Real-world efficacy of letermovir prophylaxis for cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation: A single-center retrospective analysis.

INTRODUCTION: Cytomegalovirus (CMV) infection is a common complication following allogeneic hematopoietic stem cell transplantation (aHSCT) and is associated with increased mortality. Letermovir (LET) is a novel antiviral drug used to prevent CMV infection. METHODS: We analyzed 111 consecutive patients who underwent aHSCT, retrospectively, to evaluate the efficacy of LET prophylaxis for clinically significant CMV infection (csCMVi) in real-world situations. In addition, we analyzed the influence of LET on transplant outcomes. Thirty-eight patients who were administered LET prophylactically were compared with 73 patients without LET prophylaxis after aHSCT. RESULTS: On day 180, the cumulative incidence of csCMVi in patients who received LET prophylaxis was significantly lower than that in patients without LET prophylaxis (29.7% vs. 56.2%, P < 0.001). Among the patients who developed csCMVi, the interval from aHSCT to the initiation of preemptive therapy was significantly longer in patients who received LET prophylaxis than in those who did not (129.5 days vs. 42 days, P < 0.001). The six-month overall survival was 86.1% in patients who received LET prophylaxis and 66.8% in the non-LET group (P = 0.035). CONCLUSION: LET prophylaxis was highly effective in preventing csCMVi and could potentially improve transplant outcomes, particularly when initiated early after transplantations.

Clinical efficacy of mogamulizumab for relapsed/refractory aggressive adult T-cell leukemia/lymphoma: A retrospective analysis.

OBJECTIVES: Although phase 2 studies have confirmed the efficacy of mogamulizumab for adult T-cell leukemia/lymphoma (ATL), real-world data on its benefits are limited. We assessed the benefits of mogamulizumab for relapsed/refractory ATL in clinical practice. METHODS: We retrospectively analyzed patients with acute- and lymphoma-type ATL. Among 57 patients diagnosed with ATL between January 2008 and August 2018, 42 who received salvage therapy were eligible, including 24 who received mogamulizumab. RESULTS: The overall response rate to mogamulizumab was 54.2%. Median survival time (MST) and 1-year overall survival (OS) rate from mogamulizumab initiation were 7.7 months and 42.0%, respectively. Patients with acute-type ATL showed longer MST (15.1 months) and higher 1-year OS (63.6%). MST without skin rash was 5.0 months, and 1-year OS was 34.3%; however, MST with skin rash was not reached and 1-year OS was 66.7%. Among patients who received the salvage therapy, longer MST and higher 1-year OS were observed with mogamulizumab than without mogamulizumab (P = .078; 9.2 vs. 3.9 months; 47.9% vs. 17.6%, respectively). Mogamulizumab administration improved prognosis in patients with acute-type ATL and skin rash. CONCLUSIONS: In clinical practice, mogamulizumab improved OS in patients with relapsed/refractory ATL, especially those with acute-type ATL and skin rash.

Efficacy and safety of anagrelide as a first-line drug in cytoreductive treatment-naïve essential thrombocythemia patients in a real-world setting.

OBJECTIVE: This study aimed to retrospectively assess the efficacy and safety of anagrelide in cytoreduction therapy-naïve essential thrombocythemia (ET) patients in a real-world setting. METHOD: Data from 53 ET patients who received anagrelide as a first-line therapy were reviewed for patient characteristics, antiplatelet status, cytoreduction status, therapeutic effects, adverse events, thrombohemorrhagic event development, progression to myelofibrosis or acute leukemia, and cause of death. RESULTS: The rate of achieving a platelet count of <600 × 109 /L during anagrelide monotherapy was 83.0%. Adverse events occurred in 32 of 53 patients, and tended to be slightly more severe in patients with cardiac failure; however, they were mostly tolerable. The therapeutic effect of anagrelide was consistent, regardless of genetic mutation profiles. The incidence of anemia as an adverse event was significantly higher in the CALR mutation-positive group. Favorable platelet counts were also achieved in patients for whom hydroxyurea was introduced as a replacement for anagrelide or in addition to anagrelide because of unresponsiveness or intolerance to treatment. CONCLUSION: In Japanese cytoreduction therapy-naïve ET patients, anagrelide administration as a first-line therapy demonstrated favorable effects in reducing platelet counts, and its safety profile that was generally consistent with those in previous reports.

[Successful treatment with brentuximab vedotin maintenance therapy after autologous stem cell transplantation in high-risk Hodgkin lymphoma].

A 56-year-old woman was diagnosed with classical Hodgkin lymphoma in December 2012. She achieved complete remission (CR) with six cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). In March 2015, she experienced a relapse marked by high fever, respiratory discomfort, and pain in the left thigh owing to tumor involvement of the femur. She was treated with one cycle of brentuximab vedotin (BV), followed by irradiation of the left femoral lesion. She achieved partial remission (PR) but developed recurrence after the third cycle of BV. She achieved PR again with two cycles of standard bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen; therefore, autologous stem cell transplantation (ASCT) was performed. Because the dosing interval used for BV therapy was longer than that in the recommended schedule, we could not definitively attribute her recurrence to BV resistance. Moreover, she maintained a good performance status after recurrence during subsequent cycles of BV therapy. Because of attaining PR after ASCT, she subsequently received a total of 12 BV cycles for consolidation. She achieved CR 3 months after ASCT and has remained in CR until 29 months. For patients who show relapse after initial BV therapy, retreatment with BV should be carefully considered. Patients who show relapse after achieving at least PR with initial BV therapy are potential candidates for post-ASCT BV maintenance therapy to reduce their tumor burden.

Realistic Lenalidomide Dose Adjustment Strategy for Transplant-Ineligible Elderly Patients with Relapsed/Refractory Multiple Myeloma: Japanese Real-World Experience.

Lenalidomide is an immunomodulatory drug administered orally in the treatment of multiple myeloma. Some elderly patients require a reduced lenalidomide dose because of comorbidities and/or adverse events. This study investigated the actual dose of lenalidomide in elderly patients, finding that most received reduced (5-10 mg) doses. The most common reasons for dose reduction were renal dysfunction (54% of patients), fatigue (grade ≥3; 20%), hematologic disorder (grade ≥3; 14%), and rash (grade ≥3; 9%). Their median time to progression was 11.8 months and their median overall survival was 39.2 months. The overall response rate was 73%, including 17% with a complete response, 19% with a very good partial response, and 37% with a partial response. These results showed that, contrary to western countries, most patients were treated with a reduced dose of lenalidomide in Japan. However, it is suggested that continued treatment with a tolerable dose may yield favorable outcomes.

Rapid improvement of hyperammonemic encephalopathy by bortezomib treatment in IgD-type multiple myeloma.

A 74-year-old man visited our hospital with complaints of anorexia, weight loss, and impaired activities of daily living. He presented mild consciousness disturbance at the first visit, but specific causes were identified. The IgD level was>2,000 mg/dl and bone marrow biopsy was performed after aspiration failed due to excessive density. He was diagnosed with IgD/λ multiple myeloma (MM). He lapsed into a coma with an extremely high ammonia level of 484 µg/dl on day 8 after admission. His diagnosis was established as hyperammonemic encephalopathy (HE). He was treated with dexamethasone (Dex) pulse therapy and continuous hemodiafiltration. Minor improvement of hyperammonemia was achieved. Combination therapy with bortezomib and Dex was commenced. His ammonia level rapidly decreased and his mental state improved. HE accompanied by MM is rare and further studies are needed to clarify outcomes in response to treatment using the novel agent Bor. Although HE is potentially fatal, we found Bor to be rapidly effective against HE.

Platelet-derived RANK ligand enhances CCL17 secretion from dendritic cells mediated by thymic stromal lymphopoietin.

Dendritic cells (DCs) play an integral role in cellular cascade that initiate and maintain Th2 responses in allergy. In this study, we examined the interaction between platelets and DCs to determine the role of platelets in the intervention of immune responses through modulation of DC functions. Blood-purified myeloid DCs, which had been stimulated with thymic stromal lymphopoietin (TSLP-DCs), formed aggregates with activated platelets. TSLP-DC maturation was induced after the interaction with TRAP6-activated platelets as indicated by an increase in the expression of CD86, CD40, and CD83. In addition, production of a Th2 cell-attracting chemokine, CCL17, was clearly upregulated by coculture of TSLP-DCs with TRAP6-activated platelets. We further found that an expression of RANK ligand (RANKL) on platelets was upregulated by the TRAP6 activation, and that, using the neutralizing antibody against RANKL, the platelet-derived RANKL induces the activation of TSLP-DCs. Thus, activated platelets can intervene in adaptive immune responses through induction of functional modulation of TSLP-DCs. Platelets have the ability to enhance the DC-mediated Th2 response and may contribute to the allergic inflammation. In conclusion, our study provides new insights in platelet functions and the possible mechanism of allergic responses that stem from DCs.

[Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder in a Patient with Acute Lymphocytic Leukemia].

A 27-year-old woman with acute lymphocytic leukemia, who underwent allogeneic hematopoietic stem cell transplantation, complained of nausea and blurred vision 288 days after the transplantation. Intracranial tumors were identified on brain MRI. She received whole brain radiation after open biopsy, but she died. The tumors had characteristics of diffuse large B cell lymphoma, and she was finally diagnosed with primary central nervous system post-transplant lymphoproliferative disorder. This disease is rare and has a poor outcome. Therefore, accumulation of cases and establishment of treatments for this condition are urgently needed.

Plasmacytoid dendritic cells have a cytokine-producing capacity to enhance ICOS ligand-mediated IL-10 production during T-cell priming.

Plasmacytoid dendritic cells (pDCs) have the potential to prime CD4(+) T-cells to differentiate into IL-10-producing T regulatory cells through preferential expression of inducible co-stimulatory ligand (ICOS-L). Although pDCs produce cytokines such as type-I IFNs, TNF-α, or IL-6 accompanying up-regulation of ICOS-L expression during activation in response to toll-like receptor (TLR)-ligands or IL-3, the roles of the pDC-derived cytokines in T-cell priming remain largely elusive. Therefore, we investigated the functional involvement of these cytokines in generating IL-10-producing T regulatory cells. We found that either IFN-α or IL-6 enhanced the pDC- or ICOS-L-driven generation of IL-10-producing T-cells from naive CD4(+) T-cells and their regulatory functions. However, IFN-α stimulation in the absence of ICOS-L showed only a marginal tendency to increase the T-cell production of IL-10 and thus pDC-derived type-I IFNs in response to CpG could function together with ICOS-L. In addition, IL-6 functioned to generate IL-10-producing T-cells only on T-cell priming by pDCs activated by IL-3 or under IL-4-mediated T(h)2 conditions. Thus, type-I IFNs and IL-6 act as supplementary factors for the ICOS-L-dependent IL-10-producing T-cell differentiation in pDCs activated along the TLR-dependent and IL-3-dependent pathways, respectively. We also showed that pDC-derived TNF-α induced ICOS-L expression on pDCs in an autocrine manner and that IL-6 promoted ICOS expression on T-cells, contributing to the ICOS/ICOS-L-mediated T-cell response. Our results suggest that the ICOS-L-mediated tolerogenic pDC function in adaptive immunity is backed up by the elaborate cytokine-producing ability of pDCs.

IL-33 promotes the induction and maintenance of Th2 immune responses by enhancing the function of OX40 ligand.

BACKGROUND: In Th2 immune responses, TSLP is a key player by induction of OX40-ligand (OX40L) on dendritic cells (DCs), which is the trigger to induce Th2 cell-mediated allergic cascade. Thus, TSLP-DC-OX40L axis might be the principal pathway in the inflammatory cascades in atopic dermatitis and asthma. IL-33, which is produced by epithelial cells, has been implicated in the Th2 immune responses and pathogenesis of the allergic disorders. However, the role of IL-33 in the Th2-polarizing TSLP-DC-OX40L axis still remains largely elusive. We focused on the ability of IL-33 to promote OX40L-mediated Th2 responses. METHODS: Purified human naïve or memory CD4+ T cells were stimulated with recombinant OX40L or TSLP-treated DCs (TSLP-DCs) in the presence of IL-33, and the cytokine production by the primed T cells was examined. We also performed immunohistochemical analyses for the expression of IL-33 in specimens of lymph node and skin from the patients with atopic dermatitis. RESULTS: IL-33 remarkably enhanced TSLP-DCs-driven or OX40L-driven Th2 responses from naïve T cells and the Th2 functional attributes of CRTH2+ CD4+ Th2 memory cells by the increased production of IL-5, IL-9, and IL-13. In addition, IL-33 was expressed in the nuclei of epithelial cells in not only skin lesion but also lymph nodes of the patient with atopic dermatitis, suggesting a specialized role in adaptive T cell-priming phase. CONCLUSIONS: IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.

IL-33 Promotes the Induction and Maintenance of Th2 Immune Responses by Enhancing the Function of OX40 Ligand.

BACKGROUND: In Th2 immune responses, TSLP is a key player by induction of OX40-ligand (OX40L) on dendritic cells (DCs), which is the trigger to induce Th2 cell-mediated allergic cascade. Thus, TSLP-DC-OX40L axis might be the principal pathway in the inflammatory cascades in atopic dermatitis and asthma. IL-33, which is produced by epithelial cells, has been implicated in the Th2 immune responses and pathogenesis of the allergic disorders. However, the role of IL-33 in the Th2-polarizing TSLP-DC-OX40L axis still remains largely elusive. We focused on the ability of IL-33 to promote OX40L-mediated Th2 responses. METHODS: Purified human naïve or memory CD4+ T cells were stimulated with recombinant OX40L or TSLP- treated DCs (TSLP-DCs) in the presence of IL-33, and the cytokine production by the primed T cells was examined. We also performed immunohistochemical analyses for the expression of IL-33 in specimens of lymph node and skin from the patients with atopic dermatitis. RESULTS: IL-33 remarkably enhanced TSLP-DCs-driven or OX40L-driven Th2 responses from naïve T cells and the Th2 functional attributes of CRTH2+ CD4+ Th2 memory cells by the increased production of IL-5, IL-9, and IL-13. In addition, IL-33 was expressed in the nuclei of epithelial cells in not only skin lesion but also lymph nodes of the patient with atopic dermatitis, suggesting a specialized role in adaptive T cell-priming phase. CONCLUSIONS: IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.

Multiple Myeloma with Central Nervous System Relapse Early after Autologous Stem Cell Transplantation: A Case Report and Literature Review.

Few reports have so far described central nervous system (CNS) involvement in multiple myeloma (MM), which shows a poor prognosis owing to its resistance to several treatments. We herein describe a 45-year-old woman who had MM (diagnosed with IgA-κ type) with CNS relapse early after undergoing autologous hematopoietic stem cell transplantation. Because no standard treatment for CNS lesions of MM has been established, we conducted a literature review on the cerebrospinal fluid (CSF) transferability of drugs for MM, since it was considered to be a useful tool for CNS involvement. Immunomodulatory-drugs including pomalidomide exhibit a good CSF transfer ability, and, therefore, may be beneficial against the CNS involvement of MM.

Elevation of Early Plasma Biomarkers in Patients with Clinical Risk Factors Predicts Increased Nonrelapse Mortality after Allogeneic Hematopoietic Stem Cell Transplantation.

Early prediction of nonrelapse mortality (NRM) in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) based on the results of laboratory tests is challenging. Thus, there is a need to evaluate biomarkers for prediction of NRM, a major problem that offsets the advantages of allo-HSCT. We tested the validity and efficacy of 2 plasma biomarkers, ST2 and Reg3α, based on the Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm, for early prediction of NRM in Japanese patients who underwent allo-HSCT. We conducted a multicenter retrospective study to analyze the clinical data of 112 patients with hematopoietic malignancies who underwent allo-HSCT. Patient blood samples on day 7 after allo-HSCT were obtained from 6 hospitals. The plasma concentrations of ST2 and Reg3α were used to calculate a 6-month NRM risk score. Based on the scores determined in this study, we identified 64 low-risk patients and 48 high-risk patients for the 6-month NRM. The cumulative incidence of 6-month NRM was 29.2% in the high-risk group and 10.9% in the low-risk group (P < .05). The cumulative incidence of relapse mortality was similar in the high-risk and low-risk patients. The biomarker score was predictive in patients with an unrelated donor, an HLA-mismatched donor, high/very high Disease Risk Index, and Hematopoietic Cell Transplantation Comorbidity Index ≥1. Multivariate analysis identified high biomarker probability as a significant predictor of NRM. The MAGIC algorithm based on blood samples obtained at 7 days after allo-HSCT can identify individuals at high risk for NRM among patients with clinical risk factors for NRM in a Japanese cohort.

Refractory Chronic Lymphocytic Leukemia with Central Nervous System Involvement: A Case Report with Literature Review.

There have been few reports on central nervous system (CNS) involvement in chronic lymphocytic leukemia (CLL). This is an extremely rare disease with poor prognosis, owing to resistance to various treatments. We describe a 33-year-old man with intractable CLL with CNS involvement. He was diagnosed with CLL, with diplopia as the first manifestation. Magnetic resonance imaging revealed a contrast-enhancing tumor in the right temporal lobe, which was diagnosed as CNS involvement in CLL on brain biopsy. High-dose methotrexate therapy was ineffective for this lesion, which was also resistant to subsequent whole-brain irradiation, treatment with fludarabine-cyclophosphamide-rituximab chemoimmunotherapy, and ibrutinib administration. Because no standard protocol exists for CLL with CNS involvement, it is important to accumulate case data to verify the choice of new drugs for administration at an early stage. Therefore, we also conducted a literature review of 50 case reports of CNS lesions in the last 10 years to consider the pathophysiology, diagnosis, and treatment of CNS involvement in CLL. The possibility of new therapeutic agents, eg, ibrutinib and venetoclax, or a combination of these agents and methotrexate, can be envisioned as a treatment strategy for CLL with CNS involvement.

Evaluation of azacitidine in patients with transplant-ineligible myelodysplastic syndromes and acute myeloid leukemia with myelodysplasia-related changes in a Japanese clinical setting.

Patients with high-risk myelodysplastic syndromes (MDS) treated with azacitidine (AZA) have exhibited improved overall survival. However, information on AZA in real-world settings is limited. The present study retrospectively analyzed 85 patients with MDS treated with AZA. Complete response was achieved in 24% of cases and hematologic improvement in 29%. Severe adverse events (grade ≥3) included neutropenia and infection. Multivariate analysis identified higher revised international prognostic scoring system (IPSS-R) and male sex as significant factors affecting survival. However, the present study did not identify any significant associations between patient characteristics and response to AZA. In conclusion, AZA could produce a hematologic response in ~53% of patients with MDS. Furthermore, IPSS-R may reflect MDS prognosis. Further studies are required to establish the criteria for identifying patients likely to obtain maximum benefit from AZA treatment.

Comparison of starting doses of anagrelide as a first-line therapy in patients with cytoreductive therapy-naïve essential thrombocythemia: difference between starting at 0.5 and 1.0 mg/day.

Anagrelide is widely used for cytoreductive therapy in patients with essential thrombocythemia who are at high risk for thrombosis. The recommended starting dose in the package insert of anagrelide varies by country. A high starting dose leads to an early onset of action, but causes a higher incidence of adverse events. This relationship indicates that both the onset of action and side effects of anagrelide are dose dependent. We retrospectively compared the efficacy and safety of anagrelide as a first-line drug between patients with essential thrombocythemia who started at 0.5 or 1.0 mg/day. Incidence of total adverse events and anagrelide-related palpitation, discontinuation rates, and the median daily dose of anagrelide were lower in the 0.5 mg/day group than in the 1.0 mg/day group; however, comparable platelet-lowering effects were achieved in both groups. These data suggest that a low starting dose of anagrelide followed by dose escalation may result in fewer adverse events and lower discontinuation rates, while providing desirable platelet-lowering effects. Initiating anagrelide at a lower dose may be a useful approach in actual clinical practice.

Evaluation of eltrombopag in patients with aplastic anemia in real-world experience.

BACKGROUND: Although eltrombopag has recently been approved for treating AA, the effects of its clinical use remain unknown. METHODS: We retrospectively analyzed 11 patients with AA, who had been treated with eltrombopag from August 2017 to May 2018. RESULTS: Overall response rate was 55%. There was tri-lineage recovery in four patients and platelet recovery in two. The reactive time was within 8 weeks after treatment initiation. Stage at the initial assessment, the neutrophil-to-lymphocyte ratio and platelet counts were significantly different between the responders and non-responders. CONCLUSION: Eltrombopag is a promising agent for treating patients with any degree of AA.

Neutrophil-to-lymphocyte ratio (NLR) fails to predict outcome of diffuse large B cell lymphoma.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been recognized as a poor prognostic indicator in various solid tumors. METHODS: We retrospectively analyzed 530 patients with de novo DLBCL who were diagnosed from April 2002 to November 2017. RESULTS: The median age of patients was 69 (range, 20-95) years, and 59% were male. The optimal cutoff for NLR was 5.2. NLR (5.2) was not associated with overall and progression free survival. CONCLUSION: Our study failed to reveal the predictive value of NLR and demonstrated that the NCCN-IPI might be the most powerful predictor in DLBCL.

Trend of salvage treatment in diffuse large B cell lymphoma in the outpatient chemotherapy era.

Patients with diffuse large B cell lymphoma (DLBCL) who have failed to achieve complete remission with first-line therapy can subsequently receive salvage therapy. However, there is no definite consensus on the use of salvage therapy, and little information on the optimal treatment regimen. The present study retrospectively analyzed data from 131 patients diagnosed with DLBCL between April 2002 and November 2017 who relapsed and received salvage therapy. Primary treatment included R-CHOP or R-CHOP-like regimens. The most common salvage regimen was R-DeVIC (42%), followed by R-ESHAP (23%), other aggressive regimens (12%) and palliative therapy (23%). The median overall survival (OS) was 45.7 months for R-DeVIC, 41.8 months for palliative therapy, 29.4 months for R-ESHAP, and 28.5 months for aggressive regimens (P=0.937). A total of 25 patients underwent autologous stem cell transplantation (ASCT), and the OS was 75.6 months for these patients compared with 33.5 months (range, 25.6-45.6 months) for patients who did not undergo ASCT (P=0.033). Following the establishment of an outpatient chemotherapy unit in 2014, R-DeVIC use became more common, increasing from 37% prior to 2014 to 46% after 2014, whereas R-ESHAP use decreased (31 to 17%). The present study did not identify the optimal salvage regimen for patients with DLBCL. However, salvage ASCT improved the outcome, and regimens administered via peripheral veins were demonstrated to be more common in outpatient chemotherapy settings.

Effects of recombinant thrombomodulin on long-term prognosis after allogeneic hematopoietic stem cell transplantation.

We investigated the effects of early recombinant thrombomodulin (rTM) treatment on long-term prognosis after hematopoietic stem cell transplantation (HSCT). Subjects included 300 patients who underwent allogeneic HSCT (131 in the rTM(+) group and 169 in the rTM(-) group). The control group received heparin or no anti-coagulation therapy. When we examined patients with confirmed complications (day 1-100), the frequencies of acute graft-versus-host disease (aGVHD) and thrombotic microangiopathy (TMA) were significantly lower in the rTM(+) group, while the frequencies of veno-occlusive disease did not show such differences. rTM administration was associated with significant differences in the cumulative incidence of aGVHD (any grade and II-IV grades) and TMA. The cumulative overall survival probability was significantly higher in the rTM(+) group (42.3% versus 26.2%, p = .037). Therefore, some causes of a poor prognosis included aGVHD and TMA. The present findings suggest that rTM plays a preventive role in transplant-related complications, such as aGVHD and TMA, after allogeneic HSCT.