FLT3-ITD and FLT3-TKD mutations were observed in approximately 20 and 10% of acute myeloid leukemia (AML) cases, respectively. FLT3 inhibitors such as midostaurin, gilteritinib and quizartinib show excellent response rates in patients with FLT3-mutated AML, but its duration of response may not be sufficient yet. The majority of cases gain secondary resistance either by on-target and off-target abnormalities. On-target mutations (i.e., FLT3-TKD) such as D835Y keep the TK domain in its active form, abrogating pharmacodynamics of type II FLT3 inhibitors (e.g., midostaurin and quizartinib). Second generation type I inhibitors such as gilteritinib are consistently active against FLT3-TKD as well as FLT3-ITD. However, a “gatekeeper” mutation F691L shows universal resistance to all currently available FLT3 inhibitors. Off-target abnormalities are consisted with a variety of somatic mutations such as NRAS, AXL and PIM1 that bypass or reinforce FLT3 signaling. Off-target mutations can occur just in the primary FLT3-mutated clone or be gained by the evolution of other clones. A small number of cases show primary resistance by an FL-dependent, FGF2-dependent, and stromal CYP3A4-mediated manner. To overcome these mechanisms, the development of novel agents such as covalently-coupling FLT3 inhibitor FF-10101 and the investigation of combination therapy with different class agents are now ongoing. Along with novel agents, gene sequencing may improve clinical approaches by detecting additional targetable mutations and determining individual patterns of clonal evolution.

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11–67% CR rates with 13–78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10–36% CR rates with 7–24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence.

From 2001 to 2012, 71 individuals with hematological diseases received HSCT in our institution. Of these, 41 developed disseminated intravascular coagulation (DIC) in association with various underlying conditions. The patients who developed DIC after 2008 (n = 23) were treated by recombinant human soluble thrombomodulin (rTM), and the others (n = 11) were treated by either heparin and/or antithrombin III concentrate. Seven patients did not receive any anticoagulant therapy. Of note, treatment for coagulopathy by rTM significantly improved clinical outcomes of patients at day 100 and dramatically prolonged their overall survival (P = 0.044). Taken together, rTM is useful to improve clinical outcomes of transplant recipients with coagulopathy.

Tumor cells use immune-checkpoint pathways to evade the host immune system and suppress immune cell function. These cells express programmed cell-death protein 1 ligand 1 (PD-L1)/PD-L2, which bind to the programmed cell-death protein 1 (PD-1) present on cytotoxic T cells, trigger inhibitory signaling, and reduce cytotoxicity and T-cell exhaustion. Immune-checkpoint blockade can inhibit this signal and may serve as an effective therapeutic strategy in patients with solid tumors. Several trials have been conducted on immune-checkpoint inhibitor therapy in patients with malignant lymphoma and their efficacy has been reported. For example, in Hodgkin lymphoma, immune-checkpoint blockade has resulted in response rates of 65% to 75%. However, in non-Hodgkin lymphoma, the response rate to immune-checkpoint blockade was lower. In this review, we evaluate the biology of immune-checkpoint inhibition and the current data on its efficacy in malignant lymphoma, and identify the cases in which the treatment was more effective.

The present study analyzed the incidence and clinical features of disseminated intravascular coagulation (DIC) developed in association with non-Hodgkin lymphoma (NHL). Two hundred thirty-six patients with newly diagnosed NHL were admitted to our institute since Jul. 2008 to Dec. 2014. Coagulation markers were evaluated in 161 of 236 patients at the time of diagnosis. DIC was diagnosed in 18 patients (11.2 %) based on the criteria established by Ministry of Health, Labor, and Welfare of Japan. All of the 18 patients had Ann-Arbor Stage IV advanced disease, and 17 patients were in poor performance status. Liver function panels, such as bilirubin, aminotransferases, serum choline esterase, and albumin levels, were worse in patients with DIC than those without DIC, indicating impaired production of coagulation factors. Importantly, DIC exerts significantly negative impact on prognosis of NHL; median survival of both groups was 176 versus 2430 days. The difference remains significant after statistically adjusting for age, performance status, Ann-Arbor stage, international prognostic index, and liver function panels. Nine of 18 patients with DIC received anti-coagulants, which failed to improve clinical outcome. Nevertheless, early recognition and intervention to DIC state may contribute to improve prognosis of NHL.