A case of Plasmodium vivax malaria complicated with pancytopenia due to hypoplasia of the bone marrow

The patient is a 39 year-old Japanese male who had traveled to Southeast Asia from March 14, 1987 and returned on April 2. On April 3 and 5, he had a high fever with chills and he was admitted to our hospital. Despite initial treatment with antibiotics, a high fever over 39 degrees C appeared with a 48 hour periodicity. On the 8th day after admission, malarial parasites were identified on the peripheral blood smear after repeated trials. Combined with a raised serum antibody titer, Plasmodium vivax malaria was diagnosed. He was successfully treated with the sulfadoxine 500 mg and pyrimethamine 25 mg (Fansidar) and body temperature was normalized after the 12th day. More interestingly, the patient showed pancytopenia without splenomegaly. The bone marrow aspiration revealed hypoplasia of erythroblasts, granulocytes and megakaryocytes. Because of this pancytopenia in the peripheral blood and hypoplasia of the bone marrow which improved after recovery from malarial infection, it was indicated that they were caused by the malarial infection. Generally, it is considered that anemia in malarial patients is caused by destruction of the blood cells by parasites and/or hypersplenism and compensatory hyperplasia of the bone marrow is seen. On the contrary, this case showed pancytopenia accompanied with hypoplasia of the bone marrow probably due to the malarial infection suggesting a new aspect of pathogenesis in the hematological abnormality of the malarial infection.     

Effective treatment combining antithymocyte globulin, cyclosporin A, and granulocyte colony-stimulating factor for atypical paroxysmal nocturnal hemoglobinuria accompanied by bone marrow hypoplasia

A 25-year-old man was admitted for evaluation of pancytopenia on May 2, 1997. On admission, he had pancytopenia with a normal reticulocyte count. Bone marrow aspirate specimens displayed a normal karyotype and hypocellularity without myelodysplasia. Although total bilirubin and lactate dehydrogenase levels were within their normal ranges, the haptoglobin level was low; additionally, two-color flow cytometric analysis determined that 3.3% of erythrocytes were double-negative for CD55 and CD59 expression. Atypical paroxysmal nocturnal hemoglobinuria with bone marrow hypoplasia was diagnosed. Because initial treatment with cyclosporin A was not effective, the patient was subsequently given a combination of antithymocyte globulin, cyclosporin A, and granulocyte colony-stimulating factor. Although the pancytopenia subsided, the percentage of double-negative erythrocytes in the patient's blood remained almost unchanged compared to findings obtained on admission.     

Clinical and laboratory evidence for a trilineage haematopoietic defect in patients with refractory Diamond-Blackfan anaemia

Diamond-Blackfan anaemia (DBA) is a constitutional pure red cell aplasia presenting in early childhood. In some patients, neutropenia and/or thrombocytopenia have also been observed during the course of the disease. We have followed 28 patients with steroid-refractory DBA for up to 13 years with serial peripheral blood counts and bone marrow (BM) aspirates and biopsies. In 21/28 (75%) patients, moderate to severe generalized BM hypoplasia developed, with overall cellularities ranging from 0% to 30%. Marrow hypoplasia correlated with the development of neutropenia (9/21; 43%) and/or thrombocytopenia (6/21; 29%) in many patients. No patient had either cytogenetic abnormalities or progressed to acute leukaemia, although one 13-year-old developed marked marrow fibrosis and trilineage dysplasia. We used the in vitro long-term culture-initiating cell (LTC-IC) assay to quantify multilineage, primitive haematopoietic progenitors in a representative subset of these patients. LTC-IC assays showed equivalent frequencies of cobblestone area-forming cells (CAFCs) with a mean of 5.42/10(5) cells +/- 1.9 SD and 6.13/10(5) cells +/- 2.6 SD in nine patients and six normal controls respectively. The average clonogenic cell output per LTC-IC, however, was significantly lower in DBA patients (mean 2.16 +/- 1.2 SD vs. 7. 36 +/- 2.7 SD in normal controls, P = 0.0008). Our results suggest that the underlying defect in patients with severe refractory DBA may not be limited to the erythroid lineage, as was evidenced by the development of pancytopenia, bone marrow hypoplasia and reduced clonogenic cell output in LTC-IC assays.     

A case of thyrotoxicosis with pancytopenia

We report a 49-year-old man with primary hyperthyroidism who presented with pancytopenia. The patient presented with leg edema, sinus tachycardia, cardiomegaly, and pleural effusions, all from congestive heart failure. Laboratory data showed pancytopenia and primary hyperthyroidism; echocardiogram showed diffuse hyperkinesis of the left ventricular wall and right ventricular overloading. The bone marrow was moderately hypercellular and compatible with arrested hematopoiesis. Pancytopenia and heart failure improved after administration of methimazole and diuretics. However, high levels of thyroid hormone recurred with pancytopenia 4 months after admission. Therefore, subtotal thyroidectomy was performed, and the levels of thyroid hormones and peripheral blood cell counts have remained normal. Pancytopenia may be caused by hyperthyroidism.     

Massive plasmocytosis due to methimazole-induced bone marrow toxicity.

Pancytopenia is a rare complication of the thionamide therapy reported secondary to aplastic anemia, the bone marrow being invariably hypocellular. We present a case of a 16-year-old female with Graves' disease who presented with massive bone marrow plasmocytosis mimicking multiple myeloma. The patient had already been on methimazole for a month when she was admitted to the Pediatric Unit with the diagnosis of sepsis. CBC revealed pancytopenia. Bone marrow aspirations showed hypocellular-normocellular bone marrow, 98% of plasma cells. At that time, MMI was discontinued and the patient was started on broad-spectrum antibiotics, dexamethasone, and G-CSF. Bone marrow aspiration day +4 still showed hypo-normocellular marrow, with remaining 6% plasma cells. Myeloma screen was negative; ANC >1,000 at day +7, platelets >50,000 at day +24. Twenty-four months after patient's discharge, her clinical condition, CBC, and bone marrow remained normal. To our knowledge this is the first report of pancytopenia due to MMI, where the usual hypoplasia found is replaced by massive plasmocytosis.     

Sustained remission of MDS overt leukemia associated with abrupt discontinuation of immunosuppression following relapse after the second course of allogeneic hematopoietic stem cell transplantation

The case of a 32-year-old female with relapsed myelodysplastic syndrome (MDS) after second course of allogeneic transplantation is described. The peripheral blood stem cell transplantation was performed as early as 3 months after the initial bone marrow transplantation because of rejection and relapse; however, the patient again relapsed 2 months later. Immediate discontinuation of cyclosporine resulted in the progression of pancytopenia and the development of high fever, liver dysfunction and skin eruption. The patient was then treated with dexamethasone, which successfully stabilized these symptoms. After these clinical events, a dramatic hematological response was obtained; the blast rate was reduced from 10.6 to 0% in bone marrow aspiration, and pancytopenia was restored to normal levels. Moreover, fluorescence in situ hybridization analyses with X and Y chromosome-specific probes revealed that hematopoietic precursor cells were predominantly of donor origin. The patient subsequently received donor lymphocyte infusion (DLI) from the original donor. Currently, 2 years after DLI, the patient continues to be in remission.     

Transient pancytopenia

Summary From a population-based study on the incidence of potentially drug-associated blood dyscrasias 28 cases were identified with pancytopenia. Who recovered within 90 days after diagnosis. Early recovery occured more frequently in patients showing normal or increased cellularity of the bone marrow than in patients with bone marrow hypoplasia. Median recovery times of leukocytes were 14 and 10 days and of platelets 21 and 9 days in patients with and without bone marrow hypoplasia, respectively. Age and sex distribution were similar in both groups. Of 28 patients, 11 reported a period of fever before onset of pancytopenia. Sixteen patients in whom information on drug use was available had taken a median of 4 drugs before the onset of symptoms that were related to pancytopenia. From these results we present the hypothesis that transient pancytopenia with or without marrow hypoplasia can be the expression of the same type of bone marrow injury and that drugs or viral infections should be considered as etiological factors.     

Peripheral blood remission of hairy cell leukemia after transfusion hepatitis

Hairy cell leukemia is a chronic lymphoproliferative disorder characterized clinically by splenomegaly and cytopenias. Spontaneous remissions are rare and splenectomy is often performed when the blood counts worsen and cause symptoms. Three of our patients with hairy cell leukemia developed recurrent pancytopenia and transfusion-dependent anemia after splenectomy. Each subsequently acquired transfusion hepatitis and in two patients marked hematologic improvement was noted within 2 months. Complete peripheral blood remission occurred within 17 months in all patients although bone marrow infiltration with hairy cells persisted. One patient remains in remission for 12 years; the other two succumbed to infectious illnesses but with normal blood counts. The mechanism by which hepatitis virus induces hematologic recovery in patients with hairy cell leukemia is unknown but may involve augmentation of the interferon system.     

Gemtuzumab ozogamicin-induced long-term remission in a woman with acute myelomonocytic leukemia and bone marrow relapse following allogeneic transplantation

A 56-year-old woman with acute myelomonocytic leukemia underwent myeloablative allogeneic hematopoietic stem cell transplantation (allo-SCT) from a matched unrelated donor in her first complete remission (CR). Veno-occlusive disease (VOD) prophylaxis consisted of low-dose heparin and ursodeoxycholic acid. Graft-versus-host disease (GVHD) prophylaxis comprised tacrolimus and short-term methotrexate. On day 14, VOD developed, but gradually resolved with supportive therapy. On day 58, she showed grade II acute GVHD, but this resolved spontaneously. On day 140, she developed hematological relapse with 40.2% marrow infiltration of CD33-positive blasts. Following the discontinuation of tacrolimus, gemtuzumab ozogamicin (GO) was administered. After GO administration, the patient exhibited mild VOD and severe pancytopenia with a sustained high fever for 6 weeks without evident infection. Bone marrow examination revealed severe hypoplastic marrow with 1.3% blasts 4 weeks after GO administration. Although transfusion-dependent pancytopenia persisted for 8 months after GO administration, bone marrow examination revealed the recovery of normal hematopoietic cells with 0.8% blasts. The patient has remained in CR with incomplete blood count recovery for 7 years following GO administration. Although the standard treatment for acute myeloid leukemia relapse after allo-SCT still remains to be established, GO may be a promising option.     

Late marrow allograft rejection following alpha-interferon therapy for hepatitis in a patient with paroxysmal nocturnal hemoglobinuria.

We describe a case of allograft rejection that occurred 23 months after successful bone marrow transplantation for severe aplastic anemia in a patient with paroxysmal nocturnal hemoglobinuria. The allograft rejection appears to have been induced by recombinant alpha-interferon (rINF-alpha) treatment for non-A, non-B hepatitis that developed 11 months after transplantation. During the 9 months of active hepatitis, the donor graft functioned normally; however, 3 months after rINF-alpha therapy was started, pancytopenia and a chimeric hematopoietic state developed. rINF-alpha was discontinued, cyclosporin A was reintroduced, and autologous bone marrow recovery followed. rINF-alpha treatment may be detrimental to some recipients of allogeneic bone marrow transplants.     

Spontaneous remission in myelodysplastic syndrome

 A 73-year-old man was admitted for investigation of pancytopenia. His physical examination was unremarkable and the bone marrow aspirate was compatible with myelodysplastic syndrome (RAEB). Cytogenetic analysis of the bone marrow revealed a trisomy 21. The patient received transfusions of packed red cells, and his condition remained stable for the next 7 months. He was then admitted with a chest infection and was treated with broad-spectrum antibiotics with satisfactory response. During his hospitalization there was a gradual increase in his complete blood count values, which persisted, resulting in a normal peripheral blood after 3 months. A bone marrow aspirate performed at that time revealed normal findings with no karyotypic abnormalities, indicating a spontaneous remission. The patient remained stable for the next 6 months; then he recurred with 20% blasts in his bone marrow and reappearance of trisomy 21in 42% of the metaphases examined. Several hematologic malignancies with spontaneous remissions have been described to date, but they have generally been short and recurrence is the rule, as in the case described. The role of endogenous cytokines in triggering these spontaneous remissions is under question, as the exact mechanism is unknown. Received: June 24, 1998 / Accepted: September 29, 1998     

Severe pancytopenic episodes in two cases with mosquito-allergy

Two young females were admitted one by one because of peculiar skin eruptions suggesting mosquito-allergy and severe pancytopenia with normo-hypercellular bone marrow. The outcome of the first case was fatal on account of severe pancytopenia, immune deficiency and marked jaundice 14 months after the initial pancytopenic episode. In the post-mortem examination, HMR (histiocytic medullary reticulosis) was highly suggestive since hepatosplenomegaly with increase of Kupffer cells and large histiocytes including some atypical cells were detected. The second patient was treated with splenectomy because the past treatment were unsatisfactory in the first case and another cases in literatures. After the operation, the patient sustained almost normal blood cell level for 11 months without any treatment. As for the histopathological findings of resected spleen and lymphnodes, some erythrophagocytic mature histiocytes were found, but no atypical cells was detected. The relationship with pancytopenia, mosquito-allergy and HMR was discussed on the two cases and literatures.     

Primary splenic lymphoma with hypoplastic bone marrow

A 44-year-old man was admitted because of persistent fever and pancytopenia. Because his bone marrow was hypoplastic and the karyotype of his marrow cells was normal, he was given a diagnosis of aplastic anemia, and treated with glucocorticoids and granulocyte colony-stimulating factor. Splenomegaly was later found and a splenectomy performed: pathological findings on resected tissue specimens disclosed non-Hodgkin's lymphoma, B-cell diffuse large. The patient was transferred to our hospital, where a bone marrow biopsy revealed lymphoma cells infiltrating his hypoplastic marrow. Complex chromosomal abnormalities were detected in marrow cells, but no lymphadenopathy was observed. A diagnosis of primary splenic lymphoma with infiltration of lymphoma cells into bone marrow was made, and chemotherapy was accordingly started. After multiple cycles of chemotherapy, the patient's marrow recovered to a normal state and his karyotype abnormalities disappeared. Six months later, pancytopenia reappeared and lymphoma cells were again detected in the patient's bone marrow. We reasoned that the hypoplastic state of his bone marrow was associated with the lymphoma, and that cytokines, including interferon-gamma, may have been responsible for this association.     

T-cell chronic lymphocytic leukemia with pure red cell aplasia: laboratory demonstration of persistent leukemia in spite of apparent complete clinical remission

A 40-year-old woman presented with splenomegaly, macrocytic anemia, and red cell aplasia. Although lymphocytosis was absent in the peripheral blood, large atypical lymphoid aggregates were present in the bone marrow. Splenectomy resulted in partial remission of red cell aplasia, but a gradual increase in the number of peripheral blood lymphocytes followed during the next 36 months. Flow cytometric analysis demonstrated that the majority of these peripheral blood lymphocytes had suppressor, natural killer T-cell phenotype. No other treatment was given until red cell hypoplasia worsened 42 months after initial presentation. Repeat bone marrow evaluation again demonstrated severe erythroid hypoplasia and large abnormal lymphocytic infiltrates. Cyclophosphamide given for 8 months resulted in complete resolution of the red cell aplasia and complete clinical remission of CLL. However, flow cytometric analysis revealed persistent increase in bone marrow T-cells, and bone marrow co-culture studies demonstrated residual ability of peripheral blood mononuclear cells to inhibit erythropoiesis in vitro, suggesting that residual, clinically undetectable leukemia persists in spite of complete clinical remission.     

Nontuberculous atypical mycobacterial infection with progressive pancytopenia in a patient with myelodysplastic syndrome

We describe a patient with myelodysplastic syndrome (MDS) who developed disseminated infection due to nontuberculous mycobacteria (NTM). A 64-year-old man was admitted because of persistent fever that had been unresponsive to antibiotics. Bone marrow aspiration specimens showed myelodysplasia (RA), but the origin of the fever was unclear. Cytopenia worsened to a level that required transfusion of red blood cells and platelets. Repeated bone marrow examination revealed hypoplasia with hemophagocytosis. Several weeks later, photochromogenic NTM was isolated from bone marrow specimens, sputum and broncho-alveolar lavage (BAL) fluid which had been obtained on admission. Antituberculosis treatment with clarithromycin markedly improved the patient's general condition and hematological abnormalities. Three months after resolution of the NTM infection, the peripheral blood monocyte count increased, the fever recurred, and the patient suddenly died of myocardial infarction. Disseminated infection with NTM has gained attention as a frequent complication of AIDS, and NTM can also be one of the pathogens causing disseminated infection in patients with MDS. In the present case, infection with mycobacteria that normally would have been digested by macrophages and would not have caused disseminated infection in a healthy individual, was probably related to the clinical features including high fever, severe pancytopenia and hemophagocytosis.     

Busulfan-induced sideroblastic anemia

Patients in the stable phase of chronic myelogenous leukemia (CML) are usually treated with busulfan. The bone marrow of patients with CML may be exquisitely sensitive to busulfan, and occasionally such patients develop pancytopenia, secondary to hypoplasia or aplasia of the bone marrow, which is presumed to be due to busulfan-induced marrow toxicity. We report a case of Philadelphia chromosome-positive CML who developed pancytopenia while being treated with busulfan; however, the patient's bone marrow was not hypoplastic or aplastic but rather hyperplastic with sideroblastic changes. Busulfan is not known to cause sideroblastic changes, so this was considered to herald a transformation into acute leukemia. Busulfan was stopped, and only supportive treatment was given. To our surprise approximately 22 weeks after busulfan was stopped, the sideroblastic changes had disappeared and the bone marrow again showed features of CML. This case suggests that busulfan may cause sideroblastic anemia.     

Late onset immune pancytopenia following bone marrow transplantation

A 17-year-old boy developed autoimmune pancytopenia in the absence of chronic graft-versus-host disease 170 d after allogeneic bone marrow transplantation (BMT) from his HLA identical brother. The anaemia and thrombocytopenia responded to conventional immunosuppressive treatment, but the neutropenia was refractory to this and to splenectomy and subsequent removal of splenic remnant. Following total lymphoid irradiation the neutrophil count rose to low normal levels but thrombocytopenia and anaemia secondary to marrow hypoplasia required transfusion support. Bone marrow function was finally normalized by an additional transfusion of donor marrow without prior immunosuppressive therapy. We conclude that late onset immune pancytopenia post BMT caused by antibodies of probable donor origin may be life threatening in the absence of chronic graft-versus-host disease.     

Peripheral blood stem cells collected in very early remission produce rapid and sustained autologous haemopoietic reconstitution in acute non-lymphoblastic leukaemia

Haemopoietic reconstitution was achieved in a patient with acute non-lymphoblastic leukaemia (ANLL) in relapse who was autografted with blood-derived stem cells collected during very early remission. The patient received a myeloid progenitor cell dose of 230 x 10(4) CFU-GM/kg body weight. Engraftment was evident in the bone marrow 7 days post-graft. Normal neutrophil and platelet counts were attained by day 14 and blood counts remained normal thereafter. An overshoot in peripheral blood haemopoietic progenitor levels occurred at the end of the second week, presumably the progeny of a family of early progenitor cells. The completeness of haemopoietic reconstitution is further illustrated by the satisfactory nucleated cell and myeloid progenitor cell yield when a bone marrow harvest was performed 4 1/2 months post-graft. Seven months post-graft, the patient remained in complete remission with normal blood counts and bone marrow cellularity, although haemopoietic progenitor levels were slightly reduced. The rapid recovery minimises aplasia-related risks and suggests that such autografting can be carried out safely in first remission. We propose that autografting using very early remission blood cells is a new therapeutic option for patients with acute ANLL.     

Myelodysplastic syndrome presenting as third malignancy after non-Hodgkin's lymphoma and osteosarcoma

 The patient was initially diagnosed as having non-Hodgkin's lymphoma and was cured following treatment with prednisolone, vincristine, daunorubicin, l-asparaginase, and cyclophosphamide. Seven years and two months later, he developed osteosarcoma in his right femur. He received chemotherapy consisting of methotrexate, carboplatin, etoposide, and ifosfamide and again obtained remission. After 2 years and 7 months, however, he was found to have pancytopenia with morphological abnormalities in the erythroid and myeloid series. Diagnosis of myelodysplastic syndrome (MDS) was made. Cytogenetic analysis of bone marrow cells revealed -5 and -7, which is typical for secondary MDS. This is a rare case of third malignancy presumably caused by alkylating agents. Received: 30 September 1996 / Accepted: 8 November 1996     

Prolonged Bone Marrow Failure With Monosomy 7 After Engraftment Failure Following Bone Marrow Transplantation

A patient with acute myelogenous leukemia developed prolonged bone marrow failure along with the monosomy 7 chromosome abnormality. The patient had undergone bone marrow transplantation with CD34+ selection following induction failure. However, she then suffered engraftment failure and long-term pancytopenia. Her white blood cell count gradually increased with supportive therapy including granulocyte colony-stimulating factor (G-CSF), and chromosomal analysis of bone marrow cells revealed an abnormal karyotype. Thirty months after the bone marrow transplantation we observed monosomy 7 together with the existing chromosomal abnormality in the patient's bone marrow cells. It has been reported that some patients with idiopathic and posthepatitis aplastic anemia develop clonal disorders such as myelodysplastic syndrome/acute myelogenous leukemia with monosomy 7. The findings in our case suggest that the appearance of monosomy 7 in patients with aplastic anemia may be caused by prolonged low-level hematopoiesis, with or without G-CSF stimulation.