Adult non-Hodgkin's lymphoma

** PROGNOSIS **

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment. Like Hodgkin's disease (HD), non-Hodgkin's lymphomas usually originate in lymphoid tissues and can spread to other organs. However, NHLs are much less predictable than HD and have a far greater predilection to disseminate to extranodal sites. The prognosis depends on the histologic type, stage, and treatment. The working formulation divides the NHLs into three prognostic groups: low grade, intermediate grade, and high grade. The low-grade NHLs have a relatively good prognosis, with median survival greater than five years, but usually are not curable in advanced clinical stages. Early stage (I and II) low-grade NHL can be effectively treated with radiation therapy alone. Most of the low-grade types are nodular (or follicular) in morphology. The intermediate- and high-grade types of NHL have a shorter natural history, but a significant number of these patients can be cured with aggressive combination chemotherapy regimens. In general, overall survival at five years with modern treatment for patients with NHL is approximately 50-60%. Thirty to 60% of patients with intermediate-grade lymphoma can be cured. The vast majority of relapses occur in the first two years after therapy. The risk of late relapses is higher in patients with a divergent histology of both low- and intermediate-grade.[1] While low-grade NHL is responsive to radiation therapy and chemotherapy, a continuous rate of relapse is usually seen in advanced stages. However, patients can often be retreated with considerable success as long as the disease histology remains low grade. Some data do suggest that long-term disease-free survival can be obtained in low-grade lymphoma patients who achieve complete remission with intensive treatment.[2] The patients who present with or convert to intermediate-grade forms of NHL may have sustained complete remissions with combination chemotherapy regimens. Radiation techniques differ somewhat from those used in the treatment of HD. The dose of radiation usually varies from 3,500 to 5,000 cGy based on histologic subtype, bulk of disease, and use of initial chemotherapy. Treatment with radiation therapy requires the use of linear accelerators with energy of 4-10 MeV and treatment planning simulators. Simulators are used to obtain detailed x-rays of patients in the treatment position so that radiation fields can be tailored to conform to the patient's anatomy, and individually shaped protective blocks can be fabricated to shield normal tissues for the individual patient. Treatment is usually delivered first to the neck, chest, and axilla (mantle field). Often the low mediastinum is omitted for a "mini-mantle." For subdiaphragmatic presentations, whole abdominal irradiation may be necessary. Because Waldeyer's ring, epitrochlear, and mesenteric lymph nodes may be involved in NHL, these sites are often included in the radiation fields. The majority of patients who receive radiation are usually treated on only one side of the diaphragm. Localized presentations of extranodal NHL may be treated with involved field techniques with significant (> 50%) success. The use of low-dose total body irradiation (TBI) has been used experimentally in selected patients with advanced stage, low-grade forms of NHL. In asymptomatic patients with low-grade forms of advanced NHL, treatment may be deferred until the patient becomes symptomatic as the disease progresses. When treatment is deferred, the clinical course of low-grade lymphoma patients varies; frequent and careful observation is required so that effective treatment can be initiated when the clinical course of the disease accelerates. Some patients have a prolonged indolent course while others have disease rapidly evolving into more aggressive types of lymphoma requiring immediate treatment. Intermediate- and high-grade lymphomas are increasingly seen in HIV-positive patients whose treatment requires special consideration and is further outlined in the state-of-the-art statement entitled AIDS-Related Lymphoma. For discussion of treatment options for non-AIDS-related primary CNS lymphoma, refer to the state-of-the-art statement entitled Primary CNS Lymphoma. References: 1. Cabanillas F, Velasquez WS, Hagemeister FB, et al.: Clinical, biologic, and histologic features of late relapses in diffuse large cell lymphoma. Blood 79(4): 1024-1028, 1992. 2. Licht JD, Bosserman LD, Andersen JW, et al.: Treatment of low-grade and intermediate-grade lymphoma with intensive combination chemotherapy results in long-term, disease-free survival. Cancer 66(4): 632-639, 1990.

** CELLULAR CLASSIFICATION **

There are at least six different pathologic classification systems for NHL in use throughout the world.

[1] Some place major emphasis on the overall nodal architecture, while others emphasize the morphology of the cells themselves. All can distinguish indolent lymphomas from rapidly progressive forms of NHL. Whenever possible, a pathologist should be consulted prior to biopsy, and tissue should be frozen for special studies. In terms of prognostic and therapeutic value, the importance of new diagnostic techniques such as cell surface markers and immunoglobulin and T-cell receptor gene rearrangements is not yet clear. In difficult diagnostic situations, the clonal excess of light chain immunoglobulin may differentiate malignant from reactive cells.

[2] Since the prognosis and the approach to treatment are influenced by histopathology, obtaining a careful review of biopsy specimens by a hematopathologist who is experienced in diagnosing lymphomas is extremely important. Special studies require special preparation of tissue so a pathologist should be consulted prior to the biopsy. Recent studies indicate that extent of nodularity (> 75% of node) is associated with an improved survival.

[3-5] The working formulation contains explicit translation to the other six classifications of the non-Hodgkin's lymphoma. As an example, the following table provides the modified Rappaport classification for the working formulation categories.

--Working formulation--[1] --Rappaport classification--

Low grade

A. small lymphocytic, consistent with CLL diffuse lymphocytic, (SC) well-differentiated (DLWD)

B. follicular, predominantly small nodular lymphocytic, poorly cleaved cell (FSC) differentiated (NLPD)

C. follicular, mixed small cleaved and nodular mixed, lymphocytic and large cell (FM) histiocytic (NM) Intermediate grade

D. follicular, predominantly large cell nodular histiocytic (FL) (NH)

E. diffuse, small cleaved cell* diffuse lymphocytic, poorly (DSC) differentiated (DLDP)

F. diffuse mixed, small and large cell diffuse mixed, lymphocytic and (DM) histiocytic (DM)

G. diffuse, large cell cleaved or diffuse histiocytic (DH) noncleaved cell (DL) High grade

H. immunoblastic, large cell (IBL)** diffuse histiocytic (DH)

I. lymphoblastic, convoluted or diffuse lymphoblastic nonconvoluted cell (LL) (DL)

J. small noncleaved cell, Burkitt's or diffuse undifferentiated, non-Burkitt's (SNC) Burkitt's or non-Burkitt's (DU)

* Although included here in the working formulation as an intermediate-grade lymphoma, its natural history is more typical of low-grade lymphomas and is frequently managed as a low-grade lymphoma.

** Although included here in the working formulation as a high-grade lymphoma, its natural history is more typical of an intermediate-grade lymphoma and is frequently managed as a diffuse, large cell (DL) lymphoma.

This type includes Ki-1-positive anaplastic large cell lymphoma, which is generally treated the same as diffuse, large cell lymphoma.

[6] Several subsets of non-Hodgkin's lymphoma have been recognized that are not identified in the working formulation.

[7] Mantle cell lymphomas refer to intermediate (differentiation) lymphocytic lymphomas of either mantle zone or diffuse type. These lymphomas are low-grade and express the CD5 antigen. Mucosa-associated lymphoid tissue (MALT) lymphomas and monocytoid B-cell lymphoma represent another family of low-grade lymphomas. These lymphomas typically involve extranodal tissue (GI tract, thyroid, breast, and skin). Anaplastic large-cell lymphomas may be confused with carcinomas and are associated with the Ki-1 (CD30) antigen. These are usually of T-cell origin and often present with extranodal disease, especially the skin. These are generally treated the same as diffuse, large cell lymphomas.

[6] Other non-Hodgkin's lymphomas that do not fit well into the working formulation include cutaneous T-cell lymphomas, or mycosis fungoides, which are tumors of CD4 helper lymphocytes and have a prolonged clinical course. (A separate statement containing information on cutaneous T-cell lymphoma is available in PDQ.) Adult T-cell lymphoma or leukemia is caused by infection with the retrovirus human T-cell lymphotropic virus type I and is frequently associated with hypercalcemia, a rapidly progressive course, and poor response to therapy

.[7,8] References: 1. The Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. Cancer 49

(10): 2112-2135, 1982. 2. Martin SE, Zhang HZ, Magyarosy E, et al.: Immunologic methods in cytology: definitive diagnosis of non-Hodgkin's lymphomas using immunologic markers for T- and B-cells. American Journal of Clinical Pathology 82(6): 666-673, 1984. 3. Simon R, Durrleman S, Hoppe RT, et al.: The non-Hodgkin's lymphoma pathologic classification project: long-term follow-up of 1153 patients with non-Hodgkin lymphomas. Annals of Internal Medicine 109(12): 939-945, 1988. 4. Anderson T, Chabner BA, Young RC, et al.: Malignant lymphoma: I. the histology and staging of 473 patients at the National Cancer Institute. Cancer 50(12): 2699-2707, 1982. 5. Ezdinli EZ, Costello WG, Kucuk O, et al.: Effect of the degree of nodularity on the survival of patients with nodular lymphomas. Journal of Clinical Oncology 5(3): 413-418, 1987. 6. Kadin ME: Ki-1-positive anaplastic large-cell lymphoma: a clinicopathologic entity? Journal of Clinical Oncology 9(4): 533-536, 1991. 7. Pugh WC: Is the working formulation adequate for the classification of the low grade lymphomas? Leukemia and Lymphoma 10(Suppl): 1-8, 1993. 8. Armitage JO: Treatment of non-Hodgkin's lymphoma. New England Journal of Medicine 328(14): 1023-1030, 1993.

** STAGE INFORMATION **

Stage is important in selecting a treatment for patients with NHL. Unless medically contraindicated, abdominal CT scans should be a part of the staging evaluation for all lymphoma patients. Lymphangiography may be useful in selected patients with a negative abdominal CT scan. The staging system is similar to the staging system used for Hodgkin's disease (HD). Noncontiguous lymph node involvement, uncommon in HD, is more common among patients with NHL. Involvement of Waldeyer's ring, epitrochlear nodes, and the gastrointestinal tract is also more common. Extranodal presentations are more common in NHL. A single extranodal site is occasionally the only site of involvement in patients with diffuse lymphoma. Bone marrow and hepatic involvement are especially common in patients with low-grade lymphomas. Cytologic examination of cerebrospinal fluid may be positive in patients with intermediate- or high-grade NHL. Involvement of hilar and mediastinal lymph nodes is less common than in HD. However, mediastinal adenopathy is a prominent feature of a distinct type of T-cell lymphoblastic lymphoma that occurs primarily in adolescents and young adults. The majority of patients with NHL present with advanced (stage III or IV) disease that can often be identified with limited staging procedures such as lymphangiography, CT scanning, ultrasonography, and percutaneous biopsies of the bone marrow, liver, and other accessible sites of involvement. Staging laparotomy is much less commonly performed in these patients than in patients with Hodgkin's disease. It is usually used in patients with supradiaphragmatic stage I disease. Several unusual presentations of NHL occur that often require somewhat modified approaches to staging and therapy. The reader is referred to recent reviews for a more detailed description of extranodal presentations in the CNS, gastrointestinal area, bone, orbit, skin, spleen alone, and testis.[1-12] --

Staging subclassification system --

The Ann Arbor staging system is commonly used for patients with NHL.[13,14] In this system, stages I, II, III, and IV adult non-Hodgkin's lymphoma can be subclassified into A and B categories:

B for those with well-defined generalized symptoms

A for those without.

The B designation is given to patients with any of the following:

* unexplained loss of more than 10% of body weight in the 6 months before diagnosis unexplained fever with temperatures above 38 degrees C drenching night sweats *Note: Pruritus as a systemic symptom remains controversial. This symptom is hard to define quantitatively and uniformly, but when it is recurrent, generalized, and otherwise unexplained, and when it ebbs and flows parallel to disease activity, it may be the equivalent of a B symptom. Occasionally, specialized staging systems are used. The physician should be aware of the system used in a specific report.

-- Stage I -- Stage I NHL means involvement of a single lymph node region (I), or localized involvement of a single extralymphatic organ or site (IE). -

- Stage II -- Stage II NHL means involvement of two or more lymph node regions on the same side of the diaphragm (II), or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes with or without other lymph node regions on the same side of the diaphragm (IIE). Note: The number of lymph node regions involved may be indicated by a subscript (e.g., II3). --

Stage III -- Stage III NHL means involvement of lymph node regions on both sides of the diaphragm (III) that may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), by involvement of the spleen (IIIS), or both (IIIS+E). -- Stage IV --

Stage IV NHL means disseminated (multifocal) involvement of one or more extralymphatic sites with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement. The designation "E" is used when extranodal lymphoid malignancies arise in tissues away from, but nearby, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed. Sites are identified by the following notation: N = nodes H = liver L = lung M = marrow S = spleen P = pleura O = bone D = skin Current practice assigns a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on the findings made as a result of invasive procedures beyond the initial biopsy. For example, a patient with inguinal adenopathy and a positive lymphangiogram without systemic symptoms might be found to have involvement of liver and bone marrow on percutaneous biopsy. The precise stage of such a patient would be CS IIA, PS IVA(H+)(M+). A number of other factors that are not included in the above staging system are important for the staging and prognosis of patients with NHLs. These include age, performance status, tumor size, LDH values, and number of extranodal sites.

A number of recent studies suggest that these factors should be considered when selecting treatment for patients with aggressive malignant lymphomas.[15-19] References: 1. Loeffler JS, Ervin TJ, Mauch PM, et al.: Primary lymphomas of the central nervous system: patterns of failure and factors that influence survival. Journal of Clinical Oncology 3(4): 490-494, 1985. 2. Mackintosh FR, Colby TV, Podolsky WJ, et al.: Central nervous system involvement in non-Hodgkin's lymphoma: an analysis of 105 cases. Cancer 49(3): 586-595, 1982. 3. Sheridan WP, Medley G, Brodie GN: Non-Hodgkin's lymphoma of the stomach: a prospective pilot study of surgery plus chemotherapy in early and advanced disease. Journal of Clinical Oncology 3(4): 495-500, 1985. 4. Aozasa K, Ueda T, Kurata A, et al.: Prognostic value of histologic and clinical factors in 56 patients with gastrointestinal lymphomas. Cancer 61(2): 309-315, 1988. 5. Clayton F, Butler JJ, Ayala AG, et al.: Non-Hodgkin's lymphoma in bone: pathologic and radiologic features with clinical correlates. Cancer 60(10): 2494-2501, 1987. 6. Fitzpatrick PJ, Macko S: Lymphoreticular tumors of the orbit. International Journal of Radiation Oncology, Biology, Physics 10(3): 333-340, 1984. 7. Harmon DC, Aisenberg AC, Harris NL, et al.: Lymphocyte surface markers in orbital lymphoid neoplasms. Journal of Clinical Oncology 2(7): 856-860, 1984. 8. Burke JS, Hoppe RT, Cibull ML, et al.: Cutaneous malignant lymphoma: a pathologic study of 50 cases with clinical analysis of 37. Cancer 47(2): 300-310, 1981. 9. Morel P, Dupriez B, Gosselin B, et al.: Role of early splenectomy in malignant lymphomas with prominent splenic involvement (primary lymphomas of the spleen). Cancer 71(1): 207-215, 1993. 10. Buskirk SJ, Evans RG, Banks PM, et al.: Primary lymphoma of the testis. International Journal of Radiation Oncology, Biology, Physics 8(10): 1699-1703, 1982. 11. Connors JM, Klimo P, Voss N, et al.: Testicular lymphoma: improved outcome with early brief chemotherapy. Journal of Clinical Oncology 6(5): 776-781, 1988. 12. Greer JP, Kinney MC, Collins RD, et al.: Clinical features of 31 patients with Ki-1 anaplastic large-cell lymphoma. Journal of Clinical Oncology 9(4): 539-547, 1991. 13. Non-Hodgkin's lymphoma. In: American Joint Committee on Cancer: Manual for Staging of Cancer. Philadelphia: JB Lippincott Company, 4th ed., 1992, pp 257-261. 14. The Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. Cancer 49(10): 2112-2135, 1982. 15. Coiffier B, Gisselbrecht C, Vose JM, et al.: Prognostic factors in aggressive malignant lymphomas: description and validation of a prognostic index that could identify patients requiring a more intensive therapy. Journal of Clinical Oncology 9(2): 211-219, 1991. 16. Hoskins PJ, Ng V, Spinelli JJ, et al.: Prognostic variables in patients with diffuse large-cell lymphoma treated with MACOP-B. Journal of Clinical Oncology 9(2): 220-226, 1991. 17. Shipp MA, Yeap BY, Harrington DP: The m-BACOD combination chemotherapy regimen in large-cell lymphoma: analysis of the completed trial and comparison with M-BACOD regimen. Journal of Clinical Oncology 8(1): 84-93, 1990. 18. Hayward RL, Leonard RC, Prescott RJ.: A critical analysis of prognostic factors for survival in intermediate and high grade non-Hodgkin's lymphoma. British Journal of Cancer 63(6): 945-952, 1.

** TREATMENT OPTION OVERVIEW **

State-of-the-art treatment for NHL depends on the histologic type and stage. Many of the improvements in survival have been made using clinical trials (experimental therapy) that have attempted to improve upon the best available accepted therapy (conventional or standard therapy). Even though state-of-the-art treatment in patients with lymphomas can cure a significant fraction, numerous clinical trials are in progress exploring improvements in treatment and, if possible, patients should be included in these studies. Colony stimulating factors are frequently used with intensive chemotherapy for lymphoma to allow greater dose intensity. However, one study has shown no significant alteration in drug toxicity (other than neutropenia), antibiotic use, or hospitalization with routine use of colony stimulating factors.[1] Late effects of treatment for non-Hodgkin's lymphoma are observed. Pelvic irradiation and large cumulative doses of cyclophosphamide have been associated with a high risk of permanent sterility.[2] For up to two decades after diagnosis, patients are at significantly elevated risk of second primary cancers, especially cancers of the lung, brain, kidney, bladder, melanoma, Hodgkin's disease, and acute nonlymphocytic leukemia.[3] Intermediate- and high-grade lymphomas are increasingly seen in HIV-positive patients whose treatment requires special consideration and is further outlined in the state-of-the-art statement entitled AIDS-Related Lymphoma. For discussion of treatment options for non-AIDS-related primary CNS lymphoma, refer to the state-of-the-art statement entitled Primary CNS Lymphoma. The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations. References: 1. Pettengell R, Gurney H, Radford JA, et al.: Granulocyte colony-stimulating factor to prevent dose-limiting neutropenia in non-Hodgkin's lymphoma: a randomized controlled trial. Blood 80(6): 1430-1436, 1992. 2. Pryzant RM, Meistrich ML, Wilson G, et al.: Long-term reduction in sperm count after chemotherapy with and without radiation therapy for non-Hodgkin's lymphomas. Journal of Clinical Oncology 11(2): 239-247, 1993. 3. Travis LB, Curtis RE, Glimelius B, et al.: Second cancers among long-term survivors of non-Hodgkin's lymphoma. Journal of the National Cancer Institute 85(23): 1932-1937, 1993.

** LOW-GRADE, STAGE I ADULT NON-HODGKIN'S LYMPHOMA ** -- Low grade (SL, FSC, FM) --

Although localized presentations are uncommon in NHL, the goal of treatment should be cure in those who are shown to have truly localized disease after appropriate staging procedures. Utilization of high-dose radiation therapy can achieve long-term disease control within radiation fields in a significant number of patients with stage I NHL using doses of irradiation that usually range from 3,000-4,000 cGy to involved sites. Therefore, patients should be treated at institutions that have modern megavoltage equipment and treatment planning simulators. Simulators are used to obtain detailed x-rays of patients in the treatment position so that radiation fields can be tailored to conform to the patient's anatomy, and individually shaped protective blocks can be fabricated to shield normal tissues for the individual patient. Linear accelerators with energy of 4 to 10 MeV are considered optimal equipment because of their capacity to treat large volumes quickly, at necessary distances, with sharper margins.[1-3] Treatment options: 1. Supradiaphragmatic presentation: involved field irradiation full mantle field or mini-mantle irradiation 2. Subdiaphragmatic presentation: involved field irradiation abdominal and pelvic nodal irradiation (with appropriate shielding of kidneys and liver) References: 1. Ben-Ezra J, Burke JS, Swartz WG, et al.: Small lymphocytic lymphoma: a clinicopathologic analysis of 268 cases. Blood 73(2): 579-587, 1989. 2. Gallagher CJ, Gregory WM, Jones AE, et al.: Follicular lymphoma: prognostic factors for response and survival. Journal of Clinical Oncology 4(10): 1470-1480, 1986. 3. Bush RS, Gospodarowicz M: The place of radiation therapy in the management of patients with localized non-Hodgkin's lymphomas. In: Rosenberg SA, Kaplan HS, Eds.: Malignant Lymphomas: Etiology, Immunology, Pathology, Treatment. New York: Academic Press, 1982, pp 485-502.

** INTERMEDIATE-GRADE, STAGE I ADULT NON-HODGKIN'S LYMPHOMA ** --

.Intermediate grade (FL, DSC, DM, DL) -- Traditionally, radiation therapy had been the primary treatment for patients with intermediate stage I histologic types of non-Hodgkin's lymphomas. In recent years, the success of combination chemotherapy has been so great that effective drug combinations are being used more frequently in early stages of disease. Combined modality approaches with chemotherapy and irradiation, or chemotherapy alone are now used. When such an approach is selected, performing a staging laparotomy to pathologically define the stage is not necessary. One can rely on clinical staging short of laparotomy. Radiation therapy alone can achieve long-term disease control within radiation fields in approximately 90% of treated patients, but some patients relapse, and disease-free survival is 60-70%. Adjuvant chemotherapy may improve outcome.[1] The dose of radiation ranges from 3,500-5,000 cGy and requires the use of megavoltage equipment. Therefore, patients should be treated at institutions that have modern megavoltage equipment and treatment planning simulators. Simulators are used to obtain detailed x-rays of patients in the treatment position so that radiation fields can be tailored to conform to the patient's anatomy, and individually shaped protective blocks can be fabricated to shield normal tissues for the individual patient. Linear accelerators with energy of 4 to 10 MeV are considered optimal equipment because of their capacity to treat large volumes quickly, at necessary distances, with sharper margins. Extranodal sites may be involved with diffuse lymphoma without other sites of involvement. These include the gastrointestinal tract, thyroid, and bone. Surgery plays an important role in the diagnosis and treatment of these primary extranodal lymphomas with or without adjuvant radiation or combination chemotherapy. Since extranodal site presentations often have an unpredictable pattern of relapse, chemotherapy is often used as the primary treatment modality. Treatment options: If only clinical staging has been performed: 1. Chemotherapy with radiation therapy.[2-5] CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone [3,6] ProMACE-MOPP: cyclophosphamide + etoposide + doxorubicin + mechlorethamine + procarbazine + high-dose methotrexate with leucovorin rescue + prednisone [2] 2. Chemotherapy alone. CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone [3] If complete (surgical) staging has been performed (including staging laparotomy) and the patient remains stage I: 1. Supradiaphragmatic presentation: extended field irradiation [7] mini-mantle irradiation with or without radiation to Waldeyer's ring full mantle field irradiation combined modality treatment with radiation therapy plus combination chemotherapy of several types:[8] CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone [3] ProMACE-MOPP: cyclophosphamide + etoposide + doxorubicin + mechlorethamine + procarbazine + high-dose methotrexate with leucovorin rescue + prednisone [2] 2. Subdiaphragmatic presentation: extended field irradiation [7] whole abdominopelvic irradiation (with appropriate shielding of kidneys and liver) [7] combined modality treatment with radiation therapy plus combination chemotherapy of several types: CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone [3] combination chemotherapy alone:[3] ProMACE-MOPP: cyclophosphamide + etoposide + doxorubicin + mechlorethamine + procarbazine + high-dose methotrexate with leucovorin rescue + prednisone [2] References: 1. Yahalom J, Varsos G, Fuks Z, et al.: Adjuvant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy after radiation therapy in stage I low-grade and intermediate-grade non-Hodgkin lymphoma. Cancer 71(7): 2342-2350, 1993. 2. Longo DL, Glatstein E, Duffey PL, et al.: Treatment of localized aggressive lymphomas with combination chemotherapy followed by involved-field radiation therapy. Journal of Clinical Oncology 7(9): 1295-1302, 1989. 3. Jones SE, Miller TP, Connors JM: Long-term follow-up and analysis for prognostic factors for patients with limited-stage diffuse large-cell lymphoma treated with initial chemotherapy with or without adjuvant radiotherapy. Journal of Clinical Oncology 7(9): 1186-1191, 1989. 4. Anderson JR, Vose JM, Bierman PJ, et al.: Clinical features and prognosis of follicular large-cell lymphoma: a report from the Nebraska Lymphoma Study Group. Journal of Clinical Oncology 11(2): 218-224, 1993. 5. Tondini C, Zanini M, Lombardi F, et al.: Combined modality treatment with primary CHOP chemotherapy followed by locoregional irradiation in stage I or II histologically aggressive non-Hodgkin's lymphomas. Journal of Clinical Oncology 11(4): 720-725, 1993. 6. Velasquez WS, Fuller LM, Jagannath S, et al.: Stages I and II diffuse large cell lymphomas: prognostic factors and long-term results with CHOP-Bleo and radiotherapy. Blood 77(5): 942-947, 1991. 7. Kaminski MS, Coleman CN, Colby TV, et al.: Factors predicting survival in adults with stage I and II large-cell lymphoma treated with primary radiation therapy. Annals of Internal Medicine 104(6): 747-756, 1986. 8. Mauch P, Leonard R, Skarin A, et al.: Improved survival following combined radiation therapy and chemotherapy for unfavorable prognosis stage I-II non-Hodgkin's lymphomas. Journal of Clinical Oncology 3(10): 1301-1308, 1985.

** HIGH-GRADE, STAGE I ADULT NON-HODGKIN'S LYMPHOMA ** --

Lymphoblastic lymphoma (LL), convoluted or nonconvoluted cell -- Lymphoblastic lymphoma is a very aggressive form of NHL. It often occurs in young patients, but not exclusively. It is commonly associated with large mediastinal masses and has a high predilection for disseminating to marrow and central nervous system (CNS), much like acute lymphocytic leukemia (ALL). Thus, treatment is usually patterned after ALL. Intensive combination chemotherapy is the standard treatment for this aggressive histologic type of NHL. Irradiation of areas of bulky tumor masses is sometimes given. Since these forms of NHL tend to progress so quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed. Careful review of the pathologic specimens, bone marrow aspirate and biopsy, CSF cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging work-up. Treatment options: 1. Combination chemotherapy with CNS prophylaxis: cyclophosphamide + doxorubicin + vincristine + prednisone + asparaginase plus maintenance with methotrexate + 6-mercaptopurine [1] The following regimens appear to produce similar results but have not been compared in prospective trials or are in less common use: APO: doxorubicin + vincristine + prednisone + methotrexate + 6-mercaptopurine [2] L10 or L17 protocols or modified versions thereof, as administered in adult lymphocytic leukemia (ALL).[3] 2. Combination chemotherapy with CNS prophylaxis, cranial irradiation, and intrathecal chemotherapy plus local irradiation to sites of massive involvement.[4] -- Immunoblastic lymphoma (IBL) -- Immunoblastic lymphoma (IBL) must be distinguished from LL. It may be of T-cell or B-cell origin. The natural history of the lymphomas in this category is still being defined. Those that are Ki-1 positive may represent a clinicopathologic entity but, at present, are like other IBLs, and are treated like the intermediate-grade (diffuse large cell) lymphomas.[5-7] -- Diffuse undifferentiated lymphoma (DUL) and Burkitt's lymphoma -- Treatment of these lymphomas is usually with aggressive multidrug regimens similar to those used for the advanced stage intermediate-grade lymphomas (diffuse large cell).[7] An intensive protocol using aggressive combination chemotherapy patterned after that used in childhood Burkitt's lymphoma has been described and has been very successful for patients with all but the most advanced stage. The staging system used for DUL/Burkitt's lymphoma differs from the Ann Arbor staging system. Adverse prognostic factors include bulky abdominal disease and high serum LDH. The patient must be properly staged. For patients in the high-risk group, standard treatment is successful in approximately 30%. Therefore, clinical trials should be considered. In some institutions, this includes the use of consolidative bone marrow transplantation.[8] References: 1. Coleman CN, Picozzi VJ, Cox RS, et al.: Treatment of lymphoblastic lymphoma in adults. Journal of Clinical Oncology 4(11): 1628-1637, 1986. 2. Weinstein HJ, Cassady JR, Levey R: Long-term results of the APO protocol (vincristine, doxorubicin [Adriamycin], and prednisone) for treatment of mediastinal lymphoblastic lymphoma. Journal of Clinical Oncology 1(9): 537-541, 1983. 3. Slater DE, Mertelsmann R, Koziner B, et al.: Lymphoblastic lymphoma in adults. Journal of Clinical Oncology 4(1): 57-67, 1986. 4. Tondini C, Zanini M, Lombardi F, et al.: Combined modality treatment with primary CHOP chemotherapy followed by locoregional irradiation in stage I or II histologically aggressive non-Hodgkin's lymphomas. Journal of Clinical Oncology 11(4): 720-725, 1993. 5. Connors JM, Klimo P, Fairey RN, et al.: Brief chemotherapy and involved field radiation therapy for limited-stage, histologically aggressive lymphoma. Annals of Internal Medicine 107(1): 25-30, 1987. 6. Greer JP, Kinney MC, Collins RD, et al.: Clinical features of 31 patients with Ki-1 anaplastic large-cell lymphoma. Journal of Clinical Oncology 9(4): 539-547, 1991. 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. New England Journal of Medicine 328(14): 1002-1006, 1993. 8. Bernstein JI, Coleman CN, Strickler JG, et al.: Combined modality therapy for adults with small noncleaved cell lymphoma (Burkitt's and non-Burkitt's types). Journal of Clinical Oncology 4(6): 847-858, 1986.

** LOW-GRADE, STAGE II ADULT NON-HODGKIN'S LYMPHOMA ** --

Low grade (SL, FSC, FM) -- Although localized presentations are uncommon in non-Hodgkin's lymphomas (NHL), the goal of treatment should be cure in those who are shown to have truly localized disease after appropriate staging procedures. Utilization of high-dose radiation therapy can achieve long-term disease control within radiation fields in a significant number of patients with stage II NHL using doses of irradiation that usually range from 3,000-4,000 cGy to involved sites. Therefore, patients should be treated at institutions that have modern megavoltage equipment and treatment planning simulators. Simulators are used to obtain detailed x-rays of patients in the treatment position so that radiation fields can be tailored to conform to the patient's anatomy, and individually shaped protective blocks can be fabricated to shield normal tissues for the individual patient. Linear accelerators with energy of 4 to 10 MeV are considered optimal equipment because of their capacity to treat large volumes quickly, at necessary distances, with sharper margins.[1-4] Treatment options: 1. Supradiaphragmatic presentation: involved field irradiation full mantle field or mini-mantle irradiation 2. Subdiaphragmatic presentation: involved field irradiation abdominal and pelvic nodal irradiation (with appropriate shielding of kidneys and liver) References: 1. Ben-Ezra J, Burke JS, Swartz WG, et al.: Small lymphocytic lymphoma: a clinicopathologic analysis of 268 cases. Blood 73(2): 579-587, 1989. 2. Horning SJ, Rosenberg SA: The natural history of initially untreated low-grade non-Hodgkin's lymphomas. New England Journal of Medicine 311(23): 1471-1475, 1984. 3. Hoppe RT, Kushlan P, Kaplan HS, et al.: The treatment of advanced stage favorable histology non-Hodgkin's lymphoma: a preliminary report of a randomized trial comparing single agent chemotherapy, combination chemotherapy, and whole body irradiation. Blood 58(3): 592-598, 1981. 4. Gallagher CJ, Gregory WM, Jones AE, et al.: Follicular lymphoma: prognostic factors for response and survival. Journal of Clinical Oncology 4(10): 1470-1480, 1986.

** INTERMEDIATE-GRADE, STAGE II ADULT NON-HODGKIN'S LYMPHOMA ** -

- Intermediate grade (FL, DSC, DM, DL) -- The treatment of choice for advanced stages of intermediate-grade non-Hodgkin's lymphoma (NHL) is clearly combination chemotherapy, either alone or supplemented by local field irradiation.[1] Significant cure rates ranging from 40-75% have been achieved by a number of investigators in patients with stage II disease, although large masses remain an unfavorable prognostic factor. Extranodal sites that can be involved with stage IIE diffuse lymphoma include the gastrointestinal tract, thyroid, and bone. Surgery may play a role in the diagnosis and treatment of primary gastrointestinal extranodal lymphoma, usually with adjuvant combination chemotherapy. The presence of B symptoms, more than two involved lymph node sites, and age greater than 60 are poor prognostic factors with respect to most treatments. Other factors, such as increased serum LDH level, may also confer a poor prognosis.[2,3] Treatment options: 1. Combination chemotherapy alone: Established regimens capable of producing long-term disease-free survival in 35-45% of patients. As expected, higher response rates have been seen in single institution studies than in cooperative group trials. CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone [4,5] ProMACE-CytaBOM: prednisone + doxorubicin + cyclophosphamide + etoposide + cytarabine + bleomycin + vincristine + intermediate-dose methotrexate [6] MACOP-B: methotrexate with leucovorin rescue + doxorubicin + cyclophosphamide + vincristine + prednisone + bleomycin [7] m-BACOD: intermediate-dose methotrexate + bleomycin + doxorubicin + cyclophosphamide + vincristine + dexamethasone [8] A randomized study of these four regimens showed no difference in time to treatment failure and overall survival for any regimen at 3 years.[9] The fatal toxicity was 1% for CHOP, 3% for ProMACE-CytaBOM, 5% for m-BACOD, and 6% for MACOP-B. 2. Combination chemotherapy plus irradiation (usually to site of bulky involvement).[5,10-15] 3. Radiation therapy alone in selected patients (usually elderly patients with non-bulky disease).[16] 4. Surgery with adjuvant combination chemotherapy in gastrointestinal tumors. References: 1. Armitage JO: Treatment of non-Hodgkin's lymphoma. New England Journal of Medicine 328(14): 1023-1030, 1993. 2. Coiffier B, Gisselbrecht C, Vose JM, et al.: Prognostic factors in aggressive malignant lymphomas: description and validation of a prognostic index that could identify patients requiring a more intensive therapy. Journal of Clinical Oncology 9(2): 211-219, 1991. 3. Hoskins PJ, Ng V, Spinelli JJ, et al.: Prognostic variables in patients with diffuse large-cell lymphoma treated with MACOP-B. Journal of Clinical Oncology 9(2): 220-226, 1991. 4. Fisher RI, Miller TP, Dana BW, et al.: Southwest Oncology Group clinical trials for intermediate- and high-grade non-Hodgkin's lymphomas. Seminars in Hematology 24(2, Suppl 1): 21-25, 1987. 5. Jones SE, Miller TP, Connors JM: Long-term follow-up and analysis for prognostic factors for patients with limited-stage diffuse large-cell lymphoma treated with initial chemotherapy with or without adjuvant radiotherapy. Journal of Clinical Oncology 7(9): 1186-1191, 1989. 6. 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. Journal of Clinical Oncology 9(1): 25-38, 1991. 7. Klimo P, Connors JM: Updated clinical experience with MACOP-B. Seminars in Hematology 24(2, Suppl 1): 26-34, 1987. 8. Shipp MA, Yeap BY, Harrington DP: The m-BACOD combination chemotherapy regimen in large-cell lymphoma: analysis of the completed trial and comparison with M-BACOD regimen. Journal of Clinical Oncology 8(1): 84-93, 1990. 9. 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. New England Journal of Medicine 328(14): 1002-1006, 1993. 10. Longo DL, Glatstein E, Duffey PL, et al.: Treatment of localized aggressive lymphomas with combination chemotherapy followed by involved-field radiation therapy. Journal of Clinical Oncology 7(9): 1295-1302, 1989. 11. Velasquez WS, Fuller LM, Jagannath S, et al.: Stages I and II diffuse large cell lymphomas: prognostic factors and long-term results with CHOP-Bleo and radiotherapy. Blood 77(5): 942-947, 1991. 12. Tondini C, Zanini M, Lombardi F, et al.: Combined modality treatment with primary CHOP chemotherapy followed by locoregional irradiation in stage I or II histologically aggressive non-Hodgkin's lymphomas. Journal of Clinical Oncology 11(4): 720-725, 1993. 13. Mauch P, Leonard R, Skarin A, et al.: Improved survival following combined radiation therapy and chemotherapy for unfavorable prognosis stage I-II non-Hodgkin's lymphomas. Journal of Clinical Oncology 3(10): 1301-1308, 1985. 14. Connors JM, Klimo P, Fairey RN, et al.: Brief chemotherapy and involved field radiation therapy for limited-stage, histologically aggressive lymphoma. Annals of Internal Medicine 107(1): 25-30, 1987. 15. Anderson JR, Vose JM, Bierman PJ, et al.: Clinical features and prognosis of follicular large-cell lymphoma: a report from the Nebraska Lymphoma Study Group. Journal of Clinical Oncology 11(2): 218-224, 1993. 16. Kaminski MS, Coleman CN, Colby TV, et al.: Factors predicting survival in adults with stage I and II large-cell lymphoma treated with primary radiation therapy. Annals of Internal Medicine 104(6): 747-756, 1986.

** HIGH-GRADE, STAGE II ADULT NON-HODGKIN'S LYMPHOMA ** --

Lymphoblastic lymphoma, convoluted or nonconvoluted cell -- Lymphoblastic lymphoma (LL) is a very aggressive form of non-Hodgkin's lymphoma (NHL). It often occurs in young patients, but not exclusively. It is commonly associated with large mediastinal masses and has a high predilection for disseminating to marrow and CNS, much like acute lymphocytic leukemia (ALL). Thus, treatment is usually patterned after ALL. Intensive combination chemotherapy is the standard treatment for this aggressive histologic type of NHL. Irradiation of areas of bulky tumor masses is sometimes given. Since these forms of NHL tend to progress so quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed. Careful review of the pathologic specimens, bone marrow aspirate and biopsy, CSF cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging work-up. Treatment options: 1. Combination chemotherapy with CNS prophylaxis: cyclophosphamide + doxorubicin + vincristine + prednisone + asparaginase plus maintenance with methotrexate + 6-mercaptopurine [1,2] The following regimens appear to produce similar results but have not been compared in prospective trials or are in less common use: APO: doxorubicin + vincristine + prednisone + methotrexate + 6-mercaptopurine [3] L10 or L17 protocols or modified versions thereof, as administered in adult lymphocytic leukemia (ALL).[4] 2. Combination chemotherapy with CNS prophylaxis, cranial irradiation, and intrathecal chemotherapy plus local irradiation to sites of massive involvement.[5] -- Immunoblastic lymphoma -- Immunoblastic lymphoma (IBL) must be distinguished from lymphoblastic lymphoma (LL). It may be of T-cell or B-cell origin. The natural history of the lymphomas in this category is still being defined. Those that are Ki-1 positive may represent a clinicopathologic entity but, at present, are like other IBLs, and are treated like the intermediate-grade (diffuse large cell) lymphomas.[6-9] -- Diffuse undifferentiated lymphoma and Burkitt's lymphoma -- Treatment of these lymphomas is usually with aggressive multi-drug regimens similar to those used for the advanced stage intermediate-grade lymphomas (diffuse large cell).[9] An intensive protocol using aggressive combination chemotherapy patterned after that used in childhood Burkitt's lymphoma has been described and has been very successful for patients with all but the most advanced stage. The staging system used for DUL/Burkitt's lymphoma differs from the Ann Arbor staging system. Adverse prognostic factors include bulky abdominal disease and high serum LDH. The patient must be properly staged. For patients in the high-risk group, standard treatment is successful in approximately 30%. Therefore, clinical trials should be considered. In some institutions, this includes the use of consolidative bone marrow transplantation.[7,10] References: 1. Coleman CN, Cohen JR, Burke JS, et al.: Lymphoblastic lymphoma in adults: results of a pilot protocol. Blood 57(4): 679-684, 1981. 2. Coleman CN, Picozzi VJ, Cox RS, et al.: Treatment of lymphoblastic lymphoma in adults. Journal of Clinical Oncology 4(11): 1628-1637, 1986. 3. Weinstein HJ, Cassady JR, Levey R: Long-term results of the APO protocol (vincristine, doxorubicin [Adriamycin], and prednisone) for treatment of mediastinal lymphoblastic lymphoma. Journal of Clinical Oncology 1(9): 537-541, 1983. 4. Slater DE, Mertelsmann R, Koziner B, et al.: Lymphoblastic lymphoma in adults. Journal of Clinical Oncology 4(1): 57-67, 1986. 5. Tondini C, Zanini M, Lombardi F, et al.: Combined modality treatment with primary CHOP chemotherapy followed by locoregional irradiation in stage I or II histologically aggressive non-Hodgkin's lymphomas. Journal of Clinical Oncology 11(4): 720-725, 1993. 6. Connors JM, Klimo P, Fairey RN, et al.: Brief chemotherapy and involved field radiation therapy for limited-stage, histologically aggressive lymphoma. Annals of Internal Medicine 107(1): 25-30, 1987. 7. Fisher RI, Miller TP, Dana BW, et al.: Southwest Oncology Group clinical trials for intermediate- and high-grade non-Hodgkin's lymphomas. Seminars in Hematology 24(2, Suppl 1): 21-25, 1987. 8. Greer JP, Kinney MC, Collins RD, et al.: Clinical features of 31 patients with Ki-1 anaplastic large-cell lymphoma. Journal of Clinical Oncology 9(4): 539-547, 1991. 9. 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. New England Journal of Medicine 328(14): 1002-1006, 1993. 10. Bernstein JI, Coleman CN, Strickler JG, et al.: Combined modality therapy for adults with small noncleaved cell lymphoma (Burkitt's and non-Burkitt's types). Journal of Clinical Oncology 4(6): 847-858, 1986.

** LOW-GRADE, STAGE III ADULT NON-HODGKIN'S LYMPHOMA ** -- Low grade (SL, FSC, FM) --

Optimal treatment for advanced stages of low-grade lymphoma is controversial, and numerous clinical trials are in progress to settle treatment issues. Patients should be urged to participate. The reasons for controversy relate to the fact that the vast majority of patients with advanced stages of low-grade lymphoma are not cured using current therapy, although prolonged survival is associated with these histologies for most treatment options. The rate of relapse is fairly constant over time, even in patients who have achieved complete responses to treatment. Indeed, relapse may occur many years after treatment. In this category, deferred treatment (watching carefully and waiting until the patient becomes symptomatic before initiating treatment) should be given consideration. This approach represents an area of ongoing clinical research.[1-3] The addition of alpha-interferon to combination chemotherapy results in increased disease-free and overall survival rates compared to those seen in early analyses of combination chemotherapy alone.[4,5] However, one study with more mature data did not show a significant difference in overall survival.[6] Treatment options: 1. For asymptomatic patients, deferred therapy with careful observation.[2] 2. Combination chemotherapy alone: CVP: cyclophosphamide + vincristine + prednisone [7] C(M)OPP: cyclophosphamide + vincristine + procarbazine + prednisone [8,9] CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone [10] 3. Single-agent chemotherapy:[7] cyclophosphamide chlorambucil 4. Total central lymphatic irradiation.[11] 5. Observation plus palliative radiotherapy versus intensive chemotherapy is under evaluation.[2] 6. Intensive therapy with chemotherapy and total body irradiation followed by autologous bone marrow transplantation is also under evaluation. 7. New agents.[12,13] References: 1. Rosenberg SA: The low-grade non-Hodgkin's lymphomas: challenges and opportunities. Journal of Clinical Oncology 3(3): 299-310, 1985. 2. Young RC, Longo DL, Glatstein E, et al.: The treatment of indolent lymphomas: watchful waiting V aggressive combined modality treatment. Seminars in Hematology 25(2, Suppl 2): 11-16, 1988. 3. Gallagher CJ, Gregory WM, Jones AE, et al.: Follicular lymphoma: prognostic factors for response and survival. Journal of Clinical Oncology 4(10): 1470-1480, 1986. 4. Smalley RV, Andersen JW, Hawkins MJ, et al.: Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma. New England Journal of Medicine 327(19): 1336-1341, 1992. 5. Solal-Celigny P, Lepage E, Brousse N, et al.: Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. New England Journal of Medicine 329(22): 1608-1614, 1993. 6. Andersen JW, Smalley RV: Interferon alfa plus chemotherapy for non-Hodgkin's lymphoma: five-year follow-up. New England Journal of Medicine 329(24): 1821-1822, 1993. 7. Hoppe RT, Kushlan P, Kaplan HS, et al.: The treatment of advanced stage favorable histology non-Hodgkin's lymphoma: a preliminary report of a randomized trial comparing single agent chemotherapy, combination chemotherapy, and whole body irradiation. Blood 58(3): 592-598, 1981. 8. Anderson T, DeVita VT, Simon RM, et al.: Malignant Lymphoma: II. prognostic factors and response to treatment of 473 patients at the National Cancer Institute. Cancer 50(12): 2708-2721, 1982. 9. Longo DL, Young RC, Hubbard SM, et al.: Prolonged initial remission in patients with nodular mixed lymphoma. Annals of Internal Medicine 100(5): 651-656, 1984. 10. Dana BW, Dahlberg S, Nathwani BN, et al.: Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. Journal of Clinical Oncology 11(4): 644-651, 1993. 11. Jacobs JP, Murray KJ, Schultz CJ, et al.: Central lymphatic irradiation for stage III nodular malignant lymphoma: long-term results. Journal of Clinical Oncology 11(2): 233-238, 1993. 12. Whelan JS, Davis CL, Rule S, et al.: Fludarabine phosphate for the treatment of low grade lymphoid malignancy. British Journal of Cancer 64(1): 120-123, 1991. 13. Kay AC, Saven A, Carrera CJ, et al.: 2-Chlorodeoxyadenosine treatment of low-grade lymphomas. Journal of Clinical Oncology 10(3): 371-377, 1992. **

INTERMEDIATE-GRADE, STAGE III ADULT NON-HODGKIN'S LYMPHOMA ** -- Intermediate grade (FL, DSC, DM, DL) --

The treatment of choice for advanced stages of intermediate-grade NHL is clearly combination chemotherapy, either alone or supplemented by local field irradiation.[1] The presence of B symptoms, more than two involved lymph node sites, and age greater than 60 are poor prognostic factors with respect to most treatments. Other factors, such as increased serum LDH level, may also confer a poor prognosis.[2,3] For patients with FM, FL, and DSC lymphoma with rapidly progressive disease and/or B symptoms, the addition of alpha-interferon to combination chemotherapy results in increased disease-free and overall survival rates compared to those seen in early analyses of combination chemotherapy alone.[4,5] However, one study with more mature data did not show a significant difference in overall survival.[6] Many investigators consider the natural histories of FL and DSC lymphoma subtypes as more typical of low-grade lymphomas, and therefore, are associated with a low cure rate.[7,8] Treatment options: 1. Combination chemotherapy alone: Established regimens capable of producing long-term disease-free survival in 35-45% of patients. As expected, higher response rates have been seen in single institution studies than in cooperative group trials. CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone [9,10] ProMACE-CytaBOM: prednisone + doxorubicin + cyclophosphamide + etoposide + cytarabine + bleomycin + vincristine + intermediate-dose methotrexate [11] MACOP-B: methotrexate with leucovorin rescue + doxorubicin + cyclophosphamide + vincristine + prednisone + bleomycin [12] m-BACOD: intermediate-dose methotrexate + bleomycin + doxorubicin + cyclophosphamide + vincristine + dexamethasone [13] A randomized study of these four regimens showed no difference in time to treatment failure and overall survival on any regimen at 3 years.[14] The fatal toxicity was 1% for CHOP, 3% for ProMACE-CytaBOM, 5% for m-BACOD, and 6% for MACOP-B. A randomized comparison of CHOP and m-BACOD showed no difference in time to treatment failure and overall survival at 4 years.[10] Significantly more severe and life-threatening toxicities were seen with m-BACOD. 2. Combination chemotherapy plus irradiation (usually to site of bulky involvement). Clinical trials such as those exploring the efficacy of chemotherapy with bone marrow transplantation are currently ongoing.[15,16] References: 1. Armitage JO: Treatment of non-Hodgkin's lymphoma. New England Journal of Medicine 328(14): 1023-1030, 1993. 2. Coiffier B, Gisselbrecht C, Vose JM, et al.: Prognostic factors in aggressive malignant lymphomas: description and validation of a prognostic index that could identify patients requiring a more intensive therapy. Journal of Clinical Oncology 9(2): 211-219, 1991. 3. Hoskins PJ, Ng V, Spinelli JJ, et al.: Prognostic variables in patients with diffuse large-cell lymphoma treated with MACOP-B. Journal of Clinical Oncology 9(2): 220-226, 1991. 4. Smalley RV, Andersen JW, Hawkins MJ, et al.: Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma. New England Journal of Medicine 327(19): 1336-1341, 1992. 5. Solal-Celigny P, Lepage E, Brousse N, et al.: Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. New England Journal of Medicine 329(22): 1608-1614, 1993. 6. Andersen JW, Smalley RV: Interferon alfa plus chemotherapy for non-Hodgkin's lymphoma: five-year follow-up. New England Journal of Medicine 329(24): 1821-1822, 1993. 7. Anderson JR, Vose JM, Bierman PJ, et al.: Clinical features and prognosis of follicular large-cell lymphoma: a report from the Nebraska Lymphoma Study Group. Journal of Clinical Oncology 11(2): 218-224, 1993. 8. Longo DL: What's the deal with follicular lymphomas? Journal of Clinical Oncology 11(2): 202-208, 1993. 9. Fisher RI, Miller TP, Dana BW, et al.: Southwest Oncology Group clinical trials for intermediate- and high-grade non-Hodgkin's lymphomas. Seminars in Hematology 24(2, Suppl 1): 21-25, 1987. 10. 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 diffuse non-Hodgkin's lymphoma. New England Journal of Medicine 327(19): 1342-1349, 1992. 11. 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. Journal of Clinical Oncology 9(1): 25-38, 1991. 12. Klimo P, Connors JM: Updated clinical experience with MACOP-B. Seminars in Hematology 24(2, Suppl 1): 26-34, 1987. 13. Shipp MA, Yeap BY, Harrington DP: The m-BACOD combination chemotherapy regimen in large-cell lymphoma: analysis of the completed trial and comparison with M-BACOD regimen. Journal of Clinical Oncology 8(1): 84-93, 1990. 14. 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. New England Journal of Medicine 328(14): 1002-1006, 1993. 15. Nademanee A, Schmidt GM, O'Donnell MR, et al.: High-dose chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy during first complete remission in adult patients with poor-risk aggressive lymphoma: a pilot study. Blood 80(5): 1130-1134, 1992. 16. Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. Journal of Clinical Oncology 8(5): 784-791, 1990.

** HIGH-GRADE, STAGE III ADULT NON-HODGKIN'S LYMPHOMA **

-- Lymphoblastic lymphoma, convoluted or nonconvoluted cell -- Lymphoblastic lymphoma (LL) is a very aggressive form of non-Hodgkin's lymphoma (NHL). It often occurs in young patients, but not exclusively. It is commonly associated with large mediastinal masses and has a high predilection for disseminating to marrow and CNS, much like acute lymphocytic leukemia (ALL). Thus, treatment is usually patterned after ALL. Intensive combination chemotherapy is the standard treatment for this aggressive histologic type of NHL. Irradiation of areas of bulky tumor masses is sometimes given. Since these forms of NHL tend to progress so quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed. Careful review of the pathologic specimens, bone marrow aspirate and biopsy, CSF cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging work-up. Treatment options: 1. Combination chemotherapy with CNS prophylaxis: cyclophosphamide + doxorubicin + vincristine + prednisone + asparaginase plus maintenance with methotrexate + 6-mercaptopurine [1,2] The following regimens appear to produce similar results but have not been compared in prospective trials or are in less common use: APO: doxorubicin + vincristine + prednisone + methotrexate + 6-mercaptopurine [3] L10 or L17 protocols or modified versions thereof, as administered in adult lymphocytic leukemia (ALL).[4] 2. Combination chemotherapy with CNS prophylaxis, cranial irradiation, and intrathecal chemotherapy plus local irradiation to sites of massive involvement. -- Immunoblastic lymphoma -- Immunoblastic lymphoma (IBL) must be distinguished from lymphoblastic lymphoma (LL). It may be of T- cell or B-cell origin. The natural history of the lymphomas in this category is still being defined. Those that are Ki-1 positive may represent a clinicopathologic entity but, at present, are like other IBLs, and are treated like the intermediate-grade (diffuse large cell) lymphomas.[5-8] -- Diffuse undifferentiated lymphoma and Burkitt's lymphoma -- Treatment of these lymphomas is usually with aggressive multi-drug regimens similar to those used for the advanced stage intermediate-grade lymphomas (diffuse large cell).[8] An intensive protocol using aggressive combination chemotherapy patterned after that used in childhood Burkitt's lymphoma has been described and has been very successful for patients with all but the most advanced stage. The staging system used for DUL/Burkitt's lymphoma differs from the Ann Arbor staging system. Adverse prognostic factors include bulky abdominal disease and high serum LDH. The patient must be properly staged. For patients in the high-risk group, standard treatment is successful in approximately 30%. Therefore, clinical trials should be considered. In some institutions, this includes the use of consolidative bone marrow transplantation.[6,9,10] References: 1. Coleman CN, Cohen JR, Burke JS, et al.: Lymphoblastic lymphoma in adults: results of a pilot protocol. Blood 57(4): 679-684, 1981. 2. Coleman CN, Picozzi VJ, Cox RS, et al.: Treatment of lymphoblastic lymphoma in adults. Journal of Clinical Oncology 4(11): 1628-1637, 1986. 3. Weinstein HJ, Cassady JR, Levey R: Long-term results of the APO protocol (vincristine, doxorubicin [Adriamycin], and prednisone) for treatment of mediastinal lymphoblastic lymphoma. Journal of Clinical Oncology 1(9): 537-541, 1983. 4. Slater DE, Mertelsmann R, Koziner B, et al.: Lymphoblastic lymphoma in adults. Journal of Clinical Oncology 4(1): 57-67, 1986. 5. Connors JM, Klimo P, Fairey RN, et al.: Brief chemotherapy and involved field radiation therapy for limited-stage, histologically aggressive lymphoma. Annals of Internal Medicine 107(1): 25-30, 1987. 6. Fisher RI, Miller TP, Dana BW, et al.: Southwest Oncology Group clinical trials for intermediate- and high-grade non-Hodgkin's lymphomas. Seminars in Hematology 24(2, Suppl 1): 21-25, 1987. 7. Greer JP, Kinney MC, Collins RD, et al.: Clinical features of 31 patients with Ki-1 anaplastic large-cell lymphoma. Journal of Clinical Oncology 9(4): 539-547, 1991. 8. 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. New England Journal of Medicine 328(14): 1002-1006, 1993. 9. Bernstein JI, Coleman CN, Strickler JG, et al.: Combined modality therapy for adults with small noncleaved cell lymphoma (Burkitt's and non-Burkitt's types). Journal of Clinical Oncology 4(6): 847-858, 1986. 10. Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. Journal of Clinical Oncology 8(5): 784-791, 1990.

** LOW-GRADE, STAGE IV ADULT NON-HODGKIN'S LYMPHOMA ** -

- Low grade (SL, FSC, FM) -- Optimal treatment for stage IV low-grade lymphoma is controversial. The reasons for the controversy relate to the fact that the vast majority of patients with advanced stage low-grade forms of lymphoma are not cured using current therapy, even though prolonged survival is achieved with most treatment options. The rate of relapse is fairly constant over time, even in patients who have achieved complete responses to treatment. Indeed, relapse may occur many years after treatment. For these reasons, deferred treatment (watching carefully and waiting until the patient becomes symptomatic before initiating treatment) should be given consideration. This approach represents an area of ongoing clinical research.[1-4] The addition of alpha-interferon to combination chemotherapy results in increased disease-free and overall survival rates compared to those seen in early analyses of combination chemotherapy alone.[5,6] However, one study with more mature data did not show a significant difference in overall survival.[7] Treatment options: 1. For asymptomatic patients, deferred therapy with careful observation.[1,3] 2. Combination chemotherapy alone: CVP: cyclophosphamide + vincristine + prednisone [2] C(M)OPP: cyclophosphamide + vincristine + procarbazine + prednisone [8,9] CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone [10] 3. Single-agent chemotherapy:[2] cyclophosphamide chlorambucil 4. Combined modality treatment: combination chemotherapy plus total lymphoid irradiation in a variety of sequences is being explored in clinical trials.[2] 5. Observation plus palliative radiotherapy versus intensive chemotherapy is also under evaluation.[11] 6. New agents.[12,13] References: 1. Horning SJ, Rosenberg SA: The natural history of initially untreated low-grade non-Hodgkin's lymphomas. New England Journal of Medicine 311(23): 1471-1475, 1984. 2. Hoppe RT, Kushlan P, Kaplan HS, et al.: The treatment of advanced stage favorable histology non-Hodgkin's lymphoma: a preliminary report of a randomized trial comparing single agent chemotherapy, combination chemotherapy, and whole body irradiation. Blood 58(3): 592-598, 1981. 3. Young RC, Longo DL, Glatstein E, et al.: The treatment of indolent lymphomas: watchful waiting V aggressive combined modality treatment. Seminars in Hematology 25(2, Suppl 2): 11-16, 1988. 4. Gallagher CJ, Gregory WM, Jones AE, et al.: Follicular lymphoma: prognostic factors for response and survival. Journal of Clinical Oncology 4(10): 1470-1480, 1986. 5. Smalley RV, Andersen JW, Hawkins MJ, et al.: Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma. New England Journal of Medicine 327(19): 1336-1341, 1992. 6. Solal-Celigny P, Lepage E, Brousse N, et al.: Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. New England Journal of Medicine 329(22): 1608-1614, 1993. 7. Andersen JW, Smalley RV: Interferon alfa plus chemotherapy for non-Hodgkin's lymphoma: five-year follow-up. New England Journal of Medicine 329(24): 1821-1822, 1993. 8. Anderson T, DeVita VT, Simon RM, et al.: Malignant Lymphoma: II. prognostic factors and response to treatment of 473 patients at the National Cancer Institute. Cancer 50(12): 2708-2721, 1982. 9. Longo DL, Young RC, Hubbard SM, et al.: Prolonged initial remission in patients with nodular mixed lymphoma. Annals of Internal Medicine 100(5): 651-656, 1984. 10. Dana BW, Dahlberg S, Nathwani BN, et al.: Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. Journal of Clinical Oncology 11(4): 644-651, 1993. 11. Longo DL, Biological Response Modifiers Program, DCT, NCI, NIH: Phase III Observation plus Palliative Radiotherapy vs Intensive Chemotherapy for Previously Untreated Nodular Lymphomas and Diffuse Well-Differentiated Lymphocytic Lymphomas (Summary Last Modified 04/89), BRMP-8903, clinical trial, closed, 06/23/93. 12. Whelan JS, Davis CL, Rule S, et al.: Fludarabine phosphate for the treatment of low grade lymphoid malignancy. British Journal of Cancer 64(1): 120-123, 1991. 13. Kay AC, Saven A, Carrera CJ, et al.: 2-Chlorodeoxyadenosine treatment of low-grade lymphomas. Journal of Clinical Oncology 10(3): 371-377, 1992.

** INTERMEDIATE-GRADE, STAGE IV ADULT NON-HODGKIN'S LYMPHOMA ** --

Intermediate grade (FL, DSC, DM, DL) -- The treatment of choice for stage IV intermediate-grade NHL is clearly combination chemotherapy, either alone or supplemented by local field irradiation.[1] Because patients with bone marrow involvement have significant risk of relapse within the CNS, some oncologists advocate that some prophylactic treatment be aimed at the CNS either by selecting specific agents that penetrate the nervous system well or by adding cranial irradiation and/or intrathecal chemotherapy as a part of the treatment. This hypothesis is the subject of ongoing clinical trials. The presence of B symptoms, more than two involved lymph node sites, more than one extranodal site, and age greater than 60 are poor prognostic factors with respect to most treatments. Other factors, such as increased serum LDH level, may also confer a poor prognosis.[2,3] The addition of alpha-interferon to combination chemotherapy results in increased disease-free and overall survival rates compared to those seen in early analyses of combination chemotherapy alone.[4,5] However, one study with more mature data did not show a significant difference in overall survival.[6] Many investigators consider the natural histories of FL and DSC lymphoma subtypes as more typical of low-grade lymphomas and therefore, are associated with a low cure rate.[7,8] Treatment options: 1. Combination chemotherapy alone: Established regimens capable of producing long-term disease-free survival in 35-45% of patients. As expected, higher response rates have been seen in single institution studies than in cooperative group trials. CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone [9,10] ProMACE-CytaBOM: prednisone + doxorubicin + cyclophosphamide + etoposide + cytarabine + bleomycin + vincristine + intermediate-dose methotrexate [11] MACOP-B: methotrexate with leucovorin rescue + doxorubicin + cyclophosphamide + vincristine + prednisone + bleomycin [12] m-BACOD: intermediate-dose methotrexate + bleomycin + doxorubicin + cyclophosphamide + vincristine + dexamethasone [13] A randomized study of these four regimens showed no difference in time to treatment failure and overall survival for any regimen at three years.[14] The fatal toxicity incidence was 1% for CHOP, 3% for ProMACE-CytaBOM, 5% for m-BACOD, and 6% for MACOP-B. A randomized comparison of CHOP and m-BACOD showed no difference in time to treatment failure and overall survival at 4 years.[10] Significantly more severe and life-threatening toxicities were seen with m-BACOD. 2. Combination chemotherapy plus irradiation (usually to site of bulky involvement). 3. Combination chemotherapy plus prophylactic CNS therapy in patients with bone marrow involvement. Clinical trials such as those exploring the efficacy of chemotherapy with bone marrow transplantation are currently ongoing.[15,16] References: 1. Armitage JO: Treatment of non-Hodgkin's lymphoma. New England Journal of Medicine 328(14): 1023-1030, 1993. 2. Coiffier B, Gisselbrecht C, Vose JM, et al.: Prognostic factors in aggressive malignant lymphomas: description and validation of a prognostic index that could identify patients requiring a more intensive therapy. Journal of Clinical Oncology 9(2): 211-219, 1991. 3. Hoskins PJ, Ng V, Spinelli JJ, et al.: Prognostic variables in patients with diffuse large-cell lymphoma treated with MACOP-B. Journal of Clinical Oncology 9(2): 220-226, 1991. 4. Smalley RV, Andersen JW, Hawkins MJ, et al.: Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma. New England Journal of Medicine 327(19): 1336-1341, 1992. 5. Solal-Celigny P, Lepage E, Brousse N, et al.: Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. New England Journal of Medicine 329(22): 1608-1614, 1993. 6. Andersen JW, Smalley RV: Interferon alfa plus chemotherapy for non-Hodgkin's lymphoma: five-year follow-up. New England Journal of Medicine 329(24): 1821-1822, 1993. 7. Anderson JR, Vose JM, Bierman PJ, et al.: Clinical features and prognosis of follicular large-cell lymphoma: a report from the Nebraska Lymphoma Study Group. Journal of Clinical Oncology 11(2): 218-224, 1993. 8. Longo DL: What's the deal with follicular lymphomas? Journal of Clinical Oncology 11(2): 202-208, 1993. 9. Fisher RI, Miller TP, Dana BW, et al.: Southwest Oncology Group clinical trials for intermediate- and high-grade non-Hodgkin's lymphomas. Seminars in Hematology 24(2, Suppl 1): 21-25, 1987. 10. 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 diffuse non-Hodgkin's lymphoma. New England Journal of Medicine 327(19): 1342-1349, 1992. 11. 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. Journal of Clinical Oncology 9(1): 25-38, 1991. 12. Klimo P, Connors JM: Updated clinical experience with MACOP-B. Seminars in Hematology 24(2, Suppl 1): 26-34, 1987. 13. Shipp MA, Yeap BY, Harrington DP: The m-BACOD combination chemotherapy regimen in large-cell lymphoma: analysis of the completed trial and comparison with M-BACOD regimen. Journal of Clinical Oncology 8(1): 84-93, 1990. 14. 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. New England Journal of Medicine 328(14): 1002-1006, 1993. 15. Nademanee A, Schmidt GM, O'Donnell MR, et al.: High-dose chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy during first complete remission in adult patients with poor-risk aggressive lymphoma: a pilot study. Blood 80(5): 1130-1134, 1992. 16. Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. Journal of Clinical Oncology 8(5): 784-791, 1990. **

HIGH-GRADE, STAGE IV ADULT NON-HODGKIN'S LYMPHOMA **

-- Lymphoblastic lymphoma, convoluted or nonconvoluted cell -- Lymphoblastic lymphoma (LL) is a very aggressive form of non-Hodgkin's lymphoma (NHL). It often occurs in young patients, but not exclusively. It is commonly associated with large mediastinal masses and has a high predilection for disseminating to marrow and CNS, much like acute lymphocytic leukemia (ALL). Thus, treatment is usually patterned after ALL. Intensive combination chemotherapy is the standard treatment for this aggressive histologic type of NHL. Irradiation to areas of bulky tumor masses is sometimes given. Since these forms of NHL tend to progress so quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed. Careful review of the pathologic specimens, bone marrow aspirate and biopsy, CSF cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging work-up. The standard options listed below are successful for approximately 20-30% of patients. Therefore, new approaches should be considered. If the stage IV site is marrow, an ALL-like regimen might be considered. Such regimens are being developed by the national cooperative groups. Other approaches include the use of bone marrow transplantation for consolidation. Treatment options: 1. Combination chemotherapy with CNS prophylaxis: cyclophosphamide + doxorubicin + vincristine + prednisone + asparaginase plus maintenance with methotrexate + 6-mercaptopurine [1,2] The following regimens appear to produce similar results but have not been compared in prospective trials or are in less common use: APO: doxorubicin + vincristine + prednisone + methotrexate + 6-mercaptopurine [3] L10 or L17 protocols or modified versions thereof, as administered in adult lymphocytic leukemia (ALL).[4] 2. Combination chemotherapy with CNS prophylaxis, cranial irradiation, and intrathecal chemotherapy plus local irradiation to sites of massive involvement. -- Immunoblastic lymphoma -- Immunoblastic lymphoma (IBL) must be distinguished from lymphoblastic lymphoma (LL). It may be of T- cell or B-cell origin. The natural history of the lymphomas in this category is still being defined. Those that are Ki-1 positive may represent a clinicopathologic entity but, at present, are like other IBLs, and are treated like the intermediate-grade (diffuse large cell) lymphomas.[5-8] -- Diffuse undifferentiated lymphoma and Burkitt's lymphoma -- Treatment of these lymphomas is usually with aggressive multi-drug regimens similar to those used for the advanced stage intermediate-grade lymphomas (diffuse large cell).[8] An intensive protocol using aggressive combination chemotherapy patterned after that used in childhood Burkitt's lymphoma has been described and has been very successful for patients with all but the most advanced stage. The staging system used for DUL/Burkitt's lymphoma differs from the Ann Arbor staging system. Adverse prognostic factors include bulky abdominal disease and high serum LDH. The patient must be properly staged. For patients in the high-risk group, standard treatment is successful in approximately 30%. Therefore, clinical trials should be considered. In some institutions, this includes the use of consolidative bone marrow transplantation.[6,9,10] References: 1. Coleman CN, Cohen JR, Burke JS, et al.: Lymphoblastic lymphoma in adults: results of a pilot protocol. Blood 57(4): 679-684, 1981. 2. Coleman CN, Picozzi VJ, Cox RS, et al.: Treatment of lymphoblastic lymphoma in adults. Journal of Clinical Oncology 4(11): 1628-1637, 1986. 3. Weinstein HJ, Cassady JR, Levey R: Long-term results of the APO protocol (vincristine, doxorubicin [Adriamycin], and prednisone) for treatment of mediastinal lymphoblastic lymphoma. Journal of Clinical Oncology 1(9): 537-541, 1983. 4. Slater DE, Mertelsmann R, Koziner B, et al.: Lymphoblastic lymphoma in adults. Journal of Clinical Oncology 4(1): 57-67, 1986. 5. Connors JM, Klimo P, Fairey RN, et al.: Brief chemotherapy and involved field radiation therapy for limited-stage, histologically aggressive lymphoma. Annals of Internal Medicine 107(1): 25-30, 1987. 6. Fisher RI, Miller TP, Dana BW, et al.: Southwest Oncology Group clinical trials for intermediate- and high-grade non-Hodgkin's lymphomas. Seminars in Hematology 24(2, Suppl 1): 21-25, 1987. 7. Greer JP, Kinney MC, Collins RD, et al.: Clinical features of 31 patients with Ki-1 anaplastic large-cell lymphoma. Journal of Clinical Oncology 9(4): 539-547, 1991. 8. 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. New England Journal of Medicine 328(14): 1002-1006, 1993. 9. Bernstein JI, Coleman CN, Strickler JG, et al.: Combined modality therapy for adults with small noncleaved cell lymphoma (Burkitt's and non-Burkitt's types). Journal of Clinical Oncology 4(6): 847-858, 1986. 10. Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse

. ** LOW-GRADE, RELAPSED ADULT NON-HODGKIN'S LYMPHOMA **

In general, the treatment of relapsing patients with standard agents rarely produces a cure. Sustained remissions can often be obtained in patients with low-grade lymphomas but relapse will usually ensue. Sustained remissions are distinctly rare for patients with the intermediate- and high-grade lymphomas. The low-grade lymphomas may relapse with an intermediate-grade histology (called "histologic conversion"). Not infrequently, a high-grade lymphoma may relapse as a small cell (low-grade) lymphoma. Such a situation occurs with low-grade lymphoma in the marrow and intermediate-grade lymphoma in a nodal site. Patients may present in such a manner and have chemotherapy successfully eradicate the peripheral disease while failing to eliminate the small cell component from the marrow. The clinical significance and natural history of this pattern of disease is not well defined. Favorable survival after relapse has been associated with age younger than 60, CR rather than PR, and duration of response greater than one year. However, even the most favorable subset has a 10-fold greater mortality compared with age-adjusted U.S. population rates.[1] In many institutions, bone marrow transplantation is being used for patients who have relapsed. Such an approach is still under evaluation but should be considered.[2,3] Patients who relapse with low-grade lymphoma can often have their disease controlled with palliative radiotherapy and/or chemotherapy. However, long-term freedom from second relapse is uncommon and multiple relapses will usually occur. On occasion, the patient may relapse with a more aggressive (intermediate grade) histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy should be performed. Documentation of conversion to a more aggressive histology requires an appropriate change to therapy applicable to the intermediate histologies. Rapid growth or discordant growth between various disease sites may indicate a histologic conversion. For relapse that remains low grade, chemotherapy with single alkylating agents (often given orally) or with combinations such as cyclophosphamide, vincristine and prednisone (CVP) is often used. Recently, significant activity for fludarabine and 2-chlorodeoxyadenosine has been demonstrated in relapsed low-grade lymphomas, especially in follicular small cleaved cell lymphoma.[4-6] A local relapse can be treated with irradiation. Histologic conversions should be treated with the regimens described in the intermediate-grade section. The durability of the second remission may be short and clinical trials such as bone marrow transplantation should be considered. References: 1. Weisdorf DJ, Andersen JW, Glick JH, et al.: Survival after relapse of low-grade non-Hodgkin's lymphoma: implications for marrow transplantation. Journal of Clinical Oncology 10(6): 942-947, 1992. 2. Rohatiner AZ, Freedman A, Nadler L, et al.: Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for follicular lymphoma. Annals of Oncology 5(Suppl 2): 143-146, 1994. 3. Schouten HC, Colombat P, Verdonck LF, et al.: Autologous bone marrow transplantation for low-grade non-Hodgkin's lymphoma: the European Bone Marrow Transplant Group experience. Annals of Oncology 5(Suppl 2): 147-149, 1994. 4. Hochster HS, Kim K, Green MD, et al.: Activity of fludarabine in previously treated non-Hodgkin's low-grade lymphoma: results of an Eastern Cooperative Oncology Group Study. Journal of Clinical Oncology 10(1): 28-32, 1992. 5. Kay AC, Saven A, Carrera CJ, et al.: 2-Chlorodeoxyadenosine treatment of low-grade lymphomas. Journal of Clinical Oncology 10(3): 371-377, 1992. 6. Redman JR, Cabanillas F, Velasquez WS, et al.: Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low-grade lymphoma.

** INTERMEDIATE-GRADE, RELAPSED ADULT NON-HODGKIN'S LYMPHOMA **

In general, the treatment of relapsing patients with standard agents rarely produces a cure. Sustained remissions can often be obtained in patients with low-grade lymphomas but relapse will usually ensue. Sustained remissions are distinctly rare for patients with the intermediate- and high-grade lymphomas. The low-grade lymphomas may relapse with an intermediate-grade histology (called "histologic conversion"). Not infrequently, a high-grade lymphoma may relapse as a small cell (low grade) lymphoma. Such a situation occurs with low-grade lymphoma in the marrow and intermediate-grade lymphoma in a nodal site. Patients may present in such a manner and have chemotherapy successfully eradicate the peripheral disease while failing to eliminate the small cell component from the marrow. The clinical significance and natural history of this pattern of disease is not well defined. Bone marrow transplantation is being used for patients whose lymphoma has relapsed. Preparative drug regimens have varied; some investigators also utilize total body irradiation. Autologous marrow, with or without marrow purging, and allogeneic marrow have been used following the high-dose therapy.[1-4] Preliminary studies indicate that approximately 20% of patients will have a long-term disease-free status, but the precise percentage depends on patient selection. In general, patients who responded to initial therapy and who have responded to conventional therapy for relapse prior to the bone marrow transplantation have had the best results. Peripheral stem cell transplantation has yielded results equivalent to standard autologous transplantation.[5] Since toxicity can be severe and patients require specialized team management, bone marrow transplantation should be done at institutions that have the appropriate expertise and resources available. Given the uncertainties of the content of the "best" treatment regimen and patient selection, bone marrow transplantation must be considered an area of ongoing research. Salvage of intermediate-grade patients who relapse after chemotherapy or radiotherapy is poor. Patients are often treated with one of the regimens listed in the intermediate grade section. Therapy under clinical evaluation includes bone marrow transplantation with or without colony stimulating factors.[6,7] References: 1. Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. Journal of Clinical Oncology 8(5): 784-791, 1990. 2. Phillips GL, Fay JW, Herzig RH, et al.: The treatment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 75(4): 831-838, 1990. 3. Chopra R, Goldstone AH, Pearce R, et al.: Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data. Journal of Clinical Oncology 10(11): 1690-1695, 1992. 4. Ratanatharathorn V, Uberti J, Karanes C, et al.: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. Blood 84(4): 1050-1055, 1994. 5. Vose JM, Anderson JR, Kessinger A, et al.: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. Journal of Clinical Oncology 11(10): 1846-1851, 1993. 6. Gorin NC, Coiffier B, Hayat M, et al.: Recombinant human granulocyte-macrophage colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation with unpurged and purged marrow in non-Hodgkin's lymphoma: a double-blind placebo-controlled trial. Blood 80(5): 1149-1157, 1992. 7. Bosly A, Coiffier B, Gisselbrecht C, et al.: Bone marrow transplantation prolongs survival after relapse in aggressive-lymphoma patients treated with the LNH-84 regimen. Journal of Clinical Oncology 10(10): 1615-1623, 1992.

** HIGH-GRADE, RELAPSED ADULT NON-HODGKIN'S LYMPHOMA**

In general, the treatment of relapsing patients with standard agents rarely produces a cure. Sustained remissions can often be obtained in patients with low-grade lymphomas but relapse will usually ensue. Sustained remissions are distinctly rare for patients with the intermediate- and high-grade lymphomas. The low-grade lymphomas may relapse with an intermediate-grade histology (called "histologic conversion"). Not infrequently, a high-grade lymphoma may relapse as a small cell (low-grade) lymphoma. Such a situation occurs with low-grade lymphoma in the marrow and intermediate-grade lymphoma in a nodal site. Patients may present in such a manner and have chemotherapy successfully eradicate the peripheral disease while failing to eliminate the small cell component from the marrow. Regimens using continuous-infusion chemotherapy are under evaluation and early reports indicate that they may be more efficacious than bolus regimens.[1-3] The clinical significance and natural history of this pattern of disease is not well defined. Bone marrow transplantation is being used for patients whose lymphoma has relapsed. Preparative drug regimens have varied; some investigators also utilize total body irradiation. Autologous marrow, with or without marrow purging, and allogeneic marrow have been used following the high-dose therapy with equal success.[4-7] The addition of GM-CSF after autologous BMT may result in accelerated myeloid recovery, decreasing the incidence of infections and the need for antibiotics, in some studies and not in others.[8,9] Preliminary studies indicate that approximately 20% of patients will have a long-term disease-free status, but the precise percentage depends on patient selection. In general, patients who responded to initial therapy and who have responded to conventional therapy for relapse prior to the bone marrow transplantation have had the best results. Peripheral stem cell transplantation has yielded results equivalent to standard autologous transplantation.[10,11] Since toxicity can be severe, and patients require specialized team management, bone marrow transplantation should be done at institutions that have the appropriate expertise and resources available. Given the uncertainties of the content of the "best" treatment regimen and patient selection, bone marrow transplantation must be considered an area of ongoing research. Patients with high-grade lymphomas who relapse have a poor survival with standard therapy. Clinical trials must be considered. References: 1. Wilson WH, Bryant G, Bates S, et al.: EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. Journal of Clinical Oncology 11(8): 1573-1582, 1993. 2. Sparano JA, Wiernik PH, Strack M, et al.: Infusional cyclophosphamide, doxorubicin, and etoposide in human immunodeficiency virus- and human T-cell leukemia virus type I-related non-Hodgkin's lymphoma: a highly active regimen. Blood 81(10): 2810-2815, 1993. 3. Sparano JA, Wiernik PH, Leaf A, et al.: Infusional cyclophosphamide, doxorubicin, and etoposide in relapsed and resistant non-Hodgkin's lymphoma: evidence for a schedule-dependent effect favoring infusional administration of chemotherapy. Journal of Clinical Oncology 11(6): 1071-1079, 1993. 4. Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. Journal of Clinical Oncology 8(5): 784-791, 1990. 5. Phillips GL, Fay JW, Herzig RH, et al.: The treatment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 75(4): 831-838, 1990. 6. Chopra R, Goldstone AH, Pearce R, et al.: Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data. Journal of Clinical Oncology 10(11): 1690-1695, 1992. 7. Ratanatharathorn V, Uberti J, Karanes C, et al.: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. Blood 84(4): 1050-1055, 1994. 8. Advani R, Chao NJ, Horning SJ, et al.: Granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjunct to autologous hemopoietic stem cell transplantation for lymphoma. Annals of Internal Medicine 116(3): 183-189, 1992. 9. Gorin NC, Coiffier B, Hayat M, et al.: Recombinant human granulocyte-macrophage colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation with unpurged and purged marrow in non-Hodgkin's lymphoma: a double-blind placebo-controlled trial. Blood 80(5): 1149-1157, 1992. 10. Vose JM, Anderson JR, Kessinger A, et al.: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. Journal of Clinical Oncology 11(10): 1846-1851, 1993. 11. Liberti G, Pearce R, Taghipour G, et al.: Comparison of peripheral blood stem-cell and autologous bone marrow transplantation for lymphoma patients: a case-controlled analysis of the EBMT Registry data. Annals of Oncology 5(Suppl 2): 151-153, 1994. Date Last Modified: 02/95 ******************************************************************************