Multicentre phase II study of the CyclOBEAP regimen for patients with peripheral T-cell lymphoma with analysis of biomarkers.

Peripheral T-cell lymphoma (PTCL) has a poorer prognosis than diffuse large B-cell lymphoma (DLBCL). We administered the CyclOBEAP regimen (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) to patients with DLBCL, and reported its safety and efficacy. Here, we report the results of a multicentre phase II study of the CyclOBEAP regimen in patients with PTCL. In addition, NME1 remained a prognostic factor for survival, as shown in patients who were treated with CyclOBEAP. There were 84 eligible patients and the median age was 54 years. The 5-year overall survival (OS) rate was 72% and progression-free survival (PFS) rate was 61%. The 5-year OS was 93% among the anaplastic large-cell lymphoma cases, 74% among the angioimmunoblastic T-cell lymphoma cases, and 63% among the cases of PTCL-not otherwise specified. When the patients were divided according to the International Prognostic Index or Prognostic Index for PTCL, the 5-year OS and PFS rates did not significantly differ among the risk groups. Positivity for NME1 was found to be a significant independent prognostic factor. Grade 4 neutropenia was observed in 80 patients and thrombocytopenia in nine patients. Our results suggest that the CyclOBEAP therapy is safe and effective for PTCLs. Furthermore, the NME1 protein may be an important prognostic factor in PTCL.

Lymphoproliferative disorders after immunosuppressive therapy for aplastic anemia: a case report and literature review.

A 61-year-old Japanese man was referred to our hospital in 2002 due to severe pancytopenia. Bone marrow and peripheral blood findings indicated he had severe aplastic anemia (AA). A whole-body CT scan and Ga scintigraphy revealed no abnormal findings. Antithymocyte globulin and cyclosporine A (CyA) were administered and he got transfusion independently. In September 2004, he complained of abdominal fullness and a skin eruption in the lower abdomen. An abdominal CT revealed a spleen mass and lymphoadenopathy of the pancreas head. Splenectomy was done, and he was diagnosed with a diffuse large B cell lymphoma (DLBCL) of the spleen and skin. His karyotype was associated with t(14; 18). CyA was stopped, all lesions disappeared, and then his AA relapsed. In January 2007, antithymocyte globulin/CyA was readministered. In May 2007, he complained of acute swelling in his right thigh. A biopsy from the tumor revealed DLBCL. CyA was stopped again, yet the lymphoma did not regress. He was given R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisolone), followed by 5 cycles of R-VP (rituximab, vincristine, prednisolone) and radiation therapy, resulting in a partial remission. We report DLBCL after immunosuppressive therapy for AA. Although this is a rare complication, it should be considered before beginning immunosuppressive therapy.

Accumulation of allo-MHC cross-reactive memory T cells in bone marrow.

The T cells in the bone marrow (BM) have recently been shown to be enriched with memory T cells. We investigated in this study the reactivity of minor-antigen specific memory cytotoxic T lymphocytes (CTLs) induced from the BM of in vivo primed mice using two different antigen systems. The antigen-specific CTLs could be efficiently induced from the BM of immunized mice. This CTL activity was not observed with naïve control mice, indicating that the activity was largely attributable to the memory T cells. Notably, these minor antigen specific CTLs showed cross-reactivity to allo-MHC antigens. Cold target inhibition analyses revealed that the same CTL populations were responsible for both anti-minor antigen and anti-allo-MHC reactivity. Taken collectively, these results not only confirmed functionally the enrichment of memory CTLs in the BM, but also indicated that such memory cells could cross-react with allo-MHC antigens. The possible role of these BM-resident memory T cells in the development of graft-versus-host disease (GVHD) is also discussed.

t(6;14)(q15;q32) in a patient with CD5+CD10+ diffuse large B-cell lymphoma.

A 68-year-old man presented with systemic lymph node swelling. A biopsy specimen taken from the right cervical lymph node showed that the normal architecture was replaced by a diffuse proliferation of large lymphoid cells with large atypical nuclei. Immunohistochemical analysis showed that the atypical lymphoid cells were positive for CD5, CD10, CD20, CD79a, and Bcl2, and negative for CD3 and cyclin D1. A diagnosis of diffuse large B-cell lymphoma was made. Karyotypic findings included add(5)(q13), del(6)(q13), add(17)(p11), add(19)(p11), add(19)(p13), and t(6;14)(q15;q32). The serum lactate dehydrogenase level and indirect bilirubin level were slightly elevated. Elliptocytosis was observed in the peripheral blood, and a diagnosis of hereditary spherocytosis was made from the family history. Regarding CD5+CD10+ diffuse large B-cell lymphoma with a non-random chromosomal translocation of t(6;14)(q15;q32), studies on the mechanism of lymphomagenesis are needed.

Splenic infarction after Epstein-Barr virus infection in a patient with hereditary spherocytosis.

We describe the first patient with hereditary spherocytosis (HS) known to have developed splenic infarction following infectious mononucleosis (IM). An 18-year-old Japanese man was referred to our hospital in November 2004 because of continuous fever and icterus. He had undergone cholecystectomy at the age of 14 years. On patient admission in November 2004, a physical examination showed marked hepatosplenomegaly, icterus, and jaundice. He had a white blood cell count of 14.9 x 10(9)/L with 9.5% atypical lymphocytes, a red blood cell count of 2.93 x 10(12)/L, and a hemoglobin concentration of 7.8 g/dL. Microspherocytes were observed in the patient's peripheral blood smear, and immunoglobulin M antibody to Epstein-Barr virus (EBV) viral capsid antigen was detected. The patient's diagnosis was HS with IM. On day 4 of admission, the patient complained of severe abdominal pain. Abdominal computed tomography scanning revealed findings of splenic infarction. Two months after the occurrence of splenic infarction, a splenectomy was performed. A pathohistologic examination of the resected spleen revealed no evidence of thrombosis or arterial occlusion. We assume that the cause of splenic infarction was insufficient blood flow to oxygenate the entire spleen during the acute enlargement of the spleen.

Primary pulmonary plasmacytoma involving bilateral lungs and marked hypergammaglobulinemia: differentiation from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue.

A 71-year-old woman was referred to our hospital because of hyperproteinemia and serum M-protein (IgG-lambda type). Chest computed tomographic (CT) scan revealed a tumor in each lung and transbronchial lung biopsy was performed. Histopathological examination showed monotonous medullary proliferation of morphologically mature plasma cells. These cells were cIgG+, cIg-lambda+, CD 20+, CD 79 a+, CD 138+, cIg-kappa-, and CD3-. Since there were very few non-neoplastic plasma cells and small lymphocytes in addition to the absence of reactive lymph follicles and fibrosis, the patient was diagnosed as having plasmacytoma. There was no proliferation of plasma cells in the bone marrow. Thus, the lesion was finally characterized as primary pulmonary plasmacytoma. Treatment with melphalan/prednisolone resulted in considerable decrease in the serum IgG level and regression of the pulmonary tumors. The effectiveness of the chemotherapy could confirm our diagnosis, although MALT-type lymphoma with plasmacytic differentiation cannot be completely ruled out.

Phase I/II study of the rituximab-EPOCT regimen in combination with granulocyte colony-stimulating factor in patients with relapsed or refractory follicular lymphoma including evaluation of its cardiotoxicity using B-type natriuretic peptide and troponin T levels.

PURPOSE: Standard treatment for relapsed or refractory follicular lymphoma has not been established. Doxorubicin is often given during the initial treatment. The dosage or drugs chosen for salvage therapy are limited by doxorubicin-induced cardiomyopathy. EXPERIMENTAL DESIGN: The R-EPOCT (rituximab with etoposide, vincristine, pirarubicine, cyclophosphamide, and prednisone) regimen, in which less cardiotoxic pirarubicine is used instead of doxorubicin, with granulocyte colony-stimulating factor (G-CSF) was administered to 20 patients with relapsed or refractory follicular lymphoma. The safety (especially cardiotoxicity) and efficacy of this regimen were studied. As markers of cardiotoxicity, serum troponin T and plasma B-type natriuretic peptide (BNP) levels were measured. RESULTS: Adverse reactions occurred in 14 of the 20 patients and mainly consisted of grade 3/4 hematologic toxicity. In the evaluation of cardiotoxicity, the BNP level was slightly elevated before the treatment in two patients and the BNP level did not significantly increase after R-EPOCT treatment. The troponin T level was undetectable before and after the treatment in all patients. The response rate was 100%, with complete remission in 16 patients (80%). G-CSF administration increased both Fc gamma receptor type I expression on neutrophils and antibody-dependent cellular cytotoxicity activity. There were no significant differences in the levels of Fc gamma receptor type I expression nor antibody-dependent cellular cytotoxicity activity after three or five cycles of the treatment. CONCLUSION: We conclude that the combination of R-EPOCT and G-CSF is well tolerated. This regimen was not cardiotoxic. We are planning a randomized trial to compare the efficacy between R-EPOCT and a combination of R-EPOCT with G-CSF.

Phase I study of Rituximab-CHOP regimen in combination with granulocyte colony-stimulating factor in patients with follicular lymphoma.

PURPOSE: Rituximab is an anti-CD20 monoclonal antibody, and it is used to treat B-cell lymphomas. Antibody-dependent cellular cytotoxicity (ADCC) is considered one of the mechanisms through which rituximab exerts its effects. Granulocyte colony-stimulating factor (G-CSF) enhances the cytotoxicity of neutrophils through ADCC, and it can be speculated that a combination of rituximab and G-CSF may augment the treatment efficacy of rituximab. EXPERIMENTAL DESIGN: We administered rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) treatment with G-CSF to 15 patients with follicular lymphoma, and we investigated the safety and efficacy of this regimen. We investigated ADCC activity in neutrophils and the expression of cell surface antigens including Fcgamma receptor type I [FcgammaRI (CD64)] on neutrophils to determine the optimal dose of G-CSF. RESULTS: Adverse reactions occurred in 14 of 15 patients and consisted mainly of grade 3/4 hematological toxicity. The response rate was 100%, with complete remission in 12 patients (80%) and partial remission in 3 patients (20%). At 14 months, the median length of the observation period, 2 of 12 patients had relapsed. G-CSF administration increased both FcgammaRI expression and ADCC activity. There were no significant differences in the levels of FcgammaRI expression or ADCC activity between the 2 microg/kg G-CSF and 5 microg/kg G-CSF groups, indicating that the optimal dose of G-CSF was 2 microg/kg. CONCLUSIONS: We conclude that the combination of rituximab-CHOP and G-CSF is well tolerated. We plan to carry out a randomized trial to compare efficacy between rituximab-CHOP treatment and treatment with a combination of rituximab-CHOP and G-CSF.

[Successful radiotherapy for the thoracic cord infiltration of adult T-cell leukemia/lymphoma].

A-51-year-old woman with a sixteen-year history of mixed connective tissue disease was admitted to the Kitasato University Hospital because of hypogastric pain in September 1999. Colonofiberscopy and computed tomography in the abdomen demonstrated thickening of the intestinal wall with a hemorrhagic ulcer in the terminal ileum. The histopathologic findings of the lesion revealed diffuse infiltration of atypical T-lymphocytes. The titers of anti-HTLV-I antibody and serum soluble IL-2 receptor were elevated. The diagnosis of adult T-cell leukemia/lymphoma (ATLL) infiltrating the terminal ileum was made. Combination chemotherapy including VEPA-M was undertaken, and resulted in a partial response. ATLL became refractory about June 2000. Flaccid paralysis, dysesthesia in the left lower limb and bladder-bowel disturbance emerged in a few days, July 2000. T2-weighed MRCT images demonstrated that a lesion with a high intensity signal was present in the spinal cord around Th 7. Flower-like cells were detected in the cerebrospinal fluid. Infiltration of ATLL into the thoracic cord was diagnosed. Administration of intrathecal methotrexate and prednisolone, systemic dexamethasone and local irradiation of 30 Gy improved the paralysis and the abnormal MRCT findings. Rehabilitation restored the patient's ability to walk.

[Granulocytic sarcoma of the colon in chronic myelomonocytic leukemia].

A 59-year-old man with a six-month history of chronic myelomonocytic leukemia (CMML) was admitted to the Kitasato University Hospital because of melena in September 2000. Colonofiberscopy and barium enema demonstrated an ulcerated tumorous lesion in the transverse colon. The histopathologic findings of the ulcer bed revealed diffuse infiltration of granulocytes at each stage of differentiation. The diagnosis of granulocytic sarcoma (GS) was made. Surgical resection was not indicated, because thrombocytopenia was hardly improved enough to allow surgery despite repetitive transfusion of platelet concentrates. CMML developed to refractory anemia with excess of blast in transformation in February 2001. Two courses of low dose cytarabine plus aclarubicin were ineffective on the GS in spite of a decrease in the peripheral blood blasts. Progression to acute myeloid leukemia eventually broke out, in July 2001. The patient died of leukemia complicated with pneumonia and intestinal obstruction. At present, nine cases of GS in the colon have been reported. However, these cases did not include CMML. This is the first report describing GS in the colon associated with CMML.

Ovarian follicular lymphoma: a case report and review of the literature.

Primary ovarian lymphoma is extremely rare, and such a case is reported here. The patient was a 54-year-old Japanese female with abnormal genital bleeding. Pelvic CT and MRI showed a right ovarian tumor with a diameter of 7 cm and an irregular border. With the diagnosis of a right ovarian tumor, the patient underwent a simple hysterectomy and bilateral salpingo-oophorectomy. Microscopic examination of the right ovarian tumor revealed vaguely nodular growth of small lymphoid cells. They were CD10+, Bcl-2+, Cyclin D1- and CD21-, although CD21+ follicular dendritic cell clusters were present as a background component in each vague nodule. A conventional cytogenetic analysis revealed t(14;18)(q32;q21), and somatic hypermutation of the variable region of the immunoglobulin heavy chain gene (IgH) was confirmed by direct sequencing of subcloned DNA samples derived from PCR amplicons. These findings led us to characterize the lesion as follicular lymphoma, grade 1. The patient was free of detectable disease 9 months after initiation of post-surgical chemotherapy. Since the prognosis for primary ovarian lymphoma is relatively favorable in many cases, it is important to establish therapeutic methods for the cure of this disease using chemotherapy and radiotherapy without radical surgery.