[Achievement of deep molecular response in an elderly chronic myeloid leukemia patient intolerant to imatinib and nilotinib].

A 90-year-old woman was diagnosed with chronic myeloid leukemia (CML) of the high risk type (Sokal score 1.5), and was administered imatinib (400 mg/day). However, imatinib had to be switched to nilotinib because she suffered persistent vomiting and nausea. Although a cytogenetic response was achieved, the nilotinib administration also had to be stopped because the patient developed QTc prolongation and heart failure. After she had recovered from heart failure, the patient was given dasatinib (50 mg/day). No non-hematological adverse events occurred and she achieved a molecular response with administration of dasatinib. A molecular response can be achieved through appropriate supportive care and careful selection of tyrosine kinase inhibitors, with adjustments in the doses of these drugs administered to patients with the high-risk form of CML who are intolerant to imatinib.

Immune checkpoint inhibitor-related haemophagocytic lymphohistiocytosis in a patient with non-small cell lung carcinoma.

Hemophagocytic lymphohistiocytosis (HLH) has been reported as a rare complication of immune checkpoint inhibitors (ICI); however, ICI-related HLH is a life-threatening and comparatively late adverse event. Early diagnosis is critical, and it should be included in the differential diagnosis especially in patients with cytopenia with fever and hyperferritinaemia.

[Significance of bortezomib and dexamethasone therapy for multiple myeloma showing a serum creatinine level above 2 mg/dl].

Here, we retrospectively assessed the reversibility of renal impairment and anti-myeloma effect of bortezomib and dexamethasone (BD therapy) for Japanese patients with multiple myeloma showing a serum creatinine level above 2 mg/dl. Improvement of renal impairment was observed in 6 of 7 patients following a median of 2.4 cycles of BD therapy. Three of 7 patients achieved more than partial response by BD therapy. The present study demonstrated that BD therapy was highly effective for the treatment of Japanese myeloma patients with renal impairment.

Incidence and risk of postherpetic neuralgia after varicella zoster virus infection in hematopoietic cell transplantation recipients: Hokkaido Hematology Study Group.

To assess the incidence of and risk factors associated with postherpetic neuralgia (PHN) after hematopoietic cell transplantation (HCT) varicella zoster virus (VZV) infection, we conducted a retrospective chart review of 418 consecutive patients who underwent HCT between April 2005 and March 2007. The male/female ratio was 221/197, median age at HCT was 47 years (range: 0-69 years), and autologous/allogeneic/syngeneic HCT ratio was 154/263/1. Seventy-eight patients developed VZV infection after HCT. Sixty-two patients had localized zoster, 11 patients had disseminated zoster (rash like chicken pox), and 4 patients had visceral zoster. All cases were treated with acyclovir (ACV) or valacyclovir (VACV), and there was no VZV infection-related death. Twenty-seven (35%) of the 78 patients with VZV infection suffered PHN after resolution of VZV infection. Multivariate analysis showed that advanced age is the only risk factor in autologous HCT (P = .0075; odds ratio [OR] = 1.14; 95% confidence interval [CI], 0.97-1.33). On the other hand, advanced age (P = .0097; OR = 1.06; 95% CI, 1.01-1.12), male gender (P = .0055; OR = 12.7; 95% CI, 1.61-100.1), and graft-versus-host disease (GVHD) prophylaxis with a tacrolimus-based regimen (P = .0092; OR = 9.56; 95% CI, 1.44-63.3) were associated with increased risk of PHN in allogeneic HCT. This study for the first time clarified the risk of PHN in HCT recipients.

Impact of rituximab and half-dose CHOP as primary therapy for untreated symptomatic Waldenström Macroglobulinemia: review of a combined regimen of rituximab with an alkylating agent.

BACKGROUND: Waldenström Macroglobulinemia (WM) is a rare subtype of indolent B-cell lymphoma, and prospective randomized studies on WM are scarce. The R-CHOP therapy [rituximab (R), cyclophosphamide, hydroxy-doxorubicin, vincristine, and prednisone] is a popular and recommended regimen for primary therapy, prescribed by several treatment guidelines for WM. However, treatment with R-CHOP is accompanied by severe myelosuppression and high rates of peripheral neuropathy. Therefore, we retrospectively evaluated the efficacy and toxicity of half-dose CHOP combined with R as a primary therapy for WM. METHODS: Patients with untreated symptomatic WM, treated at the Disaster Medical Center between April 2011 and September 2016, were retrospectively analyzed after administration of 6 cycles of half-dose R-CHOP for every 3 weeks. The response, median time to response, best response, progression-free survival, overall survival, and toxicities were evaluated. RESULTS: Of the 20 WM patients analyzed, 16 (80%) received half-dose R-CHOP without vincristine, and 13 (65%) responded to the treatment. With a median follow-up duration of 26.3 months, the 2-year progression-free survival and 2-year overall survival rates were 70 and 93.3%, respectively. The median time to response and best response were 6 and 9.9 weeks, respectively. Grade 3/4 leukocytopenia, neutropenia, febrile neutropenia, and Grade 1 peripheral neuropathy developed in 32, 37, 0, and 21% of patients, respectively. CONCLUSION: The half-dose R-CHOP is an effective and well-tolerated primary therapy for WM. To the best of our knowledge, this is the first study reporting the use of a reduced-dose R-CHOP regimen for the primary treatment of WM.

Gamma Heavy Chain Disease with T-cell Large Granular Lymphocytic Leukemia: A Case Report and Review of the Literature.

Gamma heavy chain disease (gHCD) is a rare lymphoproliferative disorder characterized by the production of a truncated immunoglobulin heavy chain. Although some cases of gHCD are concurrent with other lymphoid neoplasms, few have been reported. We herein present the case of a 73-year-old woman with gHCD and T-cell large granular lymphocytic leukemia. A multiparameter flow cytometry analysis revealed neoplastic cells that were positive for CD28, a marker of T-cell activation, the anti-apoptotic antigen of neoplastic plasma cells, CD38 and CD45. The results of this multiparameter flow cytometry analysis may contribute to furthering the understanding of the clinicopathological features of gHCD.

Significance of lymphocyte counts at diagnosis in the management of ITP: the relationship between lymphocyte counts and treatment success in H. pylori-infected patients.

Immune thrombocytopenic purpura (ITP) is an acquired disorder characterized by thrombocytopenia, increased platelet destruction, and the inhibition of platelet production by specific autoantibodies. Previous studies have reported improvements in ITP following the eradication of Helicobacter pylori (H. pylori) infection. We, herein, investigated the relationship between initial therapy for ITP and lymphocyte counts at diagnosis. We retrospectively examined 52 adult patients with ITP between March 1998 and March 2013. Standard H. pylori eradication therapy was performed in 31 patients, and lymphocyte counts were compared before and after this therapy. At the diagnosis of ITP, lymphocyte counts in H. pylori-infected patients were significantly higher than those in H. pylori-negative patients (1.92 ± 0.68 × 10(9)/L vs. 1.42 ± 0.67 × 10(9)/L; p = 0.010). H. pylori eradication was successful in 6/11 patients (54.5 %) and the platelet count increased in 4/11 H. pylori-positive patients (36.4 %) who received eradication therapy. On the other hand, eradication therapy was also administered to 15 patients without H. pylori infection, and responses were obtained in some H. pylori-negative patients receiving eradication therapy (9/15). Furthermore, lymphocyte counts were significantly higher in patients who achieved a complete response receiving H. pylori eradication therapy than in patients who did not achieve a complete response (2.4 ± 0.59 × 10(9)/L vs. 1.37 ± 0.60 × 10(9)/L, p = 0.0023). The response of ITP patients to the initial treatment may be predicted by measuring the lymphocyte count at diagnosis. Further studies that analyze lymphocyte subsets and the cytokine network are needed to elucidate the underlying mechanisms.

Recombinant human thrombomodulin in the treatment of acute myeloid leukemia patients complicated by disseminated intravascular coagulation: retrospective analysis of outcomes between patients treated with heparin and recombinant human thrombomodulin therapy.

BACKGROUND: Recombinant thrombomodulin (rTM) is a promising anticoagulant. Improvements in disseminated intravascular coagulation (DIC) and the amelioration of bleeding complications in DIC patients were reported to be greater with rTM therapy than with unfractionated heparin therapy. However, it remains unknown whether rTM therapy affects the outcomes of patients with acute myeloblastic leukemia (AML). DESIGN AND METHOD: We retrospectively analyzed 103 patients with AML and compared outcomes between patients treated with low molecular weight heparin therapy and rTM. The diagnostic criteria for DIC were previously proposed by the Japanese Ministry of Health and Welfare. Comparisons between qualitative variables were carried out using the χ(2) test. Survival probabilities were estimated by the Kaplan-Meier method, and differences in survival distributions were evaluated using the log-rank test. RESULTS: Forty-seven patients developed DIC due to chemotherapy or their disease status. Fourteen patients were treated with rTM, while 33 patients were treated with low-molecular-weight heparin (LMWH). The log-rank test revealed that overall survival was significantly worse in the DIC group than in the non-DIC group (P=0.003), and was signfiacntly better in the rTM group than the LMWH group (P=0.016). CONCLUSION: rTM was more efficient than LMWH because of the improvements it induced in overall survival.

Reduced-dose (two-thirds) R-CHOP chemotherapy for elderly patients with non-Hodgkin lymphoma.

Elderly patients with non-Hodgkin lymphoma (NHL) have a poor prognosis. Owing to treatment-related toxicities, there is no standard chemotherapy for the elderly patients, especially those aged 70 years or older. In this study, we retrospectively evaluated the efficacy and toxicity of reduced-dose (two-thirds) R-CHOP chemotherapy as an initial chemotherapy for 45 patients aged 70 years or older with B-cell NHL. The WHO classification of NHL included diffuse large B-cell lymphoma (DLBCL) (31), mantle cell lymphoma (5), follicular lymphoma (4), extranodal marginal zone lymphoma (1), Burkitt lymphoma (1), and B-cell lymphoma whose further types were unclassified (3). The incidences of grade 4 neutropenia and febrile neutropenia (FN) were 51.1 and 15.6%, respectively. Efficacy was evaluated in patients with DLBCL. The overall and complete response (CR) rates were 96.7 and 90.0%, respectively. Two-year event-free survival (EFS) and overall survival (OS) were 84.4 and 89.2%, respectively. There was no treatment-related mortality. In conclusion, two-thirds R-CHOP chemotherapy is a promising treatment for elderly patients with B-cell NHL in terms of its efficacy and toxicity.

[Current status of treatment for patients with idiopathic thrombocytopenic purpura in the Hokkaido area (evaluation of Helicobacter pylori eradication)].

Treatment guidelines for patients with idiopathic thrombocytopenic purpura (ITP) have been changed recently due to the clinical application of Helicobacter pylori (H. pylori) eradication but there has been no detailed multi-center analysis of the hematological effects of H. pylori eradication. The Clinical Hematology Forum consists of 11 large hematological departments and divisions in the Hokkaido area. We sent questionnaires to these 11 hematological departments and divisions in March 2003 to obtain information on current treatment strategies for patients with ITP and hematological results after the eradication of H. pylori. Questionnaires were returned by 9 (81.8%) of the 11 departments. Doctors in all hospitals had experience in diagnosis and treatment of H. pylori infection. Diagnostic examinations for H. pylori infection were performed in 54.3% of the registered cases. H. pylori infection was detected in 68.1% of the examined cases, and eradication treatment was performed in 87.7% of H. pylori-positive patients. H. pylori was eradicated in 52 (83.9%) of the 62 patients in whom the results of treatment could be evaluated. Among the patients whose platelet counts were less than 10.0 x 10(4)/microl, platelet recovery was observed in 48.8% of cases with successful eradication, a percentage similar to previously reported percentages in Japan. There was no prognostic factor to predict good responders before eradication treatment. Since the side effects of eradication treatment, including gastrointestinal symptoms and skin eruptions, were not serious, this method might become a front-line treatment for patients with ITP. Patient selection for eradication as an up-front treatment, analysis of the pathophysiology of platelet recovery after eradication and long-term effects should be investigated to make new treatment guidelines for newly diagnosed patients with ITP.

Impact of C-Myc gene-related aberrations in newly diagnosed myeloma with bortezomib/dexamethasone therapy.

Recent studies have suggested that c-Myc over-expression may be a factor indicating poor prognosis in multiple myeloma (MM), although c-Myc gene-related abnormalities, including translocation and gene amplification, have not been fully investigated in the novel agent era. Additional chromosome 8 may be considered as aggressive disease in the 1990s. To clarify the impact of these aberrations, we retrospectively analyzed newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) with bortezomib and dexamethasone induction therapy. In the present study, the high-risk group was defined as having at least one of the following present: non-hyperdiploidy, IgH/FGFR3, and del p53. Forty NDMM cases were analyzed. At the median follow-up duration of 14.1 months, 14 RRMM were recognized. The proportions of patients in the high-risk, c-Myc gene-related aberrations, and additional chromosome 8 groups at diagnosis were 45.5, 22.5, and 10 %, respectively. The proportions of patients who developed RRMM in the high-risk, c-Myc gene-related aberrations, and additional chromosome 8 groups were 41.7, 77.7, and 50 %, respectively. Furthermore, patients with c-Myc gene-related abnormalities tended to exhibit inferior progression-free survival (PFS), and those with c-Myc gene-related abnormalities and/or additional chromosome 8 showed statistically shorter PFS. Therefore, c-Myc gene-related abnormalities and additional chromosome 8 may be related to a poorer prognosis.

Bortezomib, dexamethasone, and high-dose melphalan as conditioning for stem cell transplantation in young Japanese multiple myeloma patients: a pilot study.

Autologous stem cell transplantation is recommended for younger patients with newly diagnosed multiple myeloma because of a high complete response rate and better survival. Bortezomib shows a synergistic effect with melphalan and has no prolonged hematologic toxicity, and the complete response rate after autologous stem cell transplantation is improved by combining bortezomib with melphalan for conditioning. Twelve patients were enrolled in a phase 2 study between February and November 2010, receiving bortezomib (1 mg/m(2) × 4), dexamethasone (20 mg/body × 8), and melphalan (200 mg/m(2)) for conditioning. No toxic deaths occurred. Neutrophils (absolute neutrophil count ≥0.5 × 10(9)/L) and platelets (≥20 × 10(9)/L without transfusion) recovered after a median of 5 days (range: 4-6 days) and 7 days (range: 4-8 days), respectively. No patient was admitted for exacerbation of peripheral neuropathy. Four patients obtained a stringent complete response, three patients obtained a complete response, and three patients showed a very good partial response. These results suggest that this conditioning regimen is safe and promising for young Japanese multiple myeloma patients. A prospective multicenter trial of this regimen combined with suitable induction and consolidation therapy should be performed.

Extramedullary hematopoietic pleural effusion accompanied by follicular lymphoma.

Extramedullary hematopoietic effusion (EHE) is recognized to be an unusual phenomenon accompanied by hematologic disorders. Only a few reports are available of EHE occurring in patients with lymphoma. We herein report the case of a 54-year-old man with follicular lymphoma. Bone marrow aspirates and biopsied specimens showed diffuse invasion of small cleaved atypical lymphoid cells that were positive for CD10, 20, bcl2, immunoglobulin lambda and Bcl-2-IgH rearrangement. The pleural effusion aspirates and a biopsied specimen obtained via thoracoscopy revealed megakaryocytes and immature myeloid cells in addition to lymphoma cells. To the best of our knowledge, this is the first report of EHE accompanied by lymphoma according to the World Health Organization classification.

Successful treatment of immunoglobulin D myeloma by bortezomib and dexamethasone therapy.

Immunoglobulin D (IgD) myeloma is a rare subtype and it is widely accepted as an aggressive disease. Here, we report a 66-year-old woman with IgD myeloma who had anemia, lumbago, multiple osteolytic lesions and hypercalcemia. The patient refused a blood transfusion because of her beliefs, so we administered bortezomib and dexamethasone (BD) after high-dose dexamethasone therapy. Marked improvement of anemia and elevated serum alkaline phosphatase levels was recognized. After 5 cycles of BD therapy, the patient achieved a stringent complete response according to International Myeloma Working Group Response Criteria. BD therapy might be a feasible and useful treatment option for IgD myeloma.

Clinical significance of minimal residual disease in adult acute lymphoblastic leukemia.

Monitoring minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) is a useful way for assessing treatment response and relapse. We studied the value of MRD and showed a correlation with relapse for 34 adult patients with ALL. MRD was evaluated by real-time quantitative polymerase chain reaction (RQ-PCR) with probes derived from fusion chimeric genes (BCR/ABL) (n = 12) or PCR-based detection of clonal immunoglobulin and T cell receptor gene rearrangements (n = 16), or both (n = 6). We analyzed 27 of the 34 patients who could be examined for MRD on day 100 after induction therapy. The overall survival (OS) rate (45.0%) and relapse-free survival (RFS) rate (40.0%) at 2 years in complete remission (CR) patients with MRD level ≥ 10⁻³ (n = 12) were significantly lower than those in CR patients with MRD level <10(-3) (n = 15) (OS rate 79.0%, RFS rate 79.4%) (log-rank test, P = 0.017 and 0.0007). We also applied multicolor flow cytometry for comparison with MRD results analyzed by PCR methods. The comparison of results obtained in 27 follow-up samples showed consistency in 17 samples (63.0%) (P = 0.057). MRD analysis on day 100 is important for treatment decision in adult ALL.