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Few reports are available on the treatment of patients with Waldenström macroglobulinemia (WM) and primary or secondary resistance to alkylating-agent-based regimens. From December 1993 through December 1997, 92 patients with WM resistant to first-line therapy (42) or with first relapse (50) after alkylating-agent therapy were randomly assigned to receive fludarabine (25 mg/m(2) of body-surface area on days 1-5) or cyclophosphamide, doxorubicin (Adriamycin), and prednisone (CAP; 750 mg/m(2) cyclophosphamide and 25 mg/m(2) doxorubicin on day 1 and 40 mg/m(2) prednisone on days 1-5). The first end point evaluated was the response rate after 6 treatment courses. Forty-five patients received CAP and 45 received fludarabine. Two patients died before the first course of chemotherapy. No statistical differences were observed between the 2 treatment arms with respect to hematologic toxicity or infections. Mucositis and alopecia occurred significantly more often in patients treated with CAP. Partial responses were obtained in 14 patients (30%) treated with fludarabine and 5 patients (11%) treated with CAP (P =.019). Responses were more durable in patients treated with fludarabine (19 months versus 3 months), and the event-free survival rate was significantly higher in this group (P <.01). Forty-four patients died, 22 in the fludarabine group and 22 in the CAP group. There was no statistical difference in the median overall survival time in the 2 study arms. Fludarabine was thus more active than CAP in salvage therapy of WM and should be tested as first-line therapy in a randomized comparison with alkylating agents.

Chronic lymphocytic leukaemia is the most frequent haematological cancer in adult patients, and its incidence raises with aging. Diagnosis needs several clinical and biological data, but hemogram together with the morphological and immunophenotypic analysis of the lymphoid cells take the major place. If the diagnosis is performed easily in about 65% of the patients, various clinicobiological entities were reported in the past few years that must be identified, at least because some are of adverse prognosis. Moreover, the other chronic lymphoid neoplasms, corresponding to the various low and intermediate grade non-Hodgkin's lymphomas (mainly of follicular type, marginal zone, mantle cell zone), may disseminate within the blood and the bone marrow. Those circulating lymphoma cells must be identified at diagnosis in order to perform the accurate diagnosis and to avoid an erroneous diagnosis of atypical chronic lymphocytic leukaemia. Up to 90% of lymphoid malignancies are B cell disorders, contrasting with only a few cases of T cell origin: some of those latter cases cannot be neglected however, as they may be observed in Western countries. Most recent classifications (REAL and WHO) defined all hematological malignancies: each entity referred to clinical, morphological, immunological, cytogenetic, and molecular findings. The basis of these classifications is pathophysiological, trying in each disorder to define a normal counterpart to the pathological clone. Reviewing main steps of the immune response in the normal patient, corresponding to those involving B cells, it is possible indeed to localize and demonstrate a function for many of the cells that expand in lymphoid malignancies.

This prospective phase II study was undertaken to evaluate the efficacy and toxicity of early intensive therapy followed by purged autologous bone marrow transplantation (ABMT) in patients with follicular lymphoma with high tumor burden. All patients received the VCAP regimen (vindesine, cyclophosphamide, doxorubicin and prednisone) as conventional chemotherapy and DHAP as second-line therapy. Twenty-nine consecutive patients were included in the study. Twenty-seven patients were grafted, seven in first complete remission (CR) and 20 in first partial remission (PR). Preparative therapy consisted of cyclophosphamide and total body irradiation (TBI) in all the patients. With a median follow-up of 6 years, the actuarial overall survival is 64% and the actuarial event-free survival is 55%. Two treatment-related early deaths were observed. Eleven patients were informative for serial PCR analysis of minimal residual disease after ABMT: two relapsed, four remained disease-free with PCR positivity and five were disease-free with PCR negativity. These encouraging results lay the basis of future prospective randomized trials comparing autologous stem cell transplantation as front-line treatment with conventional chemotherapy for patients with bad prognostic factors.

All trans-retinoic acid (ATRA) syndrome is a life-threatening complication of uncertain pathogenesis that can occur during the treatment of acute promyelocytic leukemia (APL) by ATRA. Since its initial description, however, no large series of ATRA syndrome has been reported in detail. We analyzed cases of ATRA syndrome observed in an ongoing European trial of treatment of newly diagnosed APL. In this trial, patients 65 years of age or less with an initial white blood cell count (WBC) less than 5,000/microL were initially randomized between ATRA followed by chemotherapy (CT) (ATRA-->CT group) or ATRA with CT started on day 3; patients with WBC greater than 5,000/microL received ATRA and CT from day 1; patients aged 66 to 75 received ATRA-->CT. In patients with initial WBC less than 5, 000/microL and allocated to ATRA-->CT, CT was rapidly added if WBC was greater than 6,000, 10,000, 15,000/microL by days 5, 10, and 15 of ATRA treatment. A total of 64 (15%) of the 413 patients included in this trial experienced ATRA syndrome during induction treatment. Clinical signs developed after a median of 7 days (range, 0 to 35 days). In two of them, they were in fact present before the onset of ATRA. In 11 patients, they occurred upon recovery from the phase of aplasia due to the addition of CT. Respiratory distress (89% of the patients), fever (81%), pulmonary infiltrates (81%), weight gain (50%), pleural effusion (47%), renal failure (39%), pericardial effusion (19%), cardiac failure (17%), and hypotension (12%) were the main clinical signs, and 63 of the 64 patients had at least three of them. Thirteen patients required mechanical ventilation and two dialysis. A total of 60 patients received CT in addition to ATRA as per protocol or based on increasing WBC; 58 also received high dose dexamethasone (DXM); ATRA was stopped when clinical signs developed in 30 patients. A total of 55 patients (86%) who experienced ATRA syndrome achieved complete remission (CR), as compared with 94% of patients who had no ATRA syndrome (P = .07) and nine (14%) died of ATRA syndrome (5 cases), sepsis (2 cases), leukemic resistance (1 patient), and central nervous system (CNS) bleeding (1 patient). None of the patients who achieved CR and received ATRA for maintenance had ATRA syndrome recurrence. No significant predictive factors of ATRA syndrome, including pretreatment WBC, could be found. Kaplan Meier estimates of relapse, event-free survival (EFS), and survival at 2 years were 32% +/- 10%, 63% +/- 8%, and 68% +/- 7% in patients who had ATRA syndrome as compared with 15% +/- 3%, 77% +/- 2%, and 80% +/- 2% in patients who had no ATRA syndrome (P = .05, P = .003, and P = .03), respectively. In a stepwise Cox model that also included pretreatment prognostic variables, ATRA syndrome remained predictive for EFS and survival. In conclusion, in this multicenter trial where CT was rapidly added to ATRA in case of high or increasing WBC counts and DXM generally also used at the earliest clinical sign, the incidence of ATRA syndrome was 15%, but ATRA syndrome was responsible for death in only 1.2% of the total number of patients treated. However, occurrence of ATRA syndrome was associated with lower EFS and survival., (Copyright 1998 by The American Society of Hematology.)

We conducted a randomized multicenter study to compare the efficacy and safety of two antibiotic regimens (cefepime [2 g b.i.d.] plus amikacin or ceftazidime [2 g t.i.d.] plus amikacin) as first-line therapy for fever in patients with hematologic malignancies and neutropenia. A total of 353 patients were randomized according to a 2:1 (cefepime:ceftazidime) ratio. Two hundred-twelve patients in the cefepime group and 107 in the ceftazidime group (90% of all patients) were evaluable for efficacy. The polymorphonuclear neutrophil count was < 100/mm3 on enrollment for 70% of the patients. The mean duration of neutropenia was 26 days. The efficacy in both study arms was comparable, although a trend in favor of cefepime was seen in terms of therapeutic success (response rate, 27% vs. 21% for the ceftazidime group). The overall response rate after glycopeptides were added to the regimens was 60% for the cefepime group and 51% for the ceftazidime group; the bacterial eradication rates were 81% vs. 76%, respectively, and the rates of new bacterial infections were 14% vs. 18%, respectively. We conclude that the combination cefepime/amikacin is at least as effective as the reference regimen of ceftazidime/amikacin in this setting.

An immunohistochemical study by avidin-biotin-peroxidase was performed on paraffin-embedded and decalcified bone marrow biopsies in 31 acute leukemias (19 myeloid and 12 lymphoblastic). The Ulex Europaeus lectin and 14 antibodies (anti-CD45, -CD34, -myeloperoxidase, -lysozyme, -CD15, -CD68, -carcinoembryonic antigen, -factor VIII-related antigen, BNH9, anti-CD45RO, -CD3, -CD20, DBB42 and DBA44) were tested. All acute myeloid leukemias from M0 to M5 type were stained by either the anti-myeloperoxidase or anti-lysozyme antibodies. CD68, CD15 and the carcinoembryonic antigen were respectively expressed in 80%, 40% and 20% of myeloid leukemias from M1 to M5 type. The Ulex Europaeus lectin and the anti-factor VIII-related antigen antibody stained only the M7 leukemia and the anti-CD3 antibody stained only the T acute lymphoblastic leukemia. DBB42 was expressed by 63% of B-lineage lymphoblastic leukemias and CD20 by 36%. No leukemia was stained by DBA44. Immunohistochemistry on bone marrow biopsy can assess the lineage of most acute leukemias with the use of a panel of antibodies such as the anti-myeloperoxidase, -lysozyme, -CD68, -CD20, DBB42, -CD3, BNH9, anti-factor VIII-related antigen antibodies and the Ulex Europaeus lectin.

Erythromelalgia is a vascular disorder of the extremities and is sometimes related to myeloproliferative syndrome with thrombocythemia. We report the cutaneous histopathology in case of erythromelalgia that revealed a thrombocythemia vera. Small arteries were occluded by thrombi of different age and narrowing of the lumen occurred by intimal proliferation of smooth muscle cells. There was no involvement of venules or capillaries. These vascular changes are highly suggestive of erythromelalgia and have not to be confused with necrotizing and/or granulomatous angiitis because of absence of fibrinoid necrosis and sparse inflammatory cells.

A case of splenic lymphoma with circulating villous lymphocytes is reported. Short surface cellular expansions were observed on blood and marrow films and by transmission electron microscopy. The immunophenotype was that of mature B cells without CD5, CD10, CD11c, or CD25 expression or tartrate-resistant acid phosphatase. Despite a basophilic plasmacytoid-like cytoplasm, this case of splenic lymphoma with circulating villous lymphocytes differed from splenic immunocytoma in that immunofluorescence and ultrastructure suggested that the neoplastic cells did not possess high levels of intracytoplasmic immunoglobulin. Treatment of cytopenia was best achieved by splenectomy and the total follow-up thus far (30 months) seems to indicate a case of low-grade malignant lymphoma.

Between May 1988 and November 1989, 68 consecutive febrile courses supervening after polychemotherapy for lymphoma outpatients (median age 50 years) were treated by the combination of oral Pefloxacin/Amoxicillin Clavulanic acid. In terms of median data, neutropenia appeared on d9 [d1-d17], and lasted 5 days [2-9] with a PMN nadir observed at 0.104 x 10(9) [0-0.5 x 10(9)/l], while fever rose on d10 [1-24]. In 59 cases (87%), fever and/or focal symptoms disappeared within 3 days, after which treatment was maintained for 7 days. Nine failures were observed, of which 2 were due to abandonment of treatment, 2 to vomiting and 5 to persistence of the original symptoms. Meti Susceptible-Staphylococci were found in blood samples from 2 patients, one of whom, with grade IV lymphoma that had proved resistant to chemotherapy, died. The treatment was found to be effective and well tolerated, offering a good alternative to hospitalization during a transient chemotherapy-induced neutropenia.

Thirty-nine children under two years of age with newly diagnosed Acute Myeloid Leukemia (AML) were consecutively admitted to the Hôpital Saint-Louis (Paris) over a ten-year period (1978-1987). Nineteen were under one year of age at diagnosis and 3 had congenital leukemia. Comparison of FAB sub-classes among the different age categories showed that AML with a monocytic component (M4 and M5) (44%), and AML with megakaryocytic elements (M7) (21%), were much more frequent in children before the age of two years. This comparison was made on a series of 1409 AML and 859 ALL diagnosed in the same hospital during a twelve years period of time. During this period of observation, the compared incidence of ALL and AML showed 50% for each category for children under 2 years, 73% ALL versus 27% AML for children under 15 years, and 18% ALL versus 82% AML for adults. Of the 29 cases subjected to cytogenetic study, 62% had clonal chromosomal abnormalities, the most frequent being a translocation involving the long arm of chromosome 11. With a 72 months median follow-up for patients who are still alive, the 6-year actuarial survival was 23%, while the event free interval for Complete Remission (CR) patients was 35%. For the M4-M5 subgroup, these results were 37% and 50% respectively with a plateau reached at 27 months. M4-M5 FAB types represented the most common leukemia at this age, and these usually correlated with translocation of the long arm of chromosome 11. We obtained an unexpectedly high rate of survival, with acceptable sequellae, for children treated with intensive chemotherapy.

Transient acanthosis nigricans (AN) was observed 3 months after bone marrow transplantation (BMT) for lymphoblastic lymphoma. The patient had no endocrine abnormality and had not received any drug known to induce AN. Forty-eight months post-BMT no malignancy recurred or appeared. Although usual hyperkeratosis, papillomatosis and acanthosis were present on skin biopsy, these were associated with the finding of keratinocyte necrosis and CD8+ lymphocytic infiltrate. It is suggested that graft-versus-host disease may be one of the triggers for AN.

A patient with hairy cell leukemia who developed mediastinal mass and fever is described. A CT-guided aspiration of the mass yielded Salmonella tiphymurium. Granulocyte response to infection was intact and could explain the favorable course of this unusual Salmonella infection. Although several reports deal with salmonellosis as a complication of immunodeficiency states, this type of infection is of rare occurrence in hairy cell leukemia.