Successful immunosuppressive therapy for a patient with hypoplastic myelodysplastic syndrome

We encountered a patient with hypoplastic myelodysplastic syndrome (MDS) who responded to immunosuppressive therapy including antithymocyte globulin and cyclosporin A (CsA). A 13-year-old girl was referred to our hospital because of pancytopenia. Bone marrow smears disclosed extreme hypocellularity without cellular atypism. A diagnosis of aplastic anemia was made, and immunosuppressive therapy consisting of ATG, CsA, granulocytecolony-stimulating factor (G-CSF), methylprednisolone, and danazol was started. A month later dysplastic cells appeared in the bone marrow. The karyotype of pretreatment bone marrow cells was 46, XX, del (13) (q12; q14). Therefore, the final diagnosis was hypoplastic MDS. CsA and danazol were continued. The patient became transfusion-independent 1 month later and dysplastic cells disappeared from bone marrow 3 months later. The chromosomal abnormality also became undetectable 6 months after the initiation of treatment. These findings indicated that immunosuppressive therapy is beneficial for patients with hypoplastic MDS.     

Myelodysplastic syndrome in a child which developed into megakaryocytic leukemia with late appearing Ph1 chromosome and rearrangement of breakpoint cluster region

A 3-year-old boy was referred to our hospital in September 1985, because of pancytopenia. His bone marrow was normocellular with 18% blasts, which had Auer rod and were positive for peroxidase staining. A diagnosis of refractory anemia with excess blasts in transformation was made according to FAB criteria. Chromosome analysis of bone marrow cells showed normal male karyotype. He attained complete remission with aclarubicin and BH-AC and continued it until August 1987 when pancytopenia and hypoplastic bone marrow developed. Chromosome analysis of bone marrow cells showed normal male karyotype and gene analysis revealed germ-line configuration of breakpoint cluster region (bcr). Overt leukemia developed in May 1988 when his WBC count increased to 60, 600/microliters with 91% blasts, which were negative for peroxidase staining, positive for anti-Ia and CDw 41 by cell surface analysis, and positive for ultrastructurally demonstrable platelet peroxidase. A diagnosis of megakaryocytic leukemia was made. Chromosome analysis of bone marrow cells showed 46, XY, t(9;22) (q34;q11) and gene analysis revealed rearrangement of bcr. He died in November 1988. Our results and review of literature suggest that late appearing ph1 chromosome and rearrangement of bcr may occur in a variety of hematologic malignancies and influence the course of disease.     

Induction of Complete Remission of Hypoplastic Leukemia with Antithymocyte Globulin

A 13-year-old boy was admitted to a local hospital because of pancytopenia. A bone marrow aspiration and biopsy revealed severely hypocellular marrow with no obvious leukemic cells. The diagnosis was severe aplastic anemia, and the patient was treated with antithymocyte globulin and cyclosporin A. A trilineage response was obtained, and the patient became transfusion-independent within 2 weeks. Two months later, the peripheral blood count normalized with an increased bone marrow cellularity. However, the patient was readmitted 5 months later for recurrence of the pancytopenia. A bone marrow aspiration revealed hypocellular marrow with morphologically blastoid cells. A surface marker study revealed the presence of a single clone that was positive for CD7, CD33, CD34, and HLA-DR. A diagnosis of hypoplastic leukemia was made on the basis of morphology and the surface marker studies. Retrospectively, the laboratory findings were the same as those seen at the onset of the disease. The patient did not respond to combination chemotherapy consisting of vincristine, prednisolone, cyclophosphamide, L-asparaginase, and doxorubicin, but administration of etoposide resulted in complete remission. An in vitro study revealed that >95% of the leukemic cells of this patient could be lysed after an incubation with antithymocyte globulin and human AB serum or baby rabbit serum. These findings suggest the efficacy of antithymocyte globulin in treating certain hypoplastic leukemias.     

Pancytopenia with hypercellular bone marrow—a possible paraneoplastic syndrome in carcinoma of the lung: A report of three cases

Three patients with idiopathic pancytopenia and hypercellular bone marrow who developed carcinoma of the lung within two years of diagnosis are reported. All three patients had macrocytic anemia associated with a megaloblastic marrow in the presence of normal serum vitamin B12 and folic acid levels. Neutropenia with monocytosis, elevated serum muramidase and LAP scores, and increased fetal hemoglobin levels were also found. In all cases Ham's tests were negative with a normal bone marrow karyotype. In all three patients, pancytopenia due to myelodysplasia, a probable preleukemic state, was diagnosed initially prior to the appearance of carcinoma of the lung. One of the patients showed improved leukocyte and platelet counts during chemotherapy, while the other two died before chemotherapy could be administered. In the light of the above findings we suggest that carcinoma of the lung may be the cause of a paraneoplastic syndrome with pancytopenia, particularly in patients with a hypercellular marrow with a normal karyotype.     

Restoration of normal hematopoiesis by bone marrow ablation and allogeneic marrow transplantation in a case of Hodgkin''s disease therapy-related preleukemia

Therapy-related leukemias are generally preceded by a preleukemic phase of several months duration, characterized by pancytopenia, abnormal bone marrow findings, and nonrandom chromosomal abnormalities in almost all cases. No specific therapeutic guidelines are recommended in this preleukemic phase or any other type of preleukemia; aggressive combination chemotherapy is usually withheld until the full expression of leukemia. A 22-yr-old man with therapy-related preleukemia following treatment of Hodgkin's disease received as primary treatment ablative chemotherapy followed by marrow transplantation from his histocompatible sister. At day 316, the patient is still in complete bone marrow recovery with a normal donor karyotype. In the light of the very poor results obtained with conventional chemotherapy regimens once the leukemic phase is established, we suggest that bone marrow transplantation, if undertaken before leukemic conversion, may be the treatment of choice in young adults with therapy-related preleukemia.     

Myelodysplasitic syndrome in two young brothers

Summary. We report the youngest cases of myelodysplastic syndrome (MDS) in two brothers aged 7 and 2 years. The maternal grandfather and maternal grandmother had been exposed to radioactive fallout after the atomic bomb attack on Hiroshima in 1945. The elder brother demonstrated pancytopenia with <1% blast cells in his peripheral blood and <5% in his bone marrow at diagnosis. The younger brother was thrombocytopenic without increased blasts. The karyotype of bone marrow cells from the elder brother was 46, XY, ?7, +der (7), t(1:7) (lqter-lq11:: 7q11–7pter), but the younger brother's karyotype was normal. Immature myeloid cells in the bone marrow from both brothers were morphologically abnormal. A diagnosis of refractory anaemia (RA) was made in both brothers. Atavism due to radioactive poisoning was suspected in the development of MDS in these two cases.     

Reversible bone marrow hypoplasia induced by alcohol

A 51-year-old man developed severe pancytopenia with bone marrow hypoplasia after consuming excessive amounts of alcohol for many years. After avoiding alcohol and eating normally for about 10 days, his blood cell counts promptly recovered to near-normal levels. Hematologic remission had lasted for 7 months until he began to drink alcohol excessively again, leading to a relapse of pancytopenia with marrow hypoplasia. His blood cell counts attained near-normal levels again after abstaining from alcohol for about a month. He developed thrombocytopenia following moderate ingestion of alcohol 7 months later, but he never developed severe pancytopenia after limiting alcohol ingestion. When bone marrow mononuclear cells from the patient and normal volunteers were cultured in the presence of ethanol, CFU-GM-derived colony formation of the patient was inhibited by much lower concentrations of ethanol than that of normal volunteers. The clinical course of the patient and the greater sensitivity of the patient's CFU-GM to ethanol toxicities indicate that massive intake of alcohol was responsible for bone marrow hypoplasia observed in this patient.     

Primary myelofibrosis successfully treated with allogeneic bone marrow transplantation]

A 31-year-old man with primary myelofibrosis initially received low dose Ara C. Splenomegaly decreased but pancytopenia continued. Allogeneic bone marrow transplantation from his sister was then performed. Busulfan and cyclophosphamide were used as a preconditioning regimen, which included neither irradiation nor splenectomy. As the bone marrow was hypoplastic after transplantation, G-CSF was given. It was useful for systemic infection. After transplantation, leukoerythroblastosis and tear drop poikilocytosis disappeared in peripheral blood. Finally, bone marrow fibrosis disappeared and hemopoiesis to normal limits recovered 17 months later. These results demonstrate that bone marrow transplantation is effective for primary myelofibrosis for which there is no otherwise curative therapy.     

Diabetes insipidus associated with dysplastic pancytopenia

This case report describes a 60-year-old man who presented with a three-year history of generalized malaise, decreased libido, polyuria, and polydipsia. He had been previously investigated for pancytopenia, and found to have a hypoplastic bone marrow. A diagnosis of central diabetes insipidus was established; the patient was also found to have a number of other defects in his hypothalamic-pituitary function. Hematologic studies again revealed peripheral pancytopenia associated with a hypoplastic megaloblastic bone marrow. Computed axial and nuclear magnetic resonance tomography failed to establish the nature of the morphologic lesion in the hypothalamus. A possible relationship between the hematologic and endocrine disturbance is discussed.     

Angioimmunoblastic T-cell lymphoma associated with hemophagocytic syndrome at onset and relapse

A 66-year-old woman was admitted with high fever, systemic lymphadenopathy, hepatosplenomegaly and pancytopenia. Bone marrow aspiration showed infiltration of atypical lymphoid cells and hemophagocytic histiocytes. The findings of lymph node biopsy were compatible with angioimmunoblastic T-cell lymphoma (AILD). A diagnosis of lymphoma-associated hemophagocytic syndrome (LAHS) was made. Treatment with the THP-COP regimen achieved clinical remission except for mild splenomegaly, but relapse of LAHS was confirmed two years after diagnosis. The patient's condition deteriorated rapidly, and she died of multi-organ failure one month later. Autopsy revealed extended, diffuse infiltration of lymphoma cells in almost all organs. Numerous macrophages showing phagocytosis of erythrocytes and nucleated cells were found in the adrenal glands, lungs, bone marrow, spleen and liver. Epstein-Barr virus genomes were not detected by in situ hybridization, but cytotoxic molecules were immunostained with TIA-1 and granzyme B in the lymphoma cells. Elevated serum levels of sIL-2R, IFN-gamma, IL-6 and M-CSF were found at the onset and relapse of lymphoma. Overproduction of these cytokines was considered to have contributed to the pathogenesis of HPS.     

Philadelphia chromosome positive acute lymphoblastic leukemia showing normal karyotype in G-banding chromosomal examination before chemotherapy

A 29-year-old male was admitted because of thrombocytopenia. A diagnosis of acute lymphoblastic leukaemia was made on the basis of a 61.6% infiltration of leukemic cells in his bone marrow. Standard G-binding chromosome analysis of bone marrow cells revealed a normal karyotype. He received combination chemotherapy, and achieved hematological complete remission. However, chromosomal analysis of bone marrow cells after 2 courses of consolidation therapy showed the Philadelphia (Ph) chromosome in two cells out of 20 analysed. We retrospectively examined the sample of bone marrow cells before chemotherapy; It showed minor BCR/ABL positivity with FISH and RT-PCR methods. The Ph chromosome disappeared after consolidation chemotherapy and allogeneic bone marrow transplantation, but the Ph chromosome reappeared at relapse. We postulated that there were two clones, both a Ph-positive clone and Ph-negative clone. At the initial diagnosis, Ph chromosome was not detected because the G-banding method analyzed only metaphase cells, which contained few Ph-positive clones. In order to offer effective therapy with molecular targeting agents, in this poor prognostic disease, it is necessary to detect Ph chromosome before the first chemotherapy and BCR/ABL detection with FISH or RT-PCR methods appears more useful than G-banding chromosome analysis.     

Philadelphia chromosome positive acute lymphoblastic leukemia showing normal karyotype in G-banding chromosomal examination before chemotherapy

A 29-year-old male was admitted because of thrombocytopenia. A diagnosis of acute lymphoblastic leukaemia was made on the basis of a 61.6% infiltration of leukemic cells in his bone marrow. Standard G-binding chromosome analysis of bone marrow cells revealed a normal karyotype. He received combination chemotherapy, and achieved hematological complete remission. However, chromosomal analysis of bone marrow cells after 2 courses of consolidation therapy showed the Philadelphia (Ph) chromosome in two cells out of 20 analysed. We retrospectively examined the sample of bone marrow cells before chemotherapy; It showed minor BCR/ABL positivity with FISH and RT-PCR methods. The Ph chromosome disappeared after consolidation chemotherapy and allogeneic bone marrow transplantation, but the Ph chromosome reappeared at relapse. We postulated that there were two clones, both a Ph-positive clone and Ph-negative clone. At the initial diagnosis, Ph chromosome was not detected because the G-banding method analyzed only metaphase cells, which contained few Ph-positive clones. In order to offer effective therapy with molecular targeting agents, in this poor prognostic disease, it is necessary to detect Ph chromosome before the first chemotherapy and BCR/ABL detection with FISH or RT-PCR methods appears more useful than G-banding chromosome analysis.     

Acute eosinophilic leukemia in a patient with preexistent myelodysplastic syndrome

A case of acute eosinophilic leukemia (EoL) that occurred in a patient with preexistent myelodysplastic syndrome is reported. The patient was initially diagnosed as having refractory anemia (RA) on the basis of pancytopenia with dysplasia and chromosomal abnormalities. Two years later, he was readmitted because of progression of pancytopenia, and bone marrow and peripheral blood showed immature dysplastic eosinophils. Clonal assay of peripheral blood mononuclear cells revealed autonomous growth of colony-forming unit eosinophils. Cytotoxic chemotherapy did not induce remission, and extensive myelofibrosis developed. Cytogenetic analysis in the RA state showed +1p- and -7 whereas complicated abnormalities including +1p-, 3q- and 7p- dominated in the EoL state.     

Hodgkin lymphoma accompanied by aplastic anemia and polyclonal expansion of large granular lymphocytes

Immunologic abnormalities have been described in patients with Hodgkin lymphoma, including autoimmune hemolytic anemia and immune thrombocytopenic purpura. The concurrent diagnoses of Hodgkin lymphoma and acquired aplastic anemia, however, is extremely rare. We report a 56-year-old Japanese female patient with severe aplastic anemia and increased large granular lymphocytes prior to the recurrence of Hodgkin lymphoma. After being in remission for 10 years from Hodgkin lymphoma, she developed progressive pancytopenia. The large granular lymphocytes (expressed CD3+ CD8+ TCRalphabeta+) had a polyclonal distribution, the serum-soluble FasL concentration was significantly elevated, and bone marrow biopsy showed severely hypocellular bone marrow without infiltration of abnormal lymphocytes. No lymphadenopathy was observed that would suggest a relapse of Hodgkin lymphoma. A diagnosis of aplastic anemia was made, and treatment with corticosteroids and cyclosporine was initiated. Two months later, she suddenly developed celiac and mediastinal lymphadenopathy. She underwent one cycle of chemotherapy before she died of progressive pancytopenia. Autopsy revealed the recurrence of Hodgkin lymphoma, nodular sclerosis in the lymph nodes and markedly hypocellular bone marrow. Although autoimmune disorders are described in Hodgkin lymphoma, our case shows a rare instance of a patient who had aplastic anemia as the first manifestation of a relapse of Hodgkin lymphoma.     

Early transformation from follicular lymphoma to Burkitt lymphoma

We report a rare case of follicular lymphoma which rapidly showed transformation to the Burkitt type of lymphoma after a treatment consisting of chemotherapy and irradiation. A 51-year-old male visited our hospital in August 2000 because of bilateral neck lymphadenopathy. He was diagnosed as having follicular lymphoma (grade 2) (clinical stage IIIA) with complex karyotypic abnormalities involving t(14 ; 18)(q32 ; q21) and CD20 expression. Initially he was followed as an outpatient without chemotherapy. Six months later, he was admitted because of hydronephrosis due to an intrapelvic tumor. He underwent chemotherapy with 4 courses of CHOP regimen following irradiation therapy and a partial response was obtained. Four months after initiation of the treatment, his disease recurred with numb chin syndrome. Bone marrow aspiration revealed bone marrow involvement by lymphoma cells which had a Burkitt-like appearance. A cytogenetic study using bone marrow blood showed complex abnormalities involving t(8 ; 22)(q24 ; q11) in addition to t(14 ; 18). In spite of salvage chemotherapy, the patient died in September 2001.     

Reversible Epstein-Barr Virus-Negative Lymphadenopathy and Bone Marrow Involved by Hodgkin’s Lymphoma in a Rheumatoid Arthritis Patient Undergoing Long-term Treatment with Low-Dose Methotrexate: A Case Report and Review of the Literature

We report a case of spontaneous regression of Epstein-Barr virus (EBV)-negative methotrexate-associated lymphadenopathy occurring with Hodgkin's lymphoma in the bone marrow of a 48-year-old woman with rheumatoid arthritis. Following 10 years of treatment with low-dose methotrexate, the patient developed pancytopenia, hypercalcemia, and elevated levels of liver enzymes over the course of 2 months. A computed tomography scan of the abdomen revealed splenomegaly and enlarged abdominal lymph nodes. A bone marrow biopsy demonstrated cellular marrow with 2 paratrabecular granuloma-like lesions composed of histiocytes, fibroblasts, small lymphocytes, a few plasma cells, and scattered CD30(+)CD15(+) Hodgkin's cells, including a classic Reed-Sternberg cell. The results of EBV studies of the bone marrow were negative. Within a month from withdrawal of methotrexate treatment, the patient's symptoms and the abnormalities in the laboratory results had regressed completely. A positron emission tomography scan failed to detect lymphadenopathy. Twelve months later, the patient remains free of symptoms.     

Therapy-related myelodysplastic syndrome with monosomy 5 after successful treatment of acute myeloid leukemia (M2)

We describe a patient who developed myelodysplastic syndrome over 2 years after achieving complete remission of acute myeloid leukemia (AML). The patient was treated in July 1998 with anthracycline, etoposide, and behenoyl cytarabine chemotherapy for AML (French-American-British classification, M2; World Health Organization classification, AML with maturation) and achieved complete remission. At presentation, no chromosomal abnormalities were detected. In December 2000, the patient's peripheral blood revealed pancytopenia, and his bone marrow was hypocellular with trilineage myelodysplasia and no blasts. Chromosomal analysis revealed complex karyotypic abnormalities, including monosomy 5. The patient was diagnosed with high-grade myelodysplastic syndrome (MDS)/refractory anemia with excess blasts (RAEB) subtype. The pancytopenia progressed rapidly, and he died 2 months after the diagnosis of MDS. Therapy-related MDS and AML (t-MDS/t-AML) developing after treatment for acute leukemia is unusual; the primary leukemia associated with most cases of t-MDS/t-AML is acute promyelocytic leukemia (APL). This unusual case suggests that AML excluding APL should be considered a primary hematologic malignancy for t-MDS/t-AML.     

Hepatosplenic αβ T-Cell Lymphoma with Myelodysplastic Syndrome

We describe a patient with hepatosplenic 33 T-cell lymphoma who showed pancytopenia and myelodysplasia. A 35-year-old man was admitted with fever, pancytopenia, and hepatosplenomegaly but with no lymphadenopathy. We also found trilineage myelodysplasia in the bone marrow on his first admission.The patient had high fever and anemia but no evidence of infection and was tentatively treated with prednisolone. This treatment resulted in a transient improvement of the cytopenia and a reduction of spleen size. However, 10 months after the first manifestation, progression of the splenomegaly and fever became apparent, and a splenectomy was performed. The pathologic findings for the spleen showed diffuse and disseminated infiltration of medium- to large-sized T-lymphocytes in the splenic red pulp. These cells were immunohistochemically positive for CD3, CD5, CD7, CD8, CD16, CD56,T-cell receptor 33 (TCR33),T-cell intracellular antigen 1, and granzyme B but were negative for CD4, CD30, CD57, and TCR33. These data suggested a diagnosis of hepatosplenic 33 T-cell lymphoma. A Southern blot analysis revealed gene rearrangement of the TCR 3-chain gene but not the immunoglobulin heavy chain gene in the spleen cells. An in situ hybridization analysis for the Epstein-Barr virus revealed negative results. The patient received 8 courses of combination chemotherapy and achieved a partial remission; however, the dysplastic features of the marrow cells persisted after the partial remission was obtained. Additional treatment with allogeneic bone marrow transplantation resulted in a transient complete remission; however, the patient relapsed 11 months later. Because he had experienced no lymphadenopathy and showed dysplastic features in the bone marrow, the diagnosis was highly dependent on the pathologic findings for the resected spleen.     

Spontaneous Regression of Blastic Plasmacytoid Dendritic Cell Neoplasm Following Sepsis by Serratia marcescens: A Case Report and Literature Review

Spontaneous regression is rare in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). An 85-year-old man presented with pancytopenia and skin lesions, and the bone marrow exhibited 79.6% CD4+, CD56+, CD123+, and TCL-1+ abnormal cells, with a normal karyotype; he was thus diagnosed with BPDCN. While being followed without chemotherapy, he was admitted due to sepsis induced by Serratia marcescens, which was successfully treated with antibiotics. Notably, his blood cell counts improved, and the skin lesions disappeared. To our knowledge, this is the first reported case of spontaneous regression of BPDCN with a decrease in tumor cells in the bone marrow following sepsis.     

Pediatric acute lymphoblastic leukemia initially presenting with bone marrow necrosis

We report on a case of pediatric acute lymphoblastic leukemia presenting with massive bone marrow necrosis. A 4-year-old boy complained of fever and leg pain. Laboratory data revealed pancytopenia, but bone marrow examination showed only necrotic materials. About one month later, repeated bone marrow examination showed leukemic cells and the necrotic marrow had disappeared. The patient was treated with standard chemotherapy and was successfully induced to complete remission. Patients with massive bone marrow necrosis should undergo bone marrow examination repeatedly to make the correct diagnosis.