Hiroshi Harano

Case Report: Fulminant Hepatitis C Viral Infection After Allogeneic Bone Marrow Transplantation

The authors describe two patients with acute leukemia who died of fulminant hepatitis caused by hepatitis C virus (HCV) after an allogeneic bone marrow transplant, the first such cases reported in Japan. Both had developed posttransfusion hepatitis during chemotherapy to induce remission and for consolidation. Six months after blood transfusion, the blood serum of each patient was positive for HCV antibody and HCV RNA. In each case, there was a transient improvement in liver function after the transplant. However, within 5 months of receiving the transplant and coincident with the withdrawal of cyclosporin A, each patient developed an acute exacerbation of hepatitis. The fulminant hepatitis in our patients may, therefore, have been caused by the reactivation of HCV induced by the immunosuppressive therapy followed by a reconstitution of the immune system.

Predictive Factors for Central Nervous System Involvement in Non-Hodgkin's Lymphoma: Significance of Very High Serum LDH Concentrations

Factors predictive for central nervous system (CNS) involvement at presentation were investigated in 152 patients with non-Hodgkins lymphoma (NHL) except for lymphoblastic cell lymphoma and small noncleaved cell lymphoma. Twelve patients developed CNS involvement during their disease course. The incidence was 7.9% of all the patients studied and 17.0% of the patients with serum LDH concentration two times the upper limit of normal (2N). By univariate analysis, stage IV disease (P =. 023), a serum LDH concentration S2N (P =. 009), and bone marrow involvement (P =. 016) were risk factors for CNS involvement. Multivariate logistic regression analysis identified a serum LDH concentration 2 N (P =. 032) as an independent predictor for CNS involvement. All 12 patients who developed CNS involvement were among the 126 patients with diffuse lymphoma, whereas none of the 17 patients with follicular lymphoma developed CNS involvement, although the difference was not statistically significant. The median survival of the patients with CNS involvement was only 4.5 months. We conclude that a serum LDH concentration 2N at presentation is a significant predictive factor for CNS involvement for NHL patients without lymphoblastic lymphoma and small noncleaved cell lymphoma. Therefore, we would suggest that CNS prophylaxis should be considered for patients with a serum LDH concentration 2N at presentation and diffuse lymphoma once a complete remission is achieved.

Diagnostic value of hemostatic parameters in bone marrow transplant-associated thrombotic microangiopathy

We investigated hemostatic parameters in a prospective study of 16 patients who received bone marrow transplants (BMT). We found a significant rise in the levels of fibrinogen, plasmin-α2 antiplasmin inhibitor complex, tissue-plasminogen activator·plasminogen activator inhibitor complex (t-PA·PAI), von Willebrand factor antigen, and thrombomodulin on day 14 after transplant compared with values before transplant. Protein C and thrombin-antithrombin III levels did not change significantly. No significant changes in prothrombin time ratio, activated partial thromboplastin time, or protein S were detected. Patients who had grades II–IV graft-versus-host disease (GVHD) (n = 6) showed a significantly higher level of t-PA·PAI on day 14 compared with those with grades 0–I GVHD (n = 10) (P = 0.0062). Three patients with grades II–IV GVHD developed thrombotic microangiopathy (TMA) on days 19, 19 and 62. In these patients, we noted significantly lower levels of fibrinogen (P = 0.0383), and significantly higher levels of t-PA·PAI (P = 0.0008) and thrombomodulin (P = 0.0001) on day 14 compared with those patients who did not develop TMA. These results suggest that prothrombotic states and endothelial damage may be caused by the conditioning regimen and/or acute GVHD during BMT; thrombomodulin values on day 14 post BMT may be useful in surveillance for TMA because of endothelial cell injury.

MIB-1 labeling index as a prognostic factor for patients with follicular lymphoma treated with rituximab plus CHOP therapy.

The MIB‐1 labeling index, which is based on Ki67 immunostaining, is widely used to evaluate the proliferation of tumor cells in lymphoma. However, its clinical significance has not been fully assessed. We retrospectively evaluated the prognostic impact of the MIB‐1 labeling index at the time of diagnosis, in 98 patients with follicular lymphoma (FL) grade 1–3b who were treated uniformly with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R‐CHOP) therapy. The 5‐year progression‐free survival (PFS) for an MIB‐1 labeling index of ≥10% (n = 60) and <10% (n = 38) was 35% and 61%, respectively (P = 0.015). The 5‐year overall survival (OS) for an MIB‐1 labeling index of ≥10% and <10% was 77% and 92%, respectively (P = 0.025). Pathological grading was not correlated with PFS or OS. In multivariate analysis, an MIB‐1 labeling index of ≥10% was independently associated with poor PFS and OS. In conclusion, an MIB‐1 labeling index of 10% is a useful cut‐off level for predicting the prognosis of patients with FL.

Acute minimally differentiated myeloid leukemia (M0) with inv(3)(q21q26).

We describe a 55-year-old Japanese man with acute minimally differentiated myeloid leukemia (M0) with an inversion in the long arm of chromosome 3, i.e., inv(3)(q21q26). Patients with this chromosomal abnormality usually show normal or elevated platelet counts. However, our case had a low platelet count with megakaryocytic dysplasia at diagnosis. Furthermore, the 3q21q26 aberration is generally detected in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome. To the best of our knowledge, it has also been reported in two cases of AML-M0 with 3q21q26 and this is the third case of AML-M0 with 3q21q26. Thus it is suggested that there is some relationship between this type of karyotype abnormality and leukemogenesis and/or thrombopoiesis.

Long-term outcome of L86 and L97 protocols for adult acute lymphoblastic leukemia

We analysed the long-term outcome of the L86 protocol using l-asparaginase (l-asp), vincristine (VCR) and prednisolone (PSL), collectively known as LVP or L97 protocol using LVP along with pirarubicin hydrochloride (THP-ADR) for 97 patients with acute lymphoblastic leukemia (ALL) diagnosed between 1986 and 2002. No significant differences were seen in the two protocols regarding the complete remission (CR) rate or survival. Seventy-five of the 97 patients (77%) achieved a CR. The overall survival (OS) and disease-free survival (DFS) rates were 32.1% and 30.4% at 10 years, respectively. By univariate analysis, we identified seven adverse factors for DFS which included the L2 subtype by French-American-British classification, hepatosplenomegaly, a white blood cell count of more than 30 × 109/L, a blast cell count of more than 10 × 109/L in the peripheral blood, hemoglobin concentration greater than 10 g/dL, a serum lactate dehydrogenase value greater than twice the upper limit of normal and the presence of the Philadelphia chromosome (Ph). According to multivariate analysis, only the presence of Ph was a significant unfavourable factor for DFS and OS. In the 30 patients under 35 years of age without Ph, the OS in the 20 patients treated with L86 and in the 10 patients treated with L97 were 48 and 86%, respectively (P = 0.011). These results indicate that intensified chemotherapy, such as the L97 protocol that includes an anthracycline, might be beneficial for younger patients who are Ph-negative.

Analysis of outcomes in patients with supra-diaphragmatic vs infra-diaphragmatic diffuse large B cell lymphoma treated with R-CHOP therapy.

The prognostic implications of infra-diaphragmatic (InD) versus supra-diaphragmatic (SpD) primary lesions in limited-stage diffuse large B-cell lymphoma (DLBCL) remains unknown. This retrospective study aimed to assess the prognostic impact of spD and InD lesions as well as presence of gastrointestinal (GI) involvements in adults with limited-stage DLBCL. We analyzed data from 178 patients with limited-stage DLBCL who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy at 7 institutions of the Yokohama City University Hematology Group between 2003 and 2009. The median age was 63 years (range, 18-80 years). The primary sites were SpD in 109 patients, and InD in 69. No statistical differences in progression-free survival (PFS) or overall survival (OS) were observed between patients with SpD lesions and those with InD lesions. However, when patients with SpD lesions, InD lesions with (n=35), and without (n=34) GI involvement were compared, the presence of GI lesions was associated with favorable PFS. The multivariate analysis revealed that SpD or InD localization had no independent effect on PFS or OS, whereas the presence of GI lesions was correlated with favorable PFS (P=0.024, HR 0.09).

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

Residual Leukemic Cell Counts in the Bone Marrow at the End Point of Intensive Induction Therapy May be a Prognostic Factor for Acute Myeloblastic Leukemia in Adults

Between January 1990 and May 1994, 59 previously untreated adult patients with acute myeloblastic leukemia (AML) were treated with a combination of behenoyl-cytosine-arabinoside (BHAC), daunorubicin (DNR), 6-mercaptopurine (6-MP) and prednisolone (PSL). Forty one patients (69.5%) achieved complete remission (CR). The Kaplan-Meier analysis revealed an actuarial probability for remaining in remission of 36% in patients who achieved remission and a survival of 29% in all patients at 5 years. A favorable factor relative to achieving CR was performance status (P=0.04). In addition the presence of 300 cells/microl or less of residual leukemic cell counts in the bone marrow at the end point of induction therapy tended to favor remission (P=0.06) using the multivariate analysis with a multiple logistic regression model. In addition the residual leukemic cells counts of less than 300/microl in the bone marrow at the end point of induction therapy was the most significant factor for durable remission (P=0.05) by the Coxs proportional hazard model. We concluded that residual leukemic cells counts in the bone marrow at the end point of intensive induction therapy is a valuable prognostic factor for adults receiving response-oriented individualized induction therapy for AML.

Genetic Counseling by Analysis of Intron 22 Inversions of the Factor VIII Gene

Ten patients with severe hemophilia A and 10 with moderate and mild hemophilia A were studied. Five of 10 unrelated patients with severe hemophilia A had the distal telo meric int22h sequence, none had the proximal sequence, and one had a unique variant factor VIII gene rearrangement. Car rier detection was done in these six families. All mothers and two daughters of the patients were to be carriers. Six of the 15 at-risk female relatives were heterozygous for the rearranged and normal allele and were carriers. These results indicate that the rearrangement assay is very useful for carrier detection in families with severe hemophilia A. Key Words: Hemophilia A—Factor VIII gene rearrangement—Genetic counseling.