Wataru Yamamoto

Central nervous system involvement in diffuse large B‐cell lymphoma

Background: Malignant lymphoma with central nervous system (CNS) involvement has an extremely poor prognosis. We retrospectively studied the risk factors for CNS involvement in patients with diffuse large B‐cell lymphoma (DLBCL) treated by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab (R) ‐CHOP chemotherapy.

Long-Term Outcome of Human Herpesvirus-6 Encephalitis after Allogeneic Stem Cell Transplantation

Human herpesvirus-6 (HHV-6) encephalitis is recognized as a relatively rare, but sometimes lethal, complication of allogeneic hematopoietic stem cell transplantation (HSCT). Although the development of new diagnostic techniques and antiviral therapy has improved, the prognosis of encephalitis is still unclear. We surveyed 197 patients who underwent allogeneic HSCT between January 2004 and March 2008 at our institution, and 8 (4.0%) were diagnosed as having HHV-6 encephalitis. Five were male and 3 were female, with a median age of 40.5 years. The median onset of HHV-6 encephalitis was 18 days after HSCT, and the median duration of antiviral therapy was 41 days. The median survival time from the onset of encephalitis was 23.1 months (range: 2.7-66.7), and 3 patients died of unrelated causes (sepsis in 2 and gastrointestinal tract bleeding in 1). Cord blood transplantation was identified as the only independent risk factor (relative risk [RR] = 4.98; P = .049) by multivariate analysis. There was no statistical significance of survival after HSCT between the patients with HHV-6 encephalitis and those without HHV-6 encephalitis (the 2-year survival rate was 60% and 52.6%, respectively; P = .617). Four of the 5 surviving patients were unable to return to society because of neuropsychological disorders, including anterograde amnesia and seizures with prominent hippocampal atrophy. Although HHV-6 encephalitis occurring after HSCT is now becoming a curable complication, its sequelae, such as neuropsychological disorders, have a marked influence on the quality of life of long-term survivors. Accordingly, it is necessary to identify risk factors for HHV-6 encephalitis and establish methods for prevention of this complication.

Beta-2 microglobulin is a strong prognostic factor in patients with DLBCL receiving R-CHOP therapy

Useful prognostic markers for patients with diffuse large B cell lymphoma (DLBCL) have been reported. To identify which biomarker best predicts the prognosis of patients with DLBCL, we performed a retrospective study that included 319 DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy between 2003 and 2012. We assessed the prognostic significance of six biomarkers [lactate dehydrogenase, soluble interleukin-2 receptor, thymidine kinase activity, beta-2 microglobulin (B2M), C-reactive protein, and ferritin] and representative clinical characteristics using progression-free survival (PFS) as the endpoint. The study group included 181 men and 138 women with a median age of 63 years (range, 22-89 years). In a multivariate analysis, the serum B2M level most strongly correlated with PFS (hazard ratio, 2.11; P=0.04). In a univariate analysis, patients with serum B2M levels >1.75μg/mL (n=210) had a worse 3-year PFS rate (71.2%) than those with B2M levels <1.75μg/mL (n=109; 90.0%). Therefore, serum B2M level at the time of diagnosis is a useful prognostic indicator in DLBCL patients receiving R-CHOP.

Cytomegalovirus Pneumonia after Anti-CC-chemokine Receptor 4 Monoclonal Antibody (Mogamulizumab) Therapy in an Angioimmunoblastic T-cell Lymphoma Patient.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive T-cell lymphoma. A 63-year-old man was diagnosed with AITL. He received 6 cycles of CHOP therapy, but showed progressive disease. Subsequently, he received ESHAP chemotherapy; however, it was not effective. He received mogamulizumab (an anti-CCR4 monoclonal antibody). After 4 cycles, his respiratory condition worsened and he was diagnosed with cytomegalovirus (CMV) pneumonia. Despite antiviral and antibiotic therapy, he died. We speculate that the combination of progressive lymphoma with mogamulizumab and chemotherapy likely caused CMV pneumonia. Because mogamulizumab therapy causes immunosuppression, if CMV pneumonia is suspected, then rapid treatment should be initiated.

Outcome and prognostic factors among patients who underwent a second transplantation for disease relapse post the first allogeneic cell transplantation

Abstract The prognosis for disease relapse after first hematopoietic cell transplantation (HCT1) is poor. Here, we present a retrospective multicenter study to evaluate the clinical outcome and the prognostic factors for second hematopoietic cell transplantation (HCT2). The cohort in this study comprised 60 patients diagnosed with acute leukemia, who underwent HCT2 due to hematological relapse after HCT1. The overall survival (OS) at two years, non-relapse mortality (NRM), and relapse mortality (RM) were 30.3%, 40.9%, and 28.8%, respectively. Multivariate analysis for OS identified the use of a donor other than matched-related (MR) donor (hazard ratios [HR] = 4.10, 95% confidence intervals [CI]: 1.72–9.74, p = .001) and high disease status (HR = 2.90, 95% CI: 1.28–6.56, p = .011) as the adverse risk factors for HCT2. On analyzing the combination of factors during HCT1 and HCT2, MR donor, reduced intensity conditioning regimen, and standard status were found to be significant as favorable prognostic factors for OS. Therefore, evaluating these prognostic factors would be helpful in taking decisions regarding post-relapse management.

Evaluation of soluble interleukin-2 receptor and serum lactate dehydrogenase in malignant lymphoma.

Dear Editor, Soluble interleukin-2 receptor (sIL-2R) is a widely used in vitro diagnostics for lymphoma. Expression of sIL-2R is induced by mononuclear cell activation [1, 2]; especially, activated T cells are known to be the main inducer of sIL2R. The upper limit of the normal range of sIL-2R is approximately 500 U/ml. On the other hand, serum lactate dehydrogenase (LDH) is believed to reflect the tumor mass. LDH is a well-known prognostic factor in lymphomas [3] such as diffuse large B cell lymphoma (DLBCL) [4] and follicular lymphoma (FL) [5], and elevated sIL-2R levels at presentation have also been reported to have prognostic value in DLBCL patients receiving the R-CHOP regimen [6]. Furthermore, we recently reported the value of sIL-2R as a prognostic indicator in DLBCL patients and established the BSIL index,^ a simple index comprising only three factors, namely, clinical stage, sIL-2R, and LDH [7]. However, there are currently few other reports concerning sIL-2R level in various lymphoma subtypes. Here, we investigated the LDH and sIL-2R patterns in eight representative subtypes of lymphoma. In the Yokohama City University Hematology Group Lymphoma Database, 3484 untreated patients were registered between 1996 and 2014. We extracted the data of 3005 patients with the following eight representative subtypes: FL, extranodal marginal zone lymphoma of mucosaassociated lymphoid tissue (MALT), mantle cell lymphoma (MCL), DLBCL, Burkitt lymphoma (BL), Hodgkin’s lymphoma (HL), peripheral T cell lymphoma (PTCL), and extranodal natural killer/T cell lymphoma (ENKL). PTCL included two histological subtypes, namely, peripheral T c e l l l ymphoma , no t o t h e rw i s e s pe c i f i e d , and angioimmunoblastic T cell lymphoma. We analyzed 2807 patients in whom both LDH and sIL-2R at presentation

Emergence of del(20q) in a patient in molecular remission of chronic myelogenous leukemia during imatinib treatment, with reduction following imatinib discontinuation

Chronic myelogeneous leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the BCR-ABL1 fusion gene, which is usually the result of the t(9;22)(q34;q11.2) translocation known as the Philadelphia chromosome (Ph) [1–3]. Current first-line therapy for CML includes tyrosine kinase inhibitors (TKIs), such as the firstgeneration TKI imatinib. Treatment with imatinib achieves high rates of cytogenetic response and major molecular response (MMR) [4–6]. Jabbour et al. [7] reported that 9% of patients with newly diagnosed CML in the chronic phase developed chromosomal abnormalities in Ph-negative metaphases during imatinib therapy. In that study, 1% of the cohort developed del(20q), but the details were unclear [7]. Here, we present an imatinib-treated patient in remission from CML who developed a cytogenetic abnormality, del(20q), in Ph-negative clones that disappeared after discontinuation of imatinib. A 29-year-old Japanese woman was referred to our department in January 2012 because of leukocytosis and thrombocytosis, which was found while she underwent examination for gastrointestinal bleeding. Peripheral blood counts showed the following: hemoglobin, 12.7 g/dL; platelets, 785  109/L, and white blood cells, 17  109/L, with 1% myelocytes, 1% metamyelocytes, 57.5% segmented neutrophils, 14% lymphocytes, 2% monocytes, 11.5% eosinophils, and 13% basophils. No organomegaly was observed. Sokal score was 0.62, and she belonged to the low risk group. The bone marrow showed marked hypercellularity with myeloid hyperplasia without an increase in blast percentage. Cytogenetic analysis of bone marrow cells at diagnosis showed 46,XX,t(9;22)(q34;q11.2) in 19/20 and 46,XX in 1/20 metaphases analyzed. Fluorescence in situ hybridization (FISH) analysis of cells in interphase was performed to detect the BCR-ABL1 fusion gene. Consequently, a BCR-ABL1 fusion signal was detected in 99/100 cells analyzed. RT-PCR analysis of bone marrow cells using primers for the majorbcr rearrangement provided 4.8  104 copies/mg RNA. Therefore, the patient was diagnosed with CML in the chronic phase. In January 2012, treatment was initiated with imatinib at 400 mg/day. Complete hematologic response (CHR) was achieved after 3 weeks, complete cytogenetic response (CCyR) after 3 months, MMR after 6 months, and molecularly undetectable leukemia (MUL) after 1 year. MUL was defined as MR4.0, 4.0 log reduction, in this case. Two years after initiating imatinib therapy, bone marrow analysis was performed, demonstrating normocellularity without dysplasia. Cytogenetic analysis showed 46,XX,del(20)(q1?) in 4/20 and 46,XX in 16/20 metaphases analyzed. FISH analysis detected del(20q) in 6/100 cells analyzed. RT-PCR analysis could not detect major-bcr-abl rearrangement, indicating that MUL was maintained. After 30 months of treatment with imatinib, cytogenetic analysis showed 47,XX, 22 in 1/20, 47,XX, mar in 1/20, and 46,XX in 18/20 metaphases. FISH analysis detected del(20q) in 1/100 cells analyzed. After 33 months of treatment, the dosage of imatinib was reduced to 300 mg/day because of grade 2 neutropenia. In January 2014, after 36 months of treatment with imatinib, neutropenia had resolved, and cytogenetic analysis showed 46,XX,del(20)(q1?) in 11/20 and 46,XX in 9/20 metaphases. FISH analysis detected del(20q) in 53/100 cells analyzed. Major-bcr-abl was not detected by RT-PCR analysis. At that time, the bone marrow showed hypocellularity but no evidence of dysplasia, such as myelodysplastic syndrome (MDS). We were concerned that the chromosomal abnormalities may increase and lead to MDS. We also hypothesised that the patient could sustain MUL after imatinib withdrawal, as she had rapidly achieved MUL and maintained this for over 2 years [8]. Therefore, imatinib treatment was stopped Leukemia & Lymphoma, 2016; 57(1): 201–202 January

Allogeneic Hematopoietic Stem Cell Transplantation after Conditioning Regimens with Fludarabine/melphalan or Fludarabine/busulfan for Patients with Hematological Malignancies: A Single-center Analysis

Objective Fludarabine plus melphalan (FM) and fludarabine plus busulfan (FB) are two major conditioning regimens for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods We retrospectively analyzed patients who underwent allo-HSCT after a conditioning regimen consisting of FM or FB with/without total body irradiation for hematological malignancies between 2005 and 2014. Results There were 41 patients who met the criteria. The median follow-up time for the survivors was 3 years. Thirty-two patients received allo-HSCT after the FM regimen and nine patients received allo-HSCT after the FB regimen. Patients who received FB were older than those who received FM (p=0.041). There was no significant difference in the 3-year overall survival between patients who had received FB and those who had received FM (29.6% vs. 56.5%, p=0.267). The 3-year cumulative incidence of relapse was significantly higher in patients who had received FB than that in patients who had received FM (66.7% vs. 17.8%, p=0.004), and FB was an independent prognostic factor for relapse by a multivariate analysis (hazard ratio, 9.8; 95% confidential interval, 2.5-39.3; p=0.001). When we restricted the evaluation to patients with acute myeloid leukemia and myelodysplastic syndrome, the 3-year cumulative incidence of relapse was also significantly higher in patients who had received FB than that in patients who had received FM (75.0% vs. 16.1%, p=0.004). Conclusion The results suggest that FM may provide better disease control than FB.

Favorable prognosis in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia patients following hematopoietic stem cell transplantation

The prognosis for adult patients with acute lymphoblastic leukemia (ALL) is poor. Standard risk subsets of ALL patients have a survival rate of about 50% that can further reduce to <10% in those with Philadelphia chromosome-positive (Ph+) ALL (1, 2). However, tyrosine kinase inhibitors (TKI) have remarkably improved outcomes in patients with Ph+ ALL (3). Here, we compare the outcomes of newly diagnosed adult Ph+ ALL and Ph-negative (Ph ) B-cell ALL (B-ALL) cases. We retrospectively analyzed 35 consecutive, newly diagnosed cases of B-ALL admitted to our center between January 2003 and September 2014, who were treated with standard induction chemotherapy. Imatinib was administered to patients with Ph+ ALL. Thirty-five patients were included (males, 18; females, 17; Ph+ ALL, 14; Ph B-ALL, 21; median age, 41 yr; range, 16–64 yr). The complete remission rate (CRR) for the first induction therapy for Ph+ ALL and Ph ALL was 100% and 90%, respectively. The five-yr overall survival (5yOS) of Ph+ ALL and Ph ALL patients was 64% and 63%, respectively (p = 0.45). The five-yr progression free survival (5yPFS) for Ph+ ALL and Ph ALL patients was 85% and 62%, respectively (p = 0.30). Next, we analyzed 24 patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT; Ph+ ALL,12; Ph ALL, 12). Patient characteristics of the patients are shown in Table 1. The 5yOS following HSCT of Ph+ ALL and Ph ALL patients was 71% and 38%, respectively (p = 0.13). The 5yPFS after HSCT of Ph+ ALL and Ph ALL patients was 72% and 33%, respectively (p = 0.04). The five-yr cumulative incidence of relapse after HSCT for Ph+ ALL and Ph ALL patients was 8% and 50%, respectively (p = 0.03). We consider two main reasons for the improved prognosis of patients with Ph+ ALL. First, TKIs have aided most patients with Ph+ ALL in achieving complete remission (3). The CRR for the first induction therapy for Ph+ ALL patients was 100% in our study. Second, the survival rate of non-myeloablative HSCT has increased in the elderly (4). Although one-third of patients with Ph+ ALL received non-myeloablative HSCT, the HSCT outcome was not as low as that in other high-risk ALL, one-fifth of whom received non-myeloablative HSCT. Conversely, the prognosis of the other high-risk ALL in this study was lower than that reported elsewhere (4, 5). One potential