Jacques-Louis Binet

Chlorambucil in Indolent Chronic Lymphocytic Leukemia

A BSTRACT Background To determine whether chlorambucil treatment benefits patients with indolent chronic lymphocytic leukemia (CLL), we conducted two randomized trials in 1535 patients with previously untreated stage A CLL. Methods In the first trial, 609 patients were randomly assigned to receive either daily chlorambucil or no treatment; in the second trial, 926 patients were randomly assigned to receive either intermittent chlorambucil plus prednisone or no treatment. Median follow-up for the first and second trials exceeded 11 and 6 years, respectively. The end points were overall survival, response to treatment, and disease progression. Results Treatment of indolent CLL did not increase survival in either trial. In the treated group, as compared with the untreated group, the relative risk of death was 1.14 (95 percent confidence interval, 0.92 to 1.41; P=0.23) in the first trial and 0.96 (95 percent confidence interval, 0.75 to 1.23; P=0.74) in the second trial, with 76 percent and 69 percent of patients, respectively, having a response to therapy. Although chlorambucil slowed disease progression, there was no effect on overall survival. In the untreated group in the first trial, 49 percent of patients did not have progression to more advanced disease and did not need therapy after follow-up of more than 11 years; however, 27 percent of patients with stage A CLL died of causes related to the disease. Conclusions Chlorambucil does not prolong survival in patients with stage A CLL. Since deferring therapy until the disease progresses to stage B or C does not compromise survival, treatment of indolent CLL is unnecessary. (N Engl J Med 1998;338:1506-14.)

Chronic Lymphocytic Leukaemia: Proposals for a Revised Prognostic Staging System

In the past the clinical course of chronic lymphocytic leukaemia (CLL) has been considered to be highly variable primarily due to a lack of understanding of prognostic factors. In the mid-1’370s Rai et al (1975) developed a simple staging system based on easily obtainable clinical and haematological data. The validity of the Rai clinical staging classification to predict the expected duration of survival of CLL patients has been confirmed by a number of subsequent publications (Phillips et al, 1977; Binet et al, 1977; Dighiero et al, 1979; Santoro et al, 1979; Rundles & Moore, 1978; Montserrat et al, 1977). This staging system brought a new perspective to clinical investigations in CLL by allowing the study of groups of patients of similar life expectancy in more comparable therapeutic trials. With use, certain limitations of the staging system have been recognized. The major inadequacies that have emerged requiring a revision of the system include: (1) the use of too many clinical groups (stages) making the design of useful therapeutic trials more difficult; and (2) a lack of consideration for the role of isolated organomegaly (e.g. splenomegaly or hepatomegaly) without lymphadenopathy in estimating the clinical prognosis of patients. An international workshop on CLL met in Paris in November 1979 and data on 295 patients were presented (Binet et al, 1981). In a second meeting in Montreal in August 1980 data on a larger number of patients were pooled. The outcome of a multivariatc analysis of more than 900 patients demonstrated three patterns of survival curves and the analysis resulted in a proposal for a new staging classification of CLL. Patients with anaemia (Hb < 10 g/dl) and/or thrombocytopenia ( < 100 x 10y/l) were found to have the poorest prognosis and were to be called group C. The prognosis of the remaining patients (approximately 80% of all the patients) was found to depend on the number of clinically relevant areas involved. Clinical enlargement of the spleen, the liver, and of lymph nodes in the cervical, axillary and inguinal regions constituted * Sponsored by the French National Cancer League and the National Leukemia Association, Inc. (U.S.A.). Participants: A. AUQUIER, Paris, France; J. BENNETT, Rochester, New York, U.S.A.; J.-L. BINET, Paris, France; K. BREMER, Essen, Germany; D. CATOVSKY, London, England; P. CHANDRA, Upton, New York, U.S.A.; C. CHASTANG, Paris, France; E. P. CRONKITE, Upton, New York, U.S.A.; G. DIGHIERO, Paris, France; D. A. G. GALTON, London, England; M. M. HANSEN, Copenhagen, Denmark; A. HUANG, Durham, N. Carolina, U.S.A.; C. JACQUILLAT, Paris, France; E. MONTSERRAT, Barcelona, Spain; H. PIGUET, Rouen, France; K. R . RAI, New Hyde Park, New York, U.S.A.; C. ROZMAN, Barcelona, Spain; W. RUNDLES, Durham, N. Carolina, U.S.A.; A. SAWITSKY, New Hyde Park, New York, U.S.A.; P. STRYCKMANS, Brussells, Belgium; C. SULTAN, Paris, France; M. WEIL, Paris, France. Correspondence: Dr A. Sawitsky, Long Island Jewish-Hillside Medical Center,. New Hyde Park, New York 11042, U.S.A.

When and How to Treat Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL), the most common form of leukemia in adults, is usually recognized first by the patients primary care physician. When the patient has other medical problems — wh...

Detection and Quantification of Platelet‐bound Antibodies with Immunoperoxidase

Summary. The use of immunocytochemical techniques enables one to quantify antibodies bound to cell membranes. We have tested the platelets of subjects with immune thrombocytopenic purpura by this method. The washed platelets were incubated in the presence of antiglobulin conjugated with an equimolar amount of peroxidase. The fixed peroxidase was revealed and quantified by an enzymatic reaction using orthodianizidine‐H2O2. From the results the number of immunoglobulin molecules per platelet was calculated. The test was calibrated so as to eliminate non‐specific fixation of the reagent. Under these conditions the platelets of subjects with idiopathic thrombocytopenic purpura bound a much larger amount of detectable immunoglobulin (800–21 000 molecules per platelet) than those of normal subjects (235 × 74 sites per platelet) or subjects with non‐immune thrombocytopenia (395 ± 203 molecules per platelet).

A Single-Center Study of 11 Patients with Intraocular Lymphoma Treated with Conventional Chemotherapy Followed by High-Dose Chemotherapy and Autologous Bone Marrow Transplantation in 5 Cases

Intraocular lymphoma (IOL) is a rare form of non Hodgkin lymphoma (NHL); it has a poor prognosis and is frequently associated with central nervous system (CNS) infiltration. We report the results of a prospective study of 11 patients with IOL who received conventional chemotherapy (CT), followed by salvage high-dose (HD) CT with autologous bone marrow transplantation (ABMT) in five cases. All 11 patients had abnormal funduscopic findings and six had CNS involvement at diagnosis. The diagnosis was based on vitrectomy in 10 cases and cerebral stereotaxic biopsy in one. Pathologic studies showed large-cell NHL in all cases. These large-cell NHL were of the B-cell type in 8 cases and of the T-cell type in two. First-line therapy consisted of a combination of cisplatin 25 mg/m2 as a 24-hour IV infusion on 4 consecutive days, VP-16 40 mg/m2 for 4 days, aracytine 2 g/m2 IV on day 5, and methylprednisolone 500 mg IV daily for 5 days (ESHAP) in 5 cases; alternating courses of ESHAP and HD methotrexate (MTX) in 4 cases; and HD MTX in 2 cases. Three patients underwent ocular and whole-brain radiation therapy. Five refractory patients subsequently received intensive CT with thiotepa 750 mg/m2, busulfan 10 mg/kg and cyclophosphamide 120 mg/kg, followed by ABMT. First-line treatment failed in 10 evaluable cases. One patient died of CNS progression at 12 months. All the patients who underwent intensive CT and ABMT entered CR; two relapsed at 6 months and three are alive in CR 15, 15 and 14 months after ABMT. Six patients are alive with persistent disease at 8, 13, 14, 15, 18 and 24 months. It seems in conclusion that, high-dose thiotepa, busulfan and cyclophosphamide followed by ABMT is effective in some cases of refractory IOL.

Intensive chemotherapy with hematopoietic cell transplantation after ESHAP therapy for relapsed or refractory non-Hodgkin's lymphoma. Results of a single-centre study of 65 patients.

This study was designed to assess the results of protracted courses of ESHAP (etoposide, cytarabine, cisplatin, methylprednisolone) therapy followed by intensive chemotherapy and hematopoietic cell transplantation (IC+HCT) for relapsed or refractory non-Hodgkins lymphoma (NHL). Treatment consisted of 3 cycles of ESHAP; responsive patients (pts) then received 3 more cycles, and IC+HCT was used for pts in maintained partial (PR) or complete (CR) remission after the sixth ESHAP. Sixty-five pts entered the study. At enrollment, 27 pts had bone marrow (BM) and/or central nervous system (CNS) lymphomatous infiltration. Disease status was primary refractory lymphoma in 41 pts (63 %), and relapse in 24 pts (37 %). Results showed that two pts were not evaluable for the therapeutic response because of early treatment-related death. Thirty-nine (62 %) pts entered PR or CR after 3 cycles of ESHAP. Eleven pts subsequently had disease progression. Twenty-eight pts were in persistent CR or PR after 6 cycles of ESHAP. Refractory pts did not show a different response rate to relapsing pts (chi2= 1.73). Five pts were excluded from IC+HCT because of an inadequate graft or treatment-related toxicity. Twenty-three (35 %) pts completed the procedure. Five pts (22 %) relapsed after IC+HCT. The overall survival rate of the 39 responsive pts is 45 % at 60 months, with a median survival time of 30 months. Median survival among the 35 pts in whom second-line chemotherapy failed is 7.1 months, with a 4-year survival rate of 3 %. Despite the poor prognostic features of this group, 45% of pts responding to the first 3 cycles of chemotherapy are in prolonged remission, suggesting that rather than to transplant after just 2 cycles of salvage therapy, pursuing second-line chemotherapy may better discriminate between patients more likely to benefit from a subsequent transplant.

Systemic infections withTrichosporon beigelii (cutaneum). Report of three new cases

Three new cases of systemic mycosis due to Trichosporon cutaneum are reported and compared with the 23 previous reports. Two patients had acute leukemia and one patient had a lymphoblastic lymphoma. Blood cultures in two patients and cerebrospinal fluid in the third patient were positive for T. cutaneum. Only one patient recovered after antimycotic therapy and concomittent remission of his leukemia. At autopsy, the two other patients showed widespread infection with T. cutaneum. The authors conclude that diagnosis and management of such infection in the immunosuppressed host are difficult and the prognosis is poor.

Is the CHOP Regimen a Good Treatment for Advanced CLL? Results from two Randomized Clinical Trials

Between 1985 and 1990, the French Cooperative Group on Chronic Lymphocytic Leukemia (CLL) randomized 287 stage B patients between intermittent chlorambucil plus prednisone (n = 140) or CHOP (n = 147), and 90 stage C patients between CHOP (n = 44) or CHOP plus methotrexate (n = 46). In stage B, although treatment response was improved with CHOP (p = 0.007, chi-square test), no difference in survival was observed between the two randomized groups (p = 0.33, score test). In stage C, no differences in treatment response and survival were shown, with median survival close to that reported with CHOP in the previous CLL-80 trial. These results associated with those from other groups raise the question whether the CHOP regimen, which has been consistently shown to improve response to therapy, is an effective treatment in advanced CLL patients.

Proposals for a Phenotypic Classification of B-Chronic Lymphocytic Leukemia, Relationship with Prognostic Factors

Immunophenotypic analysis was performed in 53 cases of B chronic lymphocytic leukemia using a large panel of monoclonal antibodies recognizing B, T, activation and myeloid antigens. Our results showed four patterns of reactivity: (a) several molecules were constantly expressed: CD19, CD20, CD24, CD37, HLA-DR, mu heavy chain, CD5, CD23, B5, CD32; (b) one antigen, CD11b, was found in 50 to 80% of the cases; (c) some markers were detected in less than 50% of the cases: CD25, CD38, CD71, CD11a, c, CD14b-c; (d) CD2 and CD16 were never detected. From these results, a phenotypic classification in three groups has been proposed and these groups were correlated with the progression of the disease, mainly with the lymphocyte doubling time of less than one year. We hypothesized that the leukemia cells could be at various stages of differentiation and/or activation according to their expression of activation and myeloid markers.

VH Gene Expression in CD5 Positive and CD5 Negative B Cell Chronic Lymphoid Malignancies

In this review, we report analyses of VH genes in mature B cell malignancies generally or occasionally bearing CD5 antigen such as B CLL, MCL, SLVL and PLL. In the majority of cases, B CLL and MCL use VH genes in germline configuration. However in some cases a higher rate of random mutations is observed. These differences are not related to CD5 expression but are accounted by Ig phenotype, since less mutations are observed in CLL cases expressing membrane mu delta, when compared to forms exclusively expressing membrane mu. PLL and SLVL cases display mutated V genes independently of CD5 expression. Although there is some evidence that CD5+ B cells constitute a separate lineage, the possibility that CD5 constitutes an activation marker cannot be ruled out. Indeed, CD5- B cells can be induced to differentiate into CD5+ B cells and VH gene analyses showed no significative differences between CD5+ and CD5- B cell lymphoproliferative disorders. In this review we have tried to examine B cell chronic malignancies on the basis of phenotype and VH gene usage. Thus we propose a tentative classification where these disorders are allocated according to these characteristics.