GM-CSF therapy inhibits chronic graft-versus-host disease via expansion of regulatory T cells.

Regulatory T cells (Tregs) attenuate excessive immune responses, making their expansion beneficial in immune-mediated diseases, including allogeneic bone marrow transplantation associated with graft-versus-host disease (GVHD). In addition to interleukin-2, Tregs require T-cell receptor and costimulatory signals from antigen-presenting cells, such as DCs, for their optimal proliferation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases DC number and may promote DC-dependent Treg proliferation. Here, we demonstrate that GM-CSF treatment increases CD4+ CD8- DCs, which are associated with Treg expansion. In a mouse model of chronic GVHD (cGVHD), GM-CSF therapy expanded Tregs, protected against the development of skin GVHD, and regulated both Th1 and Th17 responses in the peripheral lymph nodes, resulting in an attenuation of skin cGVHD. Notably, the expanded Tregs were instrumental to GM-CSF-mediated cGVHD inhibition, which was dependent upon an increased ratio of Tregs to conventional T cells rather than augmentation of suppressive function. These data suggest that GM-CSF induces Treg proliferation by expanding CD4+ CD8- DCs, which in turn regulate alloimmune responses in a cGVHD mouse model. Thus, GM-CSF could be used as a therapeutic DC modulator to induce Treg expansion and to inhibit excessive alloimmune responses in immune-related diseases.

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.

[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.

Concomitant use of interleukin-2 and tacrolimus suppresses follicular helper T cell proportion and exerts therapeutic effect against lupus nephritis in systemic lupus erythematosus-like chronic graft versus host disease.

Introduction: Defective interleukin-2 (IL-2) production contributes to immune system imbalance in patients with systemic erythematosus lupus (SLE). Recent clinical studies suggested that low-dose IL-2 treatment is beneficial for SLE and the therapeutic effect is associated with regulatory T cell (Treg) expansion. Pharmacological calcineurin inhibition induces a reduction in the number of Tregs because they require stimulation of T cell receptor signaling and IL-2 for optimal proliferation. However, the activation of T cell receptor signaling is partially dispensable for the expansion of Tregs, but not for that of conventional T cells if IL-2 is present. Aim: We examined whether addition of IL-2 restores the Treg proportion even with concurrent use of a calcineurin inhibitor and if the follicular helper T cell (Tfh) proportion is reduced in an SLE-like murine chronic graft versus host disease model. Methods: Using a parent-into-F1 model, we investigated the effect of IL-2 plus tacrolimus on Treg and Tfh proportions and the therapeutic effect. Results: Treatment with a combination of IL-2 and tacrolimus significantly delayed the initiation of proteinuria and decreased the urinary protein concentration, whereas tacrolimus or IL-2 monotherapy did not significantly attenuate proteinuria. Phosphorylation of signal transducer and activator of transcription 3, a positive regulator of Tfh differentiation, was reduced by combination treatment, whereas phosphorylation of signal transducer and activator of transcription 5, a negative regulator, was not reduced. Conclusion: Addition of calcineurin inhibitors as adjunct agents may be beneficial for IL-2-based treatment of lupus nephritis.

Early administration of lenalidomide after allogeneic hematopoietic stem cell transplantation suppresses graft-versus-host disease by inhibiting T-cell migration to the gastrointestinal tract.

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative treatment for hematopoietic malignancies. Graft-versus-host disease (GVHD) is a major complication of aHSCT. After transplantation, the balance of immune conditions, such as proinflammatory cytokine level and T-cell subset count, influences GVHD magnitude. Lenalidomide (LEN) is an immunomodulatory drug used for treating several hematological malignancies such as multiple myeloma, adult T-cell lymphoma/leukemia, and follicular lymphoma. However, the impact of LEN on immune responses after aHSCT has not been elucidated. METHODS: We analyzed the lymphocyte composition in naïve mice treated with LEN. Subsequently, we treated host mice with LEN, soon after aHSCT, and analyzed GVHD severity as well as the composition and characteristics of lymphocytes associated with GVHD. RESULTS: Using a mouse model, we demonstrated the beneficial effects of LEN for treating acute GVHD. Although natural killer cells were slightly increased by LEN, it did not significantly change T-cell proliferation and the balance of the T-cell subset in naïve mice. LEN did not modulate the suppressive function of regulatory T cells (Tregs). Unexpectedly, LEN prevented severe GVHD in a mouse acute GVHD model. Donor-derived lymphocytes were more numerous in host mice treated with LEN than in host mice treated with vehicle. Lymphocyte infiltration of the gastrointestinal tract in host mice treated with LEN was less severe compared to that in host mice treated with vehicle. The percentage of LPAM-1 (α4 ß7 -integrin)-expressing Foxp3- CD4+ T cells was significantly lower in host mice treated with LEN than in host mice treated with vehicle, whereas that of LPAM-1-expressing Tregs was comparable. CONCLUSIONS: LEN may be useful as a prophylactic agent for acute GVHD-induced mortality through the inhibition of lymphocyte migration to the gastrointestinal tract. Our data show the effect of LEN on immune responses early after aHSCT and suggest that cereblon, a molecular target of LEN, may be a therapeutic target for preventing acute GVHD-induced mortality.

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.

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.

Myodesopsia is a symptom of central nervous system blast crisis in chronic myeloid leukemia.

A 49-year-old woman diagnosed with chronic myeloid leukemia in the chronic phase was started on dasatinib treatment, after which she complained of myodesopsia. Nineteen months after diagnosis, the patient again complained of myodesopsia and developed bilateral optic neuritis. Cerebrospinal fluid analysis revealed an increase in blasts, although peripheral blood and bone marrow examination confirmed that the patient remained in a molecular response to tyrosine kinase inhibitor (TKI) therapy. The patient was diagnosed with an isolated central nervous system blast crisis, a rare occurrence with second-generation TKI therapy, and the initial presentation of myodesopsia represented a symptom of this condition.

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.

A variant of acute promyelocytic leukemia with t(4;17)(q12;q21) showed two different clinical symptoms.

A 63-year-old man was diagnosed with a rare variant of acute promyelocytic leukemia (APL) with t(4;17)(q12; q21) that showed atypical morphological features and two different clinical symptoms. He was started on standard induction chemotherapy for acute myeloid leukemia, which decreased myeloblast numbers; however, APL-like blasts remained. He then received a salvage therapy that added all-trans retinoic acid (ATRA). After ATRA commenced, APL-like blasts disappeared and cytogenetic analysis became normal. However, myeloblasts subsequently increased, and he became resistant. In summary, this patient exhibited two different clinical courses of acute myeloid leukemia and APL.

Secondary pure red cell aplasia in multiple myeloma treated with lenalidomide.

Pure red cell aplasia (PRCA) is a rare disorder characterized by marked erythroid hypoplasia with maturation arrest in the bone marrow. Secondary acquired PRCA may be associated with hematologic disorders. A few case reports have described PRCA associated with multiple myeloma (MM). However, the clinical course and mechanism of PRCA associated with MM remain unknown. We herein report two cases of PRCA associated with MM in patients undergoing treatment with lenalidomide.

Clinical significance of dasatinib-induced pleural effusion in patients with de novo chronic myeloid leukemia.

Dasatinib is currently approved for clinical use as a first-line treatment agent for newly diagnosed chronic myeloid leukemia (CML). However, only a few clinical trials have been performed to evaluate dasatinibinduced PE following first-line therapy. We investigated the incidence and clinical features of dasatinib-induced PE following first-line therapy in Japanese CML patients of real world clinical practice settings. Among 22 patients, the median age of PE-positive patients was higher than that of PE-negative patients. Major molecular response was achieved in 75% of PE-positive patients and 50% of PE-negative patients. Most patients developed PE more than 1 year after treatment. Appearance of PE is associated with better clinical response during dasatinib treatment, however it is developed at any time. Elderly and high-risk patients tend to develop PE. The clinical features of dasatinib-induced PE following first-line therapy might be late onset and might not immediately follow the increasing of large granular lymphocyte.

Blastic Epstein-Barr virus associated post-transplant lymphoproliferative disorder after allogeneic stem cell transplantation for severe aplastic anemia.

Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication of organ transplantation. Progress has recently been made in the pathological classification of PTLD. However, the clinical course has not been clarified because of the rarity of this disease. We experienced a case of PTLD with a fulminant clinical course. The patient had been under longterm immunosuppressive treatment for aplastic anemia. He received related allogeneic hematopoietic stem cell transplantation. Soon after transplantation, he developed PTLD. According to the guidelines, we reduced immunosuppression. However, the disease course was so fulminant that there was no time for the patient to respond, and he died of multi-organ failure. There may be various clinical types of PTLD, which may include some fulminant cases. In such a case, it is not sufficient to reduce immunosuppression. The patient should be carefully observed and an appropriate individual treatment should be chosen.

Combined Use of Ninjin'yoeito Improves Subjective Fatigue Caused by Lenalidomide in Patients With Multiple Myeloma: A Retrospective Study.

Lenalidomide is an immunomodulating derivative of thalidomide, which shows anti-tumor activity against myeloma cells with immunomodulation including augmentation of T-cell and natural killer cell function. Continuous treatment with this agent shows better survival benefit in patients with multiple myeloma and combined lenalidomide with dexamethasone (LEN-DEX) is a standard treatment regimen. However, fatigue is a frequent symptom resulting from lenalidomide administration. This side-effect therefore reduces quality of life for elderly patients and, furthermore, is a reason for treatment discontinuation. Unfortunately, appropriate preventive countermeasures against lenalidomide-related fatigue have not been established. Ninjin'yoeito is a traditional Chinese medicine made from the extracts of 12 herbal plants, which positively affects immunity and inflammation. It is used to treat fatigue, decreased appetite, anemia, and general malaise associated with malignant tumors and chemotherapy. We have previously reported that ninjin'yoeito significantly improved patients' subjective fatigue symptoms treated with melphalan-prednisone for multiple myeloma. In the present study, we assessed the benefits of ninjin'yoeito as a supplementary treatment for patients with myeloma, and its effect on lenalidomide treatment regime compliance. We retrospectively analyzed 36 cases of newly diagnosed or relapsed/refractory multiple myeloma. The study included patients receiving LEN-DEX with onset of general fatigue after lenalidomide administration (13 and 23 patients with or without ninjin'yoeito, respectively). Frequency of subjective fatigue was significantly decreased in patients administered ninjin'yoeito, compared to those treated with LEN-DEX alone (92.3 and 47.8 % of patients with and without ninjin'yoeito, respectively; p = 0.008). In addition, combined use of ninjin'yoeito and LEN-DEX showed a trend toward reduced rates of treatment discontinuation (7.7 % and 34.8 % of patients with and without ninjin'yoeito, respectively; p = 0.076). Our results suggest that ninjin'yoeito is an effective method for treating subjective fatigue caused by lenalidomide and may have the potential to extend lenalidomide treatment duration.

Upfront high-dose chemotherapy combined with autologous stem cell transplantation: Potential survival benefit for patients with high-risk diffuse large B-cell lymphoma.

In patients with diffuse large B-cell lymphoma (DLBCL) classified as high-intermediate risk or high risk using the International Prognosis Index, the efficacy of high-dose chemotherapy combined with upfront autologous stem cell transplantation (HDT/ASCT) remains controversial in the rituximab era. In the present study, 27 patients who had been treated with HDT/ASCT in an upfront setting were retrospectively analyzed, and compared with 77 patients with similar characteristics who had received conventional chemotherapy without HDT/ASCT (the non-upfront setting). The 3-year overall survival and progression-free survival rates in the upfront setting were 88.5% (P=0.0134 vs. non-upfront setting) and 68.4% (P=0.113 vs. non-upfront setting), respectively; in the non-upfront setting, the 3-year overall survival and progression-free survival rates were 60.8 and 50.6%, respectively. In conclusion, the results indicate that upfront HDT/ASCT in patients with high-risk DLBCL is feasible and may improve the outcome of these patients. It may be beneficial for patients to undergo HDT/ASCT as an early treatment, prior to the development of therapy resistance.

Transplant-Ineligible Symptomatic but Indolent Multiple Myeloma Shows Better Prognosis with Conventional Agents.

The survival of multiple myeloma patients has improved significantly over the last several decades. However, the median overall survival of these patients remains less than 5 years. In this report, we discuss 4 cases of multiple myeloma patients that showed long survival. Interestingly, these patients had severe organ damage at diagnosis, used only conventional agents, and did not always show deep response. Although current guidelines recommend novel agents to achieve deep response, the current cases suggest that some multiple myeloma patients may not need intensive treatment. Here, we discuss 4 cases of symptomatic but indolent transplant-ineligible myeloma.