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Diffuse large-cell lymphoma
Annals of Oncology 11 (Suppl. I): S29-S33. 2000. © 2000 Khmer Academic Publishers. Pruned in the Netherlands
Symposium article Diffuse large-cell lymphoma R. I. Fisher Coleman Professor of Oncology, Director, Cardinal Bernardin Cancer Center, Chairman, Lymphoma Committee, Southwest Oncology Group, Loyola University Chicago, Maywood, IL, USA
Summary
Historical treatment results In order to develop new, effective treatments for patients with diffuse large cell lymphoma it is essential that we review the historical treatment studies to learn from both our successes and our prior failures. A series of single institution phase II trials conducted during the 1970s and 1980s with so-called 'second and third generation' chemotherapy regimens appeared to demonstrate nearly a doubling of the complete remission (CR) rate and overall survival (OS) compared to the 'first generation' combination chemotherapy studies that had produced complete response rates (CRs) of 45%-53% with 30%-37% long-term survivors [1-5]. Unfortunately, with longer follow-up, relapses continued to occur and therefore the survival estimates decreased significantly. Furthermore confirmatory national phase II trials using these newer regimens produced CRs of only 49%-65% and survival of 50%-61% [6]. Thus ultimate conclusions concerning the efficacy of these new regimens awaited the results of prospective randomized trials. The Southwest Oncology Group (SWOG) in collaboration with the Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial (SWOG-8516) comparing standard therapy, CHOP, to the third generation chemotherapy regimens, m-BACOD, ProMACE-CytaBOM, or MACOP-B [7]. After over six years, there is still no
Key words: autologous transplantation, CHOP, diffuse large B-cell lymphoma, IPI, NHL
difference in response rate, progression-free survival with five-year estimates varying from 33%—38% or overall survival with five-year estimates varying from 45%— 46% between CHOP and the third generation regimens. However the cost and toxicity of the new regimens was higher. Other randomized trials comparing CHOP with each of the previously mentioned third generation chemotherapy regimens gave similar results [8, 9]. Thus CHOP remains the best available standard of care; the recognition of this fact has resulted in significant cost savings and the avoidance of unnecessary toxicity. However, based on the fact that fewer than 50% of all patients are cured and, as noted subsequently, we can now identify subsets of patients with even lower cure rates, it is absolutely essential that oncologists develop new and improved therapeutic approaches for patients with advanced stage, aggressive histology nonHodgkin's lymphoma.
Therapy based on prognostic factors How could we have such disparate results between the single institution phase II studies and the subsequent national phase II as well as the final national phase III trials? The International Non-Hodgkin's Lymphoma Prognostic Factors Index (IPI) utilized pretreatment
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Background: New treatments are desperately needed to improve the results obtained using CHOP chemotherapy for patients with diffuse large cell lymphoma. In order to develop successful new strategies we need to understand why prior promising therapies have failed and to develop new testable hypotheses based on our current knowledge. Patients and methods: The International Non-Hodgkin's Lymphoma Prognostic Factors Index has provided us with a methodology to compare the expected prognosis of patients on different clinical trials. Many prior, apparent improvements in treatment outcome can now be attributed to the inclusion of patients with better prognoses. Results: Current areas of investigation include: 1) the identification of new active drugs for the treatment of lymphoma,
2) the use of colony stimulating factors to allow dose escalation of the active myelotoxic drugs. 3) the use of strategies which may overcome the problem of resistance to chemotherapy, 4) the combination of monoclonal antibodies with combination chemotherapy and 5) ablative chemotherapy with autologous stem-cell support. Conclusions • Based on all of the available data, the North American Lymphoma Intergroup has developed the hypothesis that high-intermediate and high risk patients with aggressive lymphoma who receive full course standard induction therapy will benefit form the addition of high dose therapy and has antedated a clinical trial testing that hypothesis.
30 Table 1. Autotransplantation in poor-risk DLCL: Results of randomized trials.
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to chemotherapy which is the ultimate cause of treatment failure in the majority of patients, 4) the combination of monoclonal antibodies with combination chemotherapy Treatment arm favored First Initial and 5) ablative chemotherapy with autologous stem-cell author induction support. These areas are summarized as follows: therapy Transplant Conventional No difference 1) The discovery of new drugs for the treatment of Retrospective subset analysis intermediate/high-grade non-Hodgkin's lymphoma reHaioun Full course DFS, OS mains a difficult task for several reasons. The large Santini Full course DFS, PFS number of active agents and the high number of Prospective trials complete remissions means that a drug must have outAbbreviated Reyes EFS, OS Martelli Abbreviated standing single agent activity in phase II testing before it EFS, OS Kaiser Abbreviated EFS, OS is considered for evaluation as a front-line agent. Drugs that would be considered quite exciting in some solid tumors are discarded as marginally active in the lymprognostic factors in a sample of several thousand pa- phomas. Generally complete remission rates in excess of tients with aggressive lymphomas to develop a predictive 25% in phase II trials are required. In addition, many model of outcome for aggressive NHL [10]. The majority patients who are not cured by initial therapy are now of patients had received adriamycin based chemotherapy considered for high dose salvage therapy at first relapse. regimens. Five pretreatment characteristics were found Thus the pool of patients available for phase II testing to be independently statistically significant: age (^60 now consists of patients ineligible for high-dose therapy vs. >60), tumor stage I or II (localized) vs. Ill or IV or those relapsing after that treatment. Although clin(advanced), the number of extra nodal sites of involve- ical trials are continuing in many centers, at the moment ment ( ^ 1 vs. > 1), patient performance status (0 or 1 vs. there are no drugs demonstrating unequivocally high Js 2), high-intermediate risk (3), and high risk (4 or 5). levels of single agent activity in the diffuse large-cell When patients were analyzed by risk factors, they were lymphomas. found to have very different outcome with regard to 2) CSFs have allowed several groups to double the complete response rate (CR), relapse-free survival (RFS) dose intensity of marrow toxic drugs such as cyclophosand overall survival (OS). For example patients in the phamide and doxorubicin. The SWOG has completed a high risk IPI group had a CR rate of 44% and a five-year randomized phase II study of dose intensified CHOP survival rate of only 26% as compared to a CR rate of and dose intensified ProMACE-CytaBOM with G-CSF 87% and a five-year survival of 73%) in patients in the support. The Eastern Cooperative Oncology Group low-risk IPI group. Therefore, those patients with a low (ECOG) has reported a successful phase I dose escalation IPI, whose outcome is predicted to be favorable with study of ProMACE-CytaBOM [11] and subsequently conventional therapy, should be spared the added toxicity completed a phase II study of that regimen. Longer which is often associated with more aggressive experi- term follow-up is required before the results of these mental therapy. On the other hand, those with a high- studies can be evaluated. In addition, Shipp et al. intermediate or high-risk IPI, in whom a CR is unlikely reported encouraging pilot data using G-CSF to dose with conventional therapy, should be identified as can- escalate cyclophosphamide to 4 mg/m2 and doxorubicin didates for more aggressive treatment. to 70 mg/m2 in a CHOP-like regimen [12]; subsequent The IPI has provided us with a methodology to phase II testing of this regimen in the Cancer and Acute compare the patients entering various clinical trials. As Leukemia Group B (CALGB) is still being definitively can be seen in Table 1, the percent of patients with low analyzed but has not confirmed the promising early IPI scores in the National Cancer Institute original trial results. of ProMACE-CytaBOM (44%) was almost twice that in 3) Since pleiotropic drug resistance develops after the subsequent SWOG-8516 phase III study (22%) [5, 7]. treatment and relapse in a significant number of these The differences in outcome caused by these type of im- patients, SWOG has conducted phase II studies with balances in patient prognostic factors can easily exceed infusional CHOP plus verapamil and quinine aimed at any treatment differences between the actual therapies. preventing the emergence of this resistance factor. To date we have demonstrated increased bone marrow toxicity but have not yet seen improvement in relapse-free survival compared to historical controls treated with CHOP. New therapeutic approaches Quinine and verapamil are admittedly first generation Investigators are currently utilizing several different MDR inhibitors and newer, more potent inhibitors of approaches to attempt to improve these treatment out- drug resistance are currently in early clinical trials. In comes. These include: 1) the identification of new active fact, one of the newer inhibitors, PSC-388, has recently drugs for the treatment of lymphoma, 2) the use of been demonstrated to improve survival in acute leukecolony stimulating factors, CSFs, to allow dose escala- mia. tion of the active but myelotoxic drugs, 3) the use of 4) Combinations of monoclonal antibodies and strategies which may overcome the problem of resistance combination chemotherapy are now being explored.
31 While most of the studies conducted to date with monoclonal antibodies have focused on the indolent lymphomas [13], Coiffier et al. have reported an overall response rate of 37% in relapsing or refractory aggressive lymphoma patients treated with Rituximab, an antiCD20 monoclonal antibody [14]. This antibody has also been demonstrated to be quite tolerable when combined with CHOP chemotherapy [15].
High-dose therapy with stem-cell support
Support for the concept that high dose therapy after standard induction chemotherapy may only be beneficial for the high-intermediate and high risk IPI groups is provided by Santini et al. [20]. Patients were randomized to receive either standard VACOP-B chemotherapy or VACOP-B followed by autologous bone marrow transplantation. While there was no difference in the diseasefree survival (DFS) or progression-free survival (PFS) for the entire group of 124 patients; there was a statistical improvement in DFS (P - 0.008) and a favorable trend in PFS (P = 0.08) for the high-intermediate and high-risk IPI groups assigned to high-dose therapy. Once again, since the high-risk patients were not initially identified as the target population for that trial, prospective randomized trials will clearly be required to determine whether this subset of patients truly benefits from high-dose therapy. Several additional trials testing whether patients with high-intermediate and high-risk benefit from high-dose therapy have already been initiated and preliminary data in abstract form has or will soon be presented. The GELA group has reported on the preliminary results of their subsequent study LNH93-3 which randomized the high-intermediate and high-risk patients to the same sequential chemotherapy program used in LNH87 versus a new short, intensive induction chemotherapy followed by stem-cell transplant [21]. The data revealed
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Rationale for testing high-dose therapy with stem-cell support in previously untreated patients with aggressive non-Hodgkin's lymphoma was initially provided by the results of the Parma trial [16]. Patients, who had relapsed after an initial complete remission and were still under the age of 60 years with no evidence of central nervous system disease or bone marrow involvement, were first treated with two courses of conventional salvage chemotherapy. Those patients responding with a CR or PR were then considered to be chemosensitive and were randomized to involved field radiotherapy and high-dose BEAC chemotherapy versus DHAP chemotherapy for six additional months followed by involved field radiotherapy. The event-free survival (EFS) of patients randomized to high-dose therapy was 46% compared to 12% for patients continuing to receive salvage chemotherapy (P = 0.001) and OS was also superior in the high-dose therapy group (P = 0.038). This study defined high-dose therapy with stem-cell support as the treatment of choice for relapsed aggressive lymphomas patients that met the other eligibility criteria of the Parma study although it is important to note that a majority of the patients ultimately dying of aggressive lymphoma would not meet the eligibility criteria of the Parma study. This study did however also raise the question of whether the earlier use of high-dose therapy in untreated patients would prove to be beneficial. Gianni et al. also conducted a trial of 75 patients with poor risk aggressive NHL who were randomized to treatment with MACOP-B or with a novel high-dose chemotherapy regimen requiring hematopoietic progenitor cell autotransplantation [17]. If the initially assigned treatment failed, the patients were allowed to cross over to the other treatment. The toxic death rate on the highdose arm of the study was initially high (16%) but has decreased with modification of the treatment regimen. Thirty-eight patients were randomized to the high-dose therapy and thirty-seven patients were randomized to MACOP-B. After a median follow-up of 43 months there is a statistically significant improvement in relapse-free survival (93% vs. 68%, P - 0.05) and freedom from progression (88% vs. 41%, P = 0.0001) in favor of the high-dose therapy arm. Overall survival was not statistically improved however being 73% on the highdose arm vs. 62% on the MACOP-B arm. ECOG initially conducted a phase II pilot trial of this regimen and then opened a phase III comparison of the Gianni
regimen versus CHOP. Unfortunately the phase III has had very slow accrual and has recently been closed. Thus it is unclear whether the promising lead developed by Gianni will ever be confirmed, at least in the US clinical trials, although a Swiss Group for Clinical and Epidemiological Cancer Research (SAKK) Mistral study of this treatment is ongoing. The Groupe d'Etudes des Lymphomes des l'Adulte (GELA) reported an important study on a subset of 727 patients treated with the LNH87 protocol [18]. Three hundred seventy patients were randomized after achieving a CR with their standard, full course, induction therapy to a consolidation phase in which patients were randomized to sequential chemotherapy or ABMT. Only one patient died of transplant related complications. With a median follow-up of 21 months, the overall twoyear survival was 62% and disease-free survival was 58%. Overall survival and disease-free survival for all the randomized patients did not differ between the consolidation arms (P - 0.089). This trial was instituted before the publication of the IPI. Therefore, patients were not initially stratified by IPI as important prognostic factors. A subsequent retrospective analysis did reveal a relapse-free and overall survival benefit for the patients who were reclassified as having the high-intermediate and high risk characteristics according to the International Index [19]. While this type of retrospective analysis does not prove that high risk patients according to the IPI will benefit from consolidative stem cell transplantation, it does generate an important lead that needs to be follow-up in subsequent prospective randomized trials studying exactly that question.
32 Table 2 ProMACE-CytoBOM trials. Risk group
Number of patients (%)
Low Low-intermediate High-intermediate High
NC!
SWOG
41 (44) 25 (27) 23 (24) 5(5)
196(22) 324 (36) 271(30) 108(12)
Table 3. SWOG, ECOG, CALGB - phase III - S9704 early vs. delayed high-dose therapy in high-intermediate/high IPI DLCL. Preregister no later than second cycle
versus delayed high-dose therapy for patients with highintermediate and high-risk large-cell non-Hodgkin's lymphoma. The schema for the trial is shown in Table 3. Patients under the age of 65 years will each receive 5 cycles of CHOP; responding patients will then be randomized to receive either 3 more cycles of CHOP or 1 additional cycle of CHOP followed by high-dose therapy with autologous stem-cell rescue. Patients on the standard CHOP treatment who relapse will then receive the same high-dose therapy. If this study confirms the benefit of high dose therapy in this patient group, subsequent trials will attempt to increase the number of responding patients who become eligible for high-dose therapy.
J
Conclusions
Complete or Partial Responae (Enter Randomization]
|
Roapondere to ASCT
»lapa«
|
a superior survival benefit for the sequential chemotherapy control compared to the high-dose therapy arm and therefore the study was closed before the planned accrual was completed. Elsewhere at this International Conference on Malignant Lymphoma, Lugano, Switzerland, June 1999, Martelli et al. will report the preliminary results of a randomized trial comparing standard MACOP-B chemotherapy versus a shortened course of MACOP-B followed by high-dose stem-cell transplant for patients with high-intermediate and high risk. To date there are no significant differences in CR, PFS, or OS. Kaiser et al. will also update a German high-grade lymphoma study of a full course of their standard chemotherapy regimen versus a shortened course of the same drugs followed by high-dose therapy. To date there is no benefit for the high-dose therapy arm for all of the patients or a high-risk subset.
North-American high-dose therapy trial The data summarizing the results of randomized trials of autotransplantation in poor-risk DLCL are shown in Table 2. This author believes that the data supports the hypothesis that high-intermediate and high-risk patients with aggressive lymphoma who receive full course standard induction therapy will benefit form the addition of high dose therapy. Based on this hypothesis, the Lymphoma Committees and the Bone Marrow Transplant Committees of SWOG, ECOG, and CALGB (Cancer and Acute Leukemia Group B) have agreed to jointly conduct a randomized clinical trial of early
History has taught us that prospective randomized clinical trials are only successful when they are based on positive leads provided by solid phase II trials. In the past many of the promising phase II studies have appeared beneficial based on patient selection criteria and not the therapeutic result. The new prognostic factor index now allows us to evaluate the expected therapeutic results based on the mixture of patient risk categories. CHOP has remained the standard treatment for diffuse large-cell lymphomas for over 20 years. It is time to improve. Multiple rationale strategies are now being explored. Thoughtful clinical investigation is the key to future progress.
References 1. Fisher RI, HubbardSM. DeVitaVTet al. Factors predicting longterm survival in diffuse mixed, histiocytic, or undifferentiated lymphoma. Blood 1981; 58: 45-51. 2. Coltman CA, Dahlberg S, Jones SE et al. Southwest Oncology Group Studies in diffuse large-cell lymphoma: A subset analysis. In Kimura K (ed): Cancer Chemotherapy: Challenges for the Future. Tokyo: Excerpta Medica 1988: 194-202. 3. Shipp MA, Harrington DP, Klatt MM et al. Identification of major prognostic subgroups of patients with large-cell lymphoma treated with m-BACOD or M-BACOD. Ann Intern Med 1986; 104: 757-65. 4. Klimo P, Connors JM. MACOP-B chemotherapy for the treatment of diffuse large-cell lymphoma. Ann Intern Med 1985; 102: 596-602. 5. Longo DL, DeVita VT, Duffey PL et al. Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma' Results of a prospective randomized trial. J Clin Oncol 1991: 9: 25-38. 6. Fisher RI. Miller TP, Dana BWet al. Southwest Oncology Group clinical trials for intermediate-and high-grade non-Hodgkin's lymphomas. Semin Hematol 1987: 24: 21-25. 7. Fisher RI. Gaynor ER. Dahlberg S et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 1993: 328: 1002-6. 8. Gordon LI, Harrington D. Andersen J et al. Comparison of a second-generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced
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| Evaluate for Reaponae |
33
9.
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16.
17. Gianni AM. Bregni M. Siena S et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997: 336: 1290-7. 18. Haioun C. Lepage E. Gisselbrecht C et al. Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate and high-grade non-Hodgkin's lymphoma in first complete remission: A study of 464 patients. J Clin Oncol 1994; 12: 2543-51. 19. Haioun C, Lepage E, Gisselbrecht C et al. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: Updated results of the prospective study LNH87-2. J Clin Oncol 1997; 15' 1131-7. 20. Santini G, Salvagno L, Leoni P et al. VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma. Results of a prospective randomized trial by the non-Hodgkin's lymphoma cooperative study group. J Chn Oncol 1998; 16: 2796-802. 21. Reyes F. Lepage E, Morel P et al. Failure of first-line inductive high-dose chemotherapy (HDC) in poor-risk patients with aggressive lymphomas: Updated results of the randomized LNH93-3 study. Blood 1997; 90: 594a (Abstr).
Correspondence to: R. I. Fisher, MD Director, Cardinal Bernardin Cancer Center Loyola University Medical Center 2160 S. First Ave. Maywood, IL 60153 USA
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14.
diffuse non-Hodgkin"s lymphoma. N Engl J Med 1992; 327: 13429. Cooper IA. Wolf MM. Robertson TI et al. Randomized comparison of MACOP-B and CHOP in patients with intermediategrade non-Hodgkin"s lymphoma. J Clin Oncol 1994: 12: 769-78. The International Non-Hodgkin"s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 1993; 329: 987-94. Gordon LI. Andersen J, Habermann TM et al. Phase I trial of dose escalation with growth factor support in patients with previously untreated diffuse aggressive lymphomas: Determination of the maximum-tolerated dose of ProMACE-CytaBOM. J Clin Oncol 1996; 14: 1275-81. Shipp MA. Neuberg D, Janicek M et al. High-dose CHOP as. initial therapy for patients with poor-prognosis aggressive nonHodgkin's lymphoma: A dose-finding pilot study. J Clin Oncol 1995: 13: 2916-23. McLaughlin P, Grillo-Lopez AJ. Link BK et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program J Clin Oncol 1998; 16: 2825-33. Coiffier B. Haioun C, Ketterer N et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 1998; 92: 1927-32. Czuczman MS, Gnllo-Lopez AJ, White CA et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999: 17: 268-76. Philip T, Gughelmi C. Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 1995; 333: 1540-5.
Symposium article Diffuse large-cell lymphoma R. I. Fisher Coleman Professor of Oncology, Director, Cardinal Bernardin Cancer Center, Chairman, Lymphoma Committee, Southwest Oncology Group, Loyola University Chicago, Maywood, IL, USA
Summary
Historical treatment results In order to develop new, effective treatments for patients with diffuse large cell lymphoma it is essential that we review the historical treatment studies to learn from both our successes and our prior failures. A series of single institution phase II trials conducted during the 1970s and 1980s with so-called 'second and third generation' chemotherapy regimens appeared to demonstrate nearly a doubling of the complete remission (CR) rate and overall survival (OS) compared to the 'first generation' combination chemotherapy studies that had produced complete response rates (CRs) of 45%-53% with 30%-37% long-term survivors [1-5]. Unfortunately, with longer follow-up, relapses continued to occur and therefore the survival estimates decreased significantly. Furthermore confirmatory national phase II trials using these newer regimens produced CRs of only 49%-65% and survival of 50%-61% [6]. Thus ultimate conclusions concerning the efficacy of these new regimens awaited the results of prospective randomized trials. The Southwest Oncology Group (SWOG) in collaboration with the Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial (SWOG-8516) comparing standard therapy, CHOP, to the third generation chemotherapy regimens, m-BACOD, ProMACE-CytaBOM, or MACOP-B [7]. After over six years, there is still no
Key words: autologous transplantation, CHOP, diffuse large B-cell lymphoma, IPI, NHL
difference in response rate, progression-free survival with five-year estimates varying from 33%—38% or overall survival with five-year estimates varying from 45%— 46% between CHOP and the third generation regimens. However the cost and toxicity of the new regimens was higher. Other randomized trials comparing CHOP with each of the previously mentioned third generation chemotherapy regimens gave similar results [8, 9]. Thus CHOP remains the best available standard of care; the recognition of this fact has resulted in significant cost savings and the avoidance of unnecessary toxicity. However, based on the fact that fewer than 50% of all patients are cured and, as noted subsequently, we can now identify subsets of patients with even lower cure rates, it is absolutely essential that oncologists develop new and improved therapeutic approaches for patients with advanced stage, aggressive histology nonHodgkin's lymphoma.
Therapy based on prognostic factors How could we have such disparate results between the single institution phase II studies and the subsequent national phase II as well as the final national phase III trials? The International Non-Hodgkin's Lymphoma Prognostic Factors Index (IPI) utilized pretreatment
Downloaded from http://annonc.oxfordjournals.org/ at Michigan State University on March 29, 2015
Background: New treatments are desperately needed to improve the results obtained using CHOP chemotherapy for patients with diffuse large cell lymphoma. In order to develop successful new strategies we need to understand why prior promising therapies have failed and to develop new testable hypotheses based on our current knowledge. Patients and methods: The International Non-Hodgkin's Lymphoma Prognostic Factors Index has provided us with a methodology to compare the expected prognosis of patients on different clinical trials. Many prior, apparent improvements in treatment outcome can now be attributed to the inclusion of patients with better prognoses. Results: Current areas of investigation include: 1) the identification of new active drugs for the treatment of lymphoma,
2) the use of colony stimulating factors to allow dose escalation of the active myelotoxic drugs. 3) the use of strategies which may overcome the problem of resistance to chemotherapy, 4) the combination of monoclonal antibodies with combination chemotherapy and 5) ablative chemotherapy with autologous stem-cell support. Conclusions • Based on all of the available data, the North American Lymphoma Intergroup has developed the hypothesis that high-intermediate and high risk patients with aggressive lymphoma who receive full course standard induction therapy will benefit form the addition of high dose therapy and has antedated a clinical trial testing that hypothesis.
30 Table 1. Autotransplantation in poor-risk DLCL: Results of randomized trials.
Downloaded from http://annonc.oxfordjournals.org/ at Michigan State University on March 29, 2015
to chemotherapy which is the ultimate cause of treatment failure in the majority of patients, 4) the combination of monoclonal antibodies with combination chemotherapy Treatment arm favored First Initial and 5) ablative chemotherapy with autologous stem-cell author induction support. These areas are summarized as follows: therapy Transplant Conventional No difference 1) The discovery of new drugs for the treatment of Retrospective subset analysis intermediate/high-grade non-Hodgkin's lymphoma reHaioun Full course DFS, OS mains a difficult task for several reasons. The large Santini Full course DFS, PFS number of active agents and the high number of Prospective trials complete remissions means that a drug must have outAbbreviated Reyes EFS, OS Martelli Abbreviated standing single agent activity in phase II testing before it EFS, OS Kaiser Abbreviated EFS, OS is considered for evaluation as a front-line agent. Drugs that would be considered quite exciting in some solid tumors are discarded as marginally active in the lymprognostic factors in a sample of several thousand pa- phomas. Generally complete remission rates in excess of tients with aggressive lymphomas to develop a predictive 25% in phase II trials are required. In addition, many model of outcome for aggressive NHL [10]. The majority patients who are not cured by initial therapy are now of patients had received adriamycin based chemotherapy considered for high dose salvage therapy at first relapse. regimens. Five pretreatment characteristics were found Thus the pool of patients available for phase II testing to be independently statistically significant: age (^60 now consists of patients ineligible for high-dose therapy vs. >60), tumor stage I or II (localized) vs. Ill or IV or those relapsing after that treatment. Although clin(advanced), the number of extra nodal sites of involve- ical trials are continuing in many centers, at the moment ment ( ^ 1 vs. > 1), patient performance status (0 or 1 vs. there are no drugs demonstrating unequivocally high Js 2), high-intermediate risk (3), and high risk (4 or 5). levels of single agent activity in the diffuse large-cell When patients were analyzed by risk factors, they were lymphomas. found to have very different outcome with regard to 2) CSFs have allowed several groups to double the complete response rate (CR), relapse-free survival (RFS) dose intensity of marrow toxic drugs such as cyclophosand overall survival (OS). For example patients in the phamide and doxorubicin. The SWOG has completed a high risk IPI group had a CR rate of 44% and a five-year randomized phase II study of dose intensified CHOP survival rate of only 26% as compared to a CR rate of and dose intensified ProMACE-CytaBOM with G-CSF 87% and a five-year survival of 73%) in patients in the support. The Eastern Cooperative Oncology Group low-risk IPI group. Therefore, those patients with a low (ECOG) has reported a successful phase I dose escalation IPI, whose outcome is predicted to be favorable with study of ProMACE-CytaBOM [11] and subsequently conventional therapy, should be spared the added toxicity completed a phase II study of that regimen. Longer which is often associated with more aggressive experi- term follow-up is required before the results of these mental therapy. On the other hand, those with a high- studies can be evaluated. In addition, Shipp et al. intermediate or high-risk IPI, in whom a CR is unlikely reported encouraging pilot data using G-CSF to dose with conventional therapy, should be identified as can- escalate cyclophosphamide to 4 mg/m2 and doxorubicin didates for more aggressive treatment. to 70 mg/m2 in a CHOP-like regimen [12]; subsequent The IPI has provided us with a methodology to phase II testing of this regimen in the Cancer and Acute compare the patients entering various clinical trials. As Leukemia Group B (CALGB) is still being definitively can be seen in Table 1, the percent of patients with low analyzed but has not confirmed the promising early IPI scores in the National Cancer Institute original trial results. of ProMACE-CytaBOM (44%) was almost twice that in 3) Since pleiotropic drug resistance develops after the subsequent SWOG-8516 phase III study (22%) [5, 7]. treatment and relapse in a significant number of these The differences in outcome caused by these type of im- patients, SWOG has conducted phase II studies with balances in patient prognostic factors can easily exceed infusional CHOP plus verapamil and quinine aimed at any treatment differences between the actual therapies. preventing the emergence of this resistance factor. To date we have demonstrated increased bone marrow toxicity but have not yet seen improvement in relapse-free survival compared to historical controls treated with CHOP. New therapeutic approaches Quinine and verapamil are admittedly first generation Investigators are currently utilizing several different MDR inhibitors and newer, more potent inhibitors of approaches to attempt to improve these treatment out- drug resistance are currently in early clinical trials. In comes. These include: 1) the identification of new active fact, one of the newer inhibitors, PSC-388, has recently drugs for the treatment of lymphoma, 2) the use of been demonstrated to improve survival in acute leukecolony stimulating factors, CSFs, to allow dose escala- mia. tion of the active but myelotoxic drugs, 3) the use of 4) Combinations of monoclonal antibodies and strategies which may overcome the problem of resistance combination chemotherapy are now being explored.
31 While most of the studies conducted to date with monoclonal antibodies have focused on the indolent lymphomas [13], Coiffier et al. have reported an overall response rate of 37% in relapsing or refractory aggressive lymphoma patients treated with Rituximab, an antiCD20 monoclonal antibody [14]. This antibody has also been demonstrated to be quite tolerable when combined with CHOP chemotherapy [15].
High-dose therapy with stem-cell support
Support for the concept that high dose therapy after standard induction chemotherapy may only be beneficial for the high-intermediate and high risk IPI groups is provided by Santini et al. [20]. Patients were randomized to receive either standard VACOP-B chemotherapy or VACOP-B followed by autologous bone marrow transplantation. While there was no difference in the diseasefree survival (DFS) or progression-free survival (PFS) for the entire group of 124 patients; there was a statistical improvement in DFS (P - 0.008) and a favorable trend in PFS (P = 0.08) for the high-intermediate and high-risk IPI groups assigned to high-dose therapy. Once again, since the high-risk patients were not initially identified as the target population for that trial, prospective randomized trials will clearly be required to determine whether this subset of patients truly benefits from high-dose therapy. Several additional trials testing whether patients with high-intermediate and high-risk benefit from high-dose therapy have already been initiated and preliminary data in abstract form has or will soon be presented. The GELA group has reported on the preliminary results of their subsequent study LNH93-3 which randomized the high-intermediate and high-risk patients to the same sequential chemotherapy program used in LNH87 versus a new short, intensive induction chemotherapy followed by stem-cell transplant [21]. The data revealed
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Rationale for testing high-dose therapy with stem-cell support in previously untreated patients with aggressive non-Hodgkin's lymphoma was initially provided by the results of the Parma trial [16]. Patients, who had relapsed after an initial complete remission and were still under the age of 60 years with no evidence of central nervous system disease or bone marrow involvement, were first treated with two courses of conventional salvage chemotherapy. Those patients responding with a CR or PR were then considered to be chemosensitive and were randomized to involved field radiotherapy and high-dose BEAC chemotherapy versus DHAP chemotherapy for six additional months followed by involved field radiotherapy. The event-free survival (EFS) of patients randomized to high-dose therapy was 46% compared to 12% for patients continuing to receive salvage chemotherapy (P = 0.001) and OS was also superior in the high-dose therapy group (P = 0.038). This study defined high-dose therapy with stem-cell support as the treatment of choice for relapsed aggressive lymphomas patients that met the other eligibility criteria of the Parma study although it is important to note that a majority of the patients ultimately dying of aggressive lymphoma would not meet the eligibility criteria of the Parma study. This study did however also raise the question of whether the earlier use of high-dose therapy in untreated patients would prove to be beneficial. Gianni et al. also conducted a trial of 75 patients with poor risk aggressive NHL who were randomized to treatment with MACOP-B or with a novel high-dose chemotherapy regimen requiring hematopoietic progenitor cell autotransplantation [17]. If the initially assigned treatment failed, the patients were allowed to cross over to the other treatment. The toxic death rate on the highdose arm of the study was initially high (16%) but has decreased with modification of the treatment regimen. Thirty-eight patients were randomized to the high-dose therapy and thirty-seven patients were randomized to MACOP-B. After a median follow-up of 43 months there is a statistically significant improvement in relapse-free survival (93% vs. 68%, P - 0.05) and freedom from progression (88% vs. 41%, P = 0.0001) in favor of the high-dose therapy arm. Overall survival was not statistically improved however being 73% on the highdose arm vs. 62% on the MACOP-B arm. ECOG initially conducted a phase II pilot trial of this regimen and then opened a phase III comparison of the Gianni
regimen versus CHOP. Unfortunately the phase III has had very slow accrual and has recently been closed. Thus it is unclear whether the promising lead developed by Gianni will ever be confirmed, at least in the US clinical trials, although a Swiss Group for Clinical and Epidemiological Cancer Research (SAKK) Mistral study of this treatment is ongoing. The Groupe d'Etudes des Lymphomes des l'Adulte (GELA) reported an important study on a subset of 727 patients treated with the LNH87 protocol [18]. Three hundred seventy patients were randomized after achieving a CR with their standard, full course, induction therapy to a consolidation phase in which patients were randomized to sequential chemotherapy or ABMT. Only one patient died of transplant related complications. With a median follow-up of 21 months, the overall twoyear survival was 62% and disease-free survival was 58%. Overall survival and disease-free survival for all the randomized patients did not differ between the consolidation arms (P - 0.089). This trial was instituted before the publication of the IPI. Therefore, patients were not initially stratified by IPI as important prognostic factors. A subsequent retrospective analysis did reveal a relapse-free and overall survival benefit for the patients who were reclassified as having the high-intermediate and high risk characteristics according to the International Index [19]. While this type of retrospective analysis does not prove that high risk patients according to the IPI will benefit from consolidative stem cell transplantation, it does generate an important lead that needs to be follow-up in subsequent prospective randomized trials studying exactly that question.
32 Table 2 ProMACE-CytoBOM trials. Risk group
Number of patients (%)
Low Low-intermediate High-intermediate High
NC!
SWOG
41 (44) 25 (27) 23 (24) 5(5)
196(22) 324 (36) 271(30) 108(12)
Table 3. SWOG, ECOG, CALGB - phase III - S9704 early vs. delayed high-dose therapy in high-intermediate/high IPI DLCL. Preregister no later than second cycle
versus delayed high-dose therapy for patients with highintermediate and high-risk large-cell non-Hodgkin's lymphoma. The schema for the trial is shown in Table 3. Patients under the age of 65 years will each receive 5 cycles of CHOP; responding patients will then be randomized to receive either 3 more cycles of CHOP or 1 additional cycle of CHOP followed by high-dose therapy with autologous stem-cell rescue. Patients on the standard CHOP treatment who relapse will then receive the same high-dose therapy. If this study confirms the benefit of high dose therapy in this patient group, subsequent trials will attempt to increase the number of responding patients who become eligible for high-dose therapy.
J
Conclusions
Complete or Partial Responae (Enter Randomization]
|
Roapondere to ASCT
»lapa«
|
a superior survival benefit for the sequential chemotherapy control compared to the high-dose therapy arm and therefore the study was closed before the planned accrual was completed. Elsewhere at this International Conference on Malignant Lymphoma, Lugano, Switzerland, June 1999, Martelli et al. will report the preliminary results of a randomized trial comparing standard MACOP-B chemotherapy versus a shortened course of MACOP-B followed by high-dose stem-cell transplant for patients with high-intermediate and high risk. To date there are no significant differences in CR, PFS, or OS. Kaiser et al. will also update a German high-grade lymphoma study of a full course of their standard chemotherapy regimen versus a shortened course of the same drugs followed by high-dose therapy. To date there is no benefit for the high-dose therapy arm for all of the patients or a high-risk subset.
North-American high-dose therapy trial The data summarizing the results of randomized trials of autotransplantation in poor-risk DLCL are shown in Table 2. This author believes that the data supports the hypothesis that high-intermediate and high-risk patients with aggressive lymphoma who receive full course standard induction therapy will benefit form the addition of high dose therapy. Based on this hypothesis, the Lymphoma Committees and the Bone Marrow Transplant Committees of SWOG, ECOG, and CALGB (Cancer and Acute Leukemia Group B) have agreed to jointly conduct a randomized clinical trial of early
History has taught us that prospective randomized clinical trials are only successful when they are based on positive leads provided by solid phase II trials. In the past many of the promising phase II studies have appeared beneficial based on patient selection criteria and not the therapeutic result. The new prognostic factor index now allows us to evaluate the expected therapeutic results based on the mixture of patient risk categories. CHOP has remained the standard treatment for diffuse large-cell lymphomas for over 20 years. It is time to improve. Multiple rationale strategies are now being explored. Thoughtful clinical investigation is the key to future progress.
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Correspondence to: R. I. Fisher, MD Director, Cardinal Bernardin Cancer Center Loyola University Medical Center 2160 S. First Ave. Maywood, IL 60153 USA
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