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Rattigan and colleagues examine the current understanding of the role of metabolism in proliferation and survival of cancer cells. The authors review the multiple metabolic pathways beyond the “Warburg effect” that impinge on and are modified by leukemia cells. They discuss the degree with which these pathways are shared with normal hematopoietic stem cells and investigate the challenge to discover safe entry points for exploiting metabolic dependence to promote successful therapy without negatively affecting normal hematopoietic stem cells and immune cells.


Using 2 illustrative cases, Lugtenburg and Mutsaers review their approach to diffuse large B-cell lymphoma (DLBCL) in older patients. DLBCL is curable but occurs commonly in older individuals with other medical issues that may be an impediment to chemotherapy. Based on a simplified geriatric assessment, the authors discuss the role of full-dose therapy with cytokine support, lower dose therapy, and supportive care in the management of these patients.


Lynch et al report on a single-arm study of concurrent pembrolizumab with doxorubicin, vinblastine, and dacarbazine (AVD) in 30 patients with untreated classic Hodgkin lymphoma (uCHL). Complete remission was documented in 90% of patients, and 2-year progression-free survival and overall survival were 97% and 100% respectively. Interestingly, circulating tumor DNA (ctDNA) appears to be a better predictor of outcome than positron emission tomography/computed tomography (PET-CT); of 4 patients with positive PET-CT and negative ctDNA at the end of therapy, none have relapsed. Though preliminary, concurrent PD-1 inhibition plus chemotherapy is a promising therapy for previously uCHL.


Chimeric antigen receptor (CAR) T-cell therapy for acute myeloid leukemia has been disappointing, partially reflecting poor targeting of leukemic stem cells in the bone marrow. Seeking to overcome this, Biondi et al expressed the homing receptor CXCR4 in CD33.CAR-cytokine induced killer cells (CIKs) and improved chemotaxis to the bone marrow and increased antileukemic activity. However, expression of the mutant CXCR4 variant associated with WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome, in which cells are retained in the marrow and display increased homing, did not increase antileukemic efficacy as had been hypothesized, suggesting that CXCR4 acts to amplify killing by another mechanism.


There is increasing attention focused on the immune microenvironment of lymphoid malignancies that appears to protect tumor cells from immune attack. Sacco and colleagues address this question in Waldenström macroglobulinemia (WM). Transcriptomic profiling in a murine model of WM with confirmation in patient samples demonstrated increased regulatory T (Treg) cells with a characteristic signature that is induced and expanded in WM. The authors further identified crosstalk between WM cells and Tregs supported by CD40/CD40 ligand, identifying a potential clinical target for inhibiting WM growth.



The reason why only some patients are predisposed to red blood cell (RBC) alloimmunization with transfusion is unknown. Jajosky et al present intriguing observations that suggest that predisposition to alloimmunization may reflect priming of the immune system by exposure to intracellular antigens that increase the alloimmune response to unrelated RBC surface antigens. No specific antigen has been identified, and it remains to be assessed whether this is a response to a specific antigen or is rather a reflection of an overall immune dysregulation that predisposes susceptibility of priming to an array of intercellular antigens.



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