A. Van Hoof

Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias.

Detection of the FIP1L1-PDGFRA fusion gene or the corresponding cryptic 4q12 deletion supports the diagnosis of chronic eosinophilic leukemia (CEL) in patients with chronic hypereosinophilia. We retrospectively characterized 17 patients fulfilling WHO criteria for idiopathic hypereosinophilic syndrome (IHES) or CEL, using nested RT-PCR and interphase fluorescence in situ hybridization (FISH). Eight had FIP1L1-PDGFRA (+) CEL, three had FIP1L1-PDGFRA (−) CEL and six had IHES. FIP1L1-PDGFRA (+) CEL responded poorly to steroids, hydroxyurea or interferon-α, and had a high probability of eosinophilic endomyocarditis (n=4) and disease-related death (n=4). In FIP1L1-PDGFRA (+) CEL, palpable splenomegaly was present in 5/8 cases, serum vitamin B12 was always markedly increased, and marrow biopsies revealed a distinctively myeloproliferative aspect. Imatinib induced rapid complete hematological responses in 4/4 treated FIP1L1-PDGFRA (+) cases, including one female, and complete molecular remission in 2/3 evaluable cases. In the female patient, 1 log reduction of FIP1L1-PDGFRA copy number was reached as by real-time quantitative PCR (RQ-PCR). Thus, correlating IHES/CEL genotype with phenotype, FIP1L1-PDGFRA (+) CEL emerges as a homogeneous clinicobiological entity, where imatinib can induce molecular remission. While RT-PCR and interphase FISH are equally valid diagnostic tools, the role of marrow biopsy in diagnosis and of RQ-PCR in disease and therapy monitoring needs further evaluation.

Trisomy 12 is uncommon in typical chronic lymphocytic leukaemias

The incidence of trisomy 12 was studied by conventional chromosome analysis in 111 patients referred as B‐cell chronic lymphocytic leukaemia (B‐CLL). Fluorescent in situ hybridization (FISH) was also applied in 34 of those patients with either a normal karyotype or no analysable mitoses. By karyotyping, trisomy 12 was present in 11.7% (13/111), whereas additional FISH increased the incidence to 14.4% (16/111). When subdividing our cases in either typical CLL (n= 90), fulfilling the FAB classification criteria, or atypical CLL (n= 21), with one or more variations from those criteria, the incidence of +12 by metaphase analysis was 3% and 48%, respectively. Additional FISH increased the incidence to 4% and 57%. The most common aberration in atypical CLL was FMC7 positivity (n= 11), followed by CD5 negativity (n= 8), strong surface immunoglobulin staining (n= 7) and atypical morphology (n = 6). Trisomy 12 could only be demonstrated in a small proportion of neoplastic cells in all positive cases. By FISH and/or karyotyping, all available samples at diagnosis of the disease were positive.

Activity of Oral Fludarabine Phosphate in Previously Treated Chronic Lymphocytic Leukemia

PURPOSE A prospective, multicenter, open-label phase II clinical trial was conducted to assess the efficacy and safety of oral fludarabine phosphate. Reference to an historical group of patients treated with the intravenous (IV) formulation allowed the investigators to compare the two formulations. PATIENTS AND METHODS Efficacy was assessed using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) and National Cancer Institute (NCI) criteria for complete remission (CR), partial remission (PR), stable disease, or disease progression. Safety monitoring included World Health Organization (WHO) toxicity grading for all adverse events. RESULTS Seventy-eight (96.3%) of 81 recruited patients with previously treated B-cell chronic lymphocytic leukemia (CLL) received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m(2)/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. According to IWCLL criteria, the overall remission rate was 46.2% (CR, 20.5%; PR, 25.6%). The comparative figures using NCI criteria were 51.3% (CR, 17.9%; PR, 33.3%). Overall, 30 incidents of severe adverse events were reported for 22 patients. WHO grade 3 or grade 4 hematologic toxicities included granulocytopenia (53.8%), leukocytopenia (28.2%), thrombocytopenia (25.6%), and anemia (24.4%). Gastrointestinal adverse events were more common with the oral formulation than previously reported with IV fludarabine phosphate. However, these events were generally mild to moderate. CONCLUSION This study demonstrates that oral fludarabine phosphate has similar clinical efficacy to the IV formulation and a safety profile that is both predictable and essentially similar to that of the IV formulation.

Rituximab in auto-immune haemolytic anaemia and immune thrombocytopenic purpura: A Belgian retrospective multicentric study

Objectives.  For better characterizing the effect of anti‐CD20 therapy, we analysed the use of rituximab in Belgian patients experiencing auto‐immune haemolytic anaemia (AIHA) and immune thrombocytopenic purpura (ITP).

Efficacy and Safety of Oral Fludarabine Phosphate in Previously Untreated Patients With Chronic Lymphocytic Leukemia

PURPOSE A prospective, multicenter, open-label, phase II clinical trial to assess oral fludarabine phosphate treatment in terms of safety, efficacy, and quality of life. Reference to a historical group of patients treated with the intravenous (IV) formulation allowed the two formulations to be compared. PATIENTS AND METHODS Patients with previously untreated B-cell chronic lymphocytic leukemia received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m(2)/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. Efficacy was assessed using International Workshop on Chronic Lymphocytic Leukemia and National Cancer Institute criteria for response. Safety monitoring included WHO toxicity grading for adverse events. Quality of life was also assessed. RESULTS Eighty-one patients received treatment. According to International Workshop on Chronic Lymphocytic Leukemia criteria, the overall response rate was 71.6% (complete remission, 37.0%; partial remission, 34.6%). The response rate using National Cancer Institute criteria was 80.2% (complete remission, 12.3%; partial remission, 67.9%). Median time to progression was 841 days (range, 28 to 1,146 days). The most frequently reported grade 3/4 toxicity was myelosuppression. WHO grade 3/4 hematological toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). Gastrointestinal toxicity was more common with the oral formulation than with IV fludarabine phosphate, but was generally mild to moderate and did not require treatment. Statistically significant improvements in mean emotional and insomnia quality-of-life scores were seen after treatment. CONCLUSION This study demonstrates that oral fludarabine phosphate is clinically effective and generally well tolerated by patients with previously untreated B-cell chronic lymphocytic leukemia. Oral fludarabine phosphate has a similar clinical efficacy and safety profile to the IV formulation. Oral fludarabine phosphate does not adversely affect quality of life and may improve emotional and insomnia scores.

Sudan Black B positivity in acute lymphoblastic leukaemia

An adult patient with Sudan Black B (SB B) positive leukaemic lymphoblasts is described. Peroxidase and naphtol AS D chloroacetate esterase stains were negative. The diagnosis of acute lymphoblastic leukaemia (ALL) was based on morphology (FAB classification: L1), on immunological marker studies (cALL+, Tdt+, Ia+) and on electron microscopy, revealing blasts, compatible with lymphoblasts. Additional proof of the diagnosis of ALL were the diffuse lymphadenopathy and the rapid response to ALL chemotherapy.

Translocation t(14;18) is not associated with inferior outcome in chronic lymphocytic leukemia

Translocation t(14;18) is not associated with inferior outcome in chronic lymphocytic leukemia

Translocation t(1;6)(p35.3;p25.2): a new recurrent aberration in ‘unmutated’ B-CLL

Although reciprocal chromosomal translocations are not typical for B-cell chronic lymphocytic leukemia (B-CLL), we identified the novel t(1;6)(p35.3;p25.2) in eight patients with this disorder. Interestingly, all cases showed lack of somatically mutated IgVH. Clinical, morphological, immunologic, and genetic features of these patients are described. Briefly, the age ranged from 33 to 81 years (median: 62.5 years) and the sex ratio was 6M:2F. Most of the patients (6/8) presented with advanced clinical stage. Therapy was required in seven cases. After a median follow-up of 28 months, five patients are alive and three died from disease evolution. Three cases developed transformation into diffuse large B-cell lymphoma. Translocation t(1;6) was found as the primary karyotypic abnormality in three patients. Additional chromosomal aberrations included changes frequently found in unmutated B-CLL, that is, del(11)(q), trisomy 12 and 17p aberrations. Fluorescence in situ hybridization analysis performed in seven cases allowed us to map the t(1;6) breakpoints to the 1p35.3 and 6p25.2 chromosomal bands, respectively. The latter breakpoint was located in the genomic region coding for MUM1/IRF4, one of the key regulators of lymphocyte development and proliferation, suggesting involvement of this gene in the t(1;6). Molecular characterization of the t(1;6)(p35.3;p25.2), exclusively found in unmutated subtype of B-CLL, is in progress.

Bone marrow transplantation performed as first-time treatment in two cases of secondary acute myeloid leukemia

Two young patients with secondary acute myeloid leukemia were treated with allogeneic bone marrow transplantation as first-line treatment for their disease. High dose cytosine arabinoside was added to the conventional preparative regiment of cyclophosphamide and total body irradiation. No major problems were encountered to the immediate post-transplantation period. Complete remission of the acute myeloid leukemia was noted in both patients, with no evidence of recurrent disease at 15+ and 13 months. One patient developed severe pancytopenia 10 months after grafting with the presence of antibodies against platelets and granulocytes from the bone marrow donor. She died 3 months later from a generalised Aspergillus septicemia, probably precipitated by therapy with high doses of methylprednisolone. The other patient is alive in excellent clinical condition and in hematologic remission. Bone marrow transplantation must be taken into consideration as first-line therapy in any young patient who is suffering from a refractory type of leukemia and who has a suitable donor.

Relapsing Fever Imported Into Belgium: A Case Report

SummaryA case of Borrelia infection (relapsing fever) imported into Belgium is described in a 24-yearold nurse who returned from Somalia. She had repeatedly been bitten by lice and fleas and was admitted because of high fever.Microscopic examination of the peripheral blood revealed numerous, actively motile, spirochaetes. The patient was treated with penicillin and doxycycline and recovered completely. The literature on relapsing fever is briefly reviewed.