Salvage chemotherapy with mini-BEAM for relapsed or refractory non-Hodgkin's lymphoma prior to autologous bone marrow transplantation

Annals of Oncology 8: 675-680,1997. © 1997 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Salvage chemotherapy with mini-BEAM for relapsed or refractory non-Hodgkin's lymphoma prior to autologous bone marrow transplantation C. Girouard, J. Dufresne, K. Imrie, A. K. Stewart, J. Brandwein, H. M. Prince, D. Pantolony, A. Keating & M. Crump The University of Toronto Autologous Blood and Marrow Transplant Program, The University of Toronto, Toronto, Ontario, Canada

confidence interval (CI) 28-46%) with 12 patients achieving CR and 25 achieving PR. The response rate among patients Background: The role of intensive chemotherapy with autolo- treated as first salvage was 43% compared to 20% for patients gous blood and marrow transplantation (ABMT) for patients who had failed to respond to a previous salvage regimen. Only with relapsed or refractory intermediate grade non-Hodgkin's 15% of patients who failed to respond to mini-BEAM relymphoma has recently been established. However, conven- sponded to another conventional dose salvage regimen. Thirtytional dose salvage chemotherapy is frequently used to deter- eight of 104 patients ultimately demonstrated sufficient response mine chemotherapy sensitivity and reduce tumor bulk prior to to proceed to ABMT. Actuarial survival at four years is 22% for intensive therapy. Different salvage regimens have been pro- all 104 patients, and 36% for those who went on to ABMT. For posed but none appears significantly superior. The purpose of those who were not transplanted, four-year survival was 18%. this study was to determine the efficacy of mini-BEAM salvage B symptoms and tumor burden at relapse were significant chemotherapy in patients referred for ABMT and to define predictors of response to mini-BEAM in multivariate analysis, prognostic factors of response. and identified a poor prognosis group of patients unlikely to be Patients and methods: One hundred four patients referred cured by this approach. for consideration of ABMT after failure of primary anthraConclusions: Mini-BEAM does not appear to be a superior cycline-based chemotherapy received BCNU 60 mg/m2 day 1, salvage regimen in this high-risk group of relapsed or refrac2 2 etoposide 75 mg/m day 2-5, ara-C 100 mg/m ql2h day 2-5, tory NHL patients for whom ABMT was the ultimate treatmelphalan 30 mg/m2 day 6 (mini-BEAM) until maximum ment intention. Only one-third of patients referred for ABMT tumor reduction. Median age was 52 (range 18-65); 57% had ultimately proceed to transplant; alternative treatment stratfailed to achieve a complete response (CR) to doxorubicin- egies should be developed for those with a low likelihood of based chemotherapy at diagnosis and only 13% had a previous cure by this approach. CR lasting > 12 months. Seventy-six received mini-BEAM as first salvage chemotherapy. Key words: autologous BMT, refractory lymphoma, relapsed Results: The overall response rate (RR) was 37% (95% lymphoma Summary

Although non-Hodgkin's lymphoma (NHL) is generally considered a chemotherapy-sensitive tumor at diagnosis, acquired resistance to chemotherapy is frequently encountered at relapse and is the rule in primary nonresponders. Although salvage treatment can result in tumor response, the prognosis of such patients remains poor [1-4] and many centers have investigated the role of intensive therapy and autologous bone marrow transplantation (ABMT) in an attempt to improve outcome [5-9]. Studies of prognostic factors indicate that chemotherapy sensitivity is a major predictor of outcome following ABMT [10-14]. Conventional dose salvage chemotherapy has been utilized in many published series to determine chemosensitivity and to reduce tumor bulk prior to ABMT. The value of alternative salvage regimens in those patients who fail first-line salvage

chemotherapy is not well documented. Numerous salvage regimens have been proposed with a wide variation in responses reported [1, 2,4,15,16]. We previously reported a 46% partial response (PR) rate and 13% CR rate in 22 patients with refractory or relapsed NHL who were treated with BCNU, etoposide, cytosine arabinoside (ara-Q and melphalan (miniBEAM) as second line salvage following failure with DHAP (dexamethasone, ara-C and cis-platinum) [17]. Based on these encouraging results and our experience with mini-BEAM in relapsed or refractory Hodgkin's disease [18], we began to use this regimen as first-line salvage treatment for patients referred for consideration of intensive therapy and ABMT. All patients referred to our center for relapsed or refractory intermediate grade NHL who received miniBEAM as part of their salvage chemotherapy were included in this analysis. In addition to examining the

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Introduction

676 outcome with this aggressive salvage regimen, we have tried to define prognostic factors for response, to identify patients who do not benefit from this approach and who may be candidates for alternative therapy. We have also evaluated the role of second line salvage chemotherapy for patients who have failed a first line conventional salvage therapy. Patients and methods

Response assessment Those patients who achieved complete remission or good PR (denned asresidualradiographic abnormalities in previous sites of disease that were reduced to < 2 cm maximum diameter, and < 5% bone marrow involvement with lymphoma) proceeded to BM harvest or blood progenitor cell collection and ABMT. Those with no response (NR) or progressive disease (PD) were offered other second-line salvage chemotherapy regimens (DHAP, dexamethasone, ara-C, cisplatin [4]; ESHAP, etoposide, solumedrol, ara-C, cisplatin [16]; DICE, dexamethasone, ifosfamide, cisplatin, etoposide [20]) for the purpose of obtaining maximum tumor regression. Those with a PR were continued on the sameregimenuntil maximum tumor reduction was obtained.

Patients

Treatment

Following assessment at our center, patients usually returned to their primary oncologist to receive the mini-BEAM regimen, consisting of BCNU 60 mg/m2 on day 1, VP16 75 mg/m2 days 2-5, Ara-C 100 mg/m2 ql2h days 2-5 and melphalan 30 mg/m2 on day 6. The chemotherapy was generally administered as an in-patient every four weeks following hematologic recovery. Repeated cycles were administered for the purpose of maximum tumor reduction. Dose reduction was not employed in patients with prolonged neutropenia or fever during neutropenia requiring hospitalization; treatment was delayed until recovery. More recently, G-CSF (300 ug/d s.c.) was used in patients having suffered from at least one episode of febrile neutropenia requiring hospitalisation. E>elay in the administration of chemotherapy was defined as treatment received more than six weeks from the start of the previous cycle. After two to three cycles, completerestagingwasrepeatedwith CT, gallium scanning and BM biopsy if BM was previously involved. All CT scans were centrally reviewed. Complete remission was defined as total resolution of symptoms and radiological abnormalities for a minimum of four weeks. A PR was defined as a decrease of 50% or greater of the tumor measured by its maximum diameter and sustained for a minimum of four weeks. Any residual radiographic abnormalities were regarded as PR unless pathological CR was confirmed by repeat biopsy. Bone marrow was considered in CR only in the presence of a normal morphologic examination on an adequate specimen; a PR in BM was defined as one or more residual foci of abnormal lymphocytes in paratrabecular areas. Patients whose disease did not meet the above criteria were considered treatment failures.

Statistical analysis The effect of categorical factors on response (age, prior CR, duration of initial remission [CR1], immunophenotype and histologic grade) was assessed using either the chi-square test or Fisher's exact test. The influence of the following variables on response to mini-BEAM was assessed by univariate analysis: LDH, B symptoms, tumor burden, extra-nodal site, number of previous salvage regimens, bulky disease, and stage at relapse. A multivariate analysis using the log linear regression technique was used to define the prognostic relevance of selected covariates [21]. Survival estimates were computed for the entire group using the Kaplan-Meier method, with an event defined as arelapseor death [23].

Results Patient characteristics One hundred four patients, with a median age of 52 years, received at least one cycle of mini-BEAM and were evaluable for response. Patient and tumor-related characteristics are summarized in Table 1. The majority presented with intermediate grade NHL, while 18 patients had transformed from low to intermediate grade histology. Extranodal disease was documented in 77 patients, with BM involvement as the predominant site in 39 of 104 patients (37%). Sixty-two patients had intermediate or high tumor burden. Notably, 57% of the patients were primary non-responders who had failed to achieve CR with conventional dose induction chemotherapy incorporating doxorubicin (CHOP, VACOP-B, ProMACE-CytaBOM). Prior CR was achieved by 49 patients (47%); however in only 15 patients was the duration more than 12 months. For all patients in this series, mini-BEAM was part of their therapy for first relapse or incomplete response to primary therapy. Response to mini-BEAM Results are presented in Table 2. The overall response to mini-BEAM was 37%, with PR (including good PR) and CR rates of 25% and 12% respectively. In the 74 patients who received mini-BEAM asfirst-linesalvage treatment, the CR rate was 16% and PR rate 27%, for a total response rate of 43%. In the group of 30 patients who received mini-BEAM as second- or third-line salvage chemotherapy, six partial responses were seen and no

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One hundred four patients with refractory or relapsed intermediate grade NHL referred to The Toronto Hospital between 1987 to 1994 for consideration of ABMT form the basis of this analysis. All patients had failed to respond to or were in first relapse after receiving anthracycline-based chemotherapy. All diagnostic biopsy specimens underwent central pathological review and were classified according to the International Working Formulation. Intermediate grade included follicular large cell, diffuse small cleaved, diffuse mixed and diffuse large cell histologies. Anaplastic large cell (Ki-1+) and immunoblastic NHL were also managed as intermediate grade NHL. Restaging investigations prior to salvage therapy included chest, abdomen and pelvis computed tomographic scans, unilateral bone marrow biopsy (BM) and, when appropriate, gallium scan and bone scan. Adequate cardiac, renal, hepatic, and bone marrow function and ECOG performance status < 2 was required. There was no age limit for mini-BEAM as salvage treatment but only patients less than 60 years old were considered for ABMT. Tumor burden was determined according to the MD Anderson staging classification of intermediate grade NHL, with the exception that bulky disease was defined as a mass >5 cm [19].

677 Table 3. Prognostic factors for response to mini-BEAM: univariate analysis.

Table 1. Patient characteristics. Characteristics

Patients

Total Median age Stage at relapse

104 52 (range 18-68)

No.

RR (%)

P value

49 55

0.37

42 62

18(37%) 21 (38%) 21 (50%) 18(29%)

24 79

4(17%) 35 (44%)

0.02

35 69

12(34%) 27 (39%)

0.89

18 85

9 (50%) 29 (34%)

0.30

15 89

2(13%) 36(41%)

0.08

-87 17

32 (37%) 7 (41%)

0.47

41 64

19(46%) 20(31%)

0.18

42 41

16(38%) 15(37%)

0.55

Age <50 >50

35 69

15(43%) 27 (40%)

0.55

Immunophenotype T cell Bcell

9 95

5 (56%) 32 (34%)

0.41

Factor

I

11

Yes No

8

_ -_- -

r9

- --

5 72

III IV

Prior CR > 12 months < 12 months Total Refractory disease Immunophenotype

Yes No

Nasal cavity Histology Transformed Intermediate de novo LDH at relapse > 300 Tumor burden

Yes No

Histology Transformed Intermediate de novo Mediastinal bulky Yes No

CR duration < 12 months > 12 months Marrow + LDH

<300 >300

42 36 26 24

Intermediate High B symptoms at relapse

0.02

Bulky

18 86 41

Low

--

Rrcru-incr ratrs trt mini-TIFAM Ka«*H nn rfstvmu 1 tr\ nrir

therapy.

All patients Mini-BEAM first-line Mini-BEAM second-line Overall second-line Primary non-responders Relapse rs

104 74 30 59 55 49

%RR (95% CI)

%CR (95% CI)

%PR (95% CI)

37 (28-46) 43(32-54) 20(6-34) 15(6-24) 39 (26-52) 38 (24-52)

12(6-18) 16(8-24)

25(17-33) 27(17-37) 20(6-34) 13(4-22) 29(17-41) 24(12-36)

0

2(0-6) 14 5-23) 10(2-18)

patient achieved a CR. Response to therapy was usually evident after the first cycle of chemotherapy and maximal tumor reduction was achieved after two cycles. Of the 13 patients who achieved CR, 10 did so at the end of the second cycle and the remainder had demonstrated >90% tumor regression after two cycles. Of the 91 other patients, 32 received three or more cycles of miniBEAM in an attempt to achieve maximum tumor reduction; none of them obtained significant decrease in their tumor size with treatment beyond two cycles. Factors predicting response

Univariate analysis identified two variables significantly associated with response to mini-BEAM (Table 3). The

response rate for patients presenting with B symptoms at relapse was 17% (95% confidence interval (CI) 2%32%), compared with 44% (95% CI, 33%-55%) for those who were free of such symptoms (7> = 0.02). Tumor burden also significantly influenced response, with patients presenting with low tumor burden having a response rate of 50% (95% CI, 35%-65%), compared to 29% (95% CI, 18%—40%) for patients with intermediate or high tumor burden (P - 0.02). There was no difference in response rate between the intermediate or high tumor burden groups, thus they were analysed together. Notably, nine out of 12 patients achieving a CR had a low tumor burden. Sixty-six patients presenting either B symptoms, intermediate/high tumor burden, or both had a response rate of only 25% (95% CI, 15%-35%) compared with a RR of 58% (95% CI, 42%-74%) for those patients with neither of these characteristics (P = 0.001). The other parameters analysed did not have a significant impact on response rate to mini-BEAM. These included histologic grade, bone marrow involvement, LDH, immunophenotype, age and delay in the administration of the chemotherapy because of prolonged myelosupression. Importantly, achievement of CR with initial therapy at diagnosis was found not to

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CNS

Tumorburden Intermediate/high B symptoms

95 9 77 39 8 9 12 3 2 4

Extranodal disease Bone marrow Lung Skin Liver/pancreas Bowel

-

Low

15 34 49 55

B T

Tnhl* 7

Prior CR

678

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have any predictive value for response: in the group who did not respond to their first salvage attempt, only 5 having achieved a prior CR, 18 of 48 (38%) responded of 53 (10%) remain alive and two are free of recurrence to mini-BEAM, while 22 of 57 (39%) without prior at a median follow-up of 31 months. initial CR responded. There was a trend suggesting that bulky mediastinal disease was a poor prognostic factor, with only three patients out of 15 achieving a PR follow- Discussion ing mini-BEAM (P = 0.08). By multivariate analysis, only B symptoms and tumor burden were significant Although non-Hodgkin's lymphoma is curable in the and independent factors predictive for response. majority of patients, 15%—49% fail to achieve a CR with standard anthracycline-based therapy [23]. Furthermore, 20%-40% of patients who achieve a CR eventually Survival relapse [23]. Various conventional-dose chemotherapy The median survival of all 104 patients is 11 months, regimens have been proposed as salvage therapy for with an actuarial survival of 22% at three years. A total these patients but their curative potential has been quesof 38 patients (37%) demonstrated sufficient chemo- tioned. The addition of intensive therapy and ABMT therapy sensitivity to proceed to intensive therapy and has been investigated in an attempt to improve the outABMT; their median follow-up is 26 months and the come of these patients. Recently, a large randomized trial has demonstrated a survival advantage with ABMT actuarial survival is 36% at three years. over conventional chemotherapy for patients who relapse from a previous CR and who show chemotherapy Toxicity sensitivity to DHAP [24]. A number of centers have A total of 208 courses of mini-BEAM were administered reported that the major predictors of outcome following to 104 patients. The median number of courses was two ABMT for intermediate grade NHL are sensitivity to (range 1-5). Myelosuppression was the most frequently conventional-dose salvage therapy and remission status observed complication with febrile neutropenia requir- at transplant [10-14]. In light of this, we evaluated miniing hospitalisation occuring after 138 courses (66%). BEAM as a salvage regimen in a population of patients Platelet transfusions were required after 161 courses with relapsed or refractory NHL who were potential (78%), and red blood cells after 124 courses (60%). There candidates for ABMT. The primary purpose was to use was no evidence that hematologic toxicity was more this regimen to achieve maximum tumor reduction prior severe with subsequent cycles in those who received more to ABMT. than one cycle. There was no increased toxicity observed We report an overall RR of 43% with 27% PR and in 37 patients over 50 years of age. Four patients died of 16% CR rates when mini-BEAM is administered as treatment-related causes: three due to sepsis and one of first-line salvage therapy, and observed no significant cerebral hemorrhage. One other patient died within three differences whether this regimen was given to those weeks of the first course of mini-BEAM with fulminant refractory to intitial therapy or to those who had reprogressive disease and multi-organ failure. lapsed. Although the results of our study appear inferior to other published regimens, the difference seems to be largely due to patient selection [2, 4, 15, 16, 20]. The Response to second-line salvage treatment differences in patient prognostic factors, response rates Although all were treated in first relapse or salvage and toxicity for a number of published salvage regimens attempt, more than half of the patients in this series are demonstrated in Table 4. For example, the ESHAP received more than one regimen to try to reduce tumor regimen (etoposide, ara-C, cicplatin and solumedrol) volume prior to ABMT. Twenty patients who did not produced complete responses in 37% of patients, with respond to mini-BEAM as first-line salvage treatment an overall RR of 64% [16]. However, in that series, prior and three others who achieved only a PR received a CR was one of the most powerful predictors of response second salvage regimen in an attempt to produce ad- to ESHAP and 43% of patients in that cohort had an equate cytoreduction before ABMT. In the patients with initial CR duration of more than 12 months. Velasquez no response to mini-BEAM, the response rate to second et al., reported similar results with DHAP (CR rate salvage was 15% (95% CI, 7%-23%) and none of the 47%) in a group of patients with predominantly low three patients in the PR group had further tumor reduc- tumor burden by MD Anderson criteria [4]. Because of tion. A total of 53 patients were analysed for their the heterogenous patient populations enrolled in these response to all types of second salvage chemotherapy. studies, definite conclusions regarding the superiority These patients included 23 mini-BEAM failures who of one salvage regimen over another cannot be made, received alternative conventional salvage chemotherapy, and randomized trials comparing conventional-dose and 30 patients who received mini-BEAM as second or salvage therapy in this disease have not been reported. third salvage therapy after failing first-line (most com- Nonetheless, in our population of poor prognosis pamonly with DHAP or DICE). Sixteen percent of these tients, mini-BEAM does not appear a better salvage patients responded (95% CI, 11%-21%), with a CR rate regimen, despite our initial encouraging results with this of 3% (95% CI, 0.5%-6%). Among this group of patients therapy as second-line treatment [17].

679 Table 4. Comparison of published salvage regimens for intermediate grade NHL.

No. of patients CR > 6 mo CR > 1 2 m o CR > 24 mo NoCR Bulky Tumor burden (intermediate/high) B symptoms Bone marrow involved Results CR PR Mortality rate

MIME [2]

DHAP [4]

EPOCH [1]

NOPE [28]

ESHAP[17]

DICE [21]

mini-BEAM

208 89 (43%)

90

40

43

122

36

104

38 (42%)

15(14%)

53 (43%) 16(37%)

52 (58%)

53 (43%) 18(24%)

20 (47%)

77 (37%)

32 (36%) 39 (43%) 32 (36%)

46%

27 (63%) 11 (26%)

28% 6% 6%

31% 24% 11%

27% 42% 2%

34% 15% 0%

81 (39%)

55C57%)

11 (36%) 14 (38%)

62 (60%) 24 (23%) 41 (39%)

23% 44% 5%

12% 24% 4%

104(85%)

37% 27% 5%

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As chemotherapy sensitivity and low tumor burden at transplant are predictive of a better outcome after ABMT [10, 25], the predicted overall and CR rate of a particular salvage regimen become very important in the treatment strategy of a potential transplant candidate. If predictors of poor response to conventional salvage therapy for NHL can be identified, therapy for such patients could be individualized according to more specific biologic features of their disease. For example, we identified the subgroup of patients with B symptoms, intermediate/high tumor burden or both at relapse have a low likelihood of response with current salvage therapy. Use of an alternative conventional-dose regimen in patients who do not respond to first-line salvage (resistent relapse) results in a disappointingly low response rate (15% in our series) regardless of whether the initial therapy was mini-BEAM or another regimen, and these patients had a very poor outcome after ABMT, with 10% predicted to be alive at two years. We also observed limited benefit in terms of tumor reduction by continuing mini-BEAM beyond two cycles. We can then conclude, within the limits of patient selection, that response to mini-BEAM as salvage therapy for NHL appears similar to other published regimens. Non-hematologic toxicity of this regimen is minor, and approaches to ameliorate its hematologic toxicity are under investigation. We have identified prognostic variables defining subgroups of patients in whom conventional salvage chemotherapy is likely to fail and for whom ABMT is unlikely to be a realistic option for cure. Our analysis puts both high dose chemotherapy with ABMT and salvage treatment of relapsed or refractory NHL in perspective: despite the encouraging results of the Parma trial [24], the majority patients do not respond adequately to salvage chemotherapy to be rendered long term disease-free survivors with ABMT: only one-third of our patients received ABMT despite this initial treatment intention. Improving the treatment of patients at high risk of failure at diagnosis [26], evaluation of new chemotherapeutic agents [27], further development of immunotherapy [28] and radioimmunoconjugates [29] require further study.

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Received 21 Febraury 1997; accepted 11 June 1997. Correspondence to:

Dr. M. Crump The Toronto Hospital General Division Mulock-Larkin Wing 2-018 200 Elizabeth St Toronto, Ontario, M5G 2C4 Canada

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