Departments of 1 Medical Oncology; 2 Pathology, The Norwegian Radium Hospital, University of Oslo, Montebello, Oslo; 3 Department of Medicine, Section of Haematology, University Hospital, Trondheim, Norway
*Correspondence to: Dr H. Holte, Department of Medical Oncology, The Norwegian Radium Hospital, University of Oslo, Montebello, 0310 Oslo, Norway. Tel: +47-22-93-48-82; Fax: +47-22-52-55-59;; Email: harald.holte{at}klinmed.uio.no
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Abstract |
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Patients and methods: Forty-nine patients aged 1570 years admitted to the Norwegian Radium Hospital in the period 19822001 with a diagnosis of BL/BLL on histological review and who were given chemotherapy with curative intent are included in this analysis. Up to 1987 patients were given doxorubicin-based chemotherapy supplemented with intravenous and intrathecal methotrexate (MmCHOP). From 1987 to 1994, patients who obtained complete remission upon this regimen were consolidated with high-dose therapy with stem-cell support (MmCHOP + HDT). In 1995 we introduced as frontline therapy the German BerlinFrankfurtMunster (BFM) regimen.
Results: By intention to treat analyses, the progression-free survival rates for patients who received MmCHOP (n=13), MmCHOP + HDT (n=17) or BFM therapy (n=19) are 30.8%, 70.6% and 73.7%, respectively. In the groups of patients who received either the BFM regimen or MmCHOP + HDT, all patients who obtained complete remission upon induction therapy are continuously disease free. There was no treatment-related death.
Conclusions: BL/BLL in adolescents and adults can successfully be treated with 5-day blocks of intensified chemotherapy such as the BFM regimen or CHOP/methotrexate-based chemotherapy consolidated with high-dose therapy. Using the BFM regimen, continuous remissions are obtained without additional myeloablative chemotherapy.
Key words: BFM chemotherapy, Burkitt's lymphoma, high-dose therapy
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Introduction |
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Standard doxorubicin-based combination chemotherapy, such as CHOP, frequently induces remissions of short duration [2, 3
]. In an attempt to obtain durable remissions, high-dose therapy (HDT) with autologous stem-cell support was given in a few centres for patients who were in remission upon CHOP-like induction therapy [4
6
]. In the last decade, several paediatric groups have obtained impressive results for BL- and B-cell acute lymphoblastic leukaemia patients by giving blocks of intensified chemotherapy for five to seven consecutive days with 2- to 3-week intervals [7
11
]. In the German BerlinFrankfurtMunster (BFM) regimen, fractionated cyclophosphamide and ifosfamide as well as high-dose methotrexate with calcium folinate rescue and central nervous system (CNS) prophylaxis appear to be of special importance [10
12
]. The treatment is of brief duration, and it does not contain maintenance therapy. The intensity and duration of the chemotherapy is modified by the risk category of the lymphoma. Five-year disease-free and overall survival >90% in paediatric patients have been reported from this and other groups. In the German Adult Acute Lymphoblastic Leukaemia (ALL) 05/93 protocol, the BFM-90 protocol was adjusted with dose modifications for adult patients.
The Norwegian Radium Hospital (NRH) is the referral centre for diagnosis and treatment of lymphoblastic and Burkitt's lymphoma in South/East Norway, serving a population of 2 million inhabitants. During the time period 19822001, 49 patients were admitted with a diagnosis of BL/BLL and given therapy with a curative intent. All these patients are included in the current analysis. Between 1982 and 1987, 13 patients aged 1560 years received standard doxorubicin-based therapy supplemented with intravenous and intrathecal methotrexate (MmCHOP). In the following period (19871994) patients in the same age group (n=17) with chemo-responsive disease on induction with MmCHOP, were given consolidating HDT with autologous stem-cell support. From 1995, 19 patients aged 1570 years have been treated according to the BFM protocol. Here, we report on the outcome of patients treated with the various regimens.
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Patients and methods |
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Diagnosis and pathology review
All histological material from the cases included has been reviewed for the study, and the diagnoses were established according to the World Health Organisation (WHO) criteria [14].
Immunomagnetic purging and haemopoietic progenitor cell assessment
Mononuclear cell (MNC) fractions were prepared either by the use of a 2991 Cobe Cell Processor (1185, Oak Street, Lakewood, USA) and Ficoll (Lymphoprep, Nycomed, Oslo, Norway) or without Ficoll in a CS-3000 Plus Blood Cell Separator (Baxter Healthcare Corporation, Fenwal Division, Deerfield, IL, USA). One patient received stem cells harvested from blood (PBPC). The combination of antibodies used for purging with immunomagnetic beads was selected on the basis of the antigen expression of the individual B-cell lymphomas. Anti-CD19, CD20, CD22, CD23, CD37 monoclonal antibodies of IgG subtypes were used (Baxter Biotech, Deutschland GmbH, Immunotherapy Division, Munich, Germany). The purging efficacy and safety using immunomagnetic beads are described elsewhere [15, 16
]. All patients except two received a purged graft.
Treatment
From 1982 to 1987 patients up to age 60 years received eight courses of CHOP supplemented for the first six cycles with an intermediate dose of methotrexate (2 g/m2) given intravenously with calcium folinate rescue and intrathecal (12 mg) methotrexate (MmCHOP). From 1987 to 1994, patients who obtained a complete or very good partial remission upon MmCHOP were, after oral and written informed consent, included in a phase II study. In this study, approved by the Local Ethics Committee, the patients received additional high-dose therapy [cyclophosphamide 120 mg/kg and total body irradiation (TBI), 13 Gy in 10 fractions/5 days, dose to the lungs reduced to 10.4 Gy]. The harvested and purged bone marrow cells (11 of 13 patients) or purged PBPC (one patient) were subsequently thawed and reinfused through a central line. From 1995, patients received therapy according to BFM protocol-90 ([11] and Figure 1
) with methotrexate adjustments for patients >50 years as described in the German Adult ALL 05/93 protocol. In addition, patients were stratified into therapy arms by risk groups according to the protocol [12
]. Patients who only obtained a partial remission after BFM therapy were candidates for HDT with the BEAM regimen. According to the ASCO guidelines [17
], patients who were treated with the BFM regimen after 1997 received growth factor support with filgrastim injections to alleviate neutropenia.
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Results |
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Toxicity and engraftment after high-dose therapy
Bone marrow engraftment occurred in all patients, except for one patient who had previously received BFM therapy and transplanted in partial remission. He never reached absolute neutrophil count (ANC) >0.5 x 109/l and progressed 1 month after transplantation. There were no treatment-related deaths. The median time for ANC recovery (>0.5 x 109/l) was 19 days (range 927), and the median time for platelet recovery (>20 x 109/l) was 21 days (range 12196). Use of filgrastim after HDT has not been standard treatment at our institution. Thus, only three patients received filgrastim after HDT. One patient with delayed platelet engraftment had haemorrhagic cystitis with no major complications and she also had an epidural bleeding 3 months after HDT, from which she recovered without sequelae.
Toxicity and feasibility of BFM therapy
Nineteen patients received one to seven courses with BFM therapy. Thirteen patients received the planned therapy without dose reduction. Two patients received only one course due to early death, and four had minor dose reductions (510%) due to mucositis. For the 17 patients that received more than one course, five had no delay in therapy, nine had up to 1 week total delay and three 12 weeks delay. Delayed haematological reconstitution was the main cause of prolonged treatment duration. Therapy was feasible also in patients 6070 years of age, with all four patients in this age group receiving the scheduled therapy within a total delay of <2 weeks. The haematological toxicity was severe but manageable, with 55% of the courses followed by febrile neutropenia. Eighty-nine per cent of the patients experienced febrile neutropenia and 68% of the patients were in need of platelet transfusions any time during therapy. Seven patients had one or two episodes with bacteriologically documented septicaemia, but no deaths due to infection during neutropenia were observed.
Response and survival
Outcome data are presented in Table 2. Seven of 13 (19821987) and 12 of 17 (19871994) patients obtained CR after MmCHOP induction therapy and 14 of 19 patients after BFM-based therapy. All patients who obtained CR to MmCHOP + HDT or BFM are continuously disease free from BL/BLL. Two patients receiving BFM therapy died within a week of diagnosis in a mixed pattern of acute tumour cell lysis syndrome and infection. Of the three patients who did not achieve CR after initial BFM treatment, one patient received HDT, but eventually died of lymphoma. One patient treated according to the BFM-based protocol was diagnosed with a peripheral T-cell lymphoma 4 years after the diagnosis of BL and died from the T-cell lymphoma with no evidence of relapsed BL in tumour tissue. The number of patients in each treatment group with CNS progression or CNS involvement at relapse is also given in Table 2
.
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Discussion |
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The treatment results obtained during the last two decades from the use of multiagent chemotherapy regimens for children with BL or BLL is a major achievement [712
]. In addition, promising results for adult patients including those with advanced disease have been reported from several groups [9
, 18
21
]. Soussain et al. [18
] reported on 65 adult patients with BL or Burkitt's acute leukaemia who were treated with a paediatric intensive protocol. With a median follow-up of 57 months, the 3-year overall survival-rate was 74%. Mead et al. [19
] have comparable results from an international phase II study for adult patients with a similar design employing alternating blocks of intensive chemotherapy. Magrath et al. [9
], using a protocol designed for paediatric patients, reported that all 20 adult patients remained alive and free of disease with a median follow-up of 32 months.
There have been very few reports of HDT with autologous stem-cell support in BL and no randomised study reporting treatment results of HDT versus conventional multiagent chemotherapy. The 13 patients transplanted in first CR after initial treatment according to an LMB protocol in the Soussain series [18] did less well than the rest of the patients reported. The data from the EBMT registry [6
] showed a 2-year actuarial PFS of 72% for 70 adult BL patients treated in first CR compared to 37% for patients with chemo-sensitive relapse (
2 CR). Our results with MmCHOP + HDT in BL are promising, with no relapses or toxic deaths. However, our results reported here may be skewed due to the inclusion of patients with stage I disease (four patients). Those patients were, in retrospect, likely to be cured with conventional chemotherapy.
All patients, except one given MmCHOP + HDT, received a purged graft. Few studies have examined in vitro purging techniques for BL or BLL [22], and the question whether purging of the autograft is beneficial for patient outcome remains unclear. Most of the clinical studies in lymphoma patients treated with HDT and purged bone marrow have included tumours of all histology grades; thus the benefit of purging in the few included adult BL patients in these studies could not be evaluated. Recently, a study from the EBMT revealed that purging did not affect engraftment or overall survival [23
].
Compared with results from recent studies, the outcome in our analysis, both with the BFM-based regimen and with MmCHOP consolidated with HDT, was satisfactory. Consolidation with HDT after BFM-based therapy is unlikely to improve survival. Although long-term toxicity of the BFM regimen may prove considerable, considerations of documented toxicity may favour the use of BFM-based therapy compared with MmCHOP plus HDT. First, myeloablative therapy is associated with a distinct risk of developing myelodysplasia [24, 25
]. Secondly, the prescribed cumulative dose of doxorubicin is much higher with eight courses of CHOP compared to the BFM regimen (400 mg/m2 versus 100150 mg/m2). Younger patients are considered vulnerable to doxorubicin-induced cardiotoxicity at doses <300 mg/m2 [26
]. Thirdly, HDT may be associated with a higher risk of infertility compared to intensive conventional regimens [27
], although an inferior chance of childbirth after HDT compared to conventional chemotherapy could not be confirmed in a recent French study [28
]. Based on the similar treatment outcome, the favourable long-term toxicity of BFM chemotherapy and the high economic costs of HDT, we consider BFM chemotherapy as the current standard treatment for BL/BLL in patients up to 70 years of age.
Biologically, it is interesting that consolidating a remission after primary CHOP-like chemotherapy for BL with HDT yields a survival benefit while the same has been difficult to demonstrate for diffuse large B-cell and peripheral T-cell lymphomas [29, 30
]. Possibly, the daily intensive high-dose cytotoxic and/or radiotoxic therapy for five to six consecutive days is of special value for tumours where close to 100% of the tumour cells are in the cell cycle. The recommended BL therapies, of which the BFM-based regimen is one example, take advantage of the same principle by giving chemotherapy in blocks of five to seven consecutive days. Such therapies may kill virtually all tumour cells as they go through the cell cycle within that time frame.
In conclusion, CHOP/methotrexate-based chemotherapy consolidated with HDT as well as short intensive BFM-based therapy without consolidation produce similar results with significant, but feasible toxicity in patients with BL/BLL up to 60 (70) years. The outcome is superior to CHOP-based regimens strengthened with CNS prophylaxis (MmCHOP).
Received for publication November 24, 2003. Revision received February 18, 2004. Accepted for publication February 24, 2004.
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