Development of hairy cell leukemia in a patient with antiphospholipid syndrome

We present a young woman who was diagnosed as primary antiphospholipid syndrome (deep vein thrombosis and pulmonary embolism in 1999; moderate thrombocytopenia with high-positive anticardiolipin ELISA tests in 2002, and cerebral thrombosis in 2003), and then developed hairy cell leukemia (massive splenomegaly, neutropenia, hairy cells in blood smear and bone marrow trephine biopsy in 2004). A partial remission was achieved with interferon-alpha 2a therapy. After the initiation of 2-chloro-deoxyadenosine therapy, splenomegaly disappeared, the percentage of hairy cells on the bone marrow reduced below 1%, platelet count returned to normal levels. After complete remission was achieved for hairy cell leukemia proved by bone marrow trephine biopsy, antiphospholipid antibodies were found to be negative, and no further thromboembolic complications and thrombocytopenia were seen. In our literature search, we found only six cases that had both antiphospholipid antibodies and hairy cell leukemia. Our case is the first case of antiphospholipid syndrome before the development of hairy cell leukemia. Both hairy cell leukemia and antiphospholipid syndrome responded to lymphocytotoxic treatment with 2-chloro-deoxyadenosine.     

Immunomorphologic analysis of bone marrow biopsies after treatment with 2-chlorodeoxyadenosine for hairy cell leukemia

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA) induces complete remissions in 85% of patients. Complete remission has been defined as the absence of hairy cells in the bone marrow after routine morphologic examination. To determine if hairy cells could be detected in complete remission bone marrows using immunohistochemical techniques with antibodies L26 (CD20) and DBA.44, 154 bone marrow biopsies performed between 3 months and 25 months after therapy were studied. Of the biopsies, 50% exhibited staining with L26 and/or DBA.44 in five or more cells with morphologic features of hairy cells. Minimal residual disease was usually less than 1% of the total cellular population. DBA.44-positive cells were demonstrated in 91% of the biopsies, although in 48% of these the morphologic features of the positive cells were not sufficiently distinctive for hairy cells. The proportion of biopsies with residual hairy cells was similar over the 25 months of follow up, indicating a relatively stable amount of residual disease. Immunomorphologic analysis is a more sensitive method for detecting residual hairy cells than morphology alone. Although further follow up is necessary to determine the clinical significance of the L26/DBA.44-positive staining in cells with and without distinctive morphologic features of hairy cells, we conclude that many patients in a stable clinical remission may have residual hairy cells.     

Low-dose deoxycoformycin in the treatment of hairy cell leukemia

Ten patients with progressive hairy cell leukemia were treated with 2'deoxycoformycin (dCF) by intravenous bolus (4 mg/m2) given every other week. All ten patients are evaluable for response and nine of the ten patients have achieved a complete remission. In addition to clearing of hairy cells from the bone marrow, eight patients had resolution of their monocytopenia. Seven of the nine patients remain in unmaintained remission with a median duration of 6.2 months. Two patients have had relapse in the bone marrow alone and continue to have normal peripheral blood counts. They are being followed without treatment. Toxicity was minimal at this low dose with one patient having a mild reversible reduction in creatinine clearance. Four other patients had reversible neutropenia. There were no significant infections associated with treatment. Low-dose deoxycoformycin administered intravenously every other week represents an extremely effective treatment for hairy cell leukemia.     

A distinct subtype of idiopathic myelofibrosis with bone marrow features mimicking hairy cell leukemia: evidence of an autoimmune pathogenesis

A young female patient presented with severe anemia and myelofibrosis. The spleen was not enlarged on clinical examination and no leukoerythroblastosis or tear-drop poikilocytosis was found. A bone marrow biopsy disclosed severe myelofibrosis and many megakaryocytes, which appeared morphologically normal. A striking feature was a heavy spongy infiltration by large lymphocytic cells, which were tartrate-resistant acid phosphatase negative and without hairy projections. This bone marrow appearance highly resembled the clear cell appearance of the hairy cell infiltrate in hairy cell leukemia. A diagnosis of acute autoimmune myelofibrosis was made. During high-dose glucocorticoid therapy the bone marrow fibrosis completely resolved and there was an improvement of peripheral blood values. The disorder is supposed to feature a distinct clinicopathological entity within the syndrome of idiopathic myelofibrosis. The disease should be considered in the differential diagnosis of patients with myelofibrosing disorders, including acute myelofibrosis and hairy cell leukemia.     

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.     

Effect of 2-chlorodeoxyadenosine therapy on bone marrow fibrosis in hairy cell leukemia

The study shows the influence of 2-chlorodeoxyadenosine therapy on bone marrow fibrosis in patients with hairy cell leukemia. Eighteen patients were studied; bone marrow fibrosis was graded 0-4 according to the quantity and pattern of distribution of reticulin. The grade of bone marrow fibrosis was established before the therapy and then in 12- and 24-month intervals. Patients showed complete remission after the therapy and remarkable reduction of bone marrow fibrosis.     

Intensive chemotherapy of hairy cell leukemia in patients with aggressive disease

Seven patients with hairy cell leukemia were treated by intensive chemotherapy because they were considered to have a progressive disease and a poor short-term prognosis. The mean age was 47 years (range, 36 to 58). Six of seven patients had prior splenectomies with minor or transient hematologic responses. One patient had no spleen enlargement. The seven patients had never received any cytotoxic drugs and had prolonged granulocytopenia (less than 300/microL) with recurrent, severe infectious episodes. Chemotherapy included Rubidazone (zorubicine hydrochloride) 450 mg/m2 on day 1, arabinosyl cytosine 200 mg/m2/d from day 1 to day 5, and cyclophosphamide, 2,000 mg/m2 on day 5. Responses were assessed through examination of repeat bone marrow biopsy specimens and blood counts. A complete response was defined as normal blood counts associated with the disappearance of hairy cell infiltration and fibrosis on the bone marrow biopsy specimens. A partial response was defined as normal blood counts with persistence of leukemic cells in the bone marrow. Three patients achieved a complete response, and one patient had a partial response. Three patients died of infectious complications during induction chemotherapy. For the responding patients, the mean duration of aplasia was 37 +/- 5 days. Follow-up for the responding patients has been 44+, 24, 32+, and 23+ months. One patient with a complete response died while on maintenance therapy. We conclude that complete and prolonged histologic remission of hairy cell leukemia can be obtained with intensive chemotherapy. The toxicity of chemotherapy is such, however, that progressive disease after splenectomy needs to be more clearly defined.     

Unexpectedly high incidence of hypoplastic/aplastic foci in bone marrow biopsies of hairy cell leukemia patients in remission following 2-chlorodeoxyadenosine therapy

Treatment with the purine analog 2-chlorodeoxyadenosine (2-CDA) achieves a complete response in close to 90% of patients with hairy cell leukemia, with approximately 75% remaining in prolonged remission. Recently, we unexpectedly noted foci of hypoplasia and aplasia in routine follow-up bone marrow biopsies of several hairy cell leukemia patients in remission with normal blood counts. Because of this finding we examined all available biopsies to assess the incidence of this phenomenon. A total of 94 biopsies in 31 patients were reviewed. Of these, 23 were prior to 2-CDA therapy and 71 (in 30 patients) were obtained 2-76 (mean 22) months following one or more courses of treatment. Nine patients had also received prior interferon and 7 (of whom 3 had also received interferon) had undergone splenectomy. Hypocellular foci were found in only 3 (13%) of the pre-therapy biopsies. Forty-seven of the 71 post-therapy biopsies (in 23 patients) (66%) had a total of 176 hypocellular foci. Of these 47 biopsies, 39 were without evidence of disease. A simultaneous complete blood count was normal in 34 of the 47 hypoplastic biopsies (72%). This suggests that these hypoplastic areas may not be representative of the entire bone marrow and that normal hematopoiesis may take place at other sites. However, since the longest follow-up is less than 7 yr, the potential long-term significance of these findings, such as progressive bone marrow aplasia or dysplasia, may still be unrecognised.     

Response to splenectomy in 65 patients with hairy cell leukemia: an evaluation of spleen weight and bone marrow involvement

Sixty-five patients with hairy cell leukemia underwent splenectomy; 27 had a complete remission as defined by a return in WBC, RBC, and platelet counts to a defined level, and 38 had a partial remission with a return of only one or two of these parameters to the defined level. The 5-yr actuarial survival for all patients is 68%; for CR patients it is 76%, and for PR patients 62%. The response to splenectomy did not correlate with the spleen weight. Seventeen patients had a postsplenectomy platelet count of less than 200 x 10(9)/liter, and 34 patients had a postsplenectomy platelet count of 200 x 10(9)/liter or greater. A presplenectomy bone core biopsy hairy cell index (HCI) was calculated by multiplying the percent marrow cellularity by the percent of hairy cells in the marrow for 51 patients. The difference in the mean HCI between the two platelet response groups is statistically significant (p less than 0.05). Of the 15 patients with a presplenectomy HCI of 0.7 or greater, 9 (60%) did not have a satisfactory platelet response to splenectomy, whereas of 36 patients with an HCI of 0.7 or less, only 8(22%) did not have a satisfactory platelet response to splenectomy (p less than 0.01). The HCI appears to indicate the significance of underproduction of platelets as a result of marrow replacement by hairy cells.     

Hairy cell leukemia and other "hairy-cell" lymphoproliferative disorders (LPD-HC): the significance of morphologic, histologic and immunologic studies

In this report the clinical, morphologic, histologic and immunologic findings of 41 patients with hairy lymphoid cells in peripheral blood and/or bone marrow are analyzed. In 27 patients the diagnosis of hairy cell leukemia was established. 14 patients had other variants of lymphoproliferative disorders: malignant lymphoma with hairy cells--7, chronic lymphocytic leukemia with hairy cells--5, and T cell lymphoproliferative disorder with hairy cells--2 patients, respectively. Several variants of malignant lymphoma with hairy cells were defined: lymphocytic, centrocytic and lymphoplasmacytic. The importance of combined use of bone marrow biopsy and immunophenotyping for the correct diagnosis of hairy cell leukemia and other "hairy-cell" lymphoproliferative disorders is stressed. The obtained data suggest relationship between characteristic clinical manifestation (isolated splenomegaly), presence of hairy cells and CD11c-antigen expression.     

Hairy Cell Leukemia: Clinicopathological and Immunophenotypic Study

Hairy cell leukemia (HCL) is a rare neoplasm of mature small B lymphoid cells with characteristic circumferential ‘hairy projections’ involving the peripheral blood, bone marrow and splenic red pulp. With the advent of immunophenotyping and newer treatment modalities, prolonged remission can be achieved after a definitive diagnosis. Due to the rarity of this condition and presence of only a few case series from India, this work was undertaken. The aim was to study the clinico-pathologic and immunophenotypic features of all cases diagnosed as hairy cell leukemia. The cases were retrieved from Hematopathology records, between 1991 and 2012. The complete clinical details, investigations, treatment and follow-up were obtained from Medical Oncology records. The peripheral blood picture, bone marrow cytology and trephine sections along with special stains were reviewed. There were 12 cases of HCL during the study period with a M:F ratio of 11:1. Of these, ten were diagnosed as classical HCL and two as variant HCL. The most common clinical manifestations were fever, easy fatigability and weakness. Splenomegaly was present in 81.8 % cases. Though all the patients showed some form of cytopenia, there were three (25 %) patients with leucocytosis. The smears from all patients showed atypical lymphoid cells with circumferential hairy projections. TRAP was positive in 9 patients (81.8 %). Immunophenotyping was done in six cases, four were confirmed as HCL and two were diagnosed as HCL-v. The patients treated with Cladribine generally had a good response. The characteristic morphology of the hairy cells; along with correlation with the clinical features, TRAP positivity and immunophenotyping by flow cytometry is essential for diagnosis. Treatment response with Cladribine is good and has prolonged remission rates.     

Effect of alpha-interferon therapy on bone marrow fibrosis in hairy cell leukemia

Iliac crest trephine biopsy specimens from 16 patients treated with recombinant alpha 2-interferon (alpha-IFN) for hairy cell leukemia (HCL) were examined for reticulin and collagen content. These data were compared with the hairy cell index (HCl), the proportion of hairy cells to the overall cellularity of the bone marrow. Specimens were studied immediately before alpha-IFN therapy, at 6-month intervals during, and in six patients 6 months after cessation of therapy. All patients presented with increased bone marrow fibrosis ranging from focally increased reticulin to a diffuse increase in both reticulin and collagen content. This fibrosis was observed to decrease during alpha- IFN therapy inasmuch as the hairy cell population was diminished in the bone marrow in 13 patients. Regression analysis of HCl v bone marrow fibrosis showed a positive correlation (r = .73, P less than .02). Six patients demonstrated a reduction in bone marrow reticulin and collagen to normal levels during alpha-IFN therapy. Two of six patients demonstrated increased bone marrow fibrosis and HCl 6 months after cessation of alpha-IFN therapy. Three of 16 patients exhibited no decrease in bone marrow reticulin content during therapy despite a decreased bone marrow hairy cell population.     

Hairy cell leukemia presenting as a lupus-like illness

We describe a young Hispanic man who presented with features suggestive of a diagnosis of systemic lupus erythematosus. Eventually, a bone marrow biopsy was performed, and it revealed the presence of hairy cell leukemia. This case of a lupus-like syndrome should be added to the list of reported rheumatic syndromes that are associated with hairy cell leukemia.     

The degree of bone marrow infiltration in patients with hairy cell leukemia treated with splenectomy compatible with long-term hematological remission

To determine the degree of bone marrow infiltration with hairy cells which is compatible with long-term hematological remission in patients treated with splenectomy, we have investigated 7 patients surviving in hematological remission 61 to 255 months (median 184 months) after splenectomy. As hematological remission has been considered absence of hairy cells (HCs) in the peripheral blood, normalization of peripheral blood cell counts (hemoglobin 120 g/l, white cell count 4.0 x 10(9)/l, absolute granulocyte count 1.5 x 10(9)/l, platelet count 100 x 10(9)/l) and absence of lymfadenopathy and any other activity of the disease. For detection of HCs a very sensitive method of immunostaining with monoclonal antibody DBA.44 in our own modification has been used. Low values of sIL-2R which is considered to be a non invasive marker of tumor burden and activity in HCL were in agreement with the opinion that the bone marrow was the only locality of tumor involvement in splenectomized patients. Infiltration up to 20% with HCs (range 4% to 20%, median 10%) was found to be compatible with long-term hematological remission and long-term overall survival. Patient (No 1) with 30% infiltration of bone marrow with HCs, still normal peripheral blood cell counts, but a very high level of sIL-2R represents extraordinary finding which has been discussed in details.     

Successful treatment with cladribine for hypoplastic hairy cell leukemia after long-term neutropenia

A 34-year-old woman was admitted to the hospital because of swelling of her right knee, and the result of the laboratory tests indicated anemia and leukocytopenia. A bone marrow examination showed dissemination of small to medium-sized abnormal lymphocytes with abundant and pale blue cytoplasm and a circumferential "hairy" projection in the hypocellular bone marrow. These cells were positive for tartrate-resistant acid phosphatase (TRAP) and for CD 19, CD 20, CD 25, CD 103 and SmIg kappa. The patient was diagnosed as having hypoplastic hairy cell leukemia and received cladribine (2-CdA) for seven days via continuous intravenous injection. The minimum white blood cell count was 300/microl at seven days after starting the therapy (day 7) and the neutrophil count recovered to more than 1500/microl on day 118. The patient achieved complete remission on day 140 without any episodes of severe infection and has remained in complete remission for more than one year. The treatment of hypocellular HCL with 2-CdA might be useful.     

Diffuse osteosclerosis in hairy cell leukemia

We describe two patients with a new clinical pathologic syndrome of diffuse osteosclerosis in association with hairy cell leukemia. In both patients bone marrow biopsies could not be obtained due to extremely hard bones and inability to insert the biopsy needle; neither patient had a history of bony pain or fracture. The osteosclerotic process in one patient stabilized after successful treatment of her hairy cell leukemia with interferon alpha and deoxycoformycin suggesting that the osteosclerosis observed was related to the underlying malignant disease. Possible etiologic mechanisms are discussed.     

Hairy cell leukemia: a review.

Hairy cell leukemia is a chronic but steadily progressive malignancy usually of older males. Clinically, patients present with splenomegaly and/or cytopenia. The diagnosis is made by demonstration of the hairy cell in Wright's-stained peripheral blood and in bone marrow and by the characteristic histologic findings in the bone marrow biopsy and spleen sections. Infection is the most significant problem complicating the course of patients with hairy cell leukemia and the role of granulocytopenia and/or monocytopenia is undoubtedly substantial. Splenectomy has produced an objective response in improving hematologic parameters in a large number of patients and may prolong survival in those patients who respond. The precise nature of hairy cells remains unknown. The cells exhibit features of both monocytes and B-lymphocytes in morphologic, cytochemical, immunologic and functional studies. A more complete understanding of the monocytic and lymphocytic stem cells and their maturation may provide insight into the origin of the hairy cell.     

DNA-flow cytometry of blood and bone marrow in chronic myelogenous leukemia

Flow cytometric analysis of bone marrow aspirates and blood samples in 42 patients with chronic myelogenous leukemia (CML) at various disease stages was performed to determine the size of the S-phase compartment of bone marrow and blood. 25 healthy controls were studied for comparative information with both DNA-flow cytometry (DNA-FCM) and 3H-thymidine autoradiography. A correction procedure was applied for peripheral nucleated cell admixture in bone marrow aspirates. The fraction of peripheral nucleated cells in bone marrow aspirates (Fpb) in individual patients was considerable, especially in those with a very high white blood cell count (greater than 100 x 10(9)/l). The size of the S-phase compartments of bone marrow (% Sbm) in patients with CML at diagnosis and in patients at apparent hematological remission was of the same order of magnitude as in normal bone marrow. However, in 3 out of 4 patients at malignant metamorphosis in which the % Sbm could be reliably determined, this percentage was significantly higher than normal (p = 0.013). In 4 out of 11 patients at malignant metamorphosis aneuploidy was noticed. From these findings it is concluded that bone marrow cell proliferation in CML patients at diagnosis and during apparent remission is not essentially different from normal. However, at malignant metamorphosis changes occur in ploidy level and proliferative activity, which can be detected by DNA-FCM already in an early phase.     

CD5+ immunophenotype in the bone marrow but not in the peripheral blood in a patient with hairy cell leukemia

We report the case of a patient with rare CD5+ hairy cell leukemia, which was unusual, as there was also a discrepancy between the bone marrow and peripheral blood immunophenotypes. We propose that some degree of maturation within the malignant clone and the predominance of more mature CD5- hairy cells in the peripheral blood can explain this observation. The patient was treated with a conventional course of cladribine (2'-chlorodeoxyadenosine) and achieved complete remission. We conclude that the unusual CD5+ immunophenotype of this patient did not affect prognosis or change the response to standard therapy.     

Management recommendations for chronic myelomonocytic leukemia: consensus statements from the SIE,SIES, GITMO groups

With the aim of reviewing critical concepts and producing recommendations for the management of chronic myelomonocytic leukemia, key questions were selected according to the criterion of clinical relevance. Recommendations were produced using a Delphi process and four consensus conferences involving a panel of experts appointed by the Italian Society of Hematology and affiliated societies. This report presents the final statements and recommendations, covering patient evaluation at diagnosis, diagnostic criteria, risk classification, first-line therapy, monitoring, second-line therapy and allogeneic stem cell transplantation. For the first-line therapy, the panel recommended that patients with myelodysplastic-type chronic myelomonocytic leukemia and less than 10% blasts in bone marrow should be managed with supportive therapy aimed at correcting cytopenias. In patients with myelodysplastic-type chronic myelomonocytic leukemia with a high number of blasts in bone marrow (≥10%), supportive therapy should be integrated with the use of 5-azacytidine. Patients with myeloproliferative-type chronic myelomonocytic leukemia with a low number of blasts (<10%) should be treated with cytoreductive therapy. Hydroxyurea is the drug of choice to control cell proliferation and to reduce organomegaly. Patients with myeloproliferative-type chronic myelomonocytic leukemia, and a high number of blasts should receive polychemotherapy. Both in myelodysplastic-type and myeloproliferative-type chronic myelomonocytic leukemia, allogeneic stem cell transplantation should be offered within clinical trials in selected patients.