Inhibition of NOTCH4 sensitizes FLT3/ITD acute myeloid leukemia cells to FLT3 tyrosine kinase inhibition.

Internal tandem duplication mutations of FLT3 (FLT3/ITD) confer poor prognosis in AML. FLT3 tyrosine kinase inhibitors (TKIs) alone have limited and transient clinical efficacy thus calling for new targets for more effective combination therapy. In a loss-of-function RNAi screen, we identified NOTCH4 as one such potential target whose inhibition proved cytotoxic to AML cells, and also sensitized them to FLT3 inhibition. Further investigation found increased NOTCH4 expression in FLT3/ITD AML cell lines and primary patient samples. Inhibition of NOTCH4 by shRNA knockdown, CRISPR-Cas9-based knockout or γ-secretase inhibitors synergized with FLT3 TKIs to kill FLT3/ITD AML cells in vitro. NOTCH4 inhibition sensitized TKI-resistant FLT3/ITD cells to FLT3 TKI inhibition. The combination reduced phospho-ERK and phospho-AKT, indicating inhibition of MAPK and PI3K/AKT signaling pathways. It also led to changes in expression of genes involved in regulating cell cycling, DNA repair and transcription. A patient-derived xenograft model showed that the combination reduced both the level of leukemic involvement of primary human FLT3/ITD AML cells and their ability to engraft secondary recipients. In summary, these results demonstrate that NOTCH4 inhibition synergizes with FLT3 TKIs to eliminate FLT3/ITD AML cells, providing a new therapeutic target for AML with FLT3/ITD mutations.

Assessment and management of upper limb lymphoedema in advanced disease: a case study.

Lymphoedema is thought to affect around 200 000 people in the UK (NHS England, 2023). Secondary lymphoedema is a relatively common complication of cancer and cancer treatment, and in advanced disease it may present a challenging issue for community nursing staff caring for patients approaching the end of their lives. In this article, a case study considers the assessment and treatment of upper limb lymphoedema in a patient with advanced metastatic breast cancer. Management of this complex and distressing condition requires holistic assessment and collaborative care planning with the patient and their wider care team, including onward referral to specialist lymphoedema and palliative care services. The case study considers the typical presentation of lymphoedema in an upper limb, exclusion of reversible causes for oedema, awareness of palliative care emergencies such as superior vena cava obstruction, and the provision of supportive therapeutic interventions in context of the patient's expressed wishes for her ongoing care.

Transdifferentiation, phenotypic infidelity, progression, and transformation in T/NK-cell neoplasms: Report from the 2021 SH/EAHP Workshop.

OBJECTIVES: Sessions 8 and 9 of the 2021 Society for Hematopathology and the European Association for Haematopathology Workshop aimed to collect examples of transdifferentiation, lineage infidelity, progression, and transformation in precursor and mature T/natural killer (NK)-cell neoplasms. METHODS: Twenty-eight cases were submitted and analyzed, with whole-exome sequencing and genome-wide RNA expression analysis performed in a subset of the cases. RESULTS: In session 8, 7 T-lymphoblastic lymphoma/leukemia cases were received that showed transdifferentiation to clonally related mature myeloid hematopoietic neoplasms, including 6 histiocytic/dendritic cell lineage neoplasms and a mast cell sarcoma. Session 9 included 21 mature T-cell neoplasms that were grouped into 3 themes. The first one addressed phenotypic infidelity in mature T-cell lymphomas (TCLs) and included 8 TCLs expressing aberrant antigens, mimicking classic Hodgkin and non-Hodgkin B-cell lymphomas. The second theme addressed disease progression in TCL and included 5 cutaneous T-cell lymphoproliferative disorders and 2 T-cell large granular lymphocyte proliferations with subsequent progression to systemic TCL. The third theme included 6 patients with TCL with T-follicular helper phenotype, mainly angioimmunoblastic T-cell lymphoma, with concurrent/subsequent clonal hematopoiesis or myeloid neoplasms and/or subsequent/concomitant diffuse large B-cell lymphoma. CONCLUSIONS: This cohort of cases allowed us to illustrate, discuss, and review current concepts of transdifferentiation, aberrant antigen expression, and progression in various T/NK-cell neoplasms.

Progression of follicular lymphoma and related entities: Report from the 2021 SH/EAHP Workshop.

OBJECTIVES: The 2021 Society for Hematopathology and European Association for Haematopathology Workshop addressed the molecular and cytogenetic underpinnings of transformation and transdifferentiation in lymphoid neoplasms. METHODS: Session 4, "Transformations of Follicular Lymphoma," and session 5, "Transformations of Other B-Cell Lymphomas," included 45 cases. Gene alteration analysis and expression profiling were performed on cases with submitted formalin-fixed, paraffin embedded tissue. RESULTS: The findings from session 4 suggest that "diffuse large B-cell lymphoma/high-grade B-cell lymphoma with rearrangements of MYC and BCL2" is a distinct category arising from the constraints of a preexisting BCL2 translocation. TdT expression in aggressive B-cell lymphomas is associated with MYC rearrangements, immunophenotypic immaturity, and a dismal prognosis but must be differentiated from lymphoblastic -lymphoma. Cases in session 5 illustrated unusual morphologic and immunophenotypic patterns of transformation. Additionally, the findings support the role of cytogenetic abnormalities-specifically, MYC and NOTCH1 rearrangements-as well as single gene alterations, including TP53, in transformation. CONCLUSIONS: Together, these unique cases and their accompanying molecular and cytogenetic data suggest potential mechanisms for and unusual patterns of transformation in B-cell lymphomas and indicate numerous opportunities for further study.

Transformations of marginal zone lymphomas and lymphoplasmacytic lymphomas: Report from the 2021 SH/EAHP Workshop.

OBJECTIVES: To summarize the conclusions of the 2021 Society for Hematopathology/European Association for Haematopathology workshop regarding transformations of marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL). METHODS: Nineteen cases were submitted to this portion of the workshop. Additional studies were performed in cases with sufficient material. RESULTS: Cases included splenic MZL (n = 4), splenic diffuse red pulp small B-cell lymphoma (n = 2), nodal MZL (n = 4), extranodal MZL (n = 1), and LPL (n = 8). The most common transformation was to diffuse large B-cell lymphoma (DLBCL), but others included classic Hodgkin lymphoma, high-grade B-cell lymphomas with MYC and BCL6 rearrangements, plasmablastic lymphoma, and plasma cell leukemia. Two splenic MZLs with transformation to DLBCL contained t(14;19)(q32;q13.3) IGH::BCL3 rearrangements in both samples. Paired sequencing studies in 5 MZLs with transformation to clonally related DLBCL identified a variety of mutations and gene fusions at the time of transformation, including CARD11, IGH::MYC, NOTCH2, P2RY8, TBLX1X1, and IGH::CD274. CONCLUSIONS: Marginal zone lymphoma and LPL may undergo a variety of transformation events, most commonly to DLBCL, which is usually, although not always, directly clonally related to the underlying low-grade lymphoma. Multiparameter analysis including broad-based sequencing studies can assist in the diagnosis and classification of these uncommon cases.

Progression and transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma and B-cell prolymphocytic leukemia: Report from the 2021 SH/EAHP Workshop.

OBJECTIVES: Session 3 of the 2021 Workshop of the Society for Hematopathology/European Association for Haematopathology examined progression and transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and B-cell prolymphocytic leukemia (B-PLL). METHODS: Thirty-one cases were reviewed by the panel. Additional studies such as immunohistochemistry and molecular genetic testing, including whole-exome sequencing and expression profiling, were performed in select cases. RESULTS: Session 3 included 27 CLL/SLL cases and miscellaneous associated proliferations, 3 cases of B-PLL, and 1 case of small B-cell lymphoma. The criteria for -accelerated CLL/SLL are established for lymph nodes, but extranodal disease can be diagnostically challenging. Richter transformation (RT) is a broad term and includes true transformation from original CLL/SLL clone(s) and clonally unrelated neoplasms. The morphologic, immunophenotypic, and genetic spectrum is diverse with classical and highly unusual examples. T-cell proliferations can also be encountered in CLL/SLL. B-cell prolymphocytic leukemia is a rare, diagnostically challenging disease due to its overlaps with other lymphoid neoplasms. CONCLUSIONS: The workshop highlighted complexity of progression and transformation in CLL/SLL and B-PLL, as well as diagnostic caveats accompanying heterogeneous presentations of RT and other manifestations of disease progression. Molecular genetic studies are pivotal for diagnosis and determination of clonal relationship, and to predict response to treatment and identify resistance to targeted therapy.

B-cell lineage neoplasms transdifferentiating into histiocytic/dendritic cell neoplasms: diversity, differentiation lineage, genomic alterations, and therapy: Report from the 2021 SH/EAHP Workshop.

OBJECTIVES: To report findings from the 2021 Society for Hematopathology/European Association for Haematopathology Workshop within the category of B-cell lineage neoplasms' transdifferentiation into histiocytic/dendritic cell neoplasms (HDCNs). METHODS: The workshop panel reviewed 29 cases, assigned consensus diagnoses, and summarized findings. RESULTS: The specific diagnoses of transdifferentiated HDCN tumors were histiocytic sarcoma (16); Langerhans cell histiocytosis/sarcoma (5); indeterminate DC tumor (1); and HDCN, unclassifiable (1). Approximately one-third of the patients reviewed had follicular lymphoma; lymphoblastic leukemia/lymphoma; or another B-cell lymphoma, most commonly chronic lymphocytic leukemia/small lymphocytic lymphoma. There was a 3:1 preponderance toward women, median patient age was 60 years, and the median interval between the initial diagnosis of B-cell lineage neoplasm and HDCN was 4 to 5 years. The submitted cases have demonstrated substantial heterogeneity as well as overlapping immunophenotypic and other features. Comprehensive genomic DNA sequencing revealed alterations enriched in the MAPK pathway. Based on shared and distinct alterations seen in HDCNs and the preceding lymphomas, both linear and divergent clonal evolutionary pathways were inferred. Furthermore, RNA sequencing performed in a subset of cases yielded new insights into markers that could be useful for more precise cell lineage identification. The panel has thus proposed an updated algorithm for HDCN lineage assignment. The outcome of transdifferentiated HDCNs was poor, but the MAPK signaling pathway emerges as a potentially attractive therapeutic target. CONCLUSIONS: Transdifferentiated HDCNs demonstrate heterogeneity and pose diagnostic challenges with regard to exact classification, but the in-depth characterization of the submitted cases have added to our understanding of the secondary HDCNs transdifferentiated from B-cell lymphoma/leukemia. Continuous efforts focusing on deciphering the specific cell lineage and differentiation state of these tumors will be critical for their accurate classification. Comprehensive molecular characterization of HDCNs may be informative in this regard. With the list of novel pharmacologic inhibitors of the MAPK pathway continuing to expand, improved outcomes for HDCN can be expected.

Phenotypic and genotypic infidelity in B-lineage neoplasms, including transdifferentiation following targeted therapy: Report from the 2021 SH/EAHP Workshop.

OBJECTIVES: Session 2 of the 2021 Society for Hematopathology and European Association for Haematopathology Workshop collected examples of lineage infidelity and transdifferentiation in B-lineage neoplasms, including after targeted therapy. METHODS: Twenty cases were submitted. Whole-exome sequencing and genome-wide RNA expression analysis were available on a limited subsample. RESULTS: A diagnosis of B-cell acute lymphoblastic leukemia (B-ALL) was rendered on at least 1 biopsy from 13 patients. There was 1 case of acute myeloid leukemia (AML); the remaining 6 cases were mature B-cell neoplasms. Targeted therapy was administered in 7 cases of B-ALL and 4 cases of mature B-cell neoplasms. Six cases of B-ALL underwent lineage switch to AML or mixed-phenotype acute leukemia at relapse, 5 of which had rearranged KMT2A. Changes in maturational state without lineage switch were observed in 2 cases. Examples of de novo aberrant T-cell antigen expression (n = 2) were seen among the mature B-cell lymphoma cohort, and their presence correlated with alterations in tumor cell gene expression patterns. CONCLUSIONS: This cohort of cases enabled us to illustrate, discuss, and review current concepts of lineage switch and aberrant antigen expression in a variety of B-cell neoplasms and draw attention to the role targeted therapies may have in predisposing neoplasms to transdifferentiation as well as other, less expected changes in maturational status.

Progression of Hodgkin lymphoma and plasma cell neoplasms: Report from the 2021 SH/EAHP Workshop.

OBJECTIVES: To summarize cases submitted to the 2021 Society for Hematopathology/European Association for Haematopathology Workshop under the categories of progression of Hodgkin lymphoma, plasmablastic myeloma, and plasma cell myeloma. METHODS: The workshop panel reviewed 20 cases covered in this session. In addition, whole-exome sequencing (WES) and whole-genome RNA expression analysis were performed on 10 submitted cases, including 6 Hodgkin lymphoma and 4 plasma neoplasm cases. RESULTS: The cases of Hodgkin lymphoma included transformed cases to or from various types of B-cell lymphoma with 1 exception, which had T-cell differentiation. The cases of plasma cell neoplasms included cases with plasmablastic progression, progression to plasma cell leukemia, and secondary B-lymphoblastic leukemia. Gene variants identified by WES included some known to be recurrent in Hodgkin lymphoma and plasma cell neoplasm. All submitted Hodgkin lymphoma samples showed 1 or more of these mutations: SOCS1, FGFR2, KMT2D, RIT1, SPEN, STAT6, TET2, TNFAIP3, and ZNF217. CONCLUSIONS: Better molecular characterization of both of these neoplasms and mechanisms of progression will help us to better understand mechanisms of progression and perhaps develop better prognostic models, as well as identifying novel therapeutic targets.

International Consensus Classification of acute lymphoblastic leukemia/lymphoma.

The updated International Consensus Classification (ICC) of B-acute lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL) includes both revisions to subtypes previously outlined in the 2016 WHO classification and several newly described entities. The ICC classification incorporates recent clinical, cytogenetic, and molecular data, with a particular emphasis on whole transcriptome analysis and gene expression (GEX) clustering studies. B-ALL classification is modified to further subclassify BCR::ABL1-positive B-ALL and hypodiploid B-ALL. Additionally, nine new categories of B-ALL are defined, including seven that contain distinguishing gene rearrangements, as well as two new categories that are characterized by a specific single gene mutation. Four provisional entities are also included in the updated B-ALL classification, although definitive identification of these subtypes requires GEX studies. T-ALL classification is also updated to incorporate BCL11B-activating rearrangements into early T-precursor (ETP) ALL taxonomy. Additionally, eight new provisional entities are added to the T-ALL subclassification. The clinical implications of the new entities are discussed, as are practical approaches to the use of different technologies in diagnosis. The enhanced specificity of the new classification will allow for improved risk stratification and optimized treatment plans for patients with ALL.

Limited sinonasal Rosai-Dorfman disease presenting as chronic sinusitis.

AIMS: The sinonasal tract is a common extranodal site for Rosai-Dorfman disease (RDD). Recently, histiocytes with features of RDD were identified in the clinical setting of chronic sinusitis. This study evaluates whether this phenomenon should be considered part of the RDD spectrum or classified separately as RDD-like histiocytes. METHODS AND RESULTS: We prospectively collected 13 cases showing histological features of RDD in chronic sinusitis patients and identified 14 with similar findings (3.5%) via retrospective review of 403 sinus contents over 2 years. All 27 cases displayed nodular aggregates of eosinophilic histiocytes with intermixed lymphoplasmacytic inflammation, prominent eosinophils and emperipolesis. The histiocytes were positive for S100 protein and cyclin D1 and negative for CD1a and CD207. All patients presented with severe chronic sinusitis without tumour formation or systemic symptoms. Twelve patients with follow-up (55%) required repeat sinus surgery compared with just 43 other sinusitis patients evaluated (11%); features of RDD were present in their additional specimens. Two cases that underwent targeted next-generation sequencing (20%) had oncogenic mutations in NF1 and KEAP1. CONCLUSIONS: Overall, these findings confirm diagnostic histological and immunohistochemical features of RDD in a subset of chronic sinusitis specimens. While patients uniformly lack systemic involvement or tumefactive growth, they have a high risk of recurrent sinus disease. Although the relatively subtle nature of the findings raises consideration of separate classification, the presence of occasional oncogenic mutations and evidence of consistent MAPK/ERK pathway activation via cyclin D1 positivity suggests that this phenomenon represents a unique limited manifestation of RDD.

Primary CNS lymphoma in scleroderma: a case series.

Many studies have demonstrated an increased risk of cancer in patients with rheumatologic diseases, including systemic sclerosis. Less explored is the role of immunosuppressive therapy as a contributing factor in cancer emergence or detection. This series introduces two cases of patients with systemic sclerosis who demonstrated clinical improvement in their rheumatic disease process with immunosuppression, but both of whom developed neurologic symptoms in the setting of decreasing or discontinuing immunosuppressive therapy, leading to the ultimate diagnosis of Epstein Barr Virus positive (EBV+) diffuse large B cell lymphoma of the CNS. To our knowledge, primary CNS lymphoma has not been previously described in systemic sclerosis patients. Immunosuppressive therapies could promote the development of virus-associated malignancies due to decreased viral clearance. We hypothesize that removing immunosuppression could allow the immune system to generate an inflammatory response to an underlying tumor or viral antigen, contributing to development of neurologic symptoms and detection of underlying disease.

FLT3 tyrosine kinase inhibitors synergize with BCL-2 inhibition to eliminate FLT3/ITD acute leukemia cells through BIM activation.

Tyrosine kinase inhibitors (TKIs) targeting FLT3 have shown activity but when used alone have achieved limited success in clinical trials, suggesting the need for combination with other drugs. We investigated the combination of FLT3 TKIs (Gilteritinib or Sorafenib), with Venetoclax, a BCL-2 selective inhibitor (BCL-2i), on FLT3/ITD leukemia cells. The combination of a FLT3 TKI and a BCL-2i synergistically reduced cell proliferation and enhanced apoptosis/cell death in FLT3/ITD cell lines and primary AML samples. Venetoclax also re-sensitized FLT3 TKI-resistant cells to Gilteritinib or Sorafenib treatment, mediated through MAPK pathway inhibition. Gilteritinib treatment alone dissociated BIM from MCL-1 but increased the binding of BIM to BCL-2. Venetoclax treatment enhanced the binding of BIM to MCL-1 but dissociated BIM from BCL-2. Treatment with the drugs together resulted in dissociation of BIM from both BCL-2 and MCL-1, with an increased binding of BIM to the cell death mediator BAX, leading to increased apoptosis. These findings suggest that Venetoclax mitigates the unintended pro-survival effects of FLT3 TKI mainly through the dissociation of BIM and BCL-2 and also decreased BIM expression. This study provides evidence that the addition of BCL-2i enhances the effect of FLT3 TKI therapy in FLT3/ITD AML treatment.

Deep learning for diagnosis of acute promyelocytic leukemia via recognition of genomically imprinted morphologic features.

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), classified by a translocation between chromosomes 15 and 17 [t(15;17)], that is considered a true oncologic emergency though appropriate therapy is considered curative. Therapy is often initiated on clinical suspicion, informed by both clinical presentation as well as direct visualization of the peripheral smear. We hypothesized that genomic imprinting of morphologic features learned by deep learning pattern recognition would have greater discriminatory power and consistency compared to humans, thereby facilitating identification of t(15;17) positive APL. By applying both cell-level and patient-level classification linked to t(15;17) PML/RARA ground-truth, we demonstrate that deep learning is capable of distinguishing APL in both discovery and prospective independent cohort of patients. Furthermore, we extract learned information from the trained network to identify previously undescribed morphological features of APL. The deep learning method we describe herein potentially allows a rapid, explainable, and accurate physician-aid for diagnosing APL at the time of presentation in any resource-poor or -rich medical setting given the universally available peripheral smear.

Deletions in FLT-3 juxtamembrane domain define a new class of pathogenic mutations: case report and systematic analysis.

The FMS-like tyrosine kinase 3 (FLT-3) is the most frequently mutated gene in acute myeloid leukemia (AML), a high-risk feature, and now the target of tyrosine kinase inhibitors (TKIs), which are approved and in development. The most common mutation is the internal tandem duplication (ITD). We present a novel mutation, FLT-3/Q575Δ, identified in a patient with AML through next-generation sequencing (NGS). This mutation is activating, drives downstream signaling comparable to FLT-3/ITD, and can be targeted using available FLT-3 TKIs. We present the results of a systematic analysis that identified Y572Δ, E573Δ, and S574Δ as similarly activating and targetable deletions located in the FLT-3 juxtamembrane domain (JMD). These mutations target key residues in the JMD involved in the interactions within FLT-3 that regulate its activation. Our results suggest a new class of FLT-3 mutations that may have an impact on patient care and highlight the increasing importance of a systematic understanding of FLT-3 mutations other than ITD. It is likely that, as NGS becomes more commonly used in the diagnosis of patients with AML, these and other activating mutations will be discovered with increasing frequency.

Myeloid Neoplasm with PDGFRA Rearrangement Manifesting as a Retromolar Pad Mass.

Myeloid neoplasms with PDGFRA rearrangement are rare, and most commonly present with features of chronic eosinophilic leukemia; however, they rarely manifest as acute myeloid or lymphoblastic leukemia. Patients typically present with symptoms of hypereosinophilia including cardiovascular and pulmonary symptoms. An increase in mast cells is also a common feature of this disease, and there may be elevated serum tryptase with significant clinical overlap with systemic mastocytosis. Here, we present an unusual case of a myeloid neoplasm with PDGFRA rearrangement manifesting as a retromolar pad mass in a patient with a prior diagnosis of systemic mastocytosis. This case highlights the possibility of soft tissue involvement by myeloid neoplasms with PDGFRA rearrangement in the oral cavity. The identification of this entity is of significant clinical importance because many patients can be effectively treated with tyrosine kinase inhibitors.

A Phase 1 Study of IRX195183, a RARα-Selective CYP26 Resistant Retinoid, in Patients With Relapsed or Refractory AML.

Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids in vitro. We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of in vivo leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line in vitro. These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02749708.

Thrombopoietin is required for full phenotype expression in a JAK2V617F transgenic mouse model of polycythemia vera.

The myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis and primary myelofibrosis are hematopoietic stem cell disorders and share driver mutations that either directly activate the thrombopoietin receptor, MPL, or activate it indirectly through gain-of-function mutations in the gene for JAK2, its cognate tyrosine kinase. Paradoxically, MPL surface expression in hematopoietic stem cells is also reduced in the myeloproliferative neoplasms due to abnormal post-translational glycosylation and premature destruction of JAK2, suggesting that the myeloproliferative neoplasms are disorders of MPL processing since MPL is the only hematopoietic growth factor receptor in hematopoietic stem cells. To examine this possibility, we genetically manipulated MPL expression and maturation in a JAK2V617F transgenic mouse model of polycythemia vera. Elimination of MPL expression completely abrogated the polycythemia vera phenotype in this JAK2V617F transgenic mouse model, which could only be partially restored by expression of one MPL allele. Most importantly, elimination of thrombopoietin gene expression abrogated the polycythemia vera phenotype in this JAK2V617F transgenic mouse model, which could be completely restored by expression of a single thrombopoietin allele. These data indicate that polycythemia vera is in part a thrombopoietin-dependent disorder and that targeting the MPL-thrombopoietin axis could be an effective, nonmyelotoxic therapeutic strategy in this disorder.

Hemophagocytic Lymphohistiocytosis Secondary to PD-1 and IDO Inhibition in a Patient with Refractory Glioblastoma.

Immune checkpoint inhibition (ICI)-based approaches have transformed the treatment landscape of numerous solid tumors. Glioblastoma (GBM) is an aggressive and almost universally fatal disease which is in need of novel treatment options, and combinations of immune checkpoint inhibitors, including dual agent therapy, are starting to be explored in refractory GBM. Growing adoption of ICI-based approaches in solid tumors has been met with improved understanding of immune-related adverse events (IRAEs), including primary hematologic adverse events. Although management guidelines for multiple hematologic IRAEs have been established, the emergence of hemophagocytic lymphohistiocytosis (HLH) secondary to ICI therapy has only rarely been described, and its pathogenesis and optimal management are incompletely understood. We present the case of a 74-year-old male with a history of refractory GBM treated with PD-1 and indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibition who experienced acute liver injury, followed by progressive fevers, altered mental status, and cytopenias. Serum studies and examination of spleen and bone marrow pathology were consistent with HLH, which was refractory to steroids and ultimately resulted in his rapid clinical decline. Here, we review prior cases of HLH secondary to ICI therapy across solid tumors, and explore potential mechanisms contributing to the rapid onset and refractory nature of our patient's HLH syndrome. We hope to further highlight HLH as an emerging hematologic IRAE secondary to ICI therapy, and suggest that new practice guidelines begin to recognize HLH as a characteristic hematologic IRAE in patients treated with PD-1 and other immune checkpoint inhibitors.