Overcoming the leukemia stem cell resistance to intensive chemotherapy has been an area of extensive research over the last two decades. Advances and greater understanding of the molecular biology of leukemia stem cells are in rapid progress. Targeted therapies are currently being used in clinical practice with reasonable response rates, but a cure is being achieved in only a small percentage of patients, most likely due to tumor mutational heterogeneity. A genetically engineered diphtheria toxin fused with interleukin-3 (SL-401 or tagraxofusp) has shown robust activity in blastic plasmacytoid dendritic cell neoplasm and promising response rates in different myeloid malignancies, including eradication of minimal residual disease. Multiple clinical trials are being conducted using this drug and the preliminary results are encouraging. This article reviews the clinical trials for SL-401, its mechanism of action, clinical activity, and the adverse event profile.

Pseudo-thrombotic microangiopathy (pseudo-TMA) is a recognized, yet uncommon, clinical presentation of vitamin B12 deficiency. Patients with pseudo-TMA present with microangiopathic hemolytic anemia (MAHA), thrombocytopenia and schistocytes. They are often misdiagnosed as thrombotic thrombocytopenia purpura (TTP) and receive unnecessary therapy. Here, we report a case of a 60-year-old male who presented with thrombocytopenia and normocytic normochromic anemia. Anemia work-up was remarkable for severe B12 deficiency (<60 pg/mL) and a positive non-immune hemolysis panel. Peripheral smear was reviewed and showed anisocytes, poikilocytes, schistocytes and hypersegmented neutrophils. Vitamin B12 replacement (1000 mcg IM daily) was started, ADAMTS13 activity was sent and daily plasmapheresis was initiated. Over the next 3 days, the patient’s hemoglobin and platelets were stable and the hemolysis panel showed gradual improvement. On day 4, ADAMTS13 activity results came back normal at 61%. Accordingly, plasmapheresis was discontinued, parenteral B12 replacement was continued and that resulted in gradual improvement and eventually cessation of hemolysis and normalization of hemoglobin and platelets. In this patient, parietal cell autoantibodies were positive and so the diagnosis of pernicious anemia was made. Patients with severe vitamin B12 deficiency may present with features mimicking TTP such as MAHA, thrombocytopenia and schistocytosis. An early and accurate diagnosis of pseudo-TMA has a critical clinical impact with respect to administering the correct treatment with vitamin B12 replacement and avoiding, or shortening the duration of, unnecessary therapy with plasmapheresis.

The gut microbiota plays a significant role in health and disease, including cancer development and treatment. The importance of the gut microbiota in the efficacy and toxicity of novel therapies and immunotherapy is increasingly recognized. Plasma cells in multiple myeloma have the potential to survive in the gastrointestinal tract for long periods of time. The nature of the gut microbiota impacts the degree of antigen stimulation of these cells and may play a role in mutation development and clonal evolution. Furthermore, myeloma therapies such as proteasome inhibitors and alkylating agents, commonly used to treat patients, are frequently associated with gastrointestinal adverse events. Herein we review the gut microbiota and its role in hematopoiesis, pathogenesis of myeloma, and efficacy/toxicity of anti-myeloma therapies.

Bruton tyrosine kinase (BTK) inhibitors have become an important therapy for untreated and previously treated patients with chronic lymphocytic leukemia (CLL). Despite improved outcomes, rare adverse events, such as invasive fungal infections, have been reported with the use of first-generation BTK inhibitors. Invasive fungal infections carry a high morbidity and mortality risk. There have been several case reports describing the association between aspergillosis and ibrutinib treatment, but none with acalabrutinib, to our knowledge. In this case report, we describe a patient with CLL who developed an intracranial Aspergillus fumigatus infection while receiving acalabrutinib.

Immune dysregulation and alteration of the bone marrow microenvironment allowing plasma cells to escape immune surveillance are well-known factors associated with the proliferation of clonal plasma cells and development of multiple myeloma (MM). Whilst immunotherapeutic approaches are now commonplace in a wide spectrum of malignancies, this aberration of myeloma development gives rise to the biological rationale for the use of immune checkpoint inhibitors (ICIs) in MM. However, the initial experience with these agents has been challenging with limited single agent efficacy, significant toxicity, and side effects. Herein, we review the biological and immunological aspects of MM and ICIs. We discuss the basic biology of immune checkpoint inhibitors, mechanisms of resistance, and drug failure patterns, review the published clinical trial data for ICIs in MM, and look towards the future of ICIs for MM treatment.

Despite advances in treatment, outcomes remain poor for patients with penta-relapsed refractory multiple myeloma (RRMM). In this retrospective analysis, we evaluated the survival outcomes of penta-RRMM patients treated with (BCMA)- directed therapy (BDT). We identified 78 patients with penta-RRMM. Median age was 65 years, 29 (37%) had R-ISS stage III disease, 63 (81%) had high-risk cytogenetics, and 45 (58%) had extra-medullary disease. Median LOT prior to penta-refractory state was 5 (3–12). Amongst penta-RRMM, 43 (55%) were treated with BDT, 35 (45%) were not treated with BDT. Type of BDT received included belantamab mafadotin 15 (35%), Chimeric Antigen Receptor T-cell therapy 9 (21%), BCMA monoclonal antibody 6 (14%), and Bispecific T-cell engager 2 (5%). Eleven (25%) patients received more than one BDT. No significant differences were identified between baseline characteristics for the two groups. Patients treated with a BDT had better median overall survival, 17 vs. 6 months, HR 0.3 p-value < 0.001. Poor performance status, white race, and high-risk cytogenetics were associated with worse outcomes, whereas using a BDT was associated with better outcomes. Patients with penta-refractory MM have poor outcomes. Our retrospective analysis showed a significant survival benefit using BDT when compared to non-BDT for patients with penta-RRMM.