Search PubMed⌕ Search

Biomedical subjects

B Coiffier

Publications and source records attributed to B Coiffier.

At least 91 records · Page 5Linked to original sources

Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study.

Rituximab, a chimeric monoclonal antibody that binds specifically to the CD20 antigen, induced objective responses in 50% of patients with low-grade or follicular B-cell lymphoma. Because most nonfollicular B-cell lymphomas also express the CD20 antigen, we conducted a phase II study to evaluate the efficacy and tolerability of this new agent in patients with more aggressive types of lymphoma. Patients with diffuse large B-cell lymphoma (DLCL), mantle cell lymphoma (MCL), or other intermediate- or high-grade B-cell lymphomas according to the Working Formulation were included in this prospective randomized phase II study if they were in first or second relapse, if they were refractory to initial therapy, if they progressed after a partial response to initial therapy, or if they were elderly (age >60 years) and not previously treated. The patients received 8 weekly infusions of rituximab at the dose of 375 mg/m2 in arm A or one infusion of 375 mg/m2 followed by 7 weekly infusions of 500 mg/m2 in arm B. Patients were evaluated 2 months after the last rituximab infusion. Fifty-four patients were randomized from 9 centers in Europe and Australia (28 in arm A and 26 in arm B). A total of 5 complete responses (CR) and 12 partial responses (PR) were observed among the 54 enrolled patients, with no difference between the two doses. In an intent-to-treat analysis, the CR rate was 9% (CI95%, 3% to 20%) and the PR rate was 22% (CI95%, 12% to 36%), for an overall response rate of 31% (CI95%, 20% to 46%). An analysis of prognostic factors showed that response rates were lower in patients with refractory disease, patients with lymphoma not classified as DLCL, and patients with a tumor larger than 5 cm in diameter. DLCL and MCL patients had response rates of 37% and 33%, respectively. The median time to progression exceeded 246 days for the 17 responding patients. The most frequently reported adverse events were related to an infusion syndrome and were mild: 19% of the patients had a grade 3 related adverse event, slightly more in arm B, and only 1 patient had a grade 4 related adverse event in arm A. Two patients (3.7%) withdrew from treatment because of severe adverse events, one patient in each arm. In this first trial of rituximab in DLCL and MCL, patients experienced a significant clinical activity with a low toxicity. Rituximab has significant activity in DLCL and MCL patients and should be tested in combination with chemotherapy in such patients.

Adult↗

Prognostic significance of T-cell phenotype in aggressive non-Hodgkin's lymphomas. Groupe d'Etudes des Lymphomes de l'Adulte (GELA).

Peripheral T-cell lymphomas (PTCL) have been generally reported to have a worse prognosis than B-cell lymphomas (BCL). Because of their heterogeneity and scarcity, the outcomes of the different histological subtypes have not been compared. From October 1987 to March 1993, 1,883 patients with diffuse aggressive non-Hodgkin's lymphomas (NHL) included in the LNH87 protocol could be assessed for both morphology and immunophenotyping. Among them, 288 (15%) had PTCL and 1,595 (85%) had BCL. According to the Kiel classification, most PTCL were classified as angioimmunoblastic (AIL; 23%), pleomorphic medium and large T-cell (PML; 49%), or anaplastic large cell (ALCL; 20%) lymphomas. Comparing PTCL with BCL patients, the former had more disseminated disease (78% v 58%), B symptoms (57% v 40%), bone marrow involvement (31% v 17%), skin involvement (21% v 4%), and increased beta2-microglobulin (50% v 34%), whereas BCL patients had more bulky disease (41% v 26%). According to the International Prognostic Index (IPI), PTCL and BCL scores were, respectively: 0 factors, 13% and 15%; 1 factor, 17% and 22%; 2 factors, 24% and 25%; >/=3 factors, 45% and 37% (P = .09). For BCL and PTCL, respectively, complete remission rates were 63% and 54% (P = .004); the 5-year overall survival (OS) rates were 53% and 41% (P = .0004) and event-free survival (EFS) rates were 42% and 33% (P < . 0001). Comparison of the different histological subtypes of lymphoma showed that the 5-year OS rate for T-ALCL (64%) was superior to those of other PTCL (35%) as well as diffuse large B-cell (53%) NHL. When multivariate analysis was applied using the IPI score as one factor, nonanaplastic PTCL remained an independent parameter (P = . 0004). Although the poor prognosis of non-ALCL PTCL could be due in part to the presence of adverse prognostic factors at diagnosis, this study shows that the T-cell phenotype is an independent significant factor, which should be incorporated into the definition of prognostic groups.

Adolescent↗

Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin's lymphoma outcome.

Systemic release of tumor necrosis factor (TNF) and lymphotoxin-alpha (LTalpha) has been found to contribute to the severity of non-Hodgkin's lymphoma (NHL). We investigated whether genetic polymorphisms in the TNF locus, previously shown to influence TNF and LTalpha genes expression, might contribute to these cytokines production and to the clinical course of NHL. Genomic DNA from 273 lymphoma patients was typed for TNF (-308) polymorphism using an allele-specific polymerase chain reaction (PCR) and for LTalpha (+252) polymorphism with a PCR-based restriction fragment length polymorphism. The presence of the TNF allele involved in increased TNF gene transcription was associated with higher plasma levels of this cytokine at the time of lymphoma diagnosis (chi2 test, P = .013). An extended haplotype analysis showed that the presence of at least two TNF or LTalpha high-producer alleles constituted a risk factor for first-line treatment failure (chi2 test, P = .021), shorter progression-free survival (log-rank test, P = .0007), and overall survival (log-rank test, P = .012). In the subgroup of 126 patients with diffuse large-cell lymphoma, the presence of two or more TNF/LTalpha high producing alleles contributed significantly to a higher rate of relapse and progression (log-rank test, P = .045 and P = .027). In multivariate Cox regression models including the variables of the International Prognostic Index, the TNF/LTalpha haplotype status was found to be an independent risk factor for progression-free survival (relative risk 2.33, 95% confidence interval [1.17 to 4.64], P = . 0053) and overall survival (relative risk 1.92, 95% confidence interval [0.63 to 5.80], P = .081) of large-cell lymphoma patients. These results indicate that genetic polymorphism leading to increased TNF production influences the outcome of NHL and suggest a pathophysiological role for the genetic control of the immune response in lymphoid malignancies.

Adult↗

A multivariate analysis of the survival of patients with aggressive lymphoma: variations in the predictive value of prognostic factors during the course of the disease. Groupe d'Etudes des Lymphomes de l'Adulte.

BACKGROUND: Aggressive non-Hodgkin's lymphoma is now often curable with chemotherapy. The International Prognostic Index (IPI) was recently developed to predict patient survival on the basis of pretreatment clinical features. However, classical multivariate regression models such as the IPI fail to detect time-dependent changes in the predictive value of covariates. In this study, an extension of the Cox proportional hazards model was used to determine whether the value of prognostic factors might decay over time. METHODS: A total of 1271 patients younger than 60 years, entered on the LNH-84 and LNH-87 studies of an ACVBP induction regimen (consisting of doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, and IT methotrexate), were analyzed in terms of overall survival and monthly risk of dying. By a standard method, prognostic factors were identified in a training sample and confirmed in a validation sample. The independently significant covariates were then included in a step-function regression model (3-step) that permitted determination of their value in predicting the short term and long term survival of the entire population. RESULTS: During the entire follow-up period (median, 5.5 years), lactate dehydrogenase level, tumor stage, performance status, and number of extranodal sites remained independently predictive of overall survival. However, these covariates had nonproportional hazard functions. The study of their time-dependent effect with the 3-step model confirmed that they were predictive of overall survival during the short term follow-up period of 3 months to 2 years. However, during the induction period of 0-3 months and the long term follow-up period of 2-10 years, there was only 1 independently predictive factor for each of these periods: performance status and tumor stage, respectively. CONCLUSIONS: The IPI factors are relevant to short term follow-up and permit the selection of routine or experimental therapeutic regimens. In contrast, only performance status is predictive of a patient's ability to tolerate induction chemotherapy, and only tumor stage is predictive of long term survival.

Antineoplastic Agents↗

High CD34(+) cell counts decrease hematologic toxicity of autologous peripheral blood progenitor cell transplantation.

Optimal numbers of CD34(+) cells to be reinfused in patients undergoing peripheral blood progenitor cell (PBPC) transplantation after high-dose chemotherapy are still unknown. Hematologic reconstitution of 168 transplantations performed in patients with lymphoproliferative diseases was analyzed according to the number of CD34(+) cells reinfused. The number of days from PBPC reinfusion until neutrophil recovery (>1.0 x 10(9)/L) and unsustained platelet recovery (>50 x 10(9)/L) were analyzed in three groups defined by the number of CD34(+) cells reinfused: a low group with less than or equal to 2.5 x 10(6) CD34(+) cells/kg, a high group with greater than 15 x 10(6) CD34(+) cells/kg, and an intermediate group to which the former two groups were compared. The 22 low-group patients had a significantly delayed neutrophil (P < .0001) and platelet recovery (P < .0001). The 41 high-group patients experienced significantly shorter engraftment compared with the intermediate group with a median of 11 (range, 8 to 16) versus 12 (range, 7 to 17) days for neutrophil recovery (P = .003), and a median of 11 (range, 7 to 24) versus 14 (range, 8 to 180+) days for platelet recovery (P < .0001). These patients required significantly less platelet transfusions (P = .002). In a multivariate analysis, the amount of CD34(+) cells reinfused was the only variable showing significance for neutrophil and platelet recovery. High-group patients had a shorter hospital stay (P = .01) and tended to need fewer days of antibotic administration (P = .12). In conclusion, these results suggest that reinfusion of greater than 15 x 10(6) CD34(+) cells/kg after high-dose chemotherapy for lymphoproliferative diseases further shortens hematopoietic reconstitution, reduces platelet requirements, and may improve patients' quality of life.

Adolescent↗

A new death receptor 3 isoform: expression in human lymphoid cell lines and non-Hodgkin's lymphomas.

Two isoforms encoding the full-length transmembrane death receptor 3 (DR3) were isolated from mRNAs of a panel of human cell lines and tumor tissues obtained from patients with follicular non-Hodgkin's lymphoma. A new DR3 variant (DR3 beta) was characterized by 2 insertions of respectively 20- and 7-base pairs (bp) which result in a predictive translated polypeptide differing from the described DR3 molecule by a 28 amino-acid stretch in the extracellular domain. DR3 was shown to be expressed in all cell lines and lymphoma samples tested, whereas DR3 beta expression was restricted to lymphoid T-cell and immature B-cell lines and to selected cases with follicular lymphoma. These data provide new insight into the molecular heterogeneity of DR3, suggesting the presence of several receptor isoforms that can participate in lymphoid cell homeostasis.

Base Sequence↗

Frequency and significance of anemia in non-Hodgkin's lymphoma patients.

OBJECTIVES: Retrospective evaluation of anemia frequency and its prognostic value in patients with different subtypes of non-Hodgkin's lymphoma and comparison with other clinical characteristics. PATIENTS AND METHODS: Anemia was defined as a hemoglobin value less than or equal to 12 g/dl for all men and women over 50 years of age, and less than or equal to 11 g/dl for women under 50 years of age. The study included 1077 adult lymphoma patients treated between 1980 and 1995 with the following histologic subtypes: 127 patients with small lymphocytic or lymphoplasmacytoid, 62 with marginal zone, 50 with mantle-cell, 208 with follicular, 104 with T-cell lymphoma, 426 with diffuse large-cell and, finally, 73 patients with other high-grade lymphomas. RESULTS: Anemia was present in 341 patients (32%). It was an adverse prognostic factor (P < 0.0001) for overall survival (OS) and progression-free survival (PFS) but not for relapse-free survival (RFS). When patients with and those without bone marrow involvement were considered separately, anemia remained an adverse factor. Anemia was significantly associated with shorter PFS in small lymphocytic or lymphoplasmacytoid, mantle cell, diffuse large cell and high-grade lymphomas and with shorter OS in all histologic subgroups except marginal zone lymphoma. In multivariate analysis, anemia was a significant prognostic factor for OS and PFS for the population as a whole (P = 0.0001 and P = 0.0048, respectively) and in patients with bone marrow involvement (P = 0.007 and P = 0.005, respectively) but not in patients without bone marrow involvement. Finally, the addition of anemia to the International Prognostic Index led to an improvement for OS (P = 0.0004) and PFS (P = 0.0004). CONCLUSIONS: Anemia is an important adverse prognostic factor for the outcome of lymphoma patients, particularly in some histologic subgroups and in patients with bone marrow involvement.

Adult↗

Plasma levels of tumour necrosis factor and its soluble receptors correlate with clinical features and outcome of Hodgkin's disease patients.

A prospective study was performed to assess the use of plasma measurement of tumour necrosis factor (TNF), lymphotoxin alpha (LT alpha) and their soluble receptors (p55 and p75) for prognostic risk assignment in 61 patients with Hodgkin's disease. Plasma levels of TNF, p55 and p75, but not of LT alpha, were higher in Hodgkin's disease patients than in healthy controls. Plasma levels of TNF, p55 and p75 were associated with several prognostic factors for Hodgkin's disease, including those related to the host (age, performance status) and to the tumour (disease stage, extranodal site involvement, bulky tumour, serum levels of LDH and beta2-microglobulin, histology). Elevated plasma levels of TNF, p55 and p75 were also associated with several parameters reflecting an immune activation, including the presence of B symptoms, elevated serum levels of gammaglobulins, alkaline phosphatase and fibrinogen, as well as peripheral monocytosis, anaemia and low serum albumin levels. Finally, elevated TNF ligand receptor plasma markers were associated with a lower incidence of complete response to therapy and predicted shorter free-from-progression survival and overall survival of the patients. These results indicate that the plasma levels of TNF and its soluble receptors correlate with clinical features and outcome of patients with Hodgkin's disease.

Adolescent↗

Reduced progression-free survival in elderly patients receiving intensification with autologous peripheral blood stem cell reinfusion for multiple myeloma.

Between 1990 and 1997, 55 patients with high risk multiple myeloma underwent high-dose therapy with peripheral blood stem cell transplantation. Intensification consisted of high-dose L-PAM in 54 patients, and 15 patients underwent a second high-dose treatment. Thirty patients received total body irradiation. Twenty patients were more than 60 years old. Thirty-five patients were intensified during first response. The overall response rate was 78%. There were four toxic deaths. The median overall survivals after intensification and after first treatment of myeloma were greater than 48 months and 71 months, respectively. Conversely freedom from progression after intensification was short, with a median of 22 months. Freedom from progression was significantly shorter in patients older than 60 (12 months), and in patients who had received more than 75 mg/m2 of L-PAM before intensification (16 months). Although intensification is feasible in elderly patients the benefit appears to be reduced in this subgroup of patients. Prior therapy with high cumulative doses of L-PAM should be avoided in patients who will receive high-dose L-PAM for therapeutic intensification.

Adult↗

Mantle cell lymphoma: a retrospective study of 121 cases.

Mantle cell lymphoma (MCL) patients represent a difficult problem, sometimes to establish the diagnosis but mostly because of their refractoriness to standard lymphoma treatments. Which treatments to apply and to whom is not yet defined. In this study, we attempted to analyze the clinical features, to identify the major prognostic factors, and to evaluate the outcome of 121 MCL patients treated in our institution between 1979 and 1997. Clinical data, treatment modalities, and International Prognostic Index (IPI) score were evaluated. Median age was 63 years. Patients usually presented with advanced stage disease (87%), disseminated lymph nodes (57%), bone marrow involvement (79%), but with a good performance status (PS) (81%). Lymphocytosis >4000/microl and/or peripheral blood involvement was present in 36% of cases, and gastrointestinal disease in 18%. The t(11;14)(q13;q32) and/or bcl-1 rearrangement was detected in 47/57 studied cases. Median overall survival (OS) was 3.12 years and a longer survival was significantly associated with younger age (<70 years), good PS (<2), localized disease (stage I-II), fewer than two extra-nodal sites, absence of spleen or peripheral blood involvement, normal serum LDH and beta2-microglobulin levels, and hemoglobin level greater than 12 g/dl. However, the IPI failed to identify patients with longer OS and in a multiparametric analysis, only older age, hemoglobin less than 12 g/dl, poor PS, and blood involvement were associated with a poorer outcome. Treatment modalities had no impact on survival with 75% of patients relapsing or progressing. Our data showed that the poor outcome of MCL patients is mainly related to adverse patient characteristics, a highly disseminated tumor, and some unknown parameters associated with the refractoriness to standard therapy.

Adult↗

Factors associated with successful mobilization of peripheral blood progenitor cells in 200 patients with lymphoid malignancies.

Peripheral blood progenitor cells (PBPC) were mobilized and harvested in 200 patients treated for non-Hodgkin's lymphoma (n = 148), Hodgkin's disease (n = 22) and multiple myeloma (n = 30). The variables predicting the collection of a minimal (>2.5 x 10(6)/kg) or a high (>10 x 10(6)/kg) CD34+ cell count were analysed. Patients were mobilized with haemopoietic growth factors following either standard chemotherapy (n = 49) or high-dose cyclophosphamide, given alone (n = 55) or combined with high-dose VP16 (n = 86). 10 patients received haemopoietic growth factors only. The first mobilization resulted in a PBPC harvest with enough CD34+ cells in 179/200 patients (90%). High-dose cyclophosphamide, with or without VP16, did not mobilize a higher progenitor cell yield than standard chemotherapy. When performing multiple regression analysis in the 190 patients who received chemotherapy-containing mobilization, only the number of previous chemotherapy regimens and the exposure to fludarabine predicted for a failure to collect a minimal PBPC count (P=0.06 and 0.0008 respectively). The target to collect a high CD34+ cell count was negatively associated with the number of previous chemotherapy regimens (P=0.002). When only non-Hodgkin's lymphoma patients were considered for multivariate analysis, low-grade histology with fludarabine appeared to be associated with poor PBPC cell yield (P=0.08 and 0.005 respectively). This data confirms that PBPC harvest should be planned early in the disease course in transplant candidates, and can be obtained after a standard course of chemotherapy.

Adolescent↗

CD40 regulation of death domains containing receptors and their ligands on lymphoma B cells.

Within the tumour necrosis factor (TNF) family the induction of apoptosis is restricted to some ligand-receptors pairs, including TNF-TNF receptor type I (TNFRI/p55), FasL-Fas, TNF-related apoptosis-inducing ligand (TRAIL) and its death-receptors (DR)-4 and -5. The pair CD40L-CD40 belongs to the same family but rescues B cells from apoptosis. To investigate how these opposing actions are cross-linked, purified follicular lymphoma (FL) cells were activated upon a human CD40L-transfected murine fibroblastic layer, then RNA messengers for the above molecules were analysed using RT-PCR. The observed down-modulation of TRAIL and up-regulation of TNF and Fas transcripts might account for CD40-CD40L-mediated FL cell survival.

Antigens, CD↗

High-dose therapy followed by stem cell transplantation in partial response after first-line induction therapy for aggressive non-Hodgkin's lymphoma.

Patients with aggressive non-Hodgkin's lymphoma who fail to achieve a complete remission (CR) with standard induction therapy have a poor prognosis with conventional-dose salvage therapy alone. Retrospective series have suggested that early introduction of high-dose salvage therapy with autologous stem cell transplantation (ASCT) may benefit partial-responder (PR) patients. However, two randomized studies (of 69 and 51 patients with partial clinical responses) failed to demonstrate any advantage of intensive therapy. By contrast, the GELA comparative study on 94 PR-patients (residual disease being histologically documented in 53 patients) suggested that high-dose therapy with ASCT improves survival. Interpretation of all these results is complicated by the heterogeneity of patient populations with respect to initial prognostic factors, induction regimens and, in particular, the criteria used to define partial response. Gallium CT scan and magnetic resonance imaging are now used to better explore residual masses. In the future, early restaging with these imaging techniques might be used to delineate patients who are likely to achieve CR from those who will fail to induction treatment and could be candidates for experimental treatments.

Antineoplastic Combined Chemotherapy Protocols↗

High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series.

PURPOSE: The impact of treatment options on survival and late neurologic toxicity was investigated in a series of patients with primary cerebral lymphoma (PCL) and no known cause of immunosuppression. PATIENTS AND METHODS: Prognostic factors for survival and treatment-induced late neurotoxicity were investigated in a retrospective series of 226 patients with PCL. RESULTS: With a median follow-up of 76 months, the median overall survival was 16 months and 5-year survival was 19%. In a univariate analysis, age greater than 60 years, performance status, CSF protein level greater than 0.6 g/L, involvement of corpus callosum or subcortical grey structures, detectable lymphoma cells in CSF, increased serum lactate dehydrogenase (LDH), but not histological subtype, were significantly correlated with a poor survival. Treatment with chemotherapy versus radiotherapy alone (P = .05), high-dose methotrexate (HDMTX; P = .0007), and cytarabine (P = .04) correlated with a better survival in univariate analysis. Using the Cox model, age, performance status, and CSF protein were independently correlated with survival. After adjustment of these factors, treatment with an HDMTX-containing regimen remained the only treatment-related factor independently correlated with survival (P = .01). The projected incidence of treatment-induced late neurotoxicity was 26% at 6 years in this series, with a median survival from the diagnosis of late neurotoxicity of 12 months. Treatment with radiotherapy followed by chemotherapy was the only parameter correlated with late neurotoxicity in multivariate analysis (relative risk, 11.5; P = .0007). CONCLUSION: Patients with PCL treated with regimens that included HDMTX followed by radiotherapy have an improved survival, but not a higher risk of late neurotoxicity as compared with other treatment modalities in this series.

Adolescent↗

Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial.

PURPOSE: To compare progression-free survival (PFS), overall survival (OS), and toxicity of a doxorubicin-containing regimen administered alone or in combination with interferon alfa-2b (IFNalpha) in patients with low-grade follicular lymphoma (FL) and poor prognostic factors. PATIENTS AND METHODS: Two hundred sixty-eight patients with advanced-stage FL received cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP) monthly for 6 months, then every 2 months for 12 months. After randomization, 242 patients were evaluated for efficacy: 119 received CHVP alone, and 123 also received IFNalpha at a dose of 5 million units three times weekly for 18 months. RESULTS: After a 6-year median follow-up, the patients treated with CHVP + IFNalpha showed significantly longer median PFS than those who received CHVP alone (2.9 years v 1.5 years, respectively; P = .0002) and significantly longer median OS (not reached v 5.6 years, respectively; P = .008). Although some side effects, which included neutropenia, asthenia, fever, elevated serum transaminase levels, flu-like symptoms, and thrombocytopenia, were more frequently observed in patients who received the combination regimen, these reactions were moderate. IFNalpha was withdrawn because of toxicity in 10% of the patients, and a dosage reduction or temporary suspension was required in 28%. CONCLUSION: With long-term follow-up of 6 years, these results confirm that the addition of IFNalpha to a doxorubicin-containing regimen for patients with advanced-stage and clinically aggressive FL not only increased PFS, as in most other similar trials, but also prolonged OS. Toxicity was moderate. The beneficial effects of this combined chemotherapy and IFNalpha regimen on OS probably reflect the selection of FL patients with poor prognostic factors.

Antineoplastic Agents↗

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine via the Group C protocol mechanism of the National Cancer Institute: a report of 979 patients.

PURPOSE: To provide cladribine (CdA) to physicians for the treatment of patients with previously treated or untreated hairy cell leukemia (HCL), and to determine the response rate, response duration, survival, and toxicity with this agent. PATIENTS AND METHODS: This Group C phase II study was open to all eligible patients whose primary physician obtained written permission from the National Cancer Institute (NCI) to register patients onto this protocol. Of 979 patients registered, 861 were assessable for response and 895 for toxicity. RESULTS: The complete remission (CR) rate was 50% and the partial remission (PR) rate was 37%. At a median follow-up of 52 months, 12% of patients were reported to have progressed and 62 (7%) have died of disease. CONCLUSION: This large experience confirms the excellent response rates and remission duration of CdA in patients with HCL. Nevertheless, the response rates in this setting, which approximates general clinical practice, were lower than in other series. In general, CdA was well tolerated, but the potential increased risk for secondary malignancies requires additional follow-up evaluation. CdA can now be considered as one of the best agents for the treatment of HCL.

Adult↗