0963-6897/92 $5.00 + .00 Copyright © 1992 Pergamon Press Ltd.
Cell Transplantation, Vol. I, pp. 343-347, 1992 Printed in the USA. All rights reserved.
Original Contribution AUTOTRANSPLANTS IN ADVANCED NON-HODGKIN LYMPHOMA: ARE THEY EFFECTIVE? ANTONELLA SURBONE,
* JAMES O. ARMITAGE, t AND ROBERT PETER GALE:j:§
*Department of Oncology, Sante Chiara Hospital, Pisa, Italy tDepartment of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA, and :j:Department of Medicine, Division of Hematology-Oncology, UCLA School of Medicine, Los Angeles, CA, USA
o Abstract -
Bone marrow; Autotransplant; Lymphoma; Chemotherapy.
performed. In persons with favorable prognostic factors, autotransplants result in about 40% 2-year disease-free survival versus about 10% in those with unfavorable prognostic factors (32). These results in advanced intermediate and highgrade lymphomas raise the issue as to autotransplants are a better treatment than chemotherapy. Although this question is best answered in a randomized trial, none are reported. As an alternative, we compared treatment outcome between 12 reports of autotransplants and 29 reports of chemotherapy in persons with advanced intermediate and high-grade non-Hodgkin lymphoma.
INTRODUCTION
METHODS
There is considerable interest in autotransplants in lymphoma. Recent surveys from the International Autologous Bone Marrow Transplant Registry indicate about 4,000 autotransplants for lymphomas between 1985 and 1989. Almost two-thirds were for advanced intermediate and high-grade non-Hodgkin lymphomas, including large cell (diffuse histiocytic), lymphoblastic, and Burkitt lymphomas (1). Recently, more autotransplants are being performed for low-grade lymphomas has also increased. Most autotransplants are for large-cell lymphoma. Two-year disease-free survival is about 20070 in several series (3). Prognostic factors for outcome differ between studies but often include age, performance state, complicating medical conditions, remission state, and tumor mass (in persons not in remission). Another important factor is whether the lymphoma was responding to chemotherapy when the autotransplant was
A CANCERLIT search of the biomedical literature between 1986 and June 1990 was performed to identify reports of autotransplants and chemotherapy in advanced intermediate and high-grade non-Hodgkin lymphoma. The search was restricted to complete scientific reports in English; meeting reports and abstracts were not included. References from these reports were searched to identify additional relevant studies. Twelve studies of high-dose chemotherapy, with or without radiation, followed by an autotransplant (2,4,9,11,16,19,26,31-33,41,45) and 29 of chemotherapy (6-8,10,12-14,17,20-25,27-30,34-38,40, 42-44,47-49) were identified. The focus of our analysis was on large-cell lymphoma, consequently, persons identified as having follicular lymphoma and/or diffuse poorly differentiated lymphoma were excluded. Several studies included persons with different histologic subtypes such as Bur-
Recent data suggest that intensive therapy followed by a bone marrow autotransplant is effective in advanced intermediate and high-grade non-Hodgkin lymphoma (predominantly large-cell lymphoma). Twelve studies of autotransplants were analyzed to determine outcome. Results compared to data from 29 chemotherapy studies. Complete remission was reported in 53070 of autotransplant recipients versus 17070 of persons receiving chemotherapy. Two-year disease-free survival was 16 and 2%, respectively. It is uncertain whether these differences indicate superiority of autotransplants or reflect selection biases. Also unknown is whether similar results might not be obtained with similarly intensive treatment without an autotransplant.
o Keywords -
ACCEPTED
tology-Oncology, UCLA School of Medicine, Los Angeles,
6/16/92.
§Correspondence should be directed to Robert PeterGale, M.D., Ph.D., Department of Medicine, Division of Hema-
CA 90024-1678. 343
344
Cell Transplantation. Volume 1, Number 5, 1992
kitt and lymphoblastic lymphoma. However, the number of cases is less than 100/0 in chemotherapy and autotransplant series in adults. The trials we analyzed included subjects relapsing after an initial complete remission as well as those with advanced refractory disease. Persons transplanted in first remission were excluded. In almost all instances, initial treatment was with multidrug regimens, one component of which was doxorubicin. . . Outcomes analyzed included complete remISSIOn rate and 2-year disease-free survival. We relied on authors' definition of complete remission. Often this was clinical; sometimes surgical or pathological restaging was performed. Remission rate was calculated as a function of total numbers of subjects entered on study. Data are expressed as the weighted mean or median. It was not possible to calculate actuarial disease-free survival rates for the two treatments, since survival times for individual patients were often not reported. Also, many series failed to include 95% confidence interval of standard errors for survival rates. As an alternative, we calculated the minimum possible 2-year disease-free survival for each series by dividing the number of subjects alive and free of lymphoma at 2 years, (i.e., excluding those dead, relapsed, or followed for fewer than 2 years) by the total number treated. This approach gives the actual disease-free survival rate if all subjects alive and disease-free but with less than 2-years followup relapsed or died before this endpoint. This approach tends to underestimate treatment efficacy, especially in studies with short followup and many censored patients. However, since followup was similar in the chemotherapy and transplant series, this consideration is unlikely to bias comparison of the two therapies. Remission and disease-free survival rates between the two therapies were compared using the chi-square statistic.
RESULTS
Data from 12 trials of autotransplants in advanced intermediate and high-grade non-Hodgkin lymphoma in 491 subjects are indicated in Table 1. Weighted median age is 36 years (range 16-65). Although diverse pretransplant regimens were used, more than one-half of subjects received cyclophosphamide, lomustine, and etoposide. Mean weighted complete remission was 53% (range, 18-96). Mean weighted 2-year diseasefree survival was 16% (range, 11-24). Seventy-three subjects survived 2 years without relapse. Mean weighted frequency of early and/or toxic deaths was 19% (range, 4-24). There was no evidence of a substantial difference in treatment outcome with different pretransplant regimens. . Results of 29 trials of chemotherapy in advanced intermediate and high-grade lymphoma in 704 subjects are also indicated in Table 1. Weighted median age is 54 years (range, 16-83). Diverse regimens were used. The most common drugs used were methotrexate, cytarabine, doxorubicin, etoposide, cyclophosphamide, ifosphamide, mitoxantrone, and cisplatin. Mean weighted complete remission was 170/0 (range, 0-72). Mean weighted 2-year disease-free survival was 3% (range, 0-15). Nineteen subjects were alive and disease-free at 2 years. Mean weighted frequency of early and/or toxic deaths was 6% (range, 0-16). There was no evidence of a substantial difference in treatment outcome with different regimens. Results of autotransplants and chemotherapy are compared in Table 1. These data indicate higher complete remission rates (53% versus 17%; P< 0.01) and 2-year disease-free survival (16% versus 3%; P < 0.01) with autotransplants. DISCUSSION
This review of 41 studies of autotransplants and chemotherapy in advanced intermediate and high-
Table 1. Comparison of reported results with salvage chemotherapy and autologous bone marrow transplantation*
Treatment Chemotherapy ABMT§
Patients Total with Number number intermediate of of or high series patients grade NHLt 29 12
1262 563
704 491
Median age range
:j:NHL, non-Hodgkin lymphoma. . §ABMT, autologous bone marrow transplantation.
Early/toxic deaths (total)
54 (10-83) 16010 (0-73.5%) 5.5% (0-16%) 17% (0-72%) 36 (4-65) 52% (24-36%) 19% (4-24%) 53% (18-96%)
"Details on the single studies can be obtained from the authors.
teR, complete remission.
Total CR reported
CRt in intermediate or high grade NHL
Series reporting Actual any 2-year 2-year disease-free disease-free survival survival 19 (2.6%) 79 (16%)
12 (41%) 10 (83%)
Autotransplants in lymphoma. A. SURBONE, 1.0. ARMITAGE,
grade non-Hodgkin lymphoma suggests that autotransplants are more effective. Complete remission rates were 53070 versus 17%, and 2-year disease-free survival, 16% versus 3%. These data raise the question whether the apparent superiority of autotransplants is because of it is a better treatment or because of selection biases. Most autotransplant recipients are younger, have higher performance scores, and fewer complicating medical conditions than persons receivingchemotherapy. Timeto-treatment bias is also greater with autotransplants. However, a prototype disease-free survival curve in persons receiving chemotherapy suggeststhat a median delay exceeding 2 years would be needed to make chemotherapy results equivalent to autotransplants were time-to-treatment bias alone responsible for this difference in 2-year disease-free survival. However, this interval was considerably shorter in all of the autotransplant studies in our analysis. Other selection biases may also operate with autotransplant. For example, persons with bone marrow involvement, an unfavorable risk factor for chemotherapy, are often excluded from autotransplants. Whether tumor mass and response to chemotherapy differ between persons receiving autotransplants versus chemotherapy is unknown, but could be important since these factors are reported to predict response to chemotherapy and autotransplants. This is not surprising because similar risk factors are reported for chemotherapy and transplants in persons with acute myelogenous leukemia and acute lymphoblastic leukemia (15,18). Also, there may be selective reporting of both selection biases might effect reporting of chemotherapy and autotransplant studies. Considerable data suggest that relatively few potential transplant candidates with advanced intermediate and high-grade non-Hodgkin lymphoma receive autotransplants. In one population-based study this proportion was about one-third (Armitage, unpublished data). However, selection biases, like age, performance state, and concomitant medical conditions, also operate in chemotherapy trials. Several important issues regarding autotransplants were not addressed in this study, including optimal timing and the role of in vitro bone marrow treatment. These issues are best answered in randomized trials. Were autotransplants more effective than chemotherapy, the implication would be that more intensive treatment increases cures. Presently, there are no convincing data this is so in chemotherapy trials not "requiring" bone marrow rescue. However, the alkylating drugs which are used in most autotransplant studies show a steep dose-response relationship in experimental cancers (39). Doses of these drugs not typically in-
AND
R.P. GALE
345
creased in trials of more intensive chemotherapy. Instead, the common strategy is to add additional drugs, usually antimetabolites. Consequently, it is not known whether, in similar subjects, more intensive chemotherapy, especially with alkylating drugs, might not produce results comparable to autotransplants needing to infuse bone marrow. This might be achievable with recent improvements in supportive care including use of molecularly cloned hematopoietic growth factors, like granulocyte or granulocyte-macrophage colony stimulating factors (G- and GM-CSF). The answer will likely depend on the extent of dose escalation. For example, in normal monkeys, GM-CSF accelerates granulocyte recovery at total body radiation dose up 8 Gy (46). By analogy, intensive chemotherapy up to about this level might be possible without an autotransplant. Also, persons with advanced lymphoma receiving extensive prior chemotherapy will likely have more delayed and/or incomplete bone marrow recovery following intensive treatment than normal persons receiving similar treatment. This increased sensitivity may not be reversible, even with hematopoietic growth factors. Indirect evidence for this is that GM-CSF does not accelerate granulocyte recovery in autotransplant recipients whose bone marrow graft was treated with drugs like 4-hydroperoxycyclophosphamide in vitro (5). The data we reviewsuggest that results of autotransplants are superior to chemotherapy in persons with advanced intermediate and high-grade non-Hodgkin lymphoma. This conclusions effects not only use of autotransplants but also the strategy of future chemotherapy. Also, it is uncertain if the transplant is needed. Only randomized can clarify these issues. Acknowledgments-Supported in part by a grant from the Center for Advanced Studies in Leukemia. Robert Peter Gale is the Wald Foundation Scholar in Biomedical Communications. We thank Dr. Mary W. Horowitz for statistical advice and Becky Beckham for preparing the typescript. REFERENCES
1. Advisory Committee of the International Autologous Bone Marrow Transplant Registry (ABMTR). Autologous bone marrow transplants: Different indications in Europe and North America. Lancet 2:317-318; 1989. 2. Anderson, C.C.; Goldstone, A.H.; Souhami, R.L.; et al. Very high dose chemotherapy with autologous bone marrow rescue in adult patients with resistant relapsed lymphoma. Cancer Chemother. Pharmacol. 16: 170-175; 1986. 3. Armitage, 1.0. Bone marrow transplantation in patients with lymphoma. Blood 73:1749-1758; 1989. 4. Armitage, 1.0.; lagannath, S.; Spitzer, G.; et al. High
346
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
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dose therapy and autologous marrow transplantation as salvage treatment for patients with diffuse large celllymphoma. Eur. J. Cancer Clin. Oncol. 22:871-877; 1986. Auer, I.; Ribas, A.; Gale, R.P. What is the role of recombinant colony stimulating factors in bone marrow transplantation. Bone Marrow Transplant 6:79-87; 1990. Bajetta, E.; Buzzoni, R.; Valagussa, P.; Bonadonna, G. Mitoxantrone: An active agent in refractory non-Hodgkin's lymphomas. Am. J. Clin. Oncol. 11:100-103; 1988. Cabanillas, E; Hagemeister, EB.; McLaughlin, P.; et al. Results of MIME regimen for recurrent or refractory lymphoma. J. Clin. Oncol. 5:407-412; 1987. Cabanillas, E; Velasquez, W.S.; McLaughlin, P.; et al. Results of recent salvage chemotherapy regimens for lymphoma and Hodgkin's disease. Semin. Hematol. 25: 47-50; 1988. Chadha, M.; Shank, B.; Fuks, Z.; et al. Improved survival of poor prognosis diffuse histiocytic (large cell) lymphoma managed with sequential induction chemotherapy, "boost" radiation therapy, and autologous bone marrow transplantation. Int. J. Radiat. Oncol. BioI. Phys. 14:407-415; 1988. Collins, C.; Mortimer, J.; Livingstone, R.B. High-dose cyclophosphamide in the treatment of refractory lymphomas and solid tumor malignancies. Cancer 63:228232; 1989. Colombat, P.; Gorin, N.C.; Lemonnier, M.P.; etal. The role of autologous bone marrow transplantation in 46 adult patients with non-Hodgkin's lymphoma. J. Clin. Oncol. 8:630-637; 1990. Dabich, L.; Liepman, M.K. Cisplatin, VP-16-213 and MGBG (Methylglyoxal bis guanylhydrazone) combination chemotherapy in refractory lymphoma, a phase II study. Invest. New Drugs 6:231-237; 1988. Duggan, D.B.; Anderson, J.R.; Dillman, R.; et al. 2' Deoxycoformycin (pentostatin) for refractory nonHodgkin's lymphoma: A CALGB phase II study. Med. Pediatr. Oncol. 18:203-206; 1990. Foss-Abrahamsen, A.; Lenner, P.; Hedenus, M.; etal. Mitoxantrone in the treatment of patients with nonHodgkin's lymphoma. Cancer Treat. Rep. 71:12091212; 1987. Gale, R.P.; Horowitz, M.M.; Biggs, J.C.; et al. for the Advisory Committee of the International Bone Marrow Transplant Registry. Transplant or chemotherapy in acute myelogenous leukemia. Lancet 1:119-122; 1989. Gribben, J.G.; Goldstone, A.H.; Linch, D.C.; et al. Effectiveness of high-dose combination chemotherapy and autologous bone marrow transplantation for patients with non-Hodgkin's lymphomas who are still responsive to conventional-dose therapy. J. Clin. Oncol. 7:16211629; 1989. Ho, AD.; Del Valle, E; Ruckle, H.; et al. Mitoxantrone and high-dose cytarabine as salvage therapy for refractory non-Hodgkin's lymphoma. Cancer 64:1388-1392; 1989. Horowitz, M.M.; Messerer, D.; Hoelzer, D.; et al. Che-
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
motherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission. Ann. Intern. Med. 115:13-18; 1991. Hurd, D.D.; LeBien, T.W.; Lasky, L.C.; et al. Autologous bone marrow transplantation in non-Hodgkin's lymphoma: Monoclonal antibodies plus complement for ex vivo marrow treatment. Am. J. Med. 85:829-834; 1988. Jackson, D.V.; Powell, B.L.; Cruz, J.M.; et al. Infusion of etoposide and vincristine in non-Hodgkin's lymphoma. Sel. Cancer Ther. 5:129-136; 1989. Jackson, D.V., Jr.; Spurr, C.L.; Caponera, M.E.; et al. Vinblastine infusion in non-Hodgkin's lymphomas: Lack of total cross-resistance with vincristine. Cancer Invest. 5:535-539; 1987. Jones, L.; Cotter, EE.; Lord, D.; Newland, A.C. Phase 2 study of mitozantrone in combination with chlorambucil and prednisolone for relapsed and refractory nonHodgkin's lymphoma. Hematol. Oncol. 8:41-45; 1990. Kumar, L.; Bajpal, V.; Dua, H. Vincristine infusion in advanced non-Hodgkin's lymphoma. Indian J. Cancer 26:14-16; 1989. Lachant, N.A.; Anderson, J.; Ginsberg, S.J.; et al. Treatment of refractory lymphoma with methotrexate, VM-26 (teniposide), procarbazine, and dexamethasone: Cancer and leukemia group B study 7902. Med. Pediatr. Oncol. 16:375-377; 1988. Liang, T.D.; Chan, T.K. HOAP-Bleo as salvage therapy for diffuse aggressive non-Hodgkin's lymphoma. Cancer Chemother. Pharmacol. 22:169-171; 1988. Mascret, B.; Maraninchi, D.; Gastaut, J.A; et al. Treatment of malignant lymphoma with high dose of chemo or chemoradiotherapy and bone marrow transplantation. Eur. J. Cancer Clin. Oncol. 22:461-471; 1986. Nichols, C.R.; Loehrer, P.J.; Greist, A; et al. Salvage chemotherapy for lymphoma with VP-16, ifosfamide, and cisplatin. Med. Pediatr. Oncol. 16:12-16; 1988. O'Donnell, M.R.; Forman, S.J.; Levine, A.M.; et al. Cytarabine, cisplatin, and etoposide chemotherapy for refractory non-Hodgkin's lymphoma. Cancer Treat. Rep. 71:187-189; 1987. Ohnoshi, T.; Hayashi, K.; Ueoka, H.; et aI. Salvagechemotherapy for non-Hodgkin's lymphoma with a combination of mitoxantrone, etoposide, cisplatin, and prednisolone. Cancer Treat. Rep. 71:639-641; 1987. Oster, W.; Forsthuber, T.; Hennekeuser, H.H.; et al. MACOP-B chemotherapy for the treatment of high grade and intermediate grade non-Hodgkin's lymphoma. Blut 60:23-27; 1990. Petersen, EB.; Appelbaum, ER.; Hill, R.; et al. Autologous marrow transplantation for malignant lymphoma: A report of 101 cases from Seattle. J. Clin. Oncol. 8: 638-647; 1990. Philip, T.; Armitage, J.O.; Spitzer, G.; et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N. Engl. J. Med. 316:1493-1498; 1987. Phillips, G.L.; Fay, r.w.. Herzig, R.H.; et aI. The treat-
Autotransplants in lymphoma. A.
34.
35.
36.
37.
38.
39.
40.
41.
SURBONE,
ment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 75:831-838; 1990. Rybak, M.E.; Anderson, J.R.; Poulin, R.E; et al. Phase II trial of m-AMSA therapy in refractory Hodgkin's disease and non-Hodgkin's lymphoma: Cancer and leukemia group B study 7972. Cancer Treat. Rep. 70:12331234; 1986. Sangster, G.; Patton, W.N.; Harris, R.I.; et al. Treatment of refractory and relapsed non-Hodgkin's Iymphoma with ifosfmide, methotrexate and etoposide. Cancer Chemother. Pharmacol. 23:263-265; 1989. Schiller, J.H.; Ritch, P.S.; Storer, B.; Trump, D.L. A pilot study of short-course, high-dose cytosine arabinoside, etoposide, and cisplatin in refractory, aggressivehistology, non-Hodgkin's lymphomas. Am. J. C1in. Oncol. 12:502-506; 1989. Schilsky, R.L.; Williams, S.E; Ultmann, J.E.; Watson, S. Sequential hydroxyurea-cytarabine chemotherapy for refractory non-Hodgkin's lymphoma. J. Clin. Oncol. 5: 419-425; 1987. Sessa, C.; ten Bokkel Huinik, W.; C1avel, M.; et al. A phase II study of Spiro germanium in patient with advanced malignant lymphoma. Invest. New Drugs 7:219222; 1988. Skipper, H.E.; Schabel, EM. Quantitative and cytokinetic studies in experimental tumor systems. In: Holland, J.; Frei, E., eds. Cancer medicine. Philadelphia: Lea and Febiger; 1982:663-684. Takagi, T.; Sakai, C.; Oguro, M. Intermediate-dose cyto sine arabinoside in the treatment of recurrent or refractory non-Hodgkin's lymphoma. Jpn. J. Clin. Oncol. 19:123-126; 1989. Takvorian, T.; Canellos, G.P.; Ritz, J.; et al. Prolonged disease-free survival after autologous bone marrow transplantation in patients with non-Hodgkin's Iym-
J.O.
42.
43.
44.
45.
46.
47.
48.
49.
ARMITAGE, AND
R.P.
GALE
347
phoma with a poor prognosis. N. Engl. J. Med. 316: 1499-1505; 1987. Tseng, A., Jr.; Jacobs, C.; Coleman, C.N.; et al. Treatment of refractory non-Hodgkin's lymphomas of unfavorable histology with teniposide, cytarabine, and cisplatin. Cancer Treat. Rep. 71:659-660; 1987. Tura, S.; Mazza, P.; Gheriinzoni, E; et al. Phase II study of a new alkylating agent (PIT-119) in resistantrelapsed non-Hodgkin's lymphomas. Cancer Chemother. Pharmacol. 23:123-125; 1989. Velasquez, W.S.; Cabanillas, E; Salvador, P.; et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood 71:117-122; 1988. Vose, J.M.; Armitage, J.O.; Bierman, P.J.; et al. Salvage therapy for relapsed or refractory non-Hodgkin's lyrnphoma utilizing autologous bone marrow transplantation. Am. J. Med. 878:285-288; 1989. Wagemaker, G.; Vielanga, J.J.; Burger, M.; et al. Quantitative approach to hemopoietic growth factor stimulated autologous hemopoietic regeneration in Rhesus monkeys. In: Dicke, K.A.; Armitage, J.O., eds. Autologous bone marrow transplant patients. Omaha: University of Nebraska Press (in press). Warrell, R.P., Jr.; Danieu, L.; Coonley, C.J.; Atkins, C. Salvage chemotherapy of advanced lymphoma with investigational drugs: Mitoguazone, gallium nitrate, and etoposide. Cancer Treat. Rep. 71:47-51; 1987. Winter, J.N.; Gordon, L.I.; Hauck, W.W.; Variakojis, D. Etoposide and mitoguazone in refractory or recurrent non-Hodgkin's lymphomas of the unfavorable histologic subtypes. Cancer Treat. Rep. 70:1243-1244; 1986. Yoshida, T.; Nakamura, S.; Ohtake, S.; et al. Salvage chemotherapy of refractory lymphoma with adacinomycin, behenoyl ara-C, etoposide, and prednisolone. Cancer Chemother. Pharmacol. 25:135-138; 1989.
Cell Transplantation, Vol. I, pp. 343-347, 1992 Printed in the USA. All rights reserved.
Original Contribution AUTOTRANSPLANTS IN ADVANCED NON-HODGKIN LYMPHOMA: ARE THEY EFFECTIVE? ANTONELLA SURBONE,
* JAMES O. ARMITAGE, t AND ROBERT PETER GALE:j:§
*Department of Oncology, Sante Chiara Hospital, Pisa, Italy tDepartment of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA, and :j:Department of Medicine, Division of Hematology-Oncology, UCLA School of Medicine, Los Angeles, CA, USA
o Abstract -
Bone marrow; Autotransplant; Lymphoma; Chemotherapy.
performed. In persons with favorable prognostic factors, autotransplants result in about 40% 2-year disease-free survival versus about 10% in those with unfavorable prognostic factors (32). These results in advanced intermediate and highgrade lymphomas raise the issue as to autotransplants are a better treatment than chemotherapy. Although this question is best answered in a randomized trial, none are reported. As an alternative, we compared treatment outcome between 12 reports of autotransplants and 29 reports of chemotherapy in persons with advanced intermediate and high-grade non-Hodgkin lymphoma.
INTRODUCTION
METHODS
There is considerable interest in autotransplants in lymphoma. Recent surveys from the International Autologous Bone Marrow Transplant Registry indicate about 4,000 autotransplants for lymphomas between 1985 and 1989. Almost two-thirds were for advanced intermediate and high-grade non-Hodgkin lymphomas, including large cell (diffuse histiocytic), lymphoblastic, and Burkitt lymphomas (1). Recently, more autotransplants are being performed for low-grade lymphomas has also increased. Most autotransplants are for large-cell lymphoma. Two-year disease-free survival is about 20070 in several series (3). Prognostic factors for outcome differ between studies but often include age, performance state, complicating medical conditions, remission state, and tumor mass (in persons not in remission). Another important factor is whether the lymphoma was responding to chemotherapy when the autotransplant was
A CANCERLIT search of the biomedical literature between 1986 and June 1990 was performed to identify reports of autotransplants and chemotherapy in advanced intermediate and high-grade non-Hodgkin lymphoma. The search was restricted to complete scientific reports in English; meeting reports and abstracts were not included. References from these reports were searched to identify additional relevant studies. Twelve studies of high-dose chemotherapy, with or without radiation, followed by an autotransplant (2,4,9,11,16,19,26,31-33,41,45) and 29 of chemotherapy (6-8,10,12-14,17,20-25,27-30,34-38,40, 42-44,47-49) were identified. The focus of our analysis was on large-cell lymphoma, consequently, persons identified as having follicular lymphoma and/or diffuse poorly differentiated lymphoma were excluded. Several studies included persons with different histologic subtypes such as Bur-
Recent data suggest that intensive therapy followed by a bone marrow autotransplant is effective in advanced intermediate and high-grade non-Hodgkin lymphoma (predominantly large-cell lymphoma). Twelve studies of autotransplants were analyzed to determine outcome. Results compared to data from 29 chemotherapy studies. Complete remission was reported in 53070 of autotransplant recipients versus 17070 of persons receiving chemotherapy. Two-year disease-free survival was 16 and 2%, respectively. It is uncertain whether these differences indicate superiority of autotransplants or reflect selection biases. Also unknown is whether similar results might not be obtained with similarly intensive treatment without an autotransplant.
o Keywords -
ACCEPTED
tology-Oncology, UCLA School of Medicine, Los Angeles,
6/16/92.
§Correspondence should be directed to Robert PeterGale, M.D., Ph.D., Department of Medicine, Division of Hema-
CA 90024-1678. 343
344
Cell Transplantation. Volume 1, Number 5, 1992
kitt and lymphoblastic lymphoma. However, the number of cases is less than 100/0 in chemotherapy and autotransplant series in adults. The trials we analyzed included subjects relapsing after an initial complete remission as well as those with advanced refractory disease. Persons transplanted in first remission were excluded. In almost all instances, initial treatment was with multidrug regimens, one component of which was doxorubicin. . . Outcomes analyzed included complete remISSIOn rate and 2-year disease-free survival. We relied on authors' definition of complete remission. Often this was clinical; sometimes surgical or pathological restaging was performed. Remission rate was calculated as a function of total numbers of subjects entered on study. Data are expressed as the weighted mean or median. It was not possible to calculate actuarial disease-free survival rates for the two treatments, since survival times for individual patients were often not reported. Also, many series failed to include 95% confidence interval of standard errors for survival rates. As an alternative, we calculated the minimum possible 2-year disease-free survival for each series by dividing the number of subjects alive and free of lymphoma at 2 years, (i.e., excluding those dead, relapsed, or followed for fewer than 2 years) by the total number treated. This approach gives the actual disease-free survival rate if all subjects alive and disease-free but with less than 2-years followup relapsed or died before this endpoint. This approach tends to underestimate treatment efficacy, especially in studies with short followup and many censored patients. However, since followup was similar in the chemotherapy and transplant series, this consideration is unlikely to bias comparison of the two therapies. Remission and disease-free survival rates between the two therapies were compared using the chi-square statistic.
RESULTS
Data from 12 trials of autotransplants in advanced intermediate and high-grade non-Hodgkin lymphoma in 491 subjects are indicated in Table 1. Weighted median age is 36 years (range 16-65). Although diverse pretransplant regimens were used, more than one-half of subjects received cyclophosphamide, lomustine, and etoposide. Mean weighted complete remission was 53% (range, 18-96). Mean weighted 2-year diseasefree survival was 16% (range, 11-24). Seventy-three subjects survived 2 years without relapse. Mean weighted frequency of early and/or toxic deaths was 19% (range, 4-24). There was no evidence of a substantial difference in treatment outcome with different pretransplant regimens. . Results of 29 trials of chemotherapy in advanced intermediate and high-grade lymphoma in 704 subjects are also indicated in Table 1. Weighted median age is 54 years (range, 16-83). Diverse regimens were used. The most common drugs used were methotrexate, cytarabine, doxorubicin, etoposide, cyclophosphamide, ifosphamide, mitoxantrone, and cisplatin. Mean weighted complete remission was 170/0 (range, 0-72). Mean weighted 2-year disease-free survival was 3% (range, 0-15). Nineteen subjects were alive and disease-free at 2 years. Mean weighted frequency of early and/or toxic deaths was 6% (range, 0-16). There was no evidence of a substantial difference in treatment outcome with different regimens. Results of autotransplants and chemotherapy are compared in Table 1. These data indicate higher complete remission rates (53% versus 17%; P< 0.01) and 2-year disease-free survival (16% versus 3%; P < 0.01) with autotransplants. DISCUSSION
This review of 41 studies of autotransplants and chemotherapy in advanced intermediate and high-
Table 1. Comparison of reported results with salvage chemotherapy and autologous bone marrow transplantation*
Treatment Chemotherapy ABMT§
Patients Total with Number number intermediate of of or high series patients grade NHLt 29 12
1262 563
704 491
Median age range
:j:NHL, non-Hodgkin lymphoma. . §ABMT, autologous bone marrow transplantation.
Early/toxic deaths (total)
54 (10-83) 16010 (0-73.5%) 5.5% (0-16%) 17% (0-72%) 36 (4-65) 52% (24-36%) 19% (4-24%) 53% (18-96%)
"Details on the single studies can be obtained from the authors.
teR, complete remission.
Total CR reported
CRt in intermediate or high grade NHL
Series reporting Actual any 2-year 2-year disease-free disease-free survival survival 19 (2.6%) 79 (16%)
12 (41%) 10 (83%)
Autotransplants in lymphoma. A. SURBONE, 1.0. ARMITAGE,
grade non-Hodgkin lymphoma suggests that autotransplants are more effective. Complete remission rates were 53070 versus 17%, and 2-year disease-free survival, 16% versus 3%. These data raise the question whether the apparent superiority of autotransplants is because of it is a better treatment or because of selection biases. Most autotransplant recipients are younger, have higher performance scores, and fewer complicating medical conditions than persons receivingchemotherapy. Timeto-treatment bias is also greater with autotransplants. However, a prototype disease-free survival curve in persons receiving chemotherapy suggeststhat a median delay exceeding 2 years would be needed to make chemotherapy results equivalent to autotransplants were time-to-treatment bias alone responsible for this difference in 2-year disease-free survival. However, this interval was considerably shorter in all of the autotransplant studies in our analysis. Other selection biases may also operate with autotransplant. For example, persons with bone marrow involvement, an unfavorable risk factor for chemotherapy, are often excluded from autotransplants. Whether tumor mass and response to chemotherapy differ between persons receiving autotransplants versus chemotherapy is unknown, but could be important since these factors are reported to predict response to chemotherapy and autotransplants. This is not surprising because similar risk factors are reported for chemotherapy and transplants in persons with acute myelogenous leukemia and acute lymphoblastic leukemia (15,18). Also, there may be selective reporting of both selection biases might effect reporting of chemotherapy and autotransplant studies. Considerable data suggest that relatively few potential transplant candidates with advanced intermediate and high-grade non-Hodgkin lymphoma receive autotransplants. In one population-based study this proportion was about one-third (Armitage, unpublished data). However, selection biases, like age, performance state, and concomitant medical conditions, also operate in chemotherapy trials. Several important issues regarding autotransplants were not addressed in this study, including optimal timing and the role of in vitro bone marrow treatment. These issues are best answered in randomized trials. Were autotransplants more effective than chemotherapy, the implication would be that more intensive treatment increases cures. Presently, there are no convincing data this is so in chemotherapy trials not "requiring" bone marrow rescue. However, the alkylating drugs which are used in most autotransplant studies show a steep dose-response relationship in experimental cancers (39). Doses of these drugs not typically in-
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creased in trials of more intensive chemotherapy. Instead, the common strategy is to add additional drugs, usually antimetabolites. Consequently, it is not known whether, in similar subjects, more intensive chemotherapy, especially with alkylating drugs, might not produce results comparable to autotransplants needing to infuse bone marrow. This might be achievable with recent improvements in supportive care including use of molecularly cloned hematopoietic growth factors, like granulocyte or granulocyte-macrophage colony stimulating factors (G- and GM-CSF). The answer will likely depend on the extent of dose escalation. For example, in normal monkeys, GM-CSF accelerates granulocyte recovery at total body radiation dose up 8 Gy (46). By analogy, intensive chemotherapy up to about this level might be possible without an autotransplant. Also, persons with advanced lymphoma receiving extensive prior chemotherapy will likely have more delayed and/or incomplete bone marrow recovery following intensive treatment than normal persons receiving similar treatment. This increased sensitivity may not be reversible, even with hematopoietic growth factors. Indirect evidence for this is that GM-CSF does not accelerate granulocyte recovery in autotransplant recipients whose bone marrow graft was treated with drugs like 4-hydroperoxycyclophosphamide in vitro (5). The data we reviewsuggest that results of autotransplants are superior to chemotherapy in persons with advanced intermediate and high-grade non-Hodgkin lymphoma. This conclusions effects not only use of autotransplants but also the strategy of future chemotherapy. Also, it is uncertain if the transplant is needed. Only randomized can clarify these issues. Acknowledgments-Supported in part by a grant from the Center for Advanced Studies in Leukemia. Robert Peter Gale is the Wald Foundation Scholar in Biomedical Communications. We thank Dr. Mary W. Horowitz for statistical advice and Becky Beckham for preparing the typescript. REFERENCES
1. Advisory Committee of the International Autologous Bone Marrow Transplant Registry (ABMTR). Autologous bone marrow transplants: Different indications in Europe and North America. Lancet 2:317-318; 1989. 2. Anderson, C.C.; Goldstone, A.H.; Souhami, R.L.; et al. Very high dose chemotherapy with autologous bone marrow rescue in adult patients with resistant relapsed lymphoma. Cancer Chemother. Pharmacol. 16: 170-175; 1986. 3. Armitage, 1.0. Bone marrow transplantation in patients with lymphoma. Blood 73:1749-1758; 1989. 4. Armitage, 1.0.; lagannath, S.; Spitzer, G.; et al. High
346
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Cell Transplantation. Volume 1, Number 5, 1992
dose therapy and autologous marrow transplantation as salvage treatment for patients with diffuse large celllymphoma. Eur. J. Cancer Clin. Oncol. 22:871-877; 1986. Auer, I.; Ribas, A.; Gale, R.P. What is the role of recombinant colony stimulating factors in bone marrow transplantation. Bone Marrow Transplant 6:79-87; 1990. Bajetta, E.; Buzzoni, R.; Valagussa, P.; Bonadonna, G. Mitoxantrone: An active agent in refractory non-Hodgkin's lymphomas. Am. J. Clin. Oncol. 11:100-103; 1988. Cabanillas, E; Hagemeister, EB.; McLaughlin, P.; et al. Results of MIME regimen for recurrent or refractory lymphoma. J. Clin. Oncol. 5:407-412; 1987. Cabanillas, E; Velasquez, W.S.; McLaughlin, P.; et al. Results of recent salvage chemotherapy regimens for lymphoma and Hodgkin's disease. Semin. Hematol. 25: 47-50; 1988. Chadha, M.; Shank, B.; Fuks, Z.; et al. Improved survival of poor prognosis diffuse histiocytic (large cell) lymphoma managed with sequential induction chemotherapy, "boost" radiation therapy, and autologous bone marrow transplantation. Int. J. Radiat. Oncol. BioI. Phys. 14:407-415; 1988. Collins, C.; Mortimer, J.; Livingstone, R.B. High-dose cyclophosphamide in the treatment of refractory lymphomas and solid tumor malignancies. Cancer 63:228232; 1989. Colombat, P.; Gorin, N.C.; Lemonnier, M.P.; etal. The role of autologous bone marrow transplantation in 46 adult patients with non-Hodgkin's lymphoma. J. Clin. Oncol. 8:630-637; 1990. Dabich, L.; Liepman, M.K. Cisplatin, VP-16-213 and MGBG (Methylglyoxal bis guanylhydrazone) combination chemotherapy in refractory lymphoma, a phase II study. Invest. New Drugs 6:231-237; 1988. Duggan, D.B.; Anderson, J.R.; Dillman, R.; et al. 2' Deoxycoformycin (pentostatin) for refractory nonHodgkin's lymphoma: A CALGB phase II study. Med. Pediatr. Oncol. 18:203-206; 1990. Foss-Abrahamsen, A.; Lenner, P.; Hedenus, M.; etal. Mitoxantrone in the treatment of patients with nonHodgkin's lymphoma. Cancer Treat. Rep. 71:12091212; 1987. Gale, R.P.; Horowitz, M.M.; Biggs, J.C.; et al. for the Advisory Committee of the International Bone Marrow Transplant Registry. Transplant or chemotherapy in acute myelogenous leukemia. Lancet 1:119-122; 1989. Gribben, J.G.; Goldstone, A.H.; Linch, D.C.; et al. Effectiveness of high-dose combination chemotherapy and autologous bone marrow transplantation for patients with non-Hodgkin's lymphomas who are still responsive to conventional-dose therapy. J. Clin. Oncol. 7:16211629; 1989. Ho, AD.; Del Valle, E; Ruckle, H.; et al. Mitoxantrone and high-dose cytarabine as salvage therapy for refractory non-Hodgkin's lymphoma. Cancer 64:1388-1392; 1989. Horowitz, M.M.; Messerer, D.; Hoelzer, D.; et al. Che-
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
motherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission. Ann. Intern. Med. 115:13-18; 1991. Hurd, D.D.; LeBien, T.W.; Lasky, L.C.; et al. Autologous bone marrow transplantation in non-Hodgkin's lymphoma: Monoclonal antibodies plus complement for ex vivo marrow treatment. Am. J. Med. 85:829-834; 1988. Jackson, D.V.; Powell, B.L.; Cruz, J.M.; et al. Infusion of etoposide and vincristine in non-Hodgkin's lymphoma. Sel. Cancer Ther. 5:129-136; 1989. Jackson, D.V., Jr.; Spurr, C.L.; Caponera, M.E.; et al. Vinblastine infusion in non-Hodgkin's lymphomas: Lack of total cross-resistance with vincristine. Cancer Invest. 5:535-539; 1987. Jones, L.; Cotter, EE.; Lord, D.; Newland, A.C. Phase 2 study of mitozantrone in combination with chlorambucil and prednisolone for relapsed and refractory nonHodgkin's lymphoma. Hematol. Oncol. 8:41-45; 1990. Kumar, L.; Bajpal, V.; Dua, H. Vincristine infusion in advanced non-Hodgkin's lymphoma. Indian J. Cancer 26:14-16; 1989. Lachant, N.A.; Anderson, J.; Ginsberg, S.J.; et al. Treatment of refractory lymphoma with methotrexate, VM-26 (teniposide), procarbazine, and dexamethasone: Cancer and leukemia group B study 7902. Med. Pediatr. Oncol. 16:375-377; 1988. Liang, T.D.; Chan, T.K. HOAP-Bleo as salvage therapy for diffuse aggressive non-Hodgkin's lymphoma. Cancer Chemother. Pharmacol. 22:169-171; 1988. Mascret, B.; Maraninchi, D.; Gastaut, J.A; et al. Treatment of malignant lymphoma with high dose of chemo or chemoradiotherapy and bone marrow transplantation. Eur. J. Cancer Clin. Oncol. 22:461-471; 1986. Nichols, C.R.; Loehrer, P.J.; Greist, A; et al. Salvage chemotherapy for lymphoma with VP-16, ifosfamide, and cisplatin. Med. Pediatr. Oncol. 16:12-16; 1988. O'Donnell, M.R.; Forman, S.J.; Levine, A.M.; et al. Cytarabine, cisplatin, and etoposide chemotherapy for refractory non-Hodgkin's lymphoma. Cancer Treat. Rep. 71:187-189; 1987. Ohnoshi, T.; Hayashi, K.; Ueoka, H.; et aI. Salvagechemotherapy for non-Hodgkin's lymphoma with a combination of mitoxantrone, etoposide, cisplatin, and prednisolone. Cancer Treat. Rep. 71:639-641; 1987. Oster, W.; Forsthuber, T.; Hennekeuser, H.H.; et al. MACOP-B chemotherapy for the treatment of high grade and intermediate grade non-Hodgkin's lymphoma. Blut 60:23-27; 1990. Petersen, EB.; Appelbaum, ER.; Hill, R.; et al. Autologous marrow transplantation for malignant lymphoma: A report of 101 cases from Seattle. J. Clin. Oncol. 8: 638-647; 1990. Philip, T.; Armitage, J.O.; Spitzer, G.; et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N. Engl. J. Med. 316:1493-1498; 1987. Phillips, G.L.; Fay, r.w.. Herzig, R.H.; et aI. The treat-
Autotransplants in lymphoma. A.
34.
35.
36.
37.
38.
39.
40.
41.
SURBONE,
ment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 75:831-838; 1990. Rybak, M.E.; Anderson, J.R.; Poulin, R.E; et al. Phase II trial of m-AMSA therapy in refractory Hodgkin's disease and non-Hodgkin's lymphoma: Cancer and leukemia group B study 7972. Cancer Treat. Rep. 70:12331234; 1986. Sangster, G.; Patton, W.N.; Harris, R.I.; et al. Treatment of refractory and relapsed non-Hodgkin's Iymphoma with ifosfmide, methotrexate and etoposide. Cancer Chemother. Pharmacol. 23:263-265; 1989. Schiller, J.H.; Ritch, P.S.; Storer, B.; Trump, D.L. A pilot study of short-course, high-dose cytosine arabinoside, etoposide, and cisplatin in refractory, aggressivehistology, non-Hodgkin's lymphomas. Am. J. C1in. Oncol. 12:502-506; 1989. Schilsky, R.L.; Williams, S.E; Ultmann, J.E.; Watson, S. Sequential hydroxyurea-cytarabine chemotherapy for refractory non-Hodgkin's lymphoma. J. Clin. Oncol. 5: 419-425; 1987. Sessa, C.; ten Bokkel Huinik, W.; C1avel, M.; et al. A phase II study of Spiro germanium in patient with advanced malignant lymphoma. Invest. New Drugs 7:219222; 1988. Skipper, H.E.; Schabel, EM. Quantitative and cytokinetic studies in experimental tumor systems. In: Holland, J.; Frei, E., eds. Cancer medicine. Philadelphia: Lea and Febiger; 1982:663-684. Takagi, T.; Sakai, C.; Oguro, M. Intermediate-dose cyto sine arabinoside in the treatment of recurrent or refractory non-Hodgkin's lymphoma. Jpn. J. Clin. Oncol. 19:123-126; 1989. Takvorian, T.; Canellos, G.P.; Ritz, J.; et al. Prolonged disease-free survival after autologous bone marrow transplantation in patients with non-Hodgkin's Iym-
J.O.
42.
43.
44.
45.
46.
47.
48.
49.
ARMITAGE, AND
R.P.
GALE
347
phoma with a poor prognosis. N. Engl. J. Med. 316: 1499-1505; 1987. Tseng, A., Jr.; Jacobs, C.; Coleman, C.N.; et al. Treatment of refractory non-Hodgkin's lymphomas of unfavorable histology with teniposide, cytarabine, and cisplatin. Cancer Treat. Rep. 71:659-660; 1987. Tura, S.; Mazza, P.; Gheriinzoni, E; et al. Phase II study of a new alkylating agent (PIT-119) in resistantrelapsed non-Hodgkin's lymphomas. Cancer Chemother. Pharmacol. 23:123-125; 1989. Velasquez, W.S.; Cabanillas, E; Salvador, P.; et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood 71:117-122; 1988. Vose, J.M.; Armitage, J.O.; Bierman, P.J.; et al. Salvage therapy for relapsed or refractory non-Hodgkin's lyrnphoma utilizing autologous bone marrow transplantation. Am. J. Med. 878:285-288; 1989. Wagemaker, G.; Vielanga, J.J.; Burger, M.; et al. Quantitative approach to hemopoietic growth factor stimulated autologous hemopoietic regeneration in Rhesus monkeys. In: Dicke, K.A.; Armitage, J.O., eds. Autologous bone marrow transplant patients. Omaha: University of Nebraska Press (in press). Warrell, R.P., Jr.; Danieu, L.; Coonley, C.J.; Atkins, C. Salvage chemotherapy of advanced lymphoma with investigational drugs: Mitoguazone, gallium nitrate, and etoposide. Cancer Treat. Rep. 71:47-51; 1987. Winter, J.N.; Gordon, L.I.; Hauck, W.W.; Variakojis, D. Etoposide and mitoguazone in refractory or recurrent non-Hodgkin's lymphomas of the unfavorable histologic subtypes. Cancer Treat. Rep. 70:1243-1244; 1986. Yoshida, T.; Nakamura, S.; Ohtake, S.; et al. Salvage chemotherapy of refractory lymphoma with adacinomycin, behenoyl ara-C, etoposide, and prednisolone. Cancer Chemother. Pharmacol. 25:135-138; 1989.
