leukemia-free survival and overall survival were not reached in patients proceeding to alloSCT compared to 5.1 and 15.2 months, respectively, for patients who did not receive stem cell transplantation.
Treatment was well tolerated with neurological events reported in two patients (10%) and GI events in three patients (14%). Cytokine storm was reported in four patients (19%).
In conclusion, treatment with blinatumomab is effective and tolerable in adult patients with relapsed/refractory B-ALL outside of a clinical trial stetting.
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the Mucin 1 ...C-terminal subunit (MUC1-C) plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals. Cell lines, primary samples, and xenograft models of CTCL were used to assess synergy of GO-203 with decitabine, a hypomethylating agent. Present studies demonstrate that exposure of CTCL cells to decitabine in combination with GO-203, increased the generation of reactive oxygen species (ROS) levels and decreased levels of scavenger molecules, NADP, NADPH, glutathione, and TIGAR, critical to intracellular redox homeostasis. Dual exposure to GO-203 and decitabine resulted in marked downregulation of DNA methyl transferases demonstrating significant synergy of these agents in inducing global and gene specific hypomethylation. Accordingly, treatment with decitabine and GO-203 upregulated the ROS generating enzymes, NADPH oxidase 4 and dual oxidase 2 potentially due to their effect on epigenomic regulation of these proteins. In concert with these findings, exposure to decitabine and GO-203 resulted in heightened apoptotic death in CTCL cell lines, patient-derived primary samples and in a murine xenograft model. These findings indicate that decitabine intensifies MUC1-C inhibition induced redox imbalance and provides a novel combination of targeted and epigenetic agents for patients with CTCL.
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Abstract
The COVID‐19 pandemic continues to pose challenges to the treatment of hemato‐oncology patients. Emergence of COVID‐19 variants, availability of vaccine boosters and antiviral treatments ...could impact their outcome. We retrospectively studied patients with hematologic malignancies and confirmed COVID‐19 during the Omicron outbreak. Of 116 evaluated patients, 16% developed severe or critical COVID‐19. Diagnosis of chronic lymphocytic leukemia (CLL) was significantly associated with severe COVID‐19 (
p
= 0.01). The vaccine effectiveness was related to the timing of the vaccine, with patients who received a mRNA vaccine within 7–90 days prior to COVID‐19 being less likely to develop severe disease compared to all other patients (
p
= 0.019). There was no correlation between disease severity and antiviral therapies. Importantly, 45% of patients undergoing active hematological treatment had to interrupt their treatment due to COVID‐19. In conclusion, patients with hematologic malignancies are at a considerable risk for severe COVID‐19 during the Omicron outbreak, with patients with CLL being the most vulnerable. mRNA vaccines have the potential to protect hematological patients from severe COVID‐19 if administered within the previous 3 months. Hematological treatment interruption is a frequent adverse outcome of COVID‐19 infection.
This study investigated the impact of COVID‐19 on patients with hematologic malignancies during the Omicron outbreak. Of the 116 patients evaluated, 16% developed severe or critical COVID‐19. chronic lymphocytic leukemia (CLL) was found to be significantly associated with severe COVID‐19, while mRNA vaccines administered within 7–90 days prior to COVID‐19 reduced the likelihood of severe disease. Additionally, 45% of patients undergoing active hematological treatment had to interrupt their treatment due to COVID‐19.
The myeloproliferative neoplasms (MPN) are clonal diseases that confer an increased risk of thrombohemorrhagic complications. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease ...associated with an increased thrombotic risk. Small PNH clones are prevalent in aplastic anemia and myelodysplastic syndrome patients, but their prevalence in MPN patients is unknown.
Consecutive patients with MPN followed up at a single center were recruited. PNH clones were analyzed in erythrocytes and white blood cells by flow cytometry.
PNH clones were detected in 2% of patients and were more common in JAK2 V617F positive patients. We could not detect any differences in clinical manifestations or complications in patients either with or without PNH clones because of the small patient numbers.
The prevalence of PNH clones in MPN is similar to that described in myelodysplastic syndromes. Whether PNH clones influence MPN phenotype and complications should be studied prospectively in larger patient cohorts and over long-term follow-up.
Paroxysmal nocturnal hemoglobinuria (PNH) and myeloproliferative neoplasm (MPN) are diseases associated with increased thrombosis. PNH clones are commonly found in other hematologic diseases, such as myelodysplastic syndromes and aplastic anemia. The presence of PNH clones was studied in consecutive MPN patients. A prevalence of 2% and an association with the JAK2 mutation was found. Presence of a PNH clone could potentially influence the clinical course of MPN.
Macrophage activation syndrome is the most frequent life-threatening complication of adult-onset Still's disease. This is a nearly fatal case of a young patient, which has been refractory to ...corticoste- roids, anakinra, tocilizumab, cyclosporine A, and etoposide, but eventually responded miraculously to salvage therapy with ruxolitinib. We review recent pertinent data related to the therapeutic value of ruxolitinib for macrophage activation syndrome triggered by adult-onset Still's disease.
Patients with hematologic malignancies have an increased risk of severe COVID‐19 infection. Vaccination against COVID‐19 is especially important in these patients, but whether they develop an immune ...response following vaccination is unknown. We studied serologic responses to the BNT162b2 vaccine in this population. A lower proportion of patients were seropositive following vaccination (75%) than in a comparison group (99%; p < 0.001), and median (interquartile range IQR) antibody titers in patients were lower (90 12.4–185.5 and 173 133–232 AU/ml, respectively; p < 0.001). Older age, higher lactate dehydrogenase, and number of treatment lines correlated with lower seropositivity likelihood and antibody titers, while absolute lymphocyte count, globulin level, and time from last treatment to vaccination correlated with higher seropositivity likelihood and antibody titers. Chronic lymphocytic leukemia patients had the lowest seropositivity rate followed by indolent lymphoma. Patients recently treated with chemo‐immunotherapy, anti‐CD20 antibodies, BCL2, BTK or JAK2 inhibitors had significantly less seropositive responses and lower median (IQR) antibody titers (29%, 1.9 1.9–12 AU/ml; 0%, 1.9 1.9–1.9 AU/ml; 25%, 1.9 1.9–25 AU/ml; 40%, 1.9 1.9–92.8 AU/ml; and 42%, 10.9 5.7–66.4 AU/ml, respectively; p < 0.001). Serological response to BNT162b2 vaccine in patients with hematologic malignancies is considerably impaired, and they could remain at risk for severe COVID‐19 infection and death.
Myeloid-derived suppressor cells (MDSCs) play a critical role in promoting immune tolerance and disease growth. The mechanism by which tumor cells evoke the expansion of MDSCs in acute myeloid ...leukemia (AML) has not been well described. We have demonstrated that patients with AML exhibit increased presence of MDSCs in their peripheral blood, in comparison with normal controls. Cytogenetic studies demonstrated that MDSCs in patients with AML may be derived from leukemic or apparently normal progenitors. Engraftment of C57BL/6 mice with TIB-49 AML led to an expansion of CD11b+ Gr1+ MDSCs in bone marrow and spleen. Coculture of the AML cell lines MOLM-4, THP-1 or primary AML cells with donor peripheral blood mononuclear cells elicited a cell contact–dependent expansion of MDSCs. MDSCs were suppressive of autologous T-cell responses as evidenced by reduced T-cell proliferation and a switch from a Th1 to a Th2 phenotype. We hypothesized that the expansion of MDSCs in AML is accomplished by tumor-derived extracellular vesicles (EVs). Using tracking studies, we demonstrated that AML EVs are taken-up myeloid progenitor cells, resulting in the selective proliferation of MDSCs in comparison with functionally competent antigen-presenting cells. The MUC1 oncoprotein was subsequently identified as the critical driver of EV-mediated MDSC expansion. MUC1 induces increased expression of c-myc in EVs that induces proliferation in the target MDSC population via downstream effects on cell cycle proteins. Moreover, we demonstrate that the microRNA miR34a acts as the regulatory mechanism by which MUC1 drives c-myc expression in AML cells and EVs.
•MDSCs are expanded in AML and contribute to tumor-related immune suppression.•MUC1 mediates MDSC expansion via the promotion of c-myc expression in secreted extracellular vesicles.
The understanding of the basic molecular mechanisms of myeloproliferative neoplasms in the last few years led to updating of their diagnostic criteria in the recent classification of myeloid and ...lymphoid neoplasms by the WHO, which was published in 2017. The major changes relating to the diagnosis of myeloproliferative neoplasms include lowering of the hemoglobin threshold and mandatory bone marrow biopsy as major criteria for the diagnosis of polycythemia vera, as well as adding acquired mutation in either CALR or MPL in addition to the common JAK2V617F mutation as a major criterion for diagnosing essential thrombocythemia or myelofibrosis. We review the newest discoveries on the pathogenesis of myeloproliferative neoplasms, highlighting the relevant new additions to their diagnostic criteria, and relevant therapeutic considerations.
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