Angioimmunoblastic T-cell lymphoma presenting with severe plasmacytosis mimicking plasma cell leukemia.

Peripheral blood smear (A) demonstrates increased numbers of plasma cells (representative cells indicated by arrows), (B) demonstrates polytypic nature of plasma cells.

Association of Hydroxychloroquine use and Hemolytic Anemia in Patients With Low Levels of Glucose-6-Phosphate Dehydrogenase.

BACKGROUND: Glucose-6-phosphate dehydrogenase deficiency (G6PD) is linked to hemolytic anemia with certain medications and is the most common enzyme deficiency worldwide. Although the American College of Rheumatology does not recommend routine testing for G6PD prior to initiation of hydroxychloroquine (HCQ), the package insert for HCQ does recommend careful use in patients with G6PD deficiency. METHODS: We identified eligible subjects seen at our tertiary care, urban medical center between 1997 and 2018. Case records were analyzed for G6PD deficiency, HCQ use, length of exposure to HCQ, demographic characteristics, and laboratory evidence of hemolysis. RESULTS: We found 5264 patients who were prescribed HCQ, of which 49.5% (2605 patients) were screened for G6PD deficiency. Of the screened patients, 36 were found to be G6PD-deficient. Of the G6PD-deficient patients, 18 were exposed to HCQ. No evidence of hemolysis was found in these exposed patients. CONCLUSIONS: Despite more than 500 months of cumulative exposure time to HCQ, there were no cases of hemolysis. These findings are in line with recently published data and suggest that this interaction is not associated with clinically significant hemolysis in our population of mainly African American and Hispanic patients. Limitations to our study are potential bias due to case review design and lack of prior assessment of episodes of hemolysis before HCQ exposure. A high proportion of our patients were Hispanic, suggesting no increase of adverse events in this subgroup. A larger longitudinal trial would be needed to definitively answer the question of the safety of HCQ in G6PD-deficient patients.

Absolute Lymphocyte Count after BCMA CAR-T Therapy is a Predictor of Response and Outcomes in Relapsed Multiple Myeloma.

BCMA-targeting CAR-T cells used in multiple myeloma (MM) are rapidly becoming a mainstay in the treatment of relapsed/refractory (RR) disease, and CAR-T cell expansion post-infusion has been shown to inform depth and duration of response, but measuring this process remains investigational. This multicenter study describes the kinetics and prognostic impact of absolute lymphocyte count (ALC) in the first 15 days after CAR-T infusion in 156 relapsed MM patients treated with the BCMA-targeting agents cilta-cel and ide-cel. Patients with higher maximum ALC (ALCmax) had better depth of response, progression-free survival (PFS), and duration of response (DoR). Patients with ALCmax >1.0 x103/uL had a superior PFS (30.5 versus 6 months, p <0.001) compared to those ≤1.0x103/uL, while patients with ALCmax ≤0.5 x103/uL represent a high-risk group with early disease progression and short PFS (HR 3.4, 95 CI: 2 -5.8, P <0.001). In multivariate analysis, ALCmax >1.0 x103/uL and non-paraskeletal extramedullary disease were the only independent predictors of PFS and DoR after accounting for ISS staging, age, CAR-T product, high-risk cytogenetics and number of previous lines. Moreover, our flow cytometry data suggests that ALC is a surrogate for BCMA CAR-T expansion and can be used as an accessible prognostic marker. We report for the first time the association of ALC after BCMA CAR-T infusion with clinical outcomes and its utility in predicting response in RRMM patients.

Advances in the molecular characterization of multiple myeloma and mechanism of therapeutic resistance.

Recent insight in the genomic landscape of newly diagnosed multiple myeloma (NDMM) and its precursor conditions, monoclonal gammopathy of uncertain significance (MGUS), and smoldering myeloma have allowed the identification of patients with precursor conditions with a high risk of progression. These cases with "progressor" MGUS/SMM have a higher average mutation burden, have higher rates of mutations in specific genes such as MAPK, DNA repair, MYC, DIS3, and are enriched for specific mutational signatures when compared to non-progressors and are comparable to those found in NDMM. The highly preserved clonal heterogeneity seen upon progression of SMM, combined with the importance of these early variables, suggests that the identification of progressors based on these findings could complement and enhance the currently available clinical models based on tumor burden. Mechanisms leading to relapse/refractory multiple myeloma (RRMM) are of clinical interest given worse overall survival in this population. An Increased mutational burden is seen in patients with RRMM when compared to NDMM, however, there is evidence of branching evolution with many of these mutations being present at the subclonal level. Likewise, alterations in proteins associated with proteosome inhibitor and immunomodulatory drugs activity could partially explain clinical resistance to these agents. Evidence of chromosomal events leading to copy number changes is seen, with the presence of TP53 deletion, mutation, or a combination of both being present in many cases. Additional chromosomal events such as 1q gain and amplification may also interact and lead to resistance.

Smoldering Myeloma Treatment: Who, What, and When.

ABSTRACT: Smoldering multiple myeloma (MM) is a clonal plasma cell disorder characterized by excess marrow involvement and immunoglobulin production. It is the precursor of MM, differing by the lack of end-organ damage. Smoldering MM encompasses a heterogeneous group of patients, with a median risk of progression to active disease of 50% in the first 5 years. Until recently, the standard of care would dictate observation off therapy until the development of end-organ damage. The recognition of high-risk and ultrahigh-risk subgroups of smoldering MM, with more likely evolution to MM, has led to earlier initiation of therapy in the disease course. Ongoing studies to define the ideal timing and patient population are underway, as well as identification of which agents would be of greatest benefit, as the armamentarium for MM continues to grow.

Multiple Myeloma in Hispanics: Incidence, Characteristics, Survival, Results of Discovery, and Validation Using Real-World and Connect MM Registry Data.

BACKGROUND: Multiple myeloma (MM) in Hispanics has never been studied. We therefore sought to determine the clinical characteristics and overall survival in MM of Hispanics compared to non-Hispanic whites (NHW) and non-Hispanic blacks (NHB). PATIENTS AND METHODS: A single-center analysis of 939 patients diagnosed with MM from 2000 to 2017 with a large representation of NHB (n = 489), Hispanics (n = 281), and NHW (n = 169) was conducted to evaluate outcomes and disease characteristics. We used the Connect MM Registry, a large US multicenter prospective observational study with newly diagnosed MM patients, as a validation cohort. RESULTS: Hispanics had a higher incidence of MM compared to NHW. The median age at presentation was 5 years younger (median, 65 years) in Hispanics compared to NHW (median, 70 years), and patients were more likely to present with renal dysfunction (estimated glomerular filtration rate < 30 mL/min). Hispanics had a higher proportion of Revised International Staging System (R-ISS) stage I disease compared to NHW and NHB (P = .03), while there was no difference in cytogenetics between Hispanics and NHB/NHW. In the multivariate analysis, only high-risk disease and response to first-line therapy significantly affected survival. CONCLUSION: In this first and largest analysis of MM in Hispanics, we found that Hispanics present at a younger age, have a higher incidence of renal dysfunction, and have low R-ISS stage disease at presentation. With equal access to therapy, Hispanics have survival similar to NHW/NHB.

A Case of CCDC6-RET Fusion Mutation in Adult Acute Lymphoblastic Leukemia (ALL), a Known Activating Mutation Reported in ALL.

We report the case of a patient with B-Cell Acute Lymphoblastic Leukemia (ALL) who was found to harbor a gene fusion involving the CCDC6 and RET genes. Although the RET mutations have been identified before in other malignancies, and it is thought to represent a driver mutation in these neoplasms, it has yet to be described in ALL. The identification of known fusion genes conferring activating tyrosine kinase activity in neoplasms can suggest potential therapeutic role of tyrosine kinase inhibitors (TKI), an approach that has been exploited in several other fusion genes.