A Case of Hemophagocytic Lymphohistiocytosis Triggered by Disseminated Tuberculosis and Hairy Cell Leukaemia after SARS-CoV2 Infection

Hemophagocytic Lymphohistiocytosis (HLH) is a rare but life-threatening disease that can occur either as a primary condition or as a consequence of a variety of triggers, including infectious diseases. Here we present a case of secondary HLH triggered by systemic Mycobacterium tuberculosis infection in a 59-year-old immunocompromised Hairy Cell Leukemia and previous SARS-CoV2 infected patient. This case report underlines the role of Etoposide-based chemotherapy in treating the severe inflammation that is the defining factor of HLH, suggesting how, even when such therapy is not effective, it may still give the clinicians time to identify the underlying condition and start the appropriate targeted therapy. Moreover, it gives insight on our decision to treat the underlying haematological condition with a BRAF-targeted therapy rather than purine analog-based chemotherapy to reduce the risk of future severe infections.

Cyclin D1 expression in Peripheral T-Cell Lymphoma: A report of 2 cases

: Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of non-Hodgkin's lymphomas (NHL), characterized by poor outcome, accounting approximately for 10%-15% of all non-Hodgkin lymphomas in the western countries, and with a higher prevalence in Asia. Cyclin D1 immunoreactivity is characteristically seen in mantle cell lymphoma. It is also observed in hairy cell leukemia, plasma cell myeloma and a proportion of diffuse large B-cell lymphomas, however its expression in peripheral T-cell lymphoma is rarely recorded. : We report two cases of peripheral T-cell lymphoma not otherwise specified with heterogeneous nuclear Cyclin D1 immunohistochemical overexpression, due to gene copy gain, a phenomenon similar to that observed in Mantle Cell Lymphoma.: Cyclin D1 expression can be seen in PTCLs, besides mantle cell lymphoma, hairy cell leukemia and plasma cell myeloma and underline the importance of molecular biology integration tests as a diagnostic tool to escape the pitfall.

CD5-Negative, CD10-Negative Low-Grade B-Cell Lymphoproliferative Disorders of the Spleen

CD5-negative, CD10-negative low-grade B-cell lymphoproliferative disorders (CD5-CD10-LPD) of the spleen comprise a fascinating group of indolent, neoplastic, mature B-cell proliferations that are essential to accurately identify but can be difficult to diagnose. They comprise the majority of B-cell LPDs primary to the spleen, commonly presenting with splenomegaly and co-involvement of peripheral blood and bone marrow, but with little to no involvement of lymph nodes. Splenic marginal zone lymphoma is one of the prototypical, best studied, and most frequently encountered CD5-CD10-LPD of the spleen and typically involves white pulp. In contrast, hairy cell leukemia, another well-studied CD5-CD10-LPD of the spleen, involves red pulp, as do the two less common entities comprising so-called splenic B-cell lymphoma/leukemia unclassifiable: splenic diffuse red pulp small B-cell lymphoma and hairy cell leukemia variant. Although not always encountered in the spleen, lymphoplasmacytic lymphoma, a B-cell lymphoproliferative disorder consisting of a dual population of both clonal B-cells and plasma cells and the frequent presence of the MYD88 L265P mutation, is another CD5-CD10-LPD that can be seen in the spleen. Distinction of these different entities is possible through careful evaluation of morphologic, immunophenotypic, cytogenetic, and molecular features, as well as peripheral blood and bone marrow specimens. A firm understanding of this group of low-grade B-cell lymphoproliferative disorders is necessary for accurate diagnosis leading to optimal patient management.

Hairy Cell Leukemia: Morphological and Immunophenotypic Characteristics of Seven Cases and Cyclin D1 Expression

Aberrant immunophenotypic expression in hairy cell leukemia (HCL), both at medullary and extramedullary sites, is not uncommonly reported in literature. Cyclin D1 positivity in HCL may mimic mantle cell lymphoma (MCL) morphologically, especially in the presence of aberrant CD5 immunopositivity, requiring BRAFV600E mutation and/or CCND1 gene testing for confirmation. Here, we describe seven cases of HCL with clinicomorphological and immunophenotypic characteristics with an emphasis on cyclin D1 expression using immunohistochemistry (IHC) with a brief comprehensive literature review. We suggest that cyclin D1 positive HCL may be a distinct subtype which requires further immunophenotypic and molecular characterization for accurate diagnosis and planning of definitive therapy.

Spectrum of Second Primary Malignancies and Cause-Specific Mortality Among Patients with Hairy Cell Leukemia in the United States: A Population-Based Study

BACKGROUND: Hairy cell leukemia (HCL) is a rare lymphoid neoplasm with an incidence of 1,000 new cases per year and accounting for 2% of all leukemias in the United States. There is a lack of data on the spectrum of second primary malignancies (SPMs) and cause-specific mortality in the era of targeted therapies (anti-CD20, anti-CD22, and BRAF-inhibitors). We undertook this study to address the gaps in knowledge using a national registry from the United States. METHODS: We estimated the incidence of SPMs and cause-specific mortality among two-month survivors of hairy cell leukemia (HCL) using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-18 registries. We included patients from 2003-2018 with ICD-O-3 code 9940/3 from the registry. We calculated the risk of SPMs using standardized incidence ratios (SIRs), and cause-specific mortality by standardized mortality ratios (SMRs) and absolute excess risk (AER)/10,000 population. We also reported survival analysis using relative survival rates (RSRs). RSR was calculated as ratio of observed to expected survival compared to the 2000 US standard population and adjusted for age, sex, and race. Overall survival (OS) analysis was reported using Kaplan-Meier (KM) method. RESULTS: We included a total of 4,261 patients with Hairy cell leukemia in this study. The median age at diagnosis was 59 yrs (range 21-85). The median follow-up duration for entire cohort was 68 months (range 0-191 mo). A total of 538 (12.6%) patients developed SPMs at last follow-up, of which 75% were solid organ malignancies, and 25% were hematologic neoplasms. The SPM risk for cohort was significantly elevated (SIR 1.33, 95% confidence interval [CI] 1.22 - 1.45) compared with the general population. The median latency period for SPM development was 3 yrs (range 1-15 yrs). The SPM risk was statistically higher than general population among Whites with HCL (SIR 1.33, 95% CI 1.22 - 1.45), but not significant among Blacks (SIR 1.31, 95% CI 0.76 - 2.09). The SIR was slightly higher in females (SIR 1.39, 95% CI 1.12 - 1.71) when compared to males (SIR 1.32, 95% CI 1.20 - 1.45). The SIR according to age groups were as follows: age < 65 years (SIR 1.36, 95% CI 1.21 - 1.52), age > 65 years (SIR 1.31, 95% CI 1.15 - 1.48). The risk for hematopoietic SPMs was higher (SIR 2.82, 95% CI 2.31 - 3.41) compared with solid organ tumors (SIR 1.16, 95% CI 1.05 - 1.28). Specific SPMs with highest risk included non-epithelial skin cancers (SIR 5.20, 95% CI 2.59 - 9.30), Hodgkin lymphoma (SIR 4.68, 95% CI 1.52 - 10.91), non-Hodgkin lymphoma [NHL] (SIR 3.91, 95% CI 3.04 - 4.95), myeloid and monocytic leukemia (SIR 2.23, 95% CI 1.15 - 3.90), melanoma (SIR 1.60, 95% CI 1.12 - 2.20), and prostate cancer (SIR 1.45, 95% CI 1.21 - 1.72). Although the risk of developing secondary NHL was significantly high throughout the follow-up period, risk for Hodgkin lymphoma was only significant >10 yr of follow-up (SIR 9.71, 95% CI 1.18 - 35). 5-year RSR for the cohort was 94.6%. On KM analysis, the mean OS for entire cohort was 11.8 yr, but the median OS was not reached (Figure 1). At last follow-up, 770 (18%) patients had died, of which 49% were due to malignant neoplasms. There was statistically significant risk of mortality due to all malignant cancers combined (SMR 2.41, 95% CI 2.17 - 2.66), largely due to mortality from leukemia (SMR 32.62, 95% CI 28.41 - 37.25, AER 70.2) and NHL (SMR 5.49, 95% CI 3.78 - 7.71, AER 9.01) (Table 1). Interestingly, risk of mortality from non-neoplastic causes was lower than general population: cardiovascular disease (SMR 0.70, 95% CI 0.58 - 0.83), pulmonary diseases (SMR 0.44, 95% CI 0.26 to 0.70), and infectious diseases (SMR 1.27, 95% CI 0.55 - 2.51). The risk of death from leukemia was highest within first year of diagnosis of HCL and continued to slowly decline thereafter, although remained statistically significantly elevated more than other causes of death (SMR 1yr 112, AER 214; SMR 1-5 yrs 36, AER 72; SMR 5-10 yrs 20, AER 43; SMR >10 yrs 17, AER 43). CONCLUSION: Our study reveals that despite therapeutic advances in HCL, hematologic neoplasms (including leukemia) remain the leading cause of death in last two decades. Additionally, the risk of developing SPMs remains elevated in patients with HCL, and is significantly high in Whites compared with Blacks. Further studies are needed to better define the healthcare needs of HCL patients beyond initial treatment to reduce the burden of mortality from HCL and other SPMs. Figure 1 Figure 1. Disclosures Narkhede: Gilead: Research Funding; Genentech/Roche: Research Funding; Genmab: Other: Medical writing support, Research Funding; TG Therapeautics: Research Funding.

Purine Nucleoside Analogs Plus Rituximab Is an Effective Treatment Choice for Hairy Cell Leukemia-Variant: Results from a Single Center in China

Background: Hairy cell leukemia-variant (HCL-v) is one type of chronic lymphocytic proliferative disorders which was classified into splenic B-cell lymphoma/leukemia, unclassifiable. Both clinical and laboratory characteristics and treatment strategy remain elusive due to the rarity of the disease. Here, we firstly presented the diseases features and efficacy of a variety of treatment options in a large cohort from China. Methods: Thirty-three patients were diagnosed with HCL-v in Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College from June 1990 to February 2021. We analyzed the disease characteristics and treatment outcome, especially in terms of clinical manifestation, immunophenotypic and molecular evaluation and efficacy of multiple first-line treatment. Results: The median age of this cohort was 59 years (range, 34-79 years) at diagnosis, with 23 males and 10 females. Abdominal mass and relative signs (n=22) and abnormal complete blood count (n=9) were the most common chief complaints. Splenomegaly was present in 32 (97.0%) cases, among whom 26 (78.8%) cases were massive. Leukocytosis and leukopenia were presented in 23 (69.7%) patients and 5 (15.2%) patients, with a median white blood cell count of 21.58×10 9/L (range, 1.34-224.59×10 9/L). The median percentage of the leukemic cells in bone marrow tested by flow cytometry was 33% (range, 6.2%-96%), and immunophenotyping showed monoclonal B-cells positive for pan B-cell antigens (CD19, CD20, CD22, CD79b) in almost all patients (Table). CD11c was positive in all patients, and CD103 was positive in 20/26 (76.9%) patients. CD25 was negative in 30/33 (90.9%) patients, and CD23 was negative in 20/26 (76.9%) cases. CD200 was frequently expressed among patients (15/21, 71.4%). For the pathological pattern of bone marrow involvement, 20/27 (74.1%) patients showed a predominantly interstitial pattern. Moreover, Annexin A1 was negative in all (n=12) patients detected by immunohistochemistry. Conventional cytogenetic analysis showed abnormal karyotype in 10/24 (41.7%) patients, including 6 patients with complex karyotype. Fluorescence in situ hybridization analysis showed deletion of TP53 in 4/20 (20.0%) patients and IGH translocation in 5/16 (31.3%) patients. The BRAF V600E mutation was negative in all the patients (n=20). In 2 of 14 (16.7%) patients, TP53 mutation was detected by next-generation sequencing. Sixteen of nineteen (84.2%) patients showed monoclonal IGHV rearrangements, and the most common rearrangement fragment was VH4-34 (n=3, 18.8%). Six of seventeen (35.3%) patients presented with unmutated IGHV and patients with VH4-34 were all unmutated. 31 patients needed treatment finally. Treatment choices included interferon-α (IFN-α) in 11 patients, chlorambucil (CLB) in 5 patients, single purine nucleoside analogs (PNA) in 3 patients and PNA plus rituximab in 9 patients. Four patients who received IFN-α or CLB treatment also underwent splenectomy. The objective response rate was 100% for patients receiving PNA plus rituximab and 77% for cases receiving others. And people treated with PNA plus rituximab had a higher complete response rate compared to the other regimen (75% versus 12%, P = 0.004). During a median follow-up of 32 months (range, 3-207) for 29 patients, 14 (48.3%) patients experienced at least one relapse or progression, and 7 (24.1%) patients had 2 or more relapses. Of note, one case also underwent a diffuse large B-cell lymphoma transformation. The median PFS and OS were 31 months (95% CI 25.5-36.5) and 70 months (95% CI 50.5-89.5), respectively. PNA plus rituximab prolong PFS compared to the others (3-year PFS rate 80% [95%CI 20-97] versus 10% [95%CI 1-35], P = 0.012, Figure A). But no significant difference in 3-year OS rate was observed between two groups (100% [95%CI 100-100] versus 43% [95%CI 10-73], P = 0.128, Figure B). Conclusion: HCL-v is a rare disease with specific clinical and immunophenotypic features but may overlap with classic hairy cell leukemia or other splenic B-cell neoplasms. Overall, it is an indolent lymphoma with recurrent progression, and the use of PNA plus rituximab in first-line treatment can result in a deeper and longer remission. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.