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Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss-of-function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells also demonstrated sensitivity of SH2B3-mutated hematopoietic progenitor cells to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.

Current single-cell RNA-sequencing approaches have limitations that stem from the microfluidic devices or fluid handling steps required for sample processing. We develop a method that does not require specialized microfluidic devices, expertise or hardware. Our approach is based on particle-templated emulsification, which allows single-cell encapsulation and barcoding of cDNA in uniform droplet emulsions with only a vortexer. Particle-templated instant partition sequencing (PIP-seq) accommodates a wide range of emulsification formats, including microwell plates and large-volume conical tubes, enabling thousands of samples or millions of cells to be processed in minutes. We demonstrate that PIP-seq produces high-purity transcriptomes in mouse-human mixing studies, is compatible with multiomics measurements and can accurately characterize cell types in human breast tissue compared to a commercial microfluidic platform. Single-cell transcriptional profiling of mixed phenotype acute leukemia using PIP-seq reveals the emergence of heterogeneity within chemotherapy-resistant cell subsets that were hidden by standard immunophenotyping. PIP-seq is a simple, flexible and scalable next-generation workflow that extends single-cell sequencing to new applications.

B-cell maturation antigen-targeted chimeric antigen receptor T-cell therapy (BCMA CAR-T) is an effective treatment of relapsed refractory multiple myeloma (MM). However, the pattern of infectious complications is not well elucidated. We performed a single-center retrospective analysis of infection outcomes up to 1 year after BCMA CAR-T for MM from 2018 to 2020. Fifty-five patients with MM were treated with BCMA CAR-T. Before lymphodepletion (LD), 35% of patients had severe hypogammaglobulinemia and 18% had severe lymphopenia. Most patients (68%) received bridging chemotherapy (BC) before LD. In the first month after CAR-T, 98% patients had grade 3 to 4 neutropenia. At 1 year after infusion, 76% patients had hypogammaglobulinemia. With a median follow-up of 6.0 months (95% confidence interval, 4.7-7.4), there were a total of 47 infection events in 29 (53%) patients: 40% bacterial, 53% viral, and 6% fungal. Most (92%) were mild-moderate and of the lower/upper respiratory tract system (68%). Half of the infections (53%) occurred in the first 100 days after CAR-T infusion. Although no statistically significant risk factors for infection were identified, prior lines of therapy, use of BC, recent infections, and post-CAR-T lymphopenia were identified as possible risk factors that need to be further explored. This is the largest study to date to assess infectious complications after BCMA CAR-T. Despite multiple risk factors for severe immunosuppression in this cohort, relatively few life-threatening or severe infections occurred. Further larger studies are needed to better characterize the risk factors for and occurrence of infections after BCMA CAR-T.

We report a case of vaccine-induced immune thrombotic thrombocytopenia (VITT) in a young man diagnosed 13 days after Ad26.COV2.S COVID-19 (Johnson & Johnson/Janssen) vaccination. He presented to us with 5 days of progressive left leg pain, thrombocytopenia, hypofibrinogenemia, and markedly elevated d-dimers, but without radiographically demonstrable thrombosis. Despite negative imaging, we initiated treatment of presumptive VITT given the striking clinical picture that included the timing of his recent adenovirus-based COVID-19 vaccine, leg symptoms, marked thrombocytopenia, and consumptive coagulopathy. He received intravenous immune globulin, prednisone, and argatroban and was discharged 7 days later much improved. His positive platelet factor 4 enzyme-linked immunosorbent assay antibody test returned after treatment was initiated. To our knowledge, this is the first reported case of VITT following Ad26.COV2.S vaccination presenting without radiographically demonstrable thrombosis. Our patient highlights the importance of knowing vaccine status and initiating treatment as soon as possible in the right clinical setting, even in the absence of radiographic evidence of thrombus. Early VITT recognition and treatment provide an opportunity to prevent serious thrombotic complications.

The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.

The article discusses a case study of a 67-year-old Asian female with acute myelogenous leukaemia (AML) who experienced relapse after a bone marrow transplant. The patient underwent a hybrid cell therapy rescue approach involving azacitidine, donor lymphocyte infusion (DLI), and CD34+ stem cell boost to address the relapse and poor graft function. The treatment resulted in disease control, improved graft function, and resolution of chronic graft-versus-host disease (cGVHD). The study suggests that this approach could be beneficial for AML patients with poor functional status and graft function post-transplant who are not eligible for a second transplant. [Extracted from the article]

The rate of MRD clearance in AML with standard consolidation chemotherapy is not well defined. A multi-institution retrospective analysis was performed on 107 consecutively treated AML patients in morphologic complete remission with detectable MRD post-induction therapy who received standard chemotherapy consolidation. In response to standard intermediate/high-dose cytarabine consolidation therapy, 26 of 60 patients (43.3%) with MRD threshold of detection of at least 0.1% converted to MRD-negative status (undetectable with assay used), and 6 of 47 patients (12.8%) with MRD threshold of detection > 0.1% converted to MRD-negative status. Multivariable logistic regression for patients with MRD threshold of detection of at least 0.1% showed that, when controlling for age, ELN risk category, dose of cytarabine, and use of a combination agent, treatment with 1 cycle of consolidation cytarabine versus ≥2 cycles decreased the odds of conversion of AML to MRD-negative (OR = 0.24, 95% CI 0.07–0.85, p = 0.03). [ABSTRACT FROM AUTHOR]