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U-M CCC - Michigan Oncology Journal Fall 2000

Treatment of Intermediate-and High-Grade Non-Hodgkin's Lymphoma

Andrzej J. Jakubowiak, M.D., Ph.D.
Assistant Professor of Internal Medicine

Harry P. Erba, M.D., Ph.D.
Assistant Professor of Internal Medicine

Intermediate-Grade Non-Hodgkin's Lymphoma

Intermediate-grade non-Hodgkin's lymphoma (IGL) is a heterogeneous group of different entities, which are usually sensitive to treatment and frequently curable, although to a variable degree. Diffuse large cell lymphoma (DLCL) is the most common IGL and represents 30% of all non-Hodgkin's lymphomas (NHL).

Traditionally, IGL also includes follicular, predominantly large-cell lymphoma, diffuse small-cleaved-cell lymphoma, and diffuse small- and large-mixed-cell lymphoma. Several separate entities recognized by The Revised European-American Lymphoma (REAL) classification, including anaplastic large lymphoma, angioimmunoblastic T- cell lymphoma (formerly AILD), lymphomatoid granulomatosis, and primary mediastinal B-cell lymphoma, are frequently included in the intermediate category for diagnostic and therapeutic purposes. Management and clinical outcomes of IGL depend mostly on the stage of the disease according to the Ann Arbor staging system and the number of adverse prognostic factors. Prognostic stratification is most commonly done according to the International Prognostic Index (IPI), which includes the following:

1) age >60,
2) stage III or IV,
3) LDH above normal range,
4) 2 or more extranodal sites of involvement including direct extension
5) Karnofsky performance status <80.

Based on this assessment, IGL patients are considered to be in early stage if they are in stage I or II with no more than 2 adjacent sites of involvement, no individual or aggregate mass 10 cm or greater, and no more than 1 IPI risk factor. Remaining patients are considered in an advanced stage. Patients in advanced stage are further categorized as low-risk if they have 0 or 1 IPI risk factor, low-intermediate risk with 2 factors, high-intermediate risk with 3 factors and high risk with 4 or 5 factors. Recognition of the importance of prognostic indicators provide the basis for more specific choices of best treatment for given category of patients.

Treatment of Early-Stage IGL

The vast majority of patients with early-stage disease will be cured. Patients are treated with either chemotherapy alone or chemotherapy followed by radiation therapy. Standard chemotherapy for early stage IGL consists of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). To determine the role of radiation therapy in the treatment of early-stage IGL, the Southwest Oncology Group (SWOG) conducted a randomized trial that compared eight cycles of CHOP alone versus the combination of a short course of CHOP chemotherapy (three cycles) followed by radiation therapy. The combined regimen was superior to chemotherapy alone (1). There are no contraindications to use the CHOP regimen in older patients with normal cardiac function. In patients with active heart disease, regimens without doxorubicin, such as CEPP or CMOPP, can be used instead of CHOP.

Treatment of Advanced-Stage IGL

For this group of patients, CHOP is also considered the best available treatment. As a standard, patients are treated with six to eight cycles. Other regimens, including ProMACE-CytaBOM, m-BACOD, and MACOP-B, were not significantly different from CHOP in prospective randomized phase III trials in terms of disease-free and overall survival (2). Overall, the treatment of the advanced disease is not as successful as the treatment of early-stage disease, although there are significant differences between different subgroups. Patients with a low IPI have a five-year survival exceeding 70%, whereas high IPI patients have only a 26 to 31% 5-year survival. In an attempt to improve treatment outcomes in higher-risk patients, different more aggressive chemotherapy regimens have been, or are being evaluated (e.g., ESHAP, NHL-15, or dose-intensive CHOP). To date, there is no definite evidence that these combinations provide better overall survival. Experience with rituximab in low-grade lymphoma resulted in its incorporation into the up-front treatment schemes of IGL. Recently reported results of a phase II study of combination of rituximab with CHOP for untreated IGL patients indicate overall and complete response rates (97% and 61%, respectively) higher than historical controls treated with CHOP alone (3). An ongoing randomized trial conducted by ECOG and CALGB is evaluating CHOP with or without rituximab in older patients with aggressive NHL. The National Cancer Institute is evaluating a combination of EPOCH and rituximab. Multiple attempts have been made to determine whether patients with advanced IGL, particularly those with a high IPI should be treated with high- dose consolidation chemotherapy with autologous stem cell transplantation (ASCT) in the first remission. The studies of this approach to date reported mixed results (4). Subsequent subset analysis indicated that high- intermediate and high-IPI patients can benefit from high-dose therapy with ASCT (5,6). SWOG, ECOG, and CALGB are currently investigating the role of high-dose therapy in a phase III study in which high-IPI IGL patients are randomized to receive either eight cycles of CHOP or six cycles of CHOP followed by high-dose chemotherapy with TBI and ASCT. The role of radiotherapy in advanced-stage IGL is yet to be determined but high-dose chemotherapy protocols frequently include involved field radiation for bulky disease.

Relapsed/Refractory IGL

Conventional salvage chemotherapy regimens may rescue 10 to 15% of the patients with relapsed and refractory IGL. Several independent studies provided evidence that high-dose chemotherapy with ASCT is significantly better for these patients and overall survival can reach over 50% (4). Outcomes are better if the disease is chemotherapy sensitive and for patients with low IPI at the time of relapse. Patients suffering early relapse (less than 12 months) have significantly lower response rates. In addition, allogeneic bone marrow transplantation and graft-versus-lymphoma effect have been successfully used in refractory/relapsed IGL using both myeloablative (7) and non-myeloablative regimens (8,9). Patients not eligible for bone marrow transplant are given one of the standard salvage regimens. In a phase II study, rituximab was used as a single agent and showed 37% response rates in relapsed/refractory DLCL (10).

In summary, despite significant progress in recent years, a substantial number of patients with IGL still fail available therapy. Completion of ongoing trials should clarify which strategies are best for different groups of patients, particularly high-risk advanced disease. A better understanding of the biology of specific types of IGL should result in development of more biologically specific therapies. It is hoped that the evolution in alternative therapies, including molecular targeting, monoclonal antibodies and their radioimmunoconjugates, and vaccines may improve the results of treatment of IGL.

High-Grade Non-Hodgkin's Lymphoma

According to the NCI Working Formulation, high-grade non-Hodgkin's lymphomas are immunoblastic, lymphoblastic, and diffuse, small non-cleaved cell (Burkitt's and Burkitt's-like). The REAL classification fails to recognize immunoblastic lymphoma as a separate pathologic entity. The distinction between immunoblastic and diffuse large B cell lymphoma could not be made reproducibly by a group of skilled hematopathologists. Furthermore, these two histologic variants are treated similarly with many studies showing no difference in prognosis.

Lymphoblastic lymphoma is divided into precursor B-cell and precursor T-cell lymphoblastic leukemia/ lymphoma by the REAL classification. The distinction between lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) had been made on the basis of degree of bone marrow involvement in the past. However, there does not appear to be any biologic differences between LBL and ALL. The morphologic, immunophenotypic, and cytogenetic characteristics of LBL and ALL are indistinguishable. In fact, patients with LBL are now treated with ALL therapy. These regimens include anthracycline/ steroid/vincristine-based induction, early and late intensification, CNS prophylaxis, and prolonged maintenance chemotherapy. The prognosis of patients with ALL depends on patient age, immunophenotype and cytogenetic risk factors (11). Older patients with high-risk features (extreme leukocytosis at presentation, presence of the Philadelphia chromosome or translocations involving the MLL gene at chromosome 11q23) should be considered for high-dose chemotherapy with allogeneic hematopoietic stem cell transplantation in first remission (12).

Burkitt's lymphoma can be distinguished from Burkitt's-like lymphoma by both morphology and the over-expression of the c-myc oncogene in the former. Translocations involving the c-myc gene on chromosome 8 with the immunoglobulin gene loci on chromosomes 14, 22, and 2 are characteristic of Burkitt's lymphoma. These high-grade lymphomas had been associated with a poor prognosis. However, the cure rate for these diseases has increased dramatically in recent years. A complex chemotherapeutic regimen incorporating high-dose fractionated cyclophosphamide, intermediate-dose methotrexate, high-dose cytarabine and ifosfamide has resulted in disease-free survival rate of 90% for both children and adults (13). Unfortunately, these intensive protocols are complicated by significant toxicity (sepsis, neuropathy, mucositis, and death), particularly in adult patients.


1. Miller TP, Dahlber S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, LeBlanc M, Carlin S, Chase E, Fisher RI. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. 1998; 339:21

2. Fisher RI, Gaynor ER, Dahlber S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993;328:1002

3. Vose JM, Link BK, Grossbard ML, Fisher RI, Czuczman M, Grillo-Lopez A, Gilman P, Lowe A, Kunkel LA. Phase II study of rituximab in combination with CHOP in patients with previously untreated intermediate- or high-grade non-Hodgkin's lymphoma. ASH 1999, Abstract #388.

4. Johnston LJ, Horning SJ. Autologous hematopoietic cell transplantation in non-Hodgkin's lymphoma. Hematol Oncol Clin North Am. 1999;13:889. Review.

5. Haioun C, Lepage E, Gisselbrecht C, Salles B, Coiffier B, Brice P, Bosly A, Moprel P, Nouvel C, Tilly H, Lederlin P, Sebban C, , Briere J, Gaulard P, Reyes F. Survival benefit of high dose therapy over sequential chemotherapy in poor risk aggressive non-Hodgkin's lymphoma. Final analysis of the prospective LNH87-2 protocol. A GELA study. ASH 1999, Abstract #2711.

6. Santini G, Salvagno L, Leoni P, Chisesi T, De Souza C, Sertoli MR, Rubagotti A, Congiu AM, Centurioni R, Olivieri A, Tedeschi L, Vespignani M, Nati S, Soracco M, Porcellini A, Contu A, Guarnaccia C, Pescosta N, Majolino I, Spriano M, Vimercati R, Rossi E, Zambaldi G, Mangoni L, Rizzoli V, 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 Clin Oncol. 1998;16:2796.

7. Bernard M, Dauraic C, Drenou B, Leberre C, Branger B, Fauchet R, Le Priese PY, Lamy T. Long-term follow up of allogeneic bone marrow transplantation in patients with poor prognosis non-Hodgkin's lymphoma. Bone Marrow Transplant. 1999;23:329.

8. Khouri IF; Keating M; Korbling M; Przepiorka D; Anderlini P; O'Brien S; Giralt S; Ippoliti C; von Wolff B; Gajewski J; Donato M; Claxton D; Ueno N; Andersson B; Gee A; Champlin R. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998;16:2817.

9. Sykes M, Preffer F, McAfee S, Saidman SL, Weymouth D, Andrews DM, Colby C, Sackstein R, Sachs DH, Spitzer TR. Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after non-myeloablative therapy and HLA-mismatched bone-marrow transplan-tation. Lancet. 1999;353:1755.

10. Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, Johnson P, Lister A, Feuring-Buske M, Radford JA, Capdeville R, Diehl V, Reyes F. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multi-center phase II study. Blood. 1998;15;92:1927.

11. Larson RA. Dodge RK. Burns CP. Lee EJ. Stone RM. Schulman P. Duggan D. Davey FR. Sobol RE. Frankel SR. et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood. 1995;85(8):2025-37.

12 Fiere et al. Comparison of allogeneic transplantation, autologous transplantation, and chemotherapy as post induction treatment in adult ALL. Long term report of the French Group for Treatment of Adult ALL (LALA87). J Clin Oncol. 1998;17:14a.

13. Magrath I. Adde M. Shad A. Venzon D. Seibel N. Gootenberg J. Neely J. Arndt C. Nieder M. Jaffe E. Wittes RA. Horak ID. Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol. 1996;14(3):925-34.

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Continue reading:

Antibody Therapy for Non-Hodgkin's Lymphoma

New Small Lymphocytic Lymphomas

The Revised European-American Classification of Lymphoid Neoplasms (REAL Classification)

Of Interest

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Please note: The articles listed in the Cancer Center's News Archive are here for historical purposes. The information and links may no longer be up-to-date.
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