Acute leukemia successfully treated with natural interferon-alpha

Natural interferon-alpha (IFN-alpha) alone was administered to a 42-year-old man with acute leukemia, whose bone marrow revealed hypocellularity (NCC = 6 X 10(4)/microliters) and a 50% increase in blasts. Initial chemotherapy regimens, including BHAC-DMP or low dose Ara-C were ineffective. One month after starting nIFN-alpha therapy, the blasts in his bone marrow decreased below 3% and peripheral blood cell counts became normal. He has been in remission for at least 7 months.     

Evolution to megakaryoblastic leukemia observed in myelodysplastic syndrome with erythrolekemia-like features]

A 63-year-old man was admitted because of anemia and thrombocytopenia. The bone marrow was hypercellular with 66.6% erythroblasts with dysplasia and 19.8% blasts. Cytogenetically, MAKA (major karyotypic aberrations) containing 5q-, -7, -17, with karyotypic instability was observed. A diagnosis of erythroleukemia (FAB M6) was made. Six months later, immature neutrophils increased in the peripheral blood, and blasts and promyelocytes increased to 25.8% and 20.0% of marrow cells, respectively. Three months later, blasts asts increased to 33.0% in the peripheral blood. They were ultrastructually positive for platelet peroxidase. Phenotypically, 69% and 63% of blasts were positive for CD41b (GPIIb/IIIa) and CD42a (GPIb), respectively. Bone marrow biopsy showed marked proliferation of blasts and dysplastic megakaryocytes accompanied by reticulin fibrosis. These findings suggested evolution to megakaryoblastic leukemia (FAB M7). In most cases, M6 defined by the FAB criteria is stem cell disorder with multilineage involvement and major erythroid component. M6-like features may be observed in the evolutive phase to acute leukemia from myelodysplastic syndrome (MDS).     

Chronic myelomonocytic leukemia associated with translocation 1;7, marked platelet aggregation and cryofibrinogenemia: a case report]

A 64-year-old male was admitted in September 1989 with complaints of fever and muscular weakness in the extremities. A peripheral blood examination on admission revealed WBC 10,300/microliters (monocytes 32%), RBC 195 x 10(4)/microliters, Hb 7.9 g/dl, Plt 12.8 x 10(4)/microliters with trilineage dysplasia. Bone marrow biopsy was normoplastic marrow with 25.7% of monocytes including immature blasts. Cytochemical analysis of the monocytes showed positive for peroxidase and dual esterase staining. Chromosomal analysis of peripheral blood revealed 46, XY, -7, +der(1) t(1;7)(p11;p11). A diagnosis of chronic myelomonocytic leukemia was made. Hemostatic studies revealed cryofibrinogenemia, marked platelet aggregation on blood smear, hyperfibrinogenemia and a marked increase in maximal amplitude of thrombelastogram. Treatment with prednisolone and VP16, resulted in a reduction of peripheral monocytes and a disappearance of cryofibrinogen, marked platelet aggregation and a decrease in muscular weakness. Nine months after diagnosis he died of DIC, pneumonia, lung abscess and sepsis.     

Essential thrombocythemia that transformed to myelofibrosis after three years]

A 66-year-old man was presented with thrombocytosis in February, 1988. Laboratory examinations on admission revealed a white blood cell count of 17,700/microliters and a platelet count of 274.4 x 10(4)/microliters. Bone marrow aspirates showed an increase of megakaryocytes (1,294/microliters). There was no fibrosis or Ph1 chromosome. He was diagnosed as having essential thrombocythemia and was treated with thrombopheresis, carboquone and ranimustine (MCNU). Subsequently his platelet count was well controlled approximately for three years. He was readmitted because of pyrexia and left hypochondralgia in February 1991. Physical examination revealed hepatosplenomegaly. Peripheral blood revealed leukoerythroblastosis associated with the occurrence of tear drop cells. Bone marrow aspiration resulted in a dry tap and the biopsy specimen showed reticulin fibrosis. This is a fairly rare case of essential thrombocythemia that transformed to myelofibrosis.     

Essential thrombocythemia transformed to acute myeloblastic leukemia

A 48-year-old woman was referred to Tohoku University Hospital in November 1981 because of leukocytosis pointed out in a group examination. At that time white blood cell count was 26.8 x 10(3)/microliters with no blasts, platelet count 268.0 x 10(4)/microliters and hemoglobin 11.4 g/dl. Bone marrow aspirates showed marked increase of megakaryocytes (15,900/microliters). Bone marrow chromosome analysis revealed 46, XX, -18, +mar without Ph1 chromosome, and DNA analysis showed no bcr rearrangement. She was diagnosed as having essential thrombocythemia and was treated with busulfan. On November 1986, she developed remarkable leukocytosis with leukemic blasts. White blood cells reached 153 x 10(3)/microliters with 33% blasts. Her blasts were positive for peroxidase staining, but negative for platelet peroxidase on electron microscopic study and platelet specific glycoproteins. A diagnosis of acute myeloblastic leukemia (M2) was made. The patient received various combination chemotherapy, which was ineffective, and she died due to pneumonia on June, 1989. In Japan, there has been reported only 8 cases of essential thrombocythemia transformed to acute leukemia. The clinical pictures of these 9 cases were discussed.     

Myelodysplastic features in patients with long-term HIV infection and haemophilia

HIV-related bone marrow changes are consistent with myelodysplastic features (MDF). Their pathogenesis may differ from primary myelodysplastic syndromes (MDS) and is associated with various factors including the virus itself or the antiretroviral therapy. In order to evaluate the differences between HIV-related MDF and MDS, the morphological changes in peripheral blood and bone marrow, cytogenetic analysis and the response to anaemia treatment were studied in 158 HIV+ patients with haemophilia and the results were compared with those of 61 patients with primary MDS (31 with RA, 10 with RARS, 11 with RAEB, three with RAEB-t and six with CMML). The eligibility criteria for patients with MDS were primary MDS, Hb levels < 10 g dL(-1), and no significant organ disease. The peripheral blood and bone marrow examination revealed MDF in 44 HIV-infected haemophilic patients (27.8%). The median time from seroconversion was 12.5 years and the mean time under AZT therapy was 44.1 months. Nineteen of these patients (43.1%) had Hb levels < 10 g dL(-1), while neutropenia and thrombocytopenia were observed in 29.5% and 25%, respectively. Every patient of this study with Hb < 10 g dL(-1) received erythropoietin (Epo). There were statistically significant morphological alterations between HIV-related MDF and MDS: hypocellularity, plasmatocytosis and eosinophilia were more pronounced in HIV haemophiliacs with MDF, while dysplasia of erythroblasts, megakaryocytes and granulocytes was more frequent in MDS patients. No HIV haemophilic patient with MDF had more than 5% blasts in the bone marrow nor did any develop RAEB or acute leukaemia during the period of this study. The cytogenetic analysis was normal in HIV-infected patients with haemophilia whereas 42.6% of patients with MDS had an abnormal karyotype. Complete erythroid response was achieved with Epo administration in 84.2% of HIV+ haemophilic patients with anaemia compared to 19.7% of patients with MDS. These data suggest that bone marrow changes in long-term HIV patients have different characteristics from primary MDS and constitute the entity for which the name HIV-myelopathy has been proposed in the literature.     

Congenital stomatocytosis associated with aplastic anemia

A seven year-old boy with hereditary stomatocytosis complicated with aplastic anemia was reported. He was admitted to our hospital because of pale and general fatigue. On physical examination, he had severe anemia, petechiae, but no hepatosplenomegaly. Peripheral blood cell count revealed pancytopenia; RBC 103 X 10(4)/microliters, Hb 3.5 g/dl, Ret 21%, WBC 1,200/microliters, Pl 1.3 X 10(4)/microliters, and bone marrow revealed markedly hypocellular marrow. Red cell morphology demonstrated stomatocytosis. Red cell life span (51Cr T1/2) was 12 days, Coombs' test and Ham's test were negative. Indirect bilirubin was 1.1 mg/dl and marked decrease of haptoglobin was found. Family studies showed that his father and sister had stomatocytosis on peripheral blood examination, but no anemia. The patient had severe anemia because of complicated aplastic anemia. Congenital stomatocytosis with aplastic anemia is extremely rare. The authors are interested in a possible relationship between hereditary stomatocytosis and aplastic anemia although the precise mechanism remains to be elucidated.     

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.     

Acute megakaryoblastic leukemia with leukemia cutis, meningeal leukemia, and myelofibrosis]

A 64-year-old man was admitted to our hospital with leukopenia. On admission, leukocyte count in the peripheral blood was 1,600/microliters, containing 24.5% blasts of lymphoid appearance, which were negative for myeloperoxidase. A bone marrow aspiration showed hypoplasia with increased blasts (31.6%). The blasts were ultrastructurally positive for platelet peroxidase (PPO) and positive for platelet membrane glycoprotein IIb/IIIa complex. A diagnosis of acute megakaryoblastic leukemia was made. Chemotherapy with behenoyl-ara C (BH-AC) (150 mg/day) was transiently effective. However, after three months, numerous nodules without itching appeared over the entire body, particularly on the anterior chest. A biopsy of the skin lesion revealed a diffuse fibrosis with infiltrations of the blasts. Bone marrow aspirations were dry tap, and a bone marrow biopsy showed marked myelofibrosis. Then, severe headache, vomiting, and loss of consciousness developed, and a lumbar puncture revealed infiltrations of blasts. Although methotrexate was intrathecally injected, he died due to the respiratory failure. As far as we know, a case of acute megakaryoblastic leukemia with leukemia cutis and meningeal leukemia is quite rare. In addition, it is interesting that megakaryoblastic leukemia was accompanied with both the fibrosis of skin and the myelofibrosis.     

Reversible Acceleration of Disease Progression Following Cyclosporin A Treatment in a Patient With Myelodysplastic Syndrome

A 38-year-old Japanese man with myelodysplastic syndrome (MDS), whose bone marrow smears demonstrated hypercellularity, was treated with oral cyclosporin A (CsA) therapy. During the course of this therapy, the numbers of peripheral blood and bone marrow blasts increased and the level of serum lactate dehydrogenase increased. After discontinuation of CsA treatment, all of these levels rapidly decreased. We consider that CsA might accelerate disease progression in certain MDS cases.     

Successful induction chemotherapy for childhood RAEB-T with VP-16: a case report

A one-year-old boy diagnosed as refractory anemia with excess of blasts in transformation is reported. Hematological examination revealed anemia, thrombocytopenia and the presence of blasts in both peripheral blood (3.5%) and bone marrow (20.1%) specimens. Chromosomal analysis showed abnormal karyotype; 48, XY, +21, +marker, r (7). Analyses with cytochemical stainings, electronmicroscopy and monoclonal antibodies to cell surface markers could not define the lineage of blasts. Induction chemotherapy was started with VP-16 (230 mg/m2 x 5 days) as a single agent and complete remission was achieved. Thereafter, he had been treated for 11 months with the intensive chemotherapy which consisted of VP-16, cytosine arabinoside, daunorubicin, vincristine, vinblastine, 6-mercaptopurine, prednisolone, mitoxantrone and CNS prophylaxis. He has been in complete remission for 18 months. The usefulness of VP-16 to MDS in pediatric patients is documented.     

Non-specific esterase positive neutrophils in a case of refractory anemia with excess of blasts

A 61-year-old woman was admitted with complaint of fever. The peripheral blood showed pancytopenia and bone marrow aspirate showed dysplasia in trilineage blood cells with increased blasts (18.2%). Bone marrow chromosome study revealed a karyotype of 46XX, -6, 3q-, +mar in 19 cells of 20 analyzed. She was diagnosed as refractory anemia with excess of blasts (RAEB). 95% of neutrophils in the bone marrow and 84% of that in the peripheral blood were stained with non-specific esterase using alpha-naphthyl acetate as substrate. On the other hand, the positivity of neutrophils for peroxidase. Sudan black B or chloroacetate esterase was markedly decreased. The phagocytotic activity of neutrophils was increased in comparison with normal control cells. Surface marker analysis of peripheral blood myeloid cells revealed increased expression of monocyte specific markers. These findings suggested that the patient's neutrophils, which were surely neutrophils in morphology, shared also monocyte-specific characters. After treatment with low dose Ara-C, pancytopenia was recovered and blasts in the bone marrow were reduced. Also was decreased non-specific esterase positive neutrophils, indicating that the neutrophils were derived from abnormal myeloid clone.     

Prominent lymphadenopathy and double Ph1 chromosomes as initial and recurrent manifestations of chronic myelogenous leukemia in blast crisis: report of a case and review of the literature

A 60-year-old woman was admitted because of fatigue. Physical examination revealed prominent peripheral lymphadenopathy, marked tonsillar swelling and hepatosplenomegaly. The leukocyte count was 68,900/microliters with 75% lymphoid blasts and 5% basophils. The karyotype of the blood cells was 46, XX, Ph1/47, XX, Ph1, +Ph1. The diagnosis of CML in blast crisis was made. After chemotherapy using adriamycin, cyclophosphamide, vincristine, and prednisolone (CHOP), lymphadenopathy and splenomegaly reduced and lymphoid blasts disappeared from the blood and bone marrow. At that time only single Ph1 (46, XX, Ph1) clone was detected in her bone marrow. Four months later, hematological relapse accompanied by lymphadenopathy occurred and DNA analysis of the blasts showed the rearrangement of bcr gene. The simultaneous chromosomal analyses of the blood, bone marrow and lymph node revealed that almost all cells examined had the karyotype "47, XX, Ph1, + Ph1". In spite of repeated chemotherapy the patient did not improve and died. This case suggests a relationship between lymphadenopathy and double Ph1 chromosomes in CML.     

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.     

Coexistence of myeloma and primary myelodysplastic syndrome (MDS)]

Coexistence of myeloma and MDS was noted in a patient without history of exposure to cytotoxic drugs. A 73-year-old man was admitted because of fever and dyspnea on exertion. A complete blood count revealed macrocytic anemia with hemoglobin 7.1 g/dl, RBC 191 x 10(4)/microliters and MCV 111.2 fl. WBC was 6,000/microliters, with normal differentials. Bone marrow showed erythroid hyperplasia with M/E ratio of 1.36. There were marked tri-lineage cellular abnormalities, which included megaloblastic changes, multinucleated erythroblasts, hypersegmentation of neutrophils, giant neutrophils, and giant platelets. Ringed-sideroblasts were demonstrated in 20% of the erythroblasts. These findings were compatible with MDS. Although plasma cells accounted for only 9.7% of the nucleated marrow cells, there were many immature plasma cells with inclusion bodies, and the patient showed lambda-light chain type monoclonal gammopathy with corresponding Bence Jones protein. Immuno-histochemical staining of the bone marrow biopsy specimen revealed monoclonal growth of lambda-positive plasma cells. A punched-out lesion of the skull eventually developed. These findings suggest existence of myeloma. There have been some reports of coexistence of MDS and myeloma; supporting the idea of pluripotent stem cell origin of the disease. This is the first documentation of such a case in Japan.     

Myelodysplasia predominantly involving in megakaryocytic lineage successfully treated with low-dose Ara-C

A 17 year old male was admitted because of pancytopenia. Bone marrow aspiration revealed myelodysplasia, no increase of blast cells and excessive expansion of megakaryocytic lineage. Although mild increase of bone marrow reticulin fiber was observed, no hepatosplenomegaly was recognized. Therefore he was diagnosed as refractory anemia (RA) or MDS with myelofibrosis and treated with low dose Ara-C regimen. Remission was achieved in June 1987, but the relapse occurred in Oct. 1987. His bone marrow at the relapse showed more remarkable dysplastic change than before. Sequential bone marrow examinations thereafter, revealed an increase of megakaryocytic lineage, especially immature dysplastic megakaryocytes, leading to the appearance of the abnormal megakaryoblasts (detected with anti GP IIb/IIIa antibody) as well as uncharacterized blast cells in his terminal stage. Transformation from MDS to megakaryocytic leukemia was strongly suggested. He died of severe pneumonia in March 1989. The invasion of abnormal immature megakaryocytic cells including megakaryoblasts was observed in liver, spleen and lymph nodes at autopsy. There are several reports on cases having a common hematological features such as 1) pancytopenia in peripheral blood, 2) myelodysplasia, 3) excessive growth of megakaryocytic lineage, 4) myelofibrosis without hepatosplenomegaly, although other clinical features were different. We propose all these cases should be reviewed at the point of MDS mainly involved in megakaryocytic lineage.     

Spontaneous differentiation from myeloperoxidase-negative acute nonlymphocytic leukemia to acute myelomonocytic leukemia

We reported a 68-year-old woman with acute nonlymphocytic leukemia, in whom the leukemia transformed from poorly differentiated myeloperoxidase (MPO)-negative type into myelomonocytic type during the observation without chemotherapy. Hematological findings on admission revealed a leukocyte count of 3,500/microliters with 48% blasts and a platelet count of 9.2 x 10(4)/microliters. Bone marrow aspiration showed 68.2% infiltration of blasts negative for MPO. Sudan black B and esterase stains. By electron microscopy MPO was detected in the endoplasmic reticulum and nucleoenvelope of the blasts. Large vacuole-like granules were MPO-negative. She was observed without administration of any antileukemic agent or an immunopotentiator. The leukocyte count rose gradually, in association with increases in the relative and absolute counts of mature neutrophils and monocytic cells, and the platelet count. Twenty-six months after the initial diagnosis, a blood examination showed a leukocyte count of 74,300/microliters with 20.5% mature neutrophils and 15.5% monocytic and a platelet count of 31.4 x 10(4)/microliters. Cytological, cytochemical, ultrastructural and immunological studies of the bone marrow cells showed features compatible with acute myelomonocytic leukemia (FAB M4). This case is unusual in respect that poorly differentiated ANLL transformed spontaneously into moderately differentiated ANLL.     

An erythremia with acquired HbH disease and chromosomal abnormality

A 56-year-old male was admitted to the Nihon University Hospital because of general fatigue and anemia on September 21st, 1985. He had mild hepato-splenomegaly. Hematological findings showed RBC 286 x 10(4)/microliters, Hb 6.0/dl, reticulocyte count 2.5%, platelet count 9.3 x 10(4)/microliters and WBC 2,400/microliters. An erythroblast per 100 leukocytes counted in a blood film was found. Bone marrow was erythroid hyperplasia with megaloblasts. The erythroblasts were PAS positive but not ringed sideroblasts. Other laboratory data including hemolysis were all negative. This case seemed to be diagnosed as refractory anemia (RA) according to the FAB classification. Chromosomal analysis of marrow cells, however, all revealed 46, XY, 20q- at diagnosis and 46, XY, 7q- 20q- after 22 months. Furthermore, Hb electrophoresis ahd family study indicated the presence of acquired HbH disease. Neither erythroid bursts (BFU-e) nor late erythroid progenitors (CFU-e) were detected. He has had progressive anemia without proliferation of blasts for over 2 years. From these findings, we postulate that the entity of erythremia should be distinguished from RA including many heterogeneous diseases.     

Plasma thrombopoietin levels in thrombocytopenic states: implication for a regulatory role of bone marrow megakaryocytes

To evaluate the diagnostic value of thrombopoietin (TPO, c-mpl ligand) measurements, and clarify the regulatory mechanisms of TPO in normal and in thrombocytopenic conditions, the plasma TPO concentration was determined in normal individuals (n = 20), umbilical cord blood (n = 40), chronic idiopathic thrombocytopenic purpura (ITP; n = 16), in severe aplastic anaemia (SAA; n = 3), chemotherapy-induced bone marrow hypoplasia (n = 10), myelodysplastic syndrome (MDS; n = 11), and sequentially during peripheral blood progenitor cell transplantation (n = 7). A commercially available ELISA and EDTA-plasma samples were used for the analysis. The plasma TPO concentration in the normals and umbilical cord blood were 52 ± 12 pg/ml and 66 ± 12 pg/ml, respectively. The corresponding values in patients with SAA and chemotherapy-induced bone marrow hypoplasia were 1514 ± 336 pg/ml and 1950 ± 1684 pg/ml, respectively, and the TPO concentration, measured sequentially after myeloablative chemotherapy and peripheral blood progenitor cell transplantation, was inversely related to the platelet count. In contrast, the plasma TPO recorded in patients with ITP (64 ± 20 pg/ml) and MDS (68 ± 23 pg/ml) were only slightly higher than normal levels. In conclusion, TPO levels were significantly elevated in patients in which bone marrow megakaryocytes and platelets in circulation were markedly reduced, whereas TPO levels were normal in ITP patients, and only slightly increased in the MDS patients. These latter patients displayed a preserved number of megakaryocytes in bone marrow biopsies. Our data support the suggestion that megakaryocyte mass affects the plasma TPO concentration. In thrombocytopenic patients a substantially increased plasma TPO implies deficient megakaryocyte numbers. However, TPO measurements do not distinguish between ITP and thrombocytopenia due to dysmegakaryopoiesis, as seen in MDS patients.     

Refractory anemia terminating in acute megakaryoblastic leukemia (M7)

A 72-year-old man with refractory anemia (RA) developed overt megakaryoblastic leukemia after the course of RA with excess of blasts. The blasts were positive for platelet peroxidase activity and had platelet glycoproteins (GPs) such as GPIIb/IIIa and GPIIIa. The bone marrow biopsy at terminal stage disclosed marked fibrosis. The nature of the megakaryoblasts was investigated. The blasts did not differentiate morphologically into mature megakaryocytes with TPA addition. In vitro colony assay showed the failure of colony-forming unit, megakaryocyte growth in peripheral blood. The pathogenesis of myelofibrosis in our patient is discussed.