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For a substantial period, options for the treatment of multiple myeloma (MM) were limited; however, the advent of novel therapies into clinical practice in the 1990s resulted in dramatic changes in the prognosis of the disease. Subsequently, new proteasome inhibitors and immunomodulators with innovations in efficacy and toxicity were introduced; yet there remains a spectrum of patients with poor outcomes with current treatment strategies. One of the causes of disease progression in MM is the loss of the ability of the dysfunctional immune environment to control virulent cell clones. In recent years, therapies to overcome the immunosuppressive tumor microenvironment and activate the host immune system have shown promise in MM, especially in relapsed and refractory disease. Clinical use of this approach has been approved for several immunotherapies, and a number of studies are currently underway in clinical trials. This review outlines three of the newest and most promising approaches being investigated to enhance the immune system against MM: (1) overcoming immunosuppression with checkpoint inhibitors, (2) boosting immunity against tumors with vaccines, and (3) enhancing immune effectors with adoptive cell therapy. Information on the latest clinical trials in each class will be provided, and further developments will be discussed.

Gene transfer into hematopoietic cells using viral vectors has focused mostly on lymphocytes and hematopoietic stem cells (HSCs). HSCs have been considered particularly important as target cells because of their pluripotency and ability to reconstitute hematopoiesis after myeloablation and transplantation. HSCs are believed to have the ability to live a long time, perhaps a lifetime, in the recipient following bone marrow transplantation. Genetic correction of HSCs can therefore potentially last a lifetime and permanently cure hematologic disorders in which genetic deficiencies cause the pathology. Oncoretroviral vectors have been the main vectors used for HSCs because of their ability to integrate into the chromosomes of their target cells. Gene-transfer efficiency of murine HSCs is high using oncoretroviral vectors. In contrast, gene-transfer efficiency using the same viral vectors to transduce human HSCs or HSCs from large animals has been much lower. Although these difficulties may have several causes, the main reason for the low efficiency of human HSC transduction with oncoretroviral vectors is probably because of the nondividing nature of HSCs. Murine HSCs can be easily stimulated to divide in culture, whereas it is more problematic to stimulate human HSCs to divide rapidly in vitro. Because oncoretroviral vectors require dividing target cells for successful nuclear import of the preintegration complex and subsequent integration of the provirus, only the dividing fraction of the target cells can be transduced. This review focuses on gene transfer into human hematopoietic cells, particularly human HSCs. We review the clinical studies that have been reported, including the recent successful gene therapy for X-linked severe combined immunodeficiency. We discuss how the gene-transfer efficiency of human HSCs can be improved using oncoretroviral and lentiviral vectors.

Lymphomas associated with Warthin’s tumor (WT) are extremely uncommon and the majorities are of B cell type. We report the simultaneous occurrence of T-cell lymphoblastic lymphoma (T-LBL) and WT in an 81-year-old patient, who presented with fever, night sweats and enlargement of the right parotid gland. The parotidectomy specimen showed a WT with extensive replacement of the lymphoid stroma by T-LBL, but preservation of the oncocytic epithelium. Staging investigations revealed mediastinal and abdominal lymphadenopathy, bilateral pleural effusions and bone marrow infiltration, in keeping with stage IVB disease. The patient received combination chemotherapy treatment but responded poorly, and died three months after diagnosis. To our knowledge, this is the first case report of T-LBL involving WT. The present study indicates that the lymphoid stroma in WT belongs to the systemic lymphoid tissue and can be involved in disseminated lymphoma. It highlights the importance of careful examination of WT’s lymphoid stroma for the possible presence of any coexistent malignancy.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated hemolysis, venous thrombosis, and bone marrow failure. In May 2003, a 33-year-old man was admitted to a hospital with right hypochondralgia and fever. He had a history of aplastic anemia. The patient’s diagnosis of diffuse microvessel thrombosis in the hepatic vein due to an unknown cause was derived from the findings of a contrast-enhanced computed tomography examination of the abdominal region, angiographic evaluation of abdominal vessels, and pathohistologic examination of a liver biopsy sample. The patient was subsequently treated with warfarin. The abdominal pain and fever continued, however, and anemia gradually appeared. In April 2004, the patient was referred to our hospital to examine the cause of the thrombosis. On admission, slight anemia and a low serum haptoglobin level were observed. A flow cytometry evaluation of CD55 and/or CD59, CD59, and CD48 expression in erythrocytes, granulocytes, and monocytes, respectively, showed that the respective proportions of negative populations were 5.6%, 97.1%, and 96.2%. The patient then received a diagnosis of aplastic anemia/PNH syndrome, which had caused the hemolytic anemia and thrombosis, although no hemoglobinuria had been observed during his clinical course. This patient is, to our knowledge, the first reported case of a PNH patient with thrombosis present only in hepatic microvessels and not in hepatic large vessels, in spite of the presence of few hemolytic events.

The combination of cytarabine (ara-C) with fludarabine is a common approach to treating resistant acute myeloid leukemia. Success depends on a fludarabine triphosphate (F-ara-ATP)-mediated increase in the active intracellular metabolite of ara-C, ara-C 5’-triphosphate (ara-CTP). Therapy-resistant leukemia may exhibit ara-C resistance, the mechanisms of which might induce cross-resistance to fludarabine with reduced F-ara-ATP formation. The present study evaluated the effect of combining ara-C and fludarabine on ara-C-resistant leukemic cells in vitro. Two variant cell lines (R1 and R2) were 8-fold and 10-fold more ara-C resistant, respectively, than the parental HL-60 cells. Reduced deoxycytidine kinase activity was demonstrated in R1 and R2 cells, and R2 cells also showed an increase in cytosolic 5’-nucleotidase II activity. Compared with HL-60 cells, R1 and R2 cells produced smaller amounts of ara-CTP. Both variants accumulated less F-ara-ATP than HL-60 cells and showed cross-resistance to fludarabine nucleoside (F-ara-A). R2 cells, however, accumulated much smaller amounts of F-ara-ATP and were more F-ara-A resistant than R1 cells. In HL-60 and R1 cells, F-ara-A pretreatment followed by ara-C incubation produced F-ara-ATP concentrations sufficient for augmenting ara-CTP production, thereby enhancing ara-C cytotoxicity. No potentiation was observed in R2 cells. Nucleotidase might preferentially degrade F-ara-A monophosphate over ara-C monophosphate, leading to reduced F-ara-ATP production and thereby compromising the F-ara-A-mediated potentiation of ara-C cytotoxicity in R2 cells. Thus, F-ara-A-mediated enhancement of ara-C cytotoxicity depended on F-ara-ATP accumulation in ara-C-resistant leukemic cells but ultimately was associated with the mechanism of ara-C resistance.

There are few established therapies for chronic graft-versus-host disease (cGVHD) refractory to first-line treatment with steroids. We evaluated the efficacy and safety of extracorporeal photopheresis (ECP) with a third-generation TC-V device in Japanese patients with cGVHD. Fifteen patients with steroid-resistant or -intolerant cGVHD after allogeneic hematopoietic stem cell transplantation participated in this multicenter open-label study. Extracorporeal photopheresis was conducted on days 1–3, week 1; days 1–2, weeks 2–12; and days 1–2, weeks 16, 20, and 24. The composite primary endpoint consisted of evaluation of response and changes in steroid dose 24 weeks after ECP initiation. Secondary endpoints included response over time, concomitant drug dose, quality of life, and safety. Twelve patients completed scheduled ECP therapy; eight (66.7%) showed a response at week 24. In all 15 patients, the mean (± standard deviation) steroid dose decreased 0.115 ± 0.230 mg/kg/day from screening to week 24. Five serious, potentially treatment-related adverse events (heart failure, thrombosis in the device, pneumonia, edema, and wheezing) occurred; none were fatal. This study confirmed that ECP using the TC-V device was effective, with an acceptable toxicity profile. Further studies in larger cohorts are clearly warranted to determine its optimal use in Japanese patients with cGVHD.

Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma usually confined to the body cavities of predominantly immunosuppressed patients infected with human herpes virus-8 (HHV-8). In PEL, malignant cells are usually negative for B-cell markers, such as CD19, CD20, and CD79a, but are positive for activation and plasma cell-related markers, such as CD30, CD38, and CD138. It has been reported that HHV-8-unrelated PEL shows high expression of B-cell markers, which is referred to as PEL-like lymphoma. Here, we report two cases of HHV-8-unrelated HIV-negative PEL-like lymphoma in which malignant cells regressed spontaneously after effusion drainage alone. These cells expressed B-cell markers, such as CD20. No chemotherapy was given to either patient, as they were of an advanced age, and both achieved a complete response by effusion drainage alone. One showed a complete response for 16 months after effusion drainage, and the other has survived for 11 months with a complete response. This suggests that sufficient drainage of serous effusion may induce and maintain a complete response in some patients with HHV-8-unrelated HIV-negative PEL-like lymphoma, which represents an excellent treatment option for elderly patients with this disease.

The prognosis for adult acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement (CNS+) who received allogeneic hematopoietic stem cell transplantation (allo-SCT) remains unclear. We retrospectively compared the outcomes of allo-SCT for patients with CNS involvement and for patients without CNS involvement (CNS−) using a database in Japan. The eligibility criteria for this study were as follows: diagnosis of ALL, aged more than 16 years, allo-SCT between 2005 and 2012, and first SCT. Data for 2582 patients including 136 CNS+ patients and 2446 CNS− patients were used for analyses. As compared with CNS− patients, CNS+ patients were younger, had worse disease status at SCT and had poorer performance status (PS) at SCT (P < 0.01). Incidence of relapse was higher in CNS+ patients (P = 0.02), and incidence of CNS relapse was also higher (P < 0.01). The probability of 3-year overall survival (OS) was better in CNS− patients (P < 0.01) by univariate analysis. However, in patients who received SCT in CR, there was no difference in the probability of OS between CNS+ and CNS− patients (P = 0.38) and CNS involvement did not have an unfavorable effect on OS by multivariate analysis. CNS+ patients who achieved CR showed OS comparable to that of CNS− patients.

Deep vein thrombosis (DVT) is a serious pregnancy-related complication. Recent studies indicate that the genetic background for DVT differs with ethnicity. In our study, we enrolled 18 consecutive Japanese patients who had developed DVT during pregnancy and postpartum. We performed a genetic analysis of three candidate genes for DVT, protein S, protein C and antithrombin, in these patients. We found that four patients had missense mutations in the protein S gene, including the K196E mutation in two patients, the L446P mutation in one patient, and the D79Y and T630I mutations in one patient, as well as one patient with the C147Y mutation in the protein C gene. All five patients with genetic mutations had DVT in their first two trimesters. Nine of the patients without genetic mutations developed DVT in the first two trimesters, and four in the postpartum period. Thus, genetic mutations in the protein S gene were predominant in pregnant Japanese DVT women, and DVT in pregnant women with genetic mutations occurred more frequently at the early stage of pregnancy than postpartum. Considering the rapid decrease in protein S activity during pregnancy, we may need to assess thrombophilia in women before pregnancy.