In tumor microenvironment, the programmed death 1 (PD-1) immune checkpoint has a crucial role of mechanism of T cell exhaustion leading to tumor evasion. Ligands of PD-1, programmed death ligand 1/2 (PD-L1/L2) are over-expressed in tumor cells and participate in prolonged tumor progression and survivals. Recently, clinical trials for patients who failed to obtain an optimal response prior to standardized chemotherapy in several solid cancers have been focused on targeting therapy against PD-1 to reduce disease progression rates and prolonged survivals. Since various inhibitors targeting the immune checkpoint in PD-1/PD-L1 pathway in solid cancers have been introduced, promising approach using anti-PD-1 antibodies were attempted in several types of hematologic malignances. In diffuse large B cell lymphoma (DLBCL) as the most common and aggressive B cell type of non-Hodgkin’s lymphoma, anti-PD-1 and anti-PD-L1 antibodies were studies in various clinical trials. In this review, we summarized the results of several studies associated with PD-1/PD-L1 pathway as an immune evasion mechanism and described clinical trials about targeting therapy against PD-1/PD-L1 pathway in DLBCL.

Myelofibrosis (MF) is a clinical manifestation of chronic BCR-ABL1-negative chronic myeloproliferative neoplasms. Splenomegaly is one of the major clinical manifestations of MF and is directly linked to splenic extramedullary hematopoiesis (EMH). EMH is associated with abnormal trafficking patterns of clonal hematopoietic cells due to the dysregulated bone marrow (BM) microenvironment leading to progressive splenomegaly. Several recent data have emphasized the role of several cytokines for splenic EMH. Alteration of CXCL12/CXCR4 pathway could also lead to splenic EMH by migrated clonal hematopoietic cells from BM to the spleen. Moreover, low Gata1 expression was found to be significantly associated with the EMH. Several gene mutations were found to be associated with significant splenomegaly in MF. In recent data, JAK2 V617F homozygous mutation was associated with a larger spleen size. In other data, CALR mutations in MF were signigicantly associated with longer larger splenomegaly-free survivals than others. In addition, MF patients with ≥1 mutations in AZXL1, EZH1 or IDH1/2 had significantly low spleen reduction response in ruxolitinib treatment. Developments of JAK inhibitors, such as ruxolitinib, pacritinib, momelotinib, and febratinib enabled the effective management in MF patients. Especially, significant spleen reduction responses of the drugs were demonstrated in several randomized clinical studies, although those could not eradicate allele burdens of MF.

Chimeric antigen receptor (CAR) T-cell therapy has shown promising clinical impact against hematologic malignancies. CD19 is a marker on the surface of normal B cells as well as most B-cell malignancies, and thus has a role as an effective target for CAR T-cell therapy. In numerous clinical data, successes with cell therapy have provided anticancer therapy as a potential therapeutic option for patients who are resistant to standard chemotherapies. However, recent growing evidence showed the limitations of the treatment such as antigen-positive relapse due to poor CAR T-cell persistence and antigen-negative relapses associated with CAR-driven mutations, alternative splicing, epitope masking, low antigen density, and lineage switching. The understanding of the resistance mechanisms to the cell therapy has developed novel potential treatment strategies, including dual-targeting therapy (dual and tandem CAR), and armored and universal CAR T-cell therapies. In this review, we provide an overview of resistance mechanisms to CD19 CAR T-cell therapy in B-cell malignancies and also review therapeutic strategies to overcome these resistances.

FLT3 mutations are the most common genomic alteration detected in acute myeloid leukemia (AML) with a worse clinical prognosis. The highly frequent FLT3 mutations, together with the side effects associated with clinical prognosis, make FLT3 promising treatment targets and have provoked the advancement of FLT3 inhibitors. Recently, numerous FLT3 inhibitors were actively developed, and thus the outcomes of this aggressive subtype of AML were significantly improved. Recently, midostaurin and gilteritinib were approved as frontline treatment of AML and as therapeutic agents in the recurred disease by the United States Food and Drug Administration. Recently, numerous promising clinical trials attempted to seek appropriate management in frontline settings, in relapsed/refractory disease, or after stem cell transplantation in AML. This review follows numerous clinical trials about the usefulness of FLT3 inhibitors as frontline therapy, as relapsed/refractory conditioning, and as maintenance therapy of stem cell transplantation. The cumulative data of FLT3 inhibitors would be important clinical evidence for further management with FLT3 inhibitors in AML patients with FLT3 mutations.

Leptin acts as a growth factor in normal cells as well as in various types of cancer cells. We investigated the effects of leptin on human acute myelogenous leukemia (AML) cells. Lewin stimulated the proliferation of HEL cells through the phosphorylation of STAT3 and ERK1/2. The blocking of STAT3 phosphorylation with the specific inhibitor. AG490, significantly reduced leptin-induced ERK1/2 phosphorylation and cellular proliferation, whereas the blocking of ERK1/2 activation by the specific ERK1/2 inhibitor, PD98059, did not affect the STAT3 phosphorylation or leptin-induced proliferation in HEL cells. Furthermore, knockdown of leptin receptor (OB-R) expression with stealth RNA interference (RNAi) reduced the leptin-induced proliferation of HEL cells and also significantly attenuated leptin-induced STAT3 and ERK1/2 activation. These results suggest that leptin promotes AML cell growth by activating STAT3 and MAPK, although not directly dependent on ERK.

Byun YJ, et al. Blood Res. 2014 Jun;49(2):127-129. http://dx.doi.org/10.5045/br.2014.49.2.127