Two Cases of Cerebral Involvement in Malignant Lymphoma (CD20+) That Responded to Combination Therapy with Rituximab and Cladribine

Cerebral involvement frequently occurs in association with progression or relapse of malignant lymphoma. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone, the standard chemotherapy for malignant lymphoma, is an ineffective treatment for cerebral involvement because these drugs cannot cross the blood-brain barrier. Therefore, various alternative strategies have been attempted. Although high-dose methotrexate combined with whole-brain radiotherapy is widely used to treat primary central nervous system lymphoma, there is no standard therapy to treat cerebral involvement in malignant lymphoma. Furthermore, high-dose methotrexate in combination with whole-brain radiotherapy is not always effective, and high rates of neurotoxicity are often observed, particularly in the elderly. To expand the therapeutic options for central nervous system involvement in recent years, systemic chemotherapies, including rituximab, high-dose methotrexate, and other agents that act during the S, G2, and M phases of the cell cycle, have been attempted. In our hospital, cladribine, a purine analogue with a cytocidal effect on resting malignant cells (G0/G1 phase of the cell cycle), has been used in combination with rituximab, which exhibits antitumor effects on nodal and extranodal lesions of relapsed and/or refractory B cell lymphomas, particularly cerebral lesions. Here, we report 2 representative cases of patients who were treated with cladribine plus rituximab and survived for 30 months (died of sepsis) and 52 months (still alive), respectively. The outcomes of these cases suggest that cladribine plus rituximab combination therapy with whole-brain radiotherapy may be very useful as salvage therapy for secondary central nervous system lymphoma and as initial therapy for primary central nervous system lymphoma

Fatal Cytomegalovirus Pneumonia and Associated Herpes Virus Infection in a Relapsed/Refractory Multiple Myeloma Patient Treated with Bortezomib plus Dexamethasone

Multiple myeloma (MM) remains a largely incurable disease in the long term despite positive responses to first-line chemotherapy. Herein we report the case of a 68-year-old woman who died following treatment with bortezomib plus dexamethasone for refractory MM. The combination was associated with significant antitumor activity, but bacterial pneumonia/sepsis was followed by bilateral cytomegalovirus pneumonia with herpes simplex co-infection, and this was almost certainly the cause of death. Physicians need to pay careful attention when treating patients with refractory MM with bortezomib plus dexamethasone, and to be mindful that antiviral therapy may be needed in some cases

Atomic Bomb Irradiation-induced Leukemias Revisited : Summary Data of 50 Years-Long Term Follow Up Study on Survivors

Under the cooperation between Atomic Bomb Disease Institute (ABDI) of Nagasaki University School of Medicine, Institute of Nuclear Medicine of Hiroshima University and Radiation Effect Research Foundation (RERF), the Life Span Study (LSS) on 93,741 survivors (fixed cohort) and the Open City Study (OCS) on all survivors (unfixed) irrespective of whether they belonged to LSS or not, have been conducted in parallel over 45 years to ensure reliable case detection. For diagnosis and subtyping of detected leukemias, we adopted the FAB classifcation for acute leukemias and for exposure dose of individual survivors, the new dosimetry system 1986 (DS86). In LSS, 231 leukemia cases were analysed. There was strong evidence of radiation-induced risks for acute myeloid leukemia (AML), acute lymphoid leukemia (ALL) and chronic myeloid leukemia (CML), but not for adult T-cell leukemia (an endemic disease in Nagasaki area) and chronic lymphocytic leukemia. There was also significant difference between three major types with respect to the effects of age at bombing and sex, and in the temporal pattern of the elevated risks. For AML the dose response function was non-linear, whereas there was no evidence against linearity for ALL and CML. The hypothesis of a 0.5 Gy threshold could be rejected for three major types of leukemia. Excess Absolute Risk (EAR) estimates in cases per 10,000 Person Year Sievert (PYSv) were 0.6, 1.1, 0.9 for ALL, AML and CML, respectively. The corresponding relative risk at 1.0 Sv were 9.1, 3.3, 6.2, respectively. Although childhood exposure <15 age at bombing apparently induced three major types, the agerelated highest risk was observed for ALL. In OCS, 413 cases with DS86 estimates were used for analysis. Type specific incidence rates were calculated indirectly by using the over all incidence of leukemia from LSS data and multiplying these values by the corresponding proportions of cases in OCS. In conjunction with LSS data, the effects of radiation were significantly greater on the incidences of ALL and CML than on that of AML. In the high dose group there was a strong evidence for shorter incubation time and faster decline of elevated risk for ALL and CML than for AML. AML risk was apparently persistent through 1980. Thus, the differential effects of atomic bomb irradiation in inducing three major types of leukemia with respect of age-related and temporal patterns provide us insights into human leukemogenesis. Further investigation on radiation leukememogenesis undoubtedly requires molecular approach to detect type-specific genetic abnormlities including oncogenes and anti-oncogenes

Dorsal Column Degeneration after Bortezomib Therapy in a Patient with Multiple Myeloma

We present here a case of dorsal column degeneration in a female patient with multiple myeloma following exposure to bortezomib. Two days after intravenous administration of a first course of bortezomib 1 mg/m2, the patient developed rapidly-progressive numbness, pain and muscle weakness in the bilateral upper and lower limbs. Following gancyclovir treatment of subsequent cytomegalovirus viremia, the patient went on to receive a course of EPOCH (etoposide 50 mg/m2/day on days 1–4, vincristine 0.4 mg/m2/day on days 1–4, doxorubicin 10 mg/m2/day on days 1–4, cyclophosphamide 750 mg/m2/day on day 6, and prednisolone 60 mg/m2/day on days 1–6). Shortly thereafter, the patient developed bilateral Aspergillus pneumonia. Despite treatment with appropriate antifungal agents, the patient died from respiratory failure due to bilateral diffuse alveolar damage of the lungs and without recovery of severe sensory and motor neuropathy prior to her death. Post mortem examination revealed spongy degeneration of the dorsal column from the medulla oblongata to the cervical spinal cord. Bortezomib-associated peripheral neuropathy in patients with multiple myeloma has been commonly reported but appears to resolve in a majority of these patients after dose reduction or discontinuation. We believe this to be the first report of spinal cord abnormalities in a patient with multiple myeloma treated with bortezomib. Further investigation is required to ascertain the exact mechanism of this central neurotoxic effect and to identify appropriate neuroprotective strategies

A simple flow cytometric scoring system is useful for distinguishing myelodysplastic syndromes from non-clonal anemic disorders

Myelodysplastic syndromes (MDS) are a myeloid neoplasm characterized by abnormal differentiation, ineffective hematopoiesis, and genetic instability with enhanced risk of transforming to acute myeloid leukemia (AML). The diagnosis of MDS is principally made based on the percentage of blasts in the bone marrow and peripheral blood, type and degree of dysplasia and the presence of ring sideroblasts. Recently, for making an accurate diagnosis of MDS, the aberrant antigen expression detection of hematopoietic cells by flow cytometry has been reported to be a useful. However, the diagnostic systems utilized in those studies are rather complicated. We modified an existing flow cytometric scoring system (FCMSS) based on aberrancies in the myeloid lineage and evaluated its usefulness in diagnosing various anemic disorders, including myelodysplastic syndromes (MDS). The flow cytometric score was significantly higher in MDS patients than in those with other anemic disorders, the exception being megaloblastic anemia (i.e., Vitamin B12 deficiency, folate deficiency). The data suggest that our FCMSS may provide useful information for making the diagnosis of MDS and other anemic disorders

Loss of Endoreduplication as Morphogenesis of Micromegakaryocytes in Myelodysplastic Syndrome.

Morphogenesis of micromegakaryocytes in MDS was investigated in a case of refractory anemia with excess of blasts by analysing megakaryocyte colonies developed from peripheral blood mononuclear cells in a semi-solid culture containing aplastic anemia patient\u27s plasma as source for megakaryocyte colony stimulating factor and thrombopoiesis stimulationg factor. Candidate megakaryocyte colonies were individually stained for glycoprotein (GP)IIb/IIIa by immunocytochemical method. Three types of colonies were distinguished ; type I composed of 10-30 large magakaryocytes with high ploidy number, type II composed of 50-200 micromegakaryocytes with single nucleus, and type III composed of 20-50 micromegakaryocytes. Type I colonies were similar to megakaryocyte colonies obtained from three control subjects. Periodic in situ observation of type II and III colonies disclosed that large megakaryocytes never appeared during 21 days\u27 culture, suggesting mitotic growth at every generation. These findings indicate that loss of endoreduplication is primary defect in micromegakaryocyte formation by MDS clone. Quantitaive aspect of platelet formation by micromegakaryocytes could not be assessed in this study, but morphological observation in situ or on GPIIb/IIIa-stained preparation suggested reduced platelet production. Biological significance of diminished endoreduplication is yet to be determined in respect to leukemic predisposition