Identification of putative noncanonical driver mutations in patients with essential thrombocythemia.

Essential thrombocythemia (ET) cases without canonical JAK2, CALR, or MPL mutations, that is, triple-negative (TN) ET, have been found in 10%-20% of ET cases. Owing to the limited number of TN ET cases, its clinical significance remains unclear. This study evaluated TN ET's clinical characteristics and identified novel driver mutations. Among 119 patients with ET, 20 (16.8%) had no canonical JAK2/CALR/MPL mutations. Patients with TN ET tended to be younger and had lower white blood cell counts and lactate dehydrogenase values. We identified putative driver mutations in 7 (35%): MPL S204P, MPL L265F, JAK2 R683G, and JAK2 T875N were previously reported as candidate driver mutations in ET. Moreover, we identified a THPO splicing site mutation, MPL*636Wext*12, and MPL E237K. Four of the seven identified driver mutations were germline. Functional studies on MPL*636Wext*12 and MPL E237K revealed that they are gain-of-function mutants that increase MPL signaling and confer thrombopoietin hypersensitivity with very low efficiency. Patients with TN ET tended to be younger, although this was thought to be due to the inclusion of germline mutations, hereditary thrombocytosis. Accumulating the genetic and clinical characteristics of noncanonical mutations may help future clinical interventions in TN ET and hereditary thrombocytosis.

Red Blood Cell Deformation and Progressive Anemia Following Therapeutic Intervention in Patients With Adult T-Cell Leukemia/Lymphoma.

OBJECTIVES: During therapeutic intervention for adult T-cell leukemia-lymphoma (ATLL), transient red blood cell (RBC) deformations and rapid anemia progression are often observed. These RBC responses are characteristically observed during the treatment of ATLL, and we examined the details and significance of these RBC responses. METHODS: Seventeen patients with ATLL were enrolled. Peripheral blood smears and laboratory findings were collected during the first two weeks after treatment intervention. We examined the transition of erythrocyte morphology and the factors associated with the induction of anemia. RESULTS: RBC abnormalities (i.e., elliptocytes, anisocytosis, and schistocytes) rapidly progressed following therapeutic intervention in five of the six cases for whom evaluable consecutive blood smears were available, with significant improvement evident after two weeks. Changes in RBC morphology were significantly associated with the red cell distribution width (RDW). Laboratory findings from all 17 patients showed various levels of anemia progression. A transient increase in RDW values was observed in 11 cases after therapeutic intervention. The degree of progressive anemia during the two-week period was significantly correlated with increased lactate dehydrogenase and soluble interleukin-2 receptor levels and an increase in RDW (P <0.01). CONCLUSIONS: In cases of ATLL, transient progression of RBC morphological abnormalities and RDW value were observed early after therapeutic intervention. These RBC responses may be associated with tumor and tissue destruction. RBC morphology or RDW values may provide important information about the tumor dynamics and general condition of the patients.

Complete remission of aggressive Epstein-Barr virus-positive diffuse large B-cell lymphoma following withdrawal of tacrolimus and low-dose anticancer drugs.

A 66-year-old woman who had received tacrolimus for more than 11 years was admitted with high fever, generalized lymphadenopathy, and persistent gastrointestinal bleeding. Histopathological evaluation of the lymph nodes and colonic mucosa confirmed the diagnosis of Epstein-Barr virus-positive diffuse large B-cell lymphoma. After discontinuation of tacrolimus, the lymphoma did not improve, and low-dose chemotherapy was introduced, which resulted in a recovery of lymphocyte counts and induction of complete remission. Low-dose anticancer treatments that suppress tumor growth while awaiting normal lymphocyte recovery for several weeks may be a useful therapeutic option even for aggressive lymphomas that develop during immunosuppressant therapy.

Development of Intravascular Large B-cell Lymphoma during Methotrexate Treatment for Rheumatoid Arthritis.

A 56-year-old woman with rheumatoid arthritis who had been taking methotrexate (MTX) for six years visited our hospital with dyspnea and dizziness. Abdominal ultrasonography revealed mild splenomegaly. Laboratory examinations showed a marked elevation in soluble interleukin-2 receptor and lactate dehydrogenase levels. These abnormalities revealed a spontaneous regression after MTX discontinuation, however, they worsened again four months later. Skin biopsies revealed a diagnosis of intravascular large B-cell lymphoma (IVLBCL), and we diagnosed MTX-associated IVLBCL (MTX-IVLBCL) based on its characteristic course. Despite the recurrence of IVLBCL, it showed a good response to chemotherapy. MTX-IVLBCL should therefore be treated with consideration since it has different characteristics from that of de novo IVLBCL.

L-asparaginase-Based induction therapy for advanced extranodal NK/T-cell lymphoma.

We describe treatment of a patient with advanced extranodal NK/T-cell lymphoma, nasal type, with multiple subcutaneous lesions and hemophagocytic syndrome. Considering the projected poor outcome of conventional treatments, we designed an L-asparaginase-based induction therapy. L-asparaginase (4000 units/day, day 1 to day 7) combined with vincristine (1 mg, day 1) and prednisolone (100 mg/day, day 1 to day 5) was administered by intravenous infusion every 3 weeks. Within a week after treatment was started, excellent response was observed. Because of an allergic reaction to L-asparaginase, 6 courses of CHOP (adriamycin, cyclophosphamide, vincristine and prednisolone) therapy were administered as consolidation after 4 courses of L-asparaginase. The lymphoma was controlled with complete remission lasting longer than 2 years without additional treatment. These results and related reports may contribute to greater therapeutic efficacy against at least some cases of extranodal NK/T-cell lymphoma and other related diseases. Further evaluations based on clinical study are expected to clarify these results.

[Intradural recurrence of multiple myeloma during the hematological complete remission].

In December 1997, a 55-year-old man presented with left-sided back and arm pain. Pretreatment examination revealed IgG-lambda type M-protein, Bence-Jones protein and the posterior mediastinum tumor. Bone marrow examination revealed hypercellular marrow with 73.6% plasma cells. He was diagnosed as having multiple myeloma with extramedullary lesion. As a result of VAD, MP, interferon and radiation therapy, he had a hematological complete remission. After 21 months, he developed intradural relapse at cauda equina and cerebrum. Many plasma cells and IgG-lambda type M-protein were detected in the cerebrospinal fluid. Laboratory examinations showed a complete remission except for cerebral and meningeal involvement. The myeloma cells might have infiltrated the intradural space at diagnosis and expanded in the central nervous system despite chemotherapy. Because reported cases with cerebral and meningeal myeloma are increasing according to the recent advance of treatment, we must pay attention to the meningeal myeloma.

Concomitant use of radiotherapy and two topoisomerase inhibitors to treat adult T-cell leukemia with a radiotherapy-resistant bulky disease: a case series.

Concomitant chemoradiotherapy is established as the standard treatment to improve the prognosis of several types of solid tumor, but has not been the general practice for hematological malignancies. Here, I report two cases of adult T-cell leukemia (ATL) with a radiotherapy-resistant bulky disease treated with concomitant radiotherapy and two topoisomerase inhibitors: etoposide (VP-16) and irinotecan (CPT-11). Patient 1 was a 78-year-old man with chemotherapy-resistant inguinal bulky mass. Radiotherapy (total 40 Gy) for this inguinal lesion was started; however, the bulky disease was found to be resistant to radiotherapy and progressed. VP-16 and CPT-11 were administered in addition to radiotherapy (after a total of 20 Gy of radiotherapy). Patient 2 was a 71-year-old man with a solitary bulky mass in left cervical lesion. Various previous chemotherapy and radiotherapy approaches had not been able to control the disease. Six months after first radiotherapy, the bulky disease rapidly progressed with the occurrence of pain. Second radiotherapy (30 Gy) was started with simultaneous administration of CPT-11 and VP-16. In both cases, the bulky disease gradually regressed and completely disappeared by the end of radiotherapy. Thus, flexible adaptation of concomitant chemoradiotherapy including two topoisomerase inhibitors may offer a potential therapeutic option for radiotherapy-resistant bulky diseases, even in hematological malignancies.

Adult T-cell leukemia predominantly involving exocrine glands.

OBJECTIVES: We describe a rare case of adult T-cell leukemia (ATL) presenting with dry mouth and swelling of bilateral parotid and submandibular glands. The unusual involvement of these exocrine glands by malignant cells prompted us to conduct a detail characterization of these infiltrating and circulating leukemic T cells, which may provide insight to the pathogenesis of exocrine involvement in ATL. METHODS: Immunophenotyping of peripheral ATL cells and microscopic examinations of various organs prepared by autopsy were performed. Analysis of the repertoire of T-cell receptor (TCR) of parotid gland-infiltrating ATL cells using molecular and immunohistochemical examinations were also performed. RESULTS: Microscopic examinations of various organs prepared by autopsy revealed the predominant and specific exocrine gland infiltration of ATL cells. Reverse transcription-polymerase chain reaction (RT-PCR) followed by both TCR spectratyping and complementary determining region (CDR)-3 sequencing analysis of TCR Vbeta of parotid gland-infiltrating T cells revealed a relatively restricted but not single usage of TCR Vbeta. Immunohistochemical analyses of parotid gland specimens detected only a small number of TCR Valphabeta-positive cells in parotid gland-infiltrating ATL cells. CONCLUSIONS: The predominant infiltration of ATL cells in exocrine glands implied that these T cells recognized exocrine gland-specific antigen. However, the absence of both TCR Vbeta mRNA transcripts and TCR Valphabeta protein expression in most ATL cells suggested that antigen recognition via TCR may not have played a major role in adhesion and subsequent infiltration into the exocrine glands in this patient. These results provide important background information to further elucidate the pathogenesis of exocrine gland-specific inflammation.