1 Wessex Medical Oncology Unit, Royal South Hants Hospital, Southampton, UK; 2 Cancer Division, MRC Clinical Trials Unit, London, UK; 3 Lymphoma Department A, Centre of Oncology, M.Sklodowska-Curie Memorial Institute, Warsaw, Poland; 4 Clinical Haematology & Medical Oncology, Royal Melbourne Hospital, Melbourne, Australia; 5 Department of Haematology, John Radcliffe Hospital, Oxford, UK; 6 Ospedale Generale Regionale Bolzano, Bolzano, Italy; 7 Department of Haematology/Ematologica, Ospedale Cervello, Palmero, Italy; 8 Department of Haematology, Singleton Hospital, Swansea, UK; 9 Department of Clinical Haematology & Medical Oncology, Box Hill Hospital, Victoria, Australia; 10 Electron Microscopy, Southampton General Hospital, Southampton, UK
Received 11 February 2002; accepted 26 February 2002
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Abstract |
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Burkitts lymphoma (BL) is a rare and rapidly progressive form of B-cell non-Hodgkins lymphoma. Cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate (CODOX-M)/ifosfamide, etoposide and high-dose cytarabine (IVAC) is a highly effective alternating non-cross-resistant regimen developed by Magrath et al. (Magrath I., Adde M., Shad A. et al. J Clin Oncol 1996; 14: 925934) at the US National Cancer Institute. The aim was to confirm these results in a larger, international, multi-centre study using International Prognostic Index-based criteria to assign prognostic groups, whilst slightly simplifying the protocol.
Patients and methods:
A phase II study where: (i) low risk (LR) patients were treated with three cycles of modified CODOX-M; and (ii) high risk (HR) patients received treatment with four cycles of alternating modified CODOX-M and IVAC chemotherapy. Target of 60 patients, fit for protocol treatment, from 16 to 60 years of age with locally diagnosed, non-HIV-related, non-organ-transplant-related BL.
Results:
Results are given for 52 of 72 registered patients whose pathological eligibility was confirmed by central pathology review: 12 LR plus 40 HR. The majority of patients (n = 41) completed protocol treatment, but toxicity was severe, especially myelosuppression and mucositis. Overall, 2-year event-free survival (EFS) was 64.6% (95% CI 50.4% to 78.9%) and 2-year overall survival (OS) was 72.8% (95% CI 59.4% to 86.3%). For LR, 2-year EFS was 83.3% and OS was 81.5%. For HR, 2-year EFS was 59.5% and OS was 69.9%.
Conclusions:
This study confirms high cure rates with this CODOX-M/IVAC approach.
Key words: Burkitts lymphoma, chemotherapy, CODOX-M, IVAC
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Introduction |
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Burkitt-like lymphoma (B-LL) is a pathologically less well-defined lymphoma sub-type that is sometimes described as being associated with additional chromosomal translocations [1, 2, 48]. In the recent World Health Organization (WHO) Classification of Neoplasms of the Lymphoid System, B-LL has been identified as a sub-type of Burkitts lymphoma [2].
Historically BL and B-LL have been treated together as diffuse small non-cleaved lymphoma according to the Working Formulation Classification [9]. In recent years, it has been increasingly recognised that cure [event-free survival (EFS) 1 year] is possible in a large majority of these neoplasms if appropriate intensive (although relatively brief) intravenous chemotherapy is given supplemented by intrathecal drugs. Whilst these results were initially described in paediatric series [1018], recent series suggest that young adults can achieve similar results [1925].
Cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate (CODOX-M)/ifosfamide, etoposide and high-dose cytarabine (IVAC) is an alternating non-cross-resistant regimen developed at the National Cancer Institute. The treatment of 20 adults and 21 children with small, non-cleaved NHL achieved an overall 92% 2-year EFS rate (100% in adults) [26]. It was decided to attempt to confirm these results in BL, a more precisely defined neoplasm. This larger study [United Kingdom Lymphoma Group (UKLG) LY06] planned to use International Prognostic Index (IPI)-based criteria [27] to divide patients into prognostic groups, whilst simplifying the protocol in view of previous vincristine-related neuropathy.
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Patients and methods |
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Registration entry criteria were broad in order to be as inclusive as possible. Eligible patients were aged from 16 to 60 years with non-HIV, non-organ-transplant-related BL, not previously treated with chemotherapy or radiotherapy and considered sufficiently physiologically and psychologically fit to receive the treatment protocol. Patients with severe organ dysfunction related to this diagnosis (most commonly acute renal failure) were eligible and were permitted to receive a single cycle of pre-induction low-dose chemotherapy [e.g. 50% dose cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)] to improve their clinical condition.
Appropriate ethical approval was gained for each centre, informed consent was obtained and the trial adhered to the Declaration of Helsinki.
Following a diagnosis of BL from the local pathologist, patients were evaluated urgently by physical examination with assessment of WHO performance status and measurement of tumour diameters. Blood was obtained for complete blood cell count (cbc), biochemical profile, lactate dehydrogenase (LDH) and urate levels. In addition, a chest X-ray, computed tomography of the chest, abdomen and pelvis, and bone scanning were performed. Bone marrow aspirate and trephine were obtained and a diagnostic lumbar puncture performed with instillation of intrathecal cytarabine.
After investigation an Ann Arbor stage was obtained. Patients were then allocated to a risk group on the basis of the age-adjusted prognostic index modified by allocation of patients with bulky disease to the high risk (HR) group. Thus, those patients with all of the following features were regarded as low risk (LR): (i) normal LDH level; (ii) WHO performance status of 0 or 1; (iii) Ann Arbor stage III; and (iv) no tumour mass 10 cm. All remaining patients were considered HR.
Patients were registered by contacting the CTU or ALLG, who subsequently collected all data. Analyses were performed at the CTU.
Treatment
Prior to chemotherapy, patients commenced oral allopurinol followed by intensive intravenous hydration; a standard anti-tumour lysis protocol was initiated.
Low risk patients were treated with three cycles of modified CODOX-M (protocol A); HR patients received treatment with four cycles of alternating modified CODOX-M and IVAC chemotherapy (protocol B) [26].
Therefore, all patients commenced protocol treatment with CODOX-M (Table 1). Prior to the administration of high-dose methotrexate, creatinine clearance had to be >50 ml/min (24-h urine collection or radioisotope technique). Methotrexate was administered regardless of cbc. The infusion was discontinued at 24 h regardless of the dose given. Leucovorin commenced 36 h after starting methotrexate infusion and continued until the serum methotrexate level was <5 x 108 M. Filgrastim 5 µg/kg (or 1 x 263 µg ampoule) was given sub-cutaneously from day 13 until the absolute granulocyte count was >1 x 109/l, when it was discontinued.
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Evaluation of response
The primary end point was EFS, defined as progressive disease at any time or death from any cause. Overall survival (OS) was an important secondary endpoint. Additionally, patients were evaluated for response using conventional criteria. Formal response evaluation took place 34 weeks following the final chemotherapy administration. Complete remission (CR) was defined as complete resolution of all evidence of lymphoma both clinically and radiologically. Partial remission (PR) implied a >50% reduction in the sum of the product of the perpendicular diameters of all measurable lesions. Progressive disease implied >25% increase in the size of lesions as defined for PR. All remaining patients had no response (NR). It was recommended that, following restaging, patients received follow-up monthly for 4 months, then two monthly for 1 year, with decreasing follow-up thereafter. After initial response evaluation, no routine follow-up CT scans were recommended.
Pathology review
Sections from all cases were to be reviewed centrally. Slides were stained by haematoxylineosin (H&E) and Giemsa techniques, and using the Ki-67 proliferation antigen. A diagnosis of BL was accepted when characteristic morphology was present together with 100% nuclear labelling on Ki-67 stained slides [2]. During the course of this study, the category B-LL was not accepted since this was not precisely defined and was liable to subjective interpretation. No routine cytogenetics were performed on tissue samples, as these were not routinely available at the time the protocol was written.
Statistical considerations
A sample size of 60 patients meeting all the eligibility criteria, and having a diagnosis of BL confirmed on independent pathological review, was planned. Equal numbers of LR and HR patients were anticipated. This number should generate sufficient events to allow 2-year EFS rate estimation with standard error <7%.
Event-free survival and OS rates are displayed using KaplanMeier curves with time starting from the date protocol chemotherapy began. Estimates of EFS at a given time are displayed as a point estimate with the 95% confidence interval (CI) in parentheses. Exploratory analyses of a limited number of potential prognostic factors were carried out in which EFS rates were compared using the log-rank test; where categories were ordered, the log-rank test for linear trend was used.
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Results |
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Sufficient histological material for the essential independent central pathological review was available in 65 of 72 patients: a diagnosis of BL was confirmed in 52 (80%) cases. The remaining patients (n = 13) were diagnosed on review as cases of diffuse large B-cell lymphoma (DLBCL). Overall, central pathology review disagreed with the local diagnosis in 20% of registered cases. The results presented here are for this core group of 52 eligible BL patients.
Patient characteristics
Baseline characteristics are shown in Table 3. Twelve LR patients were included: all IPI = 0. The primary site included Waldeyers ring (n = 4), small bowel (n = 2), stomach (n = 1), chest (n = 1), nasopharynx (n = 1) and peripheral lymph node sites (n = 3). Forty HR patients were included. Four patients (10%) were IPI = 0, but assigned the HR protocol based on bulk disease. Disease was usually widespread at presentation; however, the most common primary sites identified were ileocaecal (nine patients, 23%) and bone marrow (five patients, 13%). Sixteen HR cases (40%) had bone marrow involvement from aspirate and/or trephine; 34 (85%) underwent evaluation of cerebrospinal fluid (CSF) for cytological involvement with lymphoma after lumbar puncture with three reporting positive. Four other HR patients were reported as having CNS involvement, including two cranial nerve palsies (one CSF positive, one not tested), one extra-dural mass and one with CSF-positive, cranial nerve palsy and an extra-dural mass. There were no cases of intra-cerebral mass. Twenty-six cases (65%) were Ann Arbor stage IV.
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High risk
Thirty patients (75%) completed the protocol-specified four cycles of alternating CODOX-M/IVAC; five patients (13%) received three cycles (reasons for stopping: one fatal disease progression, one toxic death and one fatality recorded as progression and toxicity; one excess toxicity and one patient changed treatment following local pathology revision to acute lymphoblastic leukaemiacentral pathology review disagreed); three patients (8%) received two cycles (one fatal disease progression, one toxic death and one stopped protocol treatment following small bowel perforation with development of multiple intra-abdominal collections of pus) and two patients (5%) received one cycle (one toxic death, one fatality from disease and toxicity).
Seventeen patients (43%) received all four cycles without a reported reduction from protocol-specified dose. The most commonly reduced drug was methotrexate during CODOX-M and cytarabine (IV) during IVAC. The median cycle 12 interval was 24.5 days (range 1640), cycle 23 was 20 days (range 1441) and cycle 34 was 27 days (range 1841).
Toxicities
Toxicity was severe for all patients. All had WHO grade 3/4 white blood cell count toxicities and nearly all had WHO grade 3/4 granulocyte toxicity. Figures 1 and 2 show the worst toxicity grade experienced. During the entire treatment protocol, LR patients required 025 (median 0) platelet units and 032 days (median 17) of treatment with i.v. antibiotics. High risk patients required 090 (median 8.5) platelet units and 067 days (median 19) antibiotics during chemotherapy. The majority of patients on each regimen required blood product support, especially HR patients; this may simply reflect that they received more cycles of chemotherapy.
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Response and survival
All BL patients (LR and HR)
Combining the results for the 52 LR and HR BL patients represents the overall risk-stratified approach of the protocol. Forty patients (76.5%; 95% CI 64.8% to 88.1%) attained CR and five attained PR. Overall 1-year EFS was 69.2% (95% CI 56.5% to 81.9%) and 2-year EFS 64.6% (95% CI 50.4% to 78.9%); 1-year OS was 75.0% (95% CI 63.1% to 86.8%) and 2-year OS 72.8% (95% CI 59.4% to 86.3%). Figure 3 shows EFS and OS for all 52 BL patients, combined.
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The median follow-up time was 35.9 months (range 1056 months). No patient achieving CR has relapsed: each was last known to be alive and well, with no relapse events reported, >6 months after starting chemotherapy.
Event-free survival at 1-year was 83.3% (95% CI 61.3% to 99.0%) and at 2-years 83.3% (95% CI 59.0% to 99.0%); OS rate at 1-year was 91.7% (95% CI 75.3% to 99.0%) and at 2-years 81.5% (95% CI 56.1% to 99.0%). Figures 4 and 5 show EFS and OS for LR patients, respectively.
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The median follow-up time is 32 months (range 359). Event-free survival at 1 year is 65.0% (95% CI 50.2% to 79.8%) and at 2 years is 59.5% (95% CI 43.0% to 76.0%); OS at 1 year is 70.0% (95% CI 54.4% to 85.5%) and at 2 years is 69.9% (95% CI 52.3% to 87.5%). Figures 4 and 5 display EFS and OS for HR patients.
Prognostic factors
The HR group reported here comprises one of the largest groups of consistently treated BL patients in the literature and provides an opportunity to examine prognostic factors, in particular the IPI index, not previously applied to BL patients. This is still, however, a small sample on which to perform these analyses: the findings are considered hypothesis-generating.
Table 4 shows estimates of 1-year EFS for subgroups within this group of 40 patients. A trend was noted towards worsening EFS for older patients, for poorer IPI scores (at least in the short term) and for bone marrow involvement.
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Discussion |
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The literature relating to the treatment of adult BL is scant and derived over a long period of time, and therefore, is difficult to interpret because of conflicting views about classification, the probable inclusion of substantial numbers of the less well-defined B-LL and wide variations in patient mix (e.g. median age, incidence of bone marrow involvement). Certainly the 20% rejection of cases in this series by review pathology illustrates the difficulty of diagnosis of this condition by non-expert pathologists. Many regimens have been tested in adult BL, including a Stanford regimen [19], ProMACE-based therapy [23], the French LMB protocols [22, 24], and the German B-NHL [25] regimen. These series cannot easily be compared (for the reasons cited above), but report cure rates in the range 5070%, often despite bone marrow and CNS involvement [29, 30]. Salvage rates are poor throughout.
The NCI 89-C-41 [26] regimen on which this study was based evolved from long experience of treating childhood high-grade lymphoma with relatively prolonged CODOX-M chemotherapy. IVAC was designed as a salvage regimen which, when it proved moderately effective, was used as part of initial therapy. In the series reported by Magrath et al. [26], 20 adults (five LR, 15 HR) all remained event-free with 1-year minimum follow-up. Notably, all patients had small non-cleaved lymphoma, but most were of non-Burkitt type (no central pathology review was performed). The median age was 24 years, compared with 35 years in this series; the latter is likely to be more representative of the adult population with this condition.
United Kingdom Lymphoma Group LY06 attempted to confirm the results of Magrath et al. [26] in a multi-group, international setting in a more defined group. The combined 2-year EFS and OS of 65% and 73%, respectively, confirm the high efficacy of this treatment regimen in this condition, with cure possible despite CNS or bone marrow involvement. Chemotherapy salvage after relapse was poor and subsequent survival short, as described previously [31], with no obvious role, currently, for high-dose chemotherapy according to this limited data. Furthermore, it would not be possible to support a previously described role for consolidation high-dose therapy for patients in complete remission [32, 33] as relapse rates were low (0% LR, 10% HR).
This regimen is highly toxic, short-term, particularly manifest by myelosuppression and mucositis. Most patients (particularly with HR disease) required relatively prolonged in-patient care; there was a significant toxic death rate. Almost no long-term toxicity was apparent, with preliminary data suggesting recovery of fertility, at least in females.
Prognostic factor analyses were limited by small patient numbers, but indicated a trend to a worsening EFS with increasing age and marrow involvement. Although the IPI system had not been derived for this patient group the results were not inconsistent with expectations: higher IPI scores being associated with worse EFS.
A follow-on clinico-pathological study has been initiated (CRC LY10) with broadened entry criteria: B-cell lymphoma with 100% Ki-67 staining. An attempt will be made to obtain fresh tissue, at presentation, for cytogenetics. Paraffin blocks will be reviewed centrally with fluorescence in situ hybridisation (FISH) studies performed to demonstrate 8;14 and 14;18 translocations, where present. Efforts will be made to make the pathological study all-encompassing by including all protocol-eligible patients, even if untreated, with the recruitment of leukaemic and elderly patients. In an effort to further reduce toxicity, methotrexate doses will be decreased, as will cytarabine in the elderly. This study should better define BL and B-LL clinico-pathologically, and will evaluate the efficacy of CODOX-M/IVAC in high-grade B-cell malignancy of any type.
In summary, BL is a rare neoplasm of young adults which is explosive in onset, often bulky and widespread at presentation, yet highly curable. This study demonstrated high cure rates with CODOX-M/IVAC in an international patient group which included only non-endemic BL using conventional histological criteria.
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Acknowledgements |
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Reference pathologists: Prof. D. Wright (throughout) and Dr A. Jack (March 1999 to April 1999). Coordination: Cancer Division, MRC Clinical Trials Unit (formerly the MRC Cancer Trials Office, Cambridge). MRC statisticians: Prof D. Machin (designOctober 1997), Dr M.K.B. Parmar (October 1997 to March 1998), Dr P.M. Fayers (January 1998 to September 1999), S.P. Stenning (May 1999ongoing) and Mr M.R. Sydes (January 1999ongoing). MRC Trial Co-ordinators/Clinical Trial Managers: Mrs D. Gibson (designJuly 1996), Dr S. Simnett (July 1996 to December 1997), Mr M.R. Sydes (August 1997 to February 2001) and Mrs H. Brooks (March 2001 to June 2001). ALLG Trial Co-ordinator: J. Stone.
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Footnotes |
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United Kingdom Lymphoma Group LY06 collaborators are listed in the Acknowledgements.
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