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© 2002 American Society for Clinical Oncology Intensive, Very Short-Term Chemotherapy for Advanced Burkitt’s Lymphoma in ChildrenByFrom the Departments of Pediatric Oncology and Pathology, Istituto Nazionale Tumori, Milan, Italy. Address reprint requests to Filippo Spreafico, MD, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milano, Italy; email: f.spreafico{at}istitutotumori.mi.it
PURPOSE: To improve the 63% event-free survival (EFS) achieved before 1986 in Murphy’s stage III to IV Burkitt’s lymphoma (BL), both chemotherapy and supportive care were intensified. PATIENTS AND METHODS: From May 1987 to February 2001, 60 children, median age 9 years (range, 2.1 to 17 years), with advanced BL were enrolled onto two sequential institutional studies. From 1987 to 1992, 30 patients were stratified according to the absence (regimen IA, n = 19) or presence (regimen IB, n = 11) of bone marrow (BM) or CNS involvement. After 5-week cytoreductive chemotherapy consisting of vincristine, cyclophosphamide, doxorubicin, high-dose (HD) methotrexate (MTX), and intrathecal MTX or cytarabine, HD cytarabine and cisplatin were provided as a 4-day continuous infusion. Regimen IB was intensified by adding etoposide and HD ifosfamide and escalating MTX doses. Since 1992, regardless of BM or CNS status, 30 patients have been placed on regimen II, which is identical to IB but without ifosfamide. The scheduled duration of regimen II was 45 days. RESULTS: EFS and disease-free survival at 5 years are 81% ± 5% and 87% ± 5%, respectively, for 59 assessable patients (73% ± 8% and 85% ± 7% for regimen IA + IB, 89% ± 6%, EFS and disease-free survival, for regimen II; median follow-up, 6.7 years; range, 0.6 to 13.5 years). Six patients, two of whom were receiving regimen II, died as a result of initial treatment failure or relapse, and five patients, none receiving regimen II, died as a result of treatment-related complications. CONCLUSION: This 45-day intensive chemotherapy program is the shortest schedule for disseminated BL and overcomes previously recognized risk factors such as BM and CNS infiltration.
THE PATTERN OF response to the treatment of various non-Hodgkin’s lymphomas subtypes was recognized soon after the development of effective chemotherapy regimens.1-4 In early trials, children with advanced B-cell lymphoma (mainly small non–cleaved-cell and diffuse large-cell lymphoma according to the Working Formulation and Burkitt’s lymphoma [BL] and diffuse large B-cell lymphoma according to the Revised European-American Lymphoma classification5,6) had a worse outcome, characterized by early recurrences despite a high initial complete remission (CR) rate.7-10 BL is a high-grade B-cell neoplasm and the most common lymphoma in children.11,12 BL is one of the most rapidly growing tumors in children, and because of this, it demands frequent, nonrepetitive medications. It is now acknowledged that B- and T-cell lymphoma in children must be treated differently, in the advanced stages at least: B-cell lymphoma is treated with short-pulse chemotherapy, and T-cell lymphoma treatment protocols are similar to those applied to high-risk leukemia. With this approach, survival has much improved in both subgroups.13,14 In the chemotherapy protocol that we first tailored for advanced-stage BL in 1982, 22 children were treated with a six-drug regimen (vincristine, cyclophosphamide, methotrexate [MTX], doxorubicin [DOX], high-dose [HD] cytarabine [ara-C], and cisplatin) lasting 3 months, with CNS-directed treatment based on HDMTX, HD ara-C, and intrathecal chemotherapy.15 Conclusions from that study were as follows: (1) overall survival (OS) and event-free survival (EFS) at 5 years for the whole group were 73% and 63%, respectively; (2) CNS prophylaxis was effective with no CNS relapses; and (3) three of the four patients who experienced early failure had BM involvement, CNS involvement, or both at presentation. The toxic death rate was 10%. These findings prompted us to differentiate the treatment strategy for stage IV patients from 1987. After 1992, we also tried reducing the duration of treatment without jeopardizing survival rates. Here, we report on our results achieved in advanced-stage BL by combining and sequencing different antiproliferative drugs over a short period of time.
Patients From May 1987 to February 2001, 60 consecutive previously untreated children with newly diagnosed stage III to IV BL were registered; 30 were enrolled onto regimens IA and IB in 1987 to 1992 (n = 19 for regimen IA, n = 11 for regimen IB), and 30 were assigned to regimen II from 1992 onward. One child who was enrolled onto regimen II was excluded from the evaluation of response because the case was retrospectively restaged as localized BL; however, this patient is included in the toxicity assessment. An 8-year-old boy had AIDS, and a 6-year-old boy with Drash syndrome developed BL while on immunosuppressive therapy after a kidney transplant.16 Both these children were included in the study. In addition to routine chemistry profile and physical examination, the minimal pretreatment work-up included chest x-ray, abdominal ultrasound, bone marrow (BM) aspirates and needle biopsies from iliac crests, and spinal fluid analyses. Computed tomography scan, magnetic resonance imaging scan, or both were used to evaluate specific sites of disease, especially within the abdomen, head and neck, and CNS. Diagnosis was confirmed by histology in 50 cases. Nineteen children underwent exploratory laparotomies, 15 underwent percutaneous biopsies of abdominal lesions, and in 16 patients, surgical or needle biopsy specimens were taken from other sites (eg, jaw, peritonsillar, lymph node, and brain). In the remaining 10 children, the diagnosis was based on cytologic examination of malignant peritoneal (n = 8) or pleural (n = 1) effusions or BM aspirate (n = 1). The morphologic diagnosis of BL was essentially based on the criteria described by Lennert and Feller.17 Immune markers studies confirmed B-cell origin in all 44 patients from whom fresh cell suspensions were available. Stage was assigned according to the St Jude staging system.8
Treatment
Each treatment protocol consisted of an induction phase (phase I) and a consolidation phase (phase II). From 1987 to 1992, therapy was stratified in two risk branches, depending on the absence (regimen IA) or presence (regimen IB) of BM disease, CNS disease, or both at presentation. In regimen IA, cyclophosphamide, vincristine, and DOX were given intravenously (IV) at the times shown in Fig 1. HDMTX was administered as a 6-hour infusion with a 12-hour IV alkaline prehydration and a 48-hour posthydration, followed by leucovorin rescue therapy starting 24 hours after beginning the MTX infusion, every 6 hours for 12 doses of 15 mg each (standard dose). If the creatinine clearance was lower then 60 mL/min at the time scheduled for the first dose of HDMTX, this was postponed for 1 week and replaced by DOX. In phase II therapy, HD ara-C plus cisplatin were administered as a continuous 4-day IV infusion at a total dose of 6,000 and 80 mg/m2, respectively. CNS prophylaxis consisted of intrathecal chemotherapy with alternating MTX or ara-C. Total planned duration of the program was 53 days. Regimen IB, used for patients presenting with CNS involvement or in patients with BM infiltrated by blasts (Fig 2), was the same as regimen IA, except for the following changes: the HDMTX doses were escalated, and etoposide (VP16) was added 7 days after the first HDMTX in two daily doses of 250 mg/m2 12 hours apart; the mode of HD ara-C administration was changed, giving a continuous 4-day infusion of 4 g/m2 with an extra IV push dose of 750 mg/m2 daily for 4 days. After BM recovery from HD ara-C–cisplatin, the program was concluded by a 24-hour infusion of ifosfamide at the dose of 8 g/m2. Intrathecal chemotherapy was given regardless of signs of overt CNS involvement. The planned duration of this program was 65 days. From 1992 onward, only one regimen (regimen II, Fig 3) was used for stage III to IV patients. Regimen II was identical to regimen IB but omitted the final ifosfamide course and lasted 45 days in all. Protocols were not amended to include granulocyte colony-stimulating factor (G-CSF) guidelines, but since 1997, G-CSF was used in case of fever and neutrophils less than 0.5 x 109/L according to medical decision. There was no provision for chemotherapy-dose reduction. Second-look surgery was considered in the case of residual masses being detected before HD ara-C–cisplatin administration. The treatment strategy did not provide radiation therapy, but in 1995, a 10-year-old boy received radiotherapy on a residual brain lesion.
Response Criteria and Statistics EFS and disease-free survival (DFS) were defined as the interval from registration to the earliest adverse event (induction failure, relapse, or death from any cause) and to disease progression or relapse, respectively. Children with no adverse events were censored at the latest follow-up. Actuarial curves were constructed by the Kaplan-Meier method.18 Subgroup comparisons were drawn using the log rank test.19
Patient Characteristics Fifty-nine of the 60 children registered were evaluated for response; there were 49 boys and 10 girls, whose age at diagnosis ranged from 2.1 to 17 years (median, 9 years). Median lactic acid dehydrogenase at diagnosis was 1,212 U/L (range, 223 to 23,889 U/L); median uric acid was 6.8 mg/dL (range, 2.2 to 13.8 mg/dL). The majority of patients exhibited prominent abdominal or pelvic stage III lymphoma. Thirty-seven children were classified with Murphy’s stage III disease, 19 with stage IV, and three with extensive facial stage II. The patients’ characteristics are listed in Table 1. The abdomen was involved in 52 out of 59 patients, and 26 of these had synchronous extra-abdominal disease at one or more sites. Of children with stage IV BL, five had BM involvement alone, eight were CNS positive with no BM involvement, and six had combined BM and CNS disease. In the series as a whole, 11 children were BM positive (all with < 25% blasts), and 14 displayed signs of CNS involvement at diagnosis. CNS disease included cranial nerve palsy in 10 (one displayed blasts in spinal fluid as well), meningeal spread in one, and parenchymal lymphoma in the brain in three. One child was excluded from the CNS disease group on the basis of extradural cord compression alone but was classified as stage IV because of lung and bone involvement.
Outcome Forty-eight of the 59 assessable children were alive in first CR at a median follow-up period of 6.7 years (range, 0.6 to 13.5 years). Eleven children died, six as a result of lymphoma progression and five as a result of toxicity. DFS, EFS, and OS rates at 5 years were 87% ± 5%, 81% ± 5%, and 79% ± 6%, respectively, for the group as a whole, 85% ± 7% and 73% ± 8% (EFS and OS) for the 30 patients in groups IA and IB, and 89% ± 6% (DFS and EFS) and 88% ± 6% for the 29 patients in group II. Figures 4 to 6 illustrate the Kaplan-Meier estimate of survivals for each group. The EFS for stage IV children was 82% on regimen IB (n = 11; 65 days of therapy) compared with 88% on regimen II (n = 9; 45 days) (the difference is not statistically significant). The EFS rate for all CNS-positive patients was 79%. Before the start of the HD ara-C–cisplatin consolidation phase of each treatment regimen, CR and PR were achieved in 48 and 11 patients, respectively, for an overall response rate of 98%. The disease of only one patient progressed, after the patient displayed transient signs of response to chemotherapy. Of the 11 patients who partially responded, eight achieved CR after HD ara-C–cisplatin therapy, one patient with primary CNS lymphoma did so only after irradiation, and two died as a result of toxicity. As a result of the residual abdominal masses before phase II chemotherapy, second-look surgery was performed in eight patients; five were confirmed as being tumor-free. Two additional children required laparotomy for complications, and the clinical remission status was pathologically confirmed in both cases. In all, three of the 10 surgical explorations displayed viable lymphoma before the ara-C–cisplatin phase. All patients without detectable disease are alive and in continuous CR; two of the three with viable disease died (one as a result of progression and one as a result of toxicity).
Six children experienced relapse, and one displayed no response during induction (n = 4 stage III, n = 3 stage IV). All but one relapse occurred within 4 months of completion of treatment; one histologically confirmed late recurrence occurred at 35 months. All but one of the patient who experienced relapse died as a result of lymphoma; the single exception died during second remission of allogenic BM transplant–related toxicity. BM, CNS, or both were initially positive in three of seven patients who experienced relapse (two treated with regimen IB and one treated with regimen II). The most frequent site of tumor recurrence was at the primary site: the disease of four children recurred in the abdomen (plus BM in one patient), one in multiple sites (plus BM and CNS), and one in testes; there was a single isolated CNS relapse.
Adverse Events At the start of treatment, one third of the children experienced impaired renal function as a result of kidney infiltration or acute cell lysis, with creatinine clearance less than 40 mL/min; early metabolic or renal dysfunction prompted hemodialysis in one patient. As a result of incomplete renal function recovery, the first scheduled HDMTX had to be postponed and replaced by DOX or VP16 in nine patients. During phase I of each treatment schedule, WBC less than 1.0 x 109/L and platelets less than 75,000/mm3 were observed in 65% and 41% of patients, respectively, with a slightly higher incidence in patients receiving regimens containing VP16 (regimens IB and II v regimen IA). During phase I, pancytopenia was always reversible within a few days, with febrile neutropenic episodes occurring in 85% of children, although they were never life-threatening; the episodes were the result of documented bacteremia in 18% of cases. Transient transaminitis was frequently recorded, although nadir values corresponding to National Cancer Institute common toxicity criteria grade 4 were only observed in three patients. During consolidation phase II, all children had neutropenia less than 0.1 x 109/L, within a median 3 days (range, 1 to 10 days) of the end of HD ara-C, and a WBC recovery a median of more than 1.0 x 109/L after 14 days (range, 9 to 24 days). The median period with neutropenia less than 0.5 x 109/L was 10 days. Platelet counts less than 25,000/mm3 were observed in 91% of patients within a median of 6 days (range, 1 to 10 days) after discontinuing ara-C–cisplatin. Packed RBCs and platelet transfusions were given to 94% and 81% of the children, respectively. In 97% of patients, IV antibiotics were required for temperature exceeding 38°C, although positive blood cultures for bacteria were only obtained in 30% of cases. The incidence of central venous line–related bacteremia declined over the study period: 33% of children developed a central venous line infection from 1987 to 1992 and 21% from 1992 onward. For National Cancer Institute common toxicity grade 3 to 4 mucositis, persistent anorexia, or both, total parenteral nutrition was maintained for a time ranging from 5 to 15 days (median, 11 days) in 79% of the children. Transient neurotoxicity related to HD ara-C or HD ara-C–intrathecal interaction was documented in four patients. Acute reversible encephalopathy from ifosfamide occurred in two of 11 children receiving regimen IB and was associated with transient renal function impairment and sodium loss. No severe infectious complications were observed in the human immunodeficiency virus–positive child, despite specific anti–human immunodeficiency virus therapy being temporarily discontinued.
In pediatric B-cell lymphoma, the intensive regimens currently used by cooperative groups in Europe and the United States have resulted in high EFS rates, nearing 90%.14,19 The short-pulse chemotherapy used results in a high dose intensity with a view to achieving the maximum cell death over a relatively short period of time (2 to 8 months, considering all stages). Reiter et al14 reported the Berlin-Frankfurt-Münster experience, with 89% EFS for all stages mature B-cell neoplasms in children and 78% for the advanced R3 risk group. Serial studies from the French Society for Pediatric Oncology achieved more than 80% DFS in stage III or IV (with CNS-positive patients receiving 24-Gy cranial irradiation),20,21 and the Pediatric Oncology Group reported 79% EFS for patients with stage IV disease.22 Comparable reports come from other groups too.23-25 With the first B-cell neoplasm-focused study performed at our institute before 1982, a good outcome was observed in limited-stage BL, but fewer than 60% of stage IV patients achieved cure.15 The goal of our current treatment plan is to encompass the tumor generation time, as well as to provide a smoother induction of therapy, with fewer metabolic complications and without early myelosuppression. It is noteworthy that it is not necessary to administer the maximum therapy in the early days of treatment. The median time necessary to complete the ongoing therapy was 56 days (range, 49 to 69 days), so the planned dose-intensity of the protocol was maintained in most of the patients. The HD ara-C–cisplatin consolidation course is associated with the greatest morbidity and mortality risk, but better supportive care and a more comprehensive use of G-CSF and antibiotics have enabled us to avoid deaths due to toxicity in the latest series of patients. Late sequelae, including anthracycline-induced cardiomyopathy, sterility, and second malignancies, are a concern in children, given their long life expectancy. With the cumulative DOX dose of 50 mg/m2 used in our regimens, no clinical cardiotoxicity has been observed so far. Few of the patients have had a sperm count after treatment, but it may be that fertility is preserved because of the small cumulative cyclophosphamide dose (1 g/m2). Finally, no second malignancies have been observed. Despite acute morbidity, the quality of survival is excellent, with all our patients experiencing normal growth and development. Although data from the literature do not unequivocally confirm CNS involvement or higher lactate dehydrogenase levels as independent adverse prognostic factors,14,20,22,26,27 the outcome is worse in BM- and CNS-positive patients. The prognostic impact of stage IV and B-cell acute lymphoblastic leukemia was not significant in the last non-Hodgkin’s lymphoma Berlin-Frankfurt-Munster study (NHL-BFM 90), but EFS for children with initial CNS disease was 65%. In our series, a more detailed analysis of relapsing patients, focusing on adverse prognostic factors, could not be undertaken because of the relatively small number of cases. In our experience, intensifying the therapy and improving the supportive care and management of infections have increased EFS in the latest series of children from the historical 63% to 89%, and in stage IV from 57% to 88%. Because our attempt to reduce the therapy in selected patients, as we did in regimen IA, failed (two low-risk patients out of 19 treated on regimen IA experienced relapse), from 1992 onward, only one schedule has been applied, regardless of any BM or CNS disease at diagnosis. The main changes consisted of MTX dose intensification, the addition of VP16, and a change in ara-C infusion method. These changes seem to have resulted in an improved outcome, although no evidence has emerged of a negative impact of omitting ifosfamide, thus reducing the total duration of chemotherapy. Given the low failure rate in CNS disease, we conclude that CNS-directed therapy based on six intrathecal therapy courses in conjunction with HDMTX and HD ara-C was effective in preventing CNS relapse, with no discernible risk of acute or late neurotoxicity. Considering the significant proportion of patients with viable lymphoma when second-look surgery was performed before HD ara-C course, we consider this drug crucial in eradicating residual malignant cells at the end of induction. Our results compare favorably with those of recent trials. The regimen II in current use is generally concluded in less than 2 months (median duration, 56 days v the 45 days scheduled), and to the best our knowledge, this represents the shortest treatment strategy for disseminated BL. The outcome supports the assumption that there is no benefit in prolonging therapy. The aim of our next therapeutic studies will be to reproduce the high CR rates while attempting to reduce metabolic and infectious morbidity.
1. Murphy SB, Bowman WP, Abromowitch M, et al: Results of treatment of advanced stage Burkitt’s lymphoma and B cell (Sig+) acute lymphoblastic leukaemia with high-dose fractionated cyclophosphamide and coordinate high-dose methotrexate and cytarabine. J Clin Oncol 4: 1732-1739, 1986[Abstract]
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Patte C, Philip T, Rodary C, et al: Improved survival rate in children with stage III and IV B-cell non-Hodgkin’s lymphoma using multiagent chemotherapy: Results of a study of 114 children from the French Pediatric Oncology Society. J Clin Oncol 4: 1219-1226, 1986 3. Sullivan M, Ramirez I: Curability of Burkitt’s lymphoma with high-dose cyclophosphamide, high-dose methotrexate therapy and intrathecal chemoprophylaxis. J Clin Oncol 3: 627-626, 1985[Abstract] 4. Philip T, Senior GM, Bryon PA, et al: Burkitt type lymphoma in France among non-Hodgkin malignant lymphomas in Caucasian children. Br J Cancer 45: 670-678, 1982[Medline]
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Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84: 1361-1392, 1994
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Lones MA, Auperin A, Raphael M, et al: Mature B-cell lymphoma/leukaemia in children and adolescents: Intergroup pathologist consensus with the Revised European-American Lymphoma classification. Ann Oncol 11: 47-51, 2000 7. Gasparini M, Lombardi F, Gianni MC: Childhood non-Hodgkin’s lymphoma: Prognostic relevance of clinical stages and histologic subgroups. Am J Pediatr Hematol Oncol 5: 161-171, 1983[Medline] 8. Murphy SB: Classification, staging and results of treatment of childhood non-Hodgkin lymphoma: Dissimilarities from lymphomas in adults. Semin Oncol 7: 332-339, 1980[Medline]
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Magrath IT, Janus C, Edwards BK, et al: An effective therapy for both undifferentiated (including Burkitt’s) lymphomas and lymphoblastic lymphomas in children and young adults. Blood 63: 1102-1111, 1984 11. Murphy SB, Fairchlough DL, Hutchinson RE, et al: Non-Hodgkin’s lymphoma of childhood: An analysis of the histology, staging, and response to treatment of 338 cases at single institution. J Clin Oncol 7: 186-193, 1989[Abstract] 12. Sandlund JT, Downing MD, Crist WM: Non-Hodgkin’s lymphoma in childhood. N Engl J Med 9: 1238-1284, 1996
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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 Oncol 13: 359-372, 1995
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Reiter A, Schrappe M, Tiemann M, et al: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Munster group trial NHL-BFM 90. Blood 94: 3294-3306, 1999 15. Gasparini M, Rottoli L, Massimino M, et al: Curability of advanced Burkitt’s lymphoma in children by intensive short-term chemotherapy. Eur J Cancer 29A: 692-698, 1993[CrossRef][Medline] 16. Ferrari A, Perotti D, Giardini R, et al: Disseminated Burkitt’s lymphoma after kidney transplantation: A case report in a boy with Drash syndrome. J Pediatr Hematol Oncol 19: 151-155, 1997[CrossRef][Medline] 17. Lennert K, Feller AC: Histopathology of Non-Hodgkin’s Lymphomas (Based on the Updated Kiel Classification). New York, NY, Springer, 1992 18. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef] 19. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc A 135: 185-198, 1972 20. Patte C, Michon J, Behrendt H, et al: Updated results of the LMB 89 protocol of the SFOP (French Pediatric Oncology Society) for childhood B-cell lymphoma and leukemia (ALL). Ann Oncol 7: 30, 1996 (abstr)
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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 Oncol 14: 1252-1261, 1996 23. Atra A, Gerrard M, Hobson R, et al: Improved cure rate in children with B-cell acute lymphoblastic leukaemia (B-ALL) and stage IV B-cell non-Hodgkin’s lymphoma (B-NHL): Results of the UKCCSG 9003 protocol. Br J Cancer 77: 2281-2285, 1998[Medline]
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Schwenn MR, Blattner SR, Lynch E, et al: HiC-COM: A 2-month intensive chemotherapy regimen for children with stage III and IV Burkitt’s lymphoma and B-cell acute lymphoblastic leukemia. J Clin Oncol 9: 133-138, 1991 25. Adde M, Shad A, Venzon D, et al: Additional chemotherapy agents improve treatment outcome for children and adults with advanced B-cell lymphomas. Semin Oncol 25: S33-S39, 1998 (suppl 2) 26. Cairo M, Krailo M, Morse M, et al: Disseminated non-lymphoblastic non-Hodgkin’s lymphoma (DNLNHL) of childhood: A randomized phase II trial of short intensive treatment. Ann Oncol 7: 29, 1996 (abstr) 27. Brecher ML, Schwenn MR, Coppes MJ, et al: Fractionated cyclophosphamide and back to back high dose methotrexate and cytosine arabinoside improves outcome in patients with stage III high grade small non-cleaved cell lymphomas (SNCCL): A randomised trial of the Pediatric Oncology Group. Med Pediatr Oncol 29: 526-533, 1997[CrossRef][Medline] Submitted August 13, 2001; accepted March 15, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
