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© 1999 American Society for Clinical Oncology Hyper-CVAD Program in Burkitt's-Type Adult Acute Lymphoblastic LeukemiaFrom the Departments of Leukemia, Hematopathology, and Lymphoma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, and Department of Hematology and Oncology, Children's Memorial Hospital of Chicago, Chicago, IL. Address reprint requests to Hagop Kantarjian, MD, The University of Texas M.D. Anderson Cancer Center, Box 61, 1515 Holcombe Blvd, Houston, TX 77030.
PURPOSE: To evaluate response and outcome with a front-line intensive multiagent chemotherapy regimen in adults with Burkitt's-type acute lymphoblastic leukemia (B-ALL).
PATIENTS AND METHODS: From September 1992 to June 1997, 26 consecutive adults with newly diagnosed untreated B-ALL received hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD). Their median age was 58 years (range, 17 to 79 years), and 46% were
RESULTS: Complete remission (CR) was obtained in 21 patients (81%). There were five induction deaths (19%). The median time to CR was 22 days (range, 15 to 89 days); 70% achieved CR within 4 weeks. The 3-year survival rate was 49% (± 11%); the 3-year continuous CR rate was 61% (± 11%). Twelve CR patients (57%) were in continuous CR at a median follow-up of 3+ years (range, 13+ months to 6.5+ years). Characteristics predicting for worse survival were age CONCLUSION: Hyper-CVAD is effective in adult B-ALL. Identification of patients with high risk for relapse and improved methods to detect residual disease may result in risk-oriented approaches.
BURKITT'S-TYPE ADULT acute lymphoblastic leukemia (B-ALL) is recognized as the L3 morphologic subtype of ALL as defined by the French-American-British (FAB) classification.1 It accounts for 2% to 4% of adult ALL cases. B-ALL is a high-grade malignancy, has an aggressive clinical course, and is composed of small noncleaved mature B lymphoid cells with rapid proliferative rates. In addition to its characterization by blast morphology, it is recognized by the presence of monoclonal surface immunoglobulins (sIgs), mature B-cell immunophenotype, and the characteristic translocations that involve chromosome 8 [t(8;14)(q24;q32) or the variants t(2;8)(p12;q24) and t(8;22)(q24;q11)].2 These chromosomal aberrations lead to rearrangements and inappropriate expression of the proto-oncogene c-myc located at band 8q24 [translocations of the Ig heavy chain (IgH) gene locus on chromosome 14q32 in t(8;14), of the Ig kappa (Ig  ) gene on chromosome 2p12 in t(2;8), and of Ig lambda (Ig ) gene on chromosome 22q11 in t(8;22) distal to c-myc].3 Some mature B-ALL cases are classified as L1 or L2 morphologically because they fail to meet L3 FAB criteria but exhibit sIg expression and the characteristic chromosomal abnormalities.4,5 They may be treated as B-ALL with similar responses and prognosis. Karyotypes observed in some B-cell lymphomas such as t(14;18)(q32;q21) are also found in B-ALL.6 These may occur in association with the characteristic Burkitt's karyotype and may confer a worse prognosis; some investigators have reported an increased frequency of t(14;18) in older patients with adult B-ALL.7,8 Conventional ALL therapies in childhood and adult B-ALL yielded poor results. Complete remission (CR) rates ranged from 0% to 67%, and disease-free survival rates were 0% to 33%.9-16 In the early 1980s, investigators used short-term dose-intensive chemotherapy programs that incorporated variations of high doses of cyclophosphamide, cytarabine (ara-C), and methotrexate (MTX).17-23 Unprecedented CR rates of 89% to 92% were achieved in children, with disease-free survival rates of 50% to 87%. Reduction in the incidence of CNS relapses was also noted with increasing doses of MTX and ara-C and with intensive prophylactic intrathecal therapy with or without cranial irradiation. Prophylactic cranial irradiation was initially used but was later discontinued because of concerns of delayed neurologic sequelae. Application of similar programs in adult B-ALL resulted in improved CR rates of 63% to 79%, disease-free survival rates of 50% to 65%, and survival rates of 49% to 54%.16,24,25 Recently, outcome with adult B-ALL in our institution has been improved by modifying a program designed by Murphy et al22 for childhood B-ALL. This report summarizes the results with this modified regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) as front-line therapy for adult B-ALL.
Study Group Twenty-six consecutive adults with newly diagnosed, untreated B-ALL referred to M.D. Anderson Cancer Center (Houston, TX) received Hyper-CVAD between September 1992 and June 1997. Informed consent was obtained according to institutional guidelines. Eligibility criteria were age  15 years and confirmed diagnosis of B-ALL. There were no restrictions by performance status, older age, or organ dysfunction. Six cases of human immunodeficiency virus–positive B-ALL treated with Hyper-CVAD are reported separately.26 All patients were required to have a documented morphologic diagnosis of ALL (with 25% blasts in the bone marrow or 10 x 109 peripheral blasts/L) confirmed by enzymatic stain analysis (negative myeloid and monocytic stains). Burkitt's subtype was identified by: (1) L3 morphology (FAB classification); or (2) presence of the characteristic cytogenetic translocations [t(8;14)(q24;q32) or variants t(2;8)(p12;q24) and t(8;22)(q24;q11)] or c-myc rearrangement at the molecular level in cases lacking cytogenetic data; and (3) mature B-cell immunophenotype (sIg positivity > 20% or / light-chain clonality with B-lineage–associated antigens CD19 or CD20). Work-up at diagnosis included a history with physical examination and documentation of disease in extramedullary sites (confirmed by imaging and appropriate cytologic or histologic evaluations): lumbar punctures for CSF cytologic analysis were performed at diagnosis concomitant with prophylactic intrathecal chemotherapy administration to evaluate asymptomatic disease. Baseline chest radiographs were performed in all patients; those with abnormalities underwent further imaging with computed tomography. Magnetic resonance imaging and/or computed tomography of the brain was performed in all patients with cranial nerve abnormalities or positive CNS cytology. Computed tomography of the abdomen/pelvis was performed in all but one patient (ultrasound was performed secondary to increased creatinine level) to evaluate hepatosplenic abnormalities and extramedullary disease. Laboratory evaluation included complete blood counts, differential and platelet counts, sequential multiple analysis (SMA 12) with liver and renal function studies, and coagulation profiles. Bone marrow aspirate and biopsy specimens were analyzed with (1) modified Wright's stain for morphology; (2) cytochemical stains for myeloperoxidase, chloroacetate, nonspecific esterase, periodic-acid Schiff, and terminal deoxynucleotidyl transferase (Tdt); (3) immunophenotyping for B-cell lineage antigens and sIg; and (4) karyotyping. Marrow aspiration was performed at diagnosis, on days 14 and 21 of the induction phase (course 1), and at CR. Subsequent aspirations were repeated every two to three courses thereafter until therapy was completed, followed by surveillance marrows every 3 months in the first year and every 6 months thereafter.
Therapy
Standard dose reductions were as follows: (1) ara-C to 1 g/m2 for age
Granulocyte colony-stimulating factor was initiated at least 24 hours after chemotherapy was completed at a dose of 10µg/kg subcutaneously daily and continued until the total WBC count was CNS prophylaxis included alternating intrathecal administrations of MTX 12 mg (6 mg only via Ommaya) on day 2 and ara-C 100 mg on day 7 of each course for all eight courses (16 intrathecal injections).27 Therapy for CNS leukemia resulted in augmentation of intrathecal therapy during the induction course to twice weekly until the CSF cell count was normalized and the cytologic examination was negative for evidence of malignant cells; the program was then resumed as for prophylactic therapy. No prophylactic cranial irradiation (XRT) was administered, although therapeutic XRT could be administered if indicated. Four patients received therapeutic XRT to the base of the skull with 30 Gy administered over 2 weeks in addition to intrathecal therapy for documented CNS involvement and cranial nerve palsy. Other extramedullary sites of disease were treated as appropriate; one patient received consolidation XRT to a lytic lesion of the femur.
Supportive Care
Response Criteria
Statistical Methods
Study Group Patient characteristics are listed in Table 1. The median age was 58 years (range, 17 to 79 years; median age for patients < 60 years, 38 years), 46% of the patients were 60 years, and 81% were male. The median hematologic parameters were as follows: WBC count 7.2 x 109/L (range, 1.8 to 67.4 x 109/L), hemoglobin level 9.2 g/dL (range, 5.4 to 15 g/dL), platelet count 47 x 109/L (range, 13 to 396 x 109/L), absolute peripheral blasts 7 x 109/L (range, 0 to 80 x 109/L), and bone marrow blasts 75% (range, 16% to 98%; one patient had < 25% blasts but > 10 x 109/L circulating blasts). Median lactate dehydrogenase (LDH) level was 5,635 U/L (range, 649 to 42,001 U/L), median albumin level was 3.1 g/dL (range, 2.2 to 4.2 g/dL), and median total bilirubin level was 0.7 g/dL (range, 0.2 to 1.3 g/dL).
B-ALL features are listed in Table 2. Morphologic characteristics included the L3 FAB classification in all but three patients (all three were > 90% sIg-positive, yet were classified as L1 or L2 with Burkitt's-like morphology). Histochemical stains were positive for periodic-acid Schiff in 29% and for Tdt in seven patients (27%; six Tdt-positive patients were FAB L3; one patient was FAB L2 with B-cell immunophenotype and c-myc rearrangement). Tdt positivity in B-ALL has been reported in other series.16 Five patients had common ALL antigen–positive immunophenotype. The median CD20 expression was 61% (range, 3% to 95%). Cytogenetic analysis (n = 24) showed the characteristic translocations of B-ALL or add(8)(q24) in 10 (38%) of the patients; in six patients (26%), t(14;18)(q32;q31) or add(14)(q32) was detected (two in association with the B-ALL karyotype). Hyperdiploidy was usually present with the aforementioned abnormalities (n = 7) in addition to deletions and additions of multiple other various chromosomes (including 1q11 [n = 4] as reported in other series3,30) with the malignant clones. The chromosome 1 abnormalities were observed in patients younger than 50 years, whereas t(14;18)(q32;q31) or add(14)(q32) were observed in patients older than 50 years. Five of six patients tested had evidence of c-myc rearrangement; others (n = 4) had evidence of JH rearrangement. The patient with germline c-myc had L3 morphology and B-cell immunophenotype with hyperdiploid cytogenetics. Such heterogeneity has been observed by other investigators.31-33
Eighteen patients (69%) had extramedullary disease documented at presentation: (1) four with CNS (n = 3) or leptomeningeal disease (n = 1); (2) seven with CNS leukemia concurrently with other sites such as ascitic fluid (n = 1), lymph nodes (n = 3), stomach (n = 2), or paraspinal mass (n = 1); and (3) seven without CNS involvement but disease in the small bowel (n = 1), lymph nodes (n = 2), liver (biopsy-proven; n = 1), focal splenic lesions (n = 1), or bone (n = 2). Of the 11 patients (42%) with CNS disease, six (55%) had cranial nerve palsy or other neurologic findings (one with negative cytology), whereas five (45%) were asymptomatic with positive cytopathologic examination of the CSF.
Response
The median time to induction death in five patients (19%) was 25 days (range, 19 to 60 days). Induction death occurred in one of 14 patients younger than 60 years versus four of 12 older patients (7% v 33%; P = .23). Thus, four (80%) of the five induction deaths were among patients
Survival
Factors associated with worse survival were female sex, older age, poor performance status, hemoglobin level less than 10 g/dL, platelet count less than 100 x 109/L, circulating blasts, and LDH level
By multivariate analysis, characteristics associated with worse survival were age 60 Table 2 also lists outcome with Hyper-CVAD by B-ALL features (FAB subtype, immunophenotype, and karyotype). The best outcome was observed among patients in the first category, which included mostly patients younger than 60 years with all three typical features. In comparison, the 3-year survival rate for the older third group (same features except for other karyotypes) seemed inferior (P = .03). Patient numbers were too small to allow for further comparisons.
Treatment Delivery and Toxicity
Dose reductions of MTX and/or ara-C occurred in 16 (76%) of 21 patients who received
Grade 3 to 4 hematopoietic toxicity was universal. Median time to recovery of the absolute neutrophil count to more than 0.5 x 109/L was 17 days (range, 12 to 28 days) and of the platelet count to more than 60 x 109/L was 20 days (no suppression beyond 35 days) for course 1 in all assessable patients (n = 21). Similar results were obtained with subsequent courses, although platelet recovery was slower with MTX/ara-C courses. Twelve episodes (8% incidence) of thrombocytopenia-related hemorrhage occurred in 152 assessable courses: retinal (n = 2), gastrointestinal (n = 2), CNS (n = 2, with one fatal subarachnoid hemorrhage), pulmonary (n = 1), severe epistaxis (n = 4), and antecubital hematoma (n = 1). Myelosuppression-associated infectious complications were common despite the short duration of granulocyte counts less than 0.5 x 109/L (median of 6 days per course; range, 0 to 13 days). Incidence of neutropenic febrile episodes during the induction phase was 86% for 37 assessable courses: four episodes (11%) of sepsis; 12 episodes (32%) of pneumonia with three fungal, three bacterial, one RSV, and five with unknown pathogens; one episode of bacterial meningitis; 14 episodes (38%) of fever of unknown origin; and one episode of herpes simplex virus infection. Neutropenic febrile rates for subsequent courses were 30% to 39% with Hyper-CVAD and 47% to 55% with MTX/ara-C. Twelve episodes (8%) of herpes simplex virus infections were observed in 152 assessable courses despite the use of prophylactic acyclovir, including severe disseminated facial lesions (n = 1) and perirectal ulcerations (n = 2). No long-term sequelae were identified, although six patients in CR still had mild vincristine-related peripheral neuropathy at the time of this writing. No cases of secondary malignancy were detected. One patient developed RSV pneumonia 16 months after completion of the program. He required mechanical ventilation but recovered and remained alive and in continuous CR at 3 years. One patient received interferon alfa-2a for chronic active hepatitis C and remained in remission at 5 years.
Salvage Therapy Two patients died before they could receive salvage therapy. Primary salvage chemotherapy regimens were administered in seven patients: two received Hyper-CVAD salvage, and five received other salvage regimens; no patient underwent bone marrow transplantation. No CRs were observed. Thus, all nine of these patients died, with a median survival duration of 1 month after relapse (range, 3 days to 5 months).
Historical Comparison
Outcome with VAD seemed inferior despite a younger age cohort with better features at presentation. The CR rate was 68% compared with 81% with Hyper-CVAD, and 17% of the patients were refractory to induction therapy. Induction death rates were similar (15% for VAD). The estimated 3-year continuous CR rate was better with Hyper-CVAD overall (61% v 25%; P = .04) and in patients younger than 60 years of age (3-year CR rates 83% v 27%; P < .01) but not in patients
The outcome of childhood B-ALL with conventional ALL therapy was historically poor.9-15 The development of short-term, intensive, alternating multiagent chemotherapy regimens in childhood B-ALL/lymphoma by investigators such as the French Pediatric Oncology Society,17,18 the German Study Group for childhood ALL (Berlin-Frankfurt-Munster),19,20 the United Kingdom Children's Cancer Study Group,21 and the Pediatric Oncology Group22,23 yielded unprecedented survival rates of 60% to 80% at 2 years.17-23 Murphy et al22 designed a program applying the hypothesis of Goldie and Coldman34 and expounded on a theoretical relationship between dose-intensity and efficacy. Maximizing exposure of rapidly proliferating B-ALL malignant cells to drug by hyperfractionation of the alkylating agent, and use of different non–cross-resistance agents in tandem, formed the basis for the Total Therapy B program for childhood B-ALL.23
Hyper-CVAD is a modified Murphy-like regimen applied to adult B-ALL at our institution. Our CR rate of 81% was comparable to that obtained by Hoelzer et al16 (63% and 74%; 56% for patients aged > 50 years) and Soussain et al24 (79%) with intensive programs in younger adults with B-ALL (Table 5). No patient was refractory to Hyper-CVAD administered as front-line therapy, and no deaths in remission were observed. The estimated 3-year survival rate was 49% (± 11%) and the 3-year continuous CR rate was 61% (± 11%); for patients younger than 60 years, these rates were 77% and 83%, respectively. The disease-free survival rates in other series ranged from 50% to 71%; however, most patients in such series were younger (median ages, 30 to 36 years). Only 4% to 12% were
The induction death rate (19%) with Hyper-CVAD was comparable to the 8% to 40% incidence in other series and was caused by infectious complications of myelosuppression.16,24,25 The induction death rate with Hyper-CVAD for non–B-ALL was 6%.36 Four of the five induction deaths with Hyper-CVAD were in patients aged The incidence of CNS disease at presentation (42%) in our study was also similar to other reports (12% to 63%).13,16,24,25 In the past, CNS disease constituted the most dreaded complication in B-ALL. It was also a major cause of treatment failure and patient death both at presentation and at relapse. Intensive chemotherapy regimens have nearly eliminated the impact of CNS disease on B-ALL prognosis; therefore, it is no longer a significant treatment challenge. In fact, routine XRT is not necessary, except perhaps in the presence of cranial nerve root palsies, because most patients can undergo effective prophylaxis or treatment for active disease with intrathecal chemotherapy, reducing the incidence of CNS failures to 3% to 5%.17-23 In our study, older patients had a higher incidence of 14q and complex cytogenetic abnormalities. This was observed previously by Velangi et al8 in 26 patients (median age, 61 years); eight of 14 older patients had t(14;18) or complex abnormalities. Stamatoullas et al7 reported on four patients with t(14;18) and acute B-ALL; their ages ranged from 27 to 50 years, and they had aggressive disease and extremely poor outcome (there was evidence of both c-myc and bcl-2 rearrangement in all four). Further investigations are required to determine the influence of these karyotypes on the disease biology and their association with age. The role, if any, of autologous or allogeneic SCT in B-ALL is highly questionable37,38 because (1) most patients are either cured with dose-intensive chemotherapy or relapse quickly and die rapidly before any SCT strategies could be applied (as in our study); and (2) the patients at high risk for relapse and in most need of SCT are paradoxically the older patients who are often not eligible for SCT programs. Sweetenham et al38,39 reported encouraging results with autologous SCT in Burkitt's lymphoma in first remission. However, many patients who underwent SCT may have already been cured without SCT. Allogeneic SCT was performed in nine patients with CNS disease at diagnosis and in first remission from intensive therapy for B-ALL; 78% were alive in continuous CR ranging from 1.5 to 5 years.40 However, as shown in our study, CNS involvement at presentation is no longer an adverse prognosis factor. In the series by Hoelzer et al16 and Soussain et al,24 some patients underwent SCT. In the first study, six patients (median age, 26 years) underwent SCT (five allogeneic with four in first CR; one autologous): three patients were disease-free survivors at 2.4, 6.9, and 7 years. In the second study, eight patients underwent SCT in first CR: the 3-year overall survival rate was 57% for both stage IV Burkitt's lymphoma and B-ALL. These results were inferior to the 3-year survival rate of 73% in patients who did not undergo SCT. The observations of early relapse and poor outcome with salvage chemotherapy (median survival, 1 month from relapse) highlight the selective nature of patients reported to have undergone SCT for relapse,8,37 because most patients (as in our study) would have relapsed and died before institution of SCT, which suggests that time lag and natural patient selection may affect outcome. None of the patients in our study underwent SCT as consolidation or salvage therapy due to early relapse before preparation for SCT, older age, or poor performance status. In summary, the results of Hyper-CVAD were favorable except in high-risk (mostly older) patients. In this subgroup, alternative investigational and supportive care strategies need to be explored.
1. Bennett JM, Catovsky D, Daniel M-T, et al: Proposals for the classification of the acute leukaemias. Br J Hematol33:451-458, 1976[Medline]
2.
Bloomfield CD, Goldman AI, Alimena G, et al: Chromosomal abnormalities identify high-risk and low-risk patients with acute lymphoblastic leukemia. Blood67:415-420, 1986
3.
Faderl S, Kantarjian HM, Talpaz M, et al: Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood91:3995-4019, 1998 4. Hammami A, Chan WC, Michels SD, et al: Mature B-cell acute leukemia: A clinical, morphological, immunological, and cytogenetic study of nine cases. Hematologic Pathol5:109-118, 1991 5. Finlay JL, Borcherding W: Acute B-lymphocytic leukemia with L1 morphology: A report of two pediatric cases. Leukemia2:60-62, 1988[Medline] 6. Gladstone B, Kadam PR, Balsara BR, et al: Cytogenetic studies on patients of acute lymphoblastic leukemia Burkitt's type with (8;14) & (14;18) translocations. Indian J Med Res99:264-266, 1994[Medline] 7. Stamatoullas A, Bastard C, Lesesve JF, et al: Acute B-cell leukemia with t(14;18). Blood90:503, 1997 (abstr 2243) 8. Velangi M, Jackson G, Bown N, et al: Pattern of cytogenetics in the northern region 1983-1997. Br J Haematol102:108, 1998 (abstr 425)
9.
Baccarani M, Corbelli G, Amadori S, et al: Adolescent and adult lymphoblastic leukemia: Prognostic features and outcome of therapy—A study of 293 patients. Blood60:677-684, 1982 10. Lazzarino M, Morra MJ, Alessandrino EP, et al: Adult acute lymphoblastic leukemia. Response to therapy according to presenting features in 62 patients. Eur J Cancer Clin Oncol18:813-819, 1982[Medline] 11. Kantarjian HM, Walters RS, Keating MJ, et al: Results of the vincristine, doxorubicin, and dexamethasone regimen in adults with standard- and high-risk acute lymphocytic leukemia. J Clin Oncol8:994-1004, 1990[Abstract] 12. Kantarjian HM, O'Brien S, Smith T, et al: Acute lymphocytic leukemia in the elderly: Characteristics and outcome with the vincristine-Adriamycin-dexamethasone (VAD) regimen. Br J Haematol88:94-100, 1994[Medline]
13.
Gill PS, Meyer PR, Pavlova Z, et al: B cell acute lymphocytic leukemia in adults: Clinical, morphologic, and immunologic findings. J Clin Oncol4:737-743, 1986 14. Bernasconi C, Brusamolino E, Pagnucco G, et al: Burkitt's lymphoma/leukemia: A clinico-pathologic study on 24 adult patients. Leukemia5:90-94, 1991 (suppl 1) 15. Ostronoff M, Soussain C, Zambon E, et al: Burkitt's lymphoma in adults: A retrospective study of 46 cases. Nouv Rev Fr Hematol34:389-397, 1992
16.
Hoelzer D, Ludwig WD, Thiel E, et al: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood87:495-508, 1996
17.
Patte C, Philip T, Rodary C, et al: High survival rate in advanced-stage B-cell lymphomas and leukemias without CNS involvement with a short intensive polychemotherapy: Results from the French Pediatric Oncology Society of a randomized trial of 216 children. J Clin Oncol9:123-132, 1991
18.
Patte C, Philip T, Rodary C, et al: Improved survival rate in children with stage III and stage IV B cell non-Hodgkin's lymphoma and leukemia using multi-agent chemotherapy: Results of a study of 114 children from the French Pediatric Oncology Society. J Clin Oncol4:1219-1226, 1986
19.
Reiter A, Schrappe M, Parwaresch R, et al: Non-Hodgkin's lymphomas of childhood and adolescence: Results of a treatment stratified for biologic subtypes and stage—A report of the Berlin-Frankfurt-Munster Group. J Clin Oncol13:359-372, 1995
20.
Reiter A, Schrappe M, Ludwig W-D, et al: Favourable outcome of B-cell acute lymphoblastic leukemia in childhood: A report of three consecutive studies of the BFM Group. Blood80:2471-2478, 1992 21. Hann IM, Eden OB, Barnes J, et al: ‘MACHO’ chemotherapy for stage IV B cell lymphoma and B cell acute lymphoblastic leukemia of childhood. Br J Haematol76:359-364, 1990[Medline] 22. Murphy SB, Bowman WP, Abromowitch M, et al: Results of the treatment of advanced-stage Burkitt's lymphoma and B cell (Sig+) acute lymphoblastic leukemia with high-dose fractionated cyclophosphamide and coordinated high-dose methotrexate and cytarabine. J Clin Oncol4:1732-1739, 1986[Abstract]
23.
Bowman WP, Shuster JJ, Cook B, et al: Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: A Pediatric Oncology Group study. J Clin Oncol14:1252-1261, 1996
24.
Soussain C, Patte C, Ostronoff M, et al: Small noncleaved cell lymphoma and leukemia in adults: A retrospective study of 65 adults treated with the LMB pediatric protocols. Blood85:664-674, 1995 25. Fenaux P, Lai JL, Miaux O, et al: Burkitt cell acute leukaemia (L3 ALL) in adults: A report of 18 cases. Br J Haematol71:371-376, 1989[Medline] 26. Cortes J, Koller C, Thomas D, et al: Treatment of AIDS-related Burkitt's leukemia or lymphoma with the hyper-CVAD regimen. Blood92:401, 1998 (abstr 1656)
27.
Cortes J, O'Brien SM, Pierce S, et al: The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood86:2091-2097, 1995 28. Kaplan EL, Meier P: Non-parametric estimation form incomplete observations. J Am Stat Assoc53:457-481, 1965 29. Cox DR: Regression models and life tables. J R Stat Soc [B]34:187-220, 1972 30. Kornblau SM, Goodacre A, Cabanillas F: Chromosomal abnormalities in adult non-endemic Burkitt's lymphoma and leukemia: 22 new reports and a review of 148 cases from the literature. Hematol Oncol9:63-78, 1991[Medline] 31. Imamura N, Mtasiwa DM, Ota H, et al: FAB L3 type of B-cell acute lymphoblastic leukemia (B-ALL) without chromosome abnormalities. Am J Hematol35:216-218, 1990[Medline] 32. Advani Sh, Ahuya HG, Gopal R, et al: Clinical and phenotypic heterogeneity in L3-acute lymphoblastic leukemia. Indian J Cancer25:108-113, 1988[Medline] 33. Lai JL, Fenaux P, Zandecki M, et al: Cytogenetic studies in 30 patients with Burkitt's lymphoma or L3 acute lymphoblastic leukemia with special reference to additional chromosome abnormalities. Ann Genet32:26-32, 1989[Medline]
34.
Goldie JH, Coldman AJ: The genetic origin of drug resistance in neoplasm: Implications for systemic therapy. Cancer Res44:3643-3653, 1984 35. Todeschini G, Tecchio C, Degani D, et al: Eighty-one percent event-free survival in advanced Burkitt's lymphoma/leukemia: No differences in outcome between pediatric and adult patients treated with the same intensive pediatric protocol. Ann Oncol8:77-81, 1997 (suppl 1) 36. Kantarjian H, O'Brien S, Keating MJ, et al: Update of the hyper-CVAD dose-intensive regimen in adult acute lymphocytic leukemia. Blood92:313, 1998 (abstr 1285) 37. Philip T, Meckenstock R, Deconnick E, et al: Treatment of poor prognosis Burkitt's lymphoma in adults with the Societe Francaise d'Oncologie Pediatrique LMB protocol: A study of the Federation Nationale des Centres de Lutte Contre le Cancer (FNLCC). Eur J Cancer 28A:1954-1959, 1992 38. Sweetenham J, Pearce R, Taghipour G, et al: Adult Burkitt's and Burkitt-like non-Hodgkin's lymphoma: Outcome for patients treated with high-dose therapy and autologous stem-cell transplantation in first remission or at relapse—Results from the European Group for Blood and Marrow Transplantation. J Clin Oncol14:2465-2472, 1996[Abstract] 39. Sweetenham JW, Proctor SJ, Blaise D, et al: High-dose therapy and autologous bone marrow transplantation in first complete remission for adult patients with high-grade non-Hodgkin's lymphoma: The EBMT experience. Ann Oncol 5:S155-S159, 1994 (suppl 2) 40. Troussard X, Leblond V, Kuentz M, et al: Allogeneic bone marrow transplantation in adults with Burkitt's lymphoma or acute lymphoblastic leukemia in first complete remission. J Clin Oncol8:809-812, 1990[Abstract] Submitted August 7, 1998; accepted March 23, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
15 x 109/L or 
2 or Fisher's exact tests. Survival was measured from the date of initiation of therapy until death from any cause. CR duration was measured from the date of CR until documented relapse. Toxic deaths in CR were considered as failures at the time of death on the remission duration curves; thus, CR duration and disease-free survival for patients who achieved CR were interchangeable in this analysis. A cutoff date of June 30, 1998, was established for analyzing the data for this report. Survival and remission duration curves were plotted according to the methods of Kaplan and Meier, with differences among them analyzed by the log-rank test.
