Diffuse Small Noncleaved-Cell, Non-Burkitt's Lymphoma in Adults: A High-Grade Lymphoma Responsive to ProMACE-Based Combination Chemotherapy

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1 Diffuse Small Noncleaved-Cell, Non-Burkitt's Lymphoma in Adults: A High-Grade Lymphoma Responsive to ProMACE-Based Combination Chemotherapy By Dan L. Longo, Patricia L. Duffey, Elaine S. Jaffe, Mark Raffeld, Susan M. Hubbard, Richard I. Fisher, Robert E. Wittes, Vincent T. DeVita, Jr, and Robert C. Young Purse: To review the efficacy of cyclophosphamide, oxorubicin, etoposide, methotrexate with leucovorin, and prednisone (ProMACE)-based combination chemotherapy programs in the treatment of patients with diffuse small noncleaved-cell non-burkitt's lymphoma. Patients and Methods: Thirty-three patients with diffuse small noncleaved-cell non-burkitt's lymphoma were accrued: eight with localized disease were treated with modified ProMACE-mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) plus involved-field radiation therapy, and 25 with advanced-stage disease were treated with ProMACE/MOPP flexitherapy (n = 8), ProMACE-MOPP (n = 9), or ProMACE-cytarabine, bleomycin, vincristine, and methotrexate with leucovorin (CytaBOM) (n = 8). The median follow-up duration is 1 years. Results: All eight patients with localized disease aclieved a complete response, none have relapsed, and one died of intercurrent illness. Among patients with ad- S MALL NONCLEAVED-CELL lymphomas may be divided into Burkitt's and non-burkitt's varieties on morphologic grounds that are subtle to even the most experienced hematopathologists. The distinction is often based on the degree of heterogeneity of nuclear size and shape: sheets of homogeneous cells are characteristic of Burkitt's lymphoma, whereas the non-burkitt's subset contains cells that are more variable in size with heterogeneity in nuclear shape and chromatin condensation.' 4 Even experts often disagree on which lymphomas belong in which subset. 4 This group of lymphomas account for one third to one half of lymphomas in children, but before 1985 were rare in adults, accounting for approximately 2% of cases in most large series.' The incidence of small noncleaved-cell lymphomas appears to be increasing in adults, mainly as a result of the increased risk of lymphoma in patients infected with the human immunodeficiency virus (HIV). 6 Because of the rarity of small noncleaved-cell lymphoma in immunocompetent adults, consensus on whether Burkitt's and non-burkitt's lymphomas should be treated differently has been difficult to reach.' A number of clinicopathologic studies reported in the early 198s 1 ' 2, 8, 9 demonstrated that the use of so-called firstgeneration chemotherapy programs such as cyclophosphamide, mechlorethamine, vincristine, procarbazine, and prednisone (C-MOPP); bleomycin, doxorubicin, cyclovanced-stage disease, five of eight (63%) flexitherapytreated patients, six of nine (%) ProMACE-MOPPtreated patients, and eight of eight (1%) ProMACE- CytaBOM-treated patients achieved a complete response. If the two ProMACE-MOPP-based groups are considered together, disease-free and overall survival rates at 15 years are projected at 61% and 35%, respectively. In contrast, only one patient has relapsed from a ProMACE-CytaBOM-induced complete remission, and overall survival of ProMACE-CytaBOM-treated patients (88%) is significantly higher than that for flexitherapy and ProMACE-MOPP (P 2 =.4). Conclusion: Adult patients with diffuse small noncleaved-cell non-burkitt's lymphoma may be effectively treated with regimens that are effective in other aggressive lymphomas (eg, diffuse large-cell lymphoma). J Clin Oncol 12: , This is a US government work. There are no restrictions on its use. phosphamide, vincristine, and prednisone (BACOP); and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) that produced long-term survival in about one third of patients with diffuse large-cell lymphoma, produced much poorer results in patients with small noncleaved-cell lymphoma, non-burkitt's variety. In one series,2 patients with Burkitt's lymphoma treated with one of the early more aggressive childhood lymphoma treat- From the Division of Cancer Treatment and the Division of Cancer Biology, Diagnosis, and Centers, National Cancer Institute; Medicine Branch, Clinical Oncology Program, Division of Cancer Treatment; International Cancer Information Center, National Cancer Institute; Hematopathology Section, Laboratory of Pathology, Division of Cancer Biology, Diagnosis, and Centers, National Cancer Institute, Bethesda; Biological Response Modifiers Program, Division of Cancer Treatment, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD; Loyola University Stritch School of Medicine, Maywood, IL; Yale University School of Medicine, New Haven, CT; and Fox Chase Cancer Center, Philadelphia, PA. Submitted April 5, 1994; accepted June 3, Address reprint requests to Dan L. Longo, MD, Biological Response Modifiers Program, Division of Cancer Treatment, National Cancer Institute-Frederick Cancer Research and Development Center, Building 576, Room 1, Frederick, MD This is a US government work. There are no restrictions on its use X/94/121-22$./ Journal of Clinical Oncology, Vol 12, No 1 (October), 1994: pp

2 2154 ment regimens had a 5-year survival rate of 42%, while patients with non-burkitt's lymphoma treated with early adult lymphoma regimens (with or without surgery and radiation therapy) had a 5-year survival rate of 11%. After it was shown that children with Burkitt's and non-burkitt's lymphomas had similar survival rates (6%) with the use of improved childhood lymphoma regimens,"' similar regimens were used in adult patients with Burkitt's and non-burkitt's lymphomas with similar improvements in treatment outcome.12,13 However, recent studies of patients with small noncleaved-cell lymphoma have documented significant genetic differences between Burkitt's and non-burkitt's lymphoma." 4 Burkitt's lymphomas nearly universally contain c-myc gene rearrangements to immunoglobulin genes (most often the heavy-chain gene on chromosome 14); however, none of 11 non-burkitt's small noncleavedcell lymphomas had c-myc rearrangements. In light of these genetic differences and previously described differences in pattern of clinical involvement of disease (eg, non-burkitt's tumors are more often nodal in presentation, while Burkitt's are more often extranodal), it is appropriate to reevaluate the possibility that the non-burkitt's tumors share clinical response characteristics with other diffuse follicular center-cell tumors such as diffuse large-cell lymphoma. Such an analysis is complicated by the rarity of the tumor. Most series of modern adult aggressive lymphoma treatment5-2 have contained too few patients with small noncleaved-cell non-burkitt's lymphoma to draw conclusions. In an effort to define the effectiveness of second- and third-generation lymphoma treatment regimens in patients with small noncleaved-cell non-burkitt's lymphoma, we reviewed all cases accrued on consecutive National Cancer Institute studies conducted over the last 16 years in which cyclophosphamide, doxorubicin, etoposide, methotrexate with leucovorin, and prednisone (ProMACE)-based chemotherapy regimens were used.'1516,21 Although the number of patients with diffuse small noncleaved-cell non-burkitt's lymphoma is small, it appears that certain subsets can be effectively treated with regimens used to treat adult diffuse large-cell lymphoma, regimens that are generally administered in the outpatient setting and are generally less toxic and less complex than childhood lymphoma regimens. PATIENTS AND METHODS Among 49 previously untreated patients entered on National Cancer Institute treatment protocols for aggressive histology lymphoma (defined as follicular large-cell, diffuse large-cell, diffuse large-cell immunoblastic, diffuse mixed, and diffuse small noncleaved-cell non-burkitt's lymphomas) since August 1977, Table 1. Patient Characteristics LONGO ET AL Characteristic No. % Total patients 1 Age, years > > > Median 36 Range 19-8 Males Kornofsky status < Constitutional symptoms 6 18 Stage I, IE 8 24 II, IIE 9 27 III 6 18 IV 1 31 LDH level (U/mL) < > > Bone marrow involvement 3 9 Extronodal sites Treatment Modified ProMACE-MOPP + RT 8 24 ProMACE/MOPP flexitherapy 9 27 ProMACE-MOPP 8 24 ProMACE-CytaBOM 8 24 Abbreviation: RT, radiation therapy. (8.1%) had small noncleaved-cell non-burkitt's lymphoma as read in the Laboratory of Pathology, National Cancer Institute (E.J.S., M.R.). Extent of disease was determined by a previously described standardized staging evaluation." 6 The characteristics of these patients are listed in Table 1. Treatments were as previously reported.s'' 6 ' 2 ' After 1981, patients with stage I disease received modified ProMACE-MOPP (cyclophosphamide 5 mg/m2 on day 1, doxorubicin in 2 mg/m2 on day 1, etoposide 1 mg/m 2 on day 1, mechlorethamine 5 mg/m 2 on day 8, vincristine 1.4 mg/m2 on day 8, procarbazine 75 mg/m 2 on days 8 to 14, methotrexate 12 mg/m2 on day 15 with leucovorin rescue, and prednisone 6 mg/m 2 on days 1 to 14) with involved-field radiation therapy. 2 1 Patients with advanced stages of disease (stages II to IV) received ProMACE/MOPP flexitherapy (cyclophosphamide 65 mg/m 2 on days 1 and 8, doxorubicin 25 mg/m2 on days 1 and 8, etoposide 12 mg/m 2 on days 1 and 8, methotrexate 3 g/m 2 on day 15 with leucovorin rescue, prednisone 6 mg/m2 on days 1 to 14 for two to three cycles followed by mechlorethamine 6 mg/m 2 on days I and 8, vincristine 1.4 mg/m 2 on days 1 and 8, procarbazine 1 mg/m2 on days I to 14, prednisone 4 mg/m 2 on days 1 to 14 for two to three cycles, then two to three cycles ProMACE) from August 1977 through May 1982.' From June 1982 through April 1988, patients with stage II to IV disease were randomized between ProMACE-MOPP (cyclophosphamide 65 mg/m 2 on day 1, doxorubicin 25 mg/m 2 on day 1, etoposide 12 mg/m 2 on day 1, mechlorethamine 6 mg/m 2 on day 8, vincristine 1.4 mg/m 2 on day 8, procarbaz-

3 DIFFUSE SMALL NONCLEAVED-CELL NON-BURKITT'S LYMPHOMA 2155 Table 2. Results of Treatment Variable No. % Patients Complete responders Relapses 5 19 Deaths Induction failure 6 Relapse 2 Free of disease 5 Related to primary treatment toxicity 2 Related to salvage treatment toxicity 2 Unrelated to lymphoma or treatment 1 Median follow-up, years 1 ine 1 mg/m 2 on days 8 to 14, methotrexate 5 mg/m 2 on day 15 with leucovorin rescue, and prednisone 6 mg/m 2 on days 1 to 14) and ProMACE-CytaBOM (cyclophosphamide 65 mg/m 2 on day 1, doxorubicin 25 mg/m 2 on day 1, etoposide 12 mg/m 2 on day 1, cytarabine 3 mg/m 2 on day 8, vincristine 1.4 mg/m 2 on day 8, bleomycin 1 mg/m 2 on day 8, methotrexate 12 mg/m 2 on day 8 with leucovorin rescue, and prednisone 6 mg/m 2 on days I to 14)."6 After April 1988, all patients with stage II to IV disease received ProMACE-CytaBOM.16 Hematopoietic growth factors were not used in any of these patients. Patients with bone or bone marrow involvement were routinely given whole-brain irradiation for CNS prophylaxis after they achieved a complete remission. The high-dose methotrexate in the treatment regimens was considered adequate prophylactic therapy for the spinal cord. The median follow-up duration of this group of patients is 1 years. The median follow-up duration of patients treated with flexitherapy is 14.4 years, with ProMACE-MOPP (regular and modified) 9.8 years, and with ProMACE-CytaBOM 9.7 years. Duration of survival was calculated from the start of therapy until death. Duration of complete response was calculated from the last day of treatment until objective evidence of relapse. All curves are plotted by the life-table method. 22 Comparisons among patient groups were made using two-sided Mantel-Haenszel tests. 23 Univariate prognostic factor analysis was performed using the following variables: performance status, age, sex, stage, B symptoms, serum lactate dehydrogenase (LDH) levels, presence and number of extranodal disease, presence of a large (> 1 cm) mass, and treatment. RESULTS Twenty-seven of patients (82%) achieved a complete response to therapy and five of the complete responders (19%) have relapsed (Table 2). Thirteen patients (39%) have died, including all six patients who did not achieve a complete response and two of the relapsed patients; five patients have died free of disease. Among five patients who died without evidence of lymphoma, two died during initial evaluation or therapy (one of Pneumocystis carinii pneumonia on ProMACE-CytaBOM before the institution of co-trimoxazole prophylaxis, one of bleeding from a liver biopsy before therapy with Pro- MACE/MOPP flexitherapy), two died as a result of toxicity from salvage treatment regimens, and one died in the perioperative period of a second coronary artery bypass surgery procedure 4 years after completing treatment for localized lymphoma. The overall survival rate of patients with small noncleaved-cell non-burkitt's lymphoma is projected to be 6% at 15 years (Fig 1A): 88% for patients with stage I disease and 51% for patients with more advanced disease (Fig 1B). The disease-free survival rate of complete responders is projected to be 8% at 15 years (Fig 2A): 1% for patients with stage I disease and 71% for patients with stage II to IV disease (Fig 2B). The influence of potential prognostic factors on complete response rate, relapse rate, disease-free survival, and overall survival is listed in Table 3. Because of the rarity of this lymphoma cell type, our ability to detect important influences on treatment outcome is reduced. However, with univariate analysis, overall survival was significantly higher for stage I patients (88%) compared with stage II (44%; P 2 =.25) and with stage IV patients (48%; P 2 =.28). Patients with LDH levels more than 5 U/mL had significantly poorer complete response, disease-free M z I:2 3 En Z Ld wn. A 1_ B 9 so so 9 so c 3 to oo it B g s s2 Fig 1. (A) Kaplan-Meier plot of overall survival of patients with diffuse small noncleaved-cell non-burkitt's lymphoma. Curve plateau is at 6%. (*) 13 of died. (B) Same as (A), broken down by stage. (*) Stage I, 1 of 8 died; () stages II to IV, 12 of 25 died. P 2 =.7..6

4 LONGO ET AL A 1 9 z 8 7 X 6 cc W 5 H z 2 a , o B 1 9 tý 7 ) H Z U c2 M o1 years) was significantly poorer than that of patients treated with ProMACE-CytaBOM (88% at 15 years; if *3-6 The apparent differences in outcome between Pro- MACE-MOPP and ProMACE-CytaBOM are not clearly related to disproportionate treatment delays in the Pro- MACE-MOPP-treated patients. Three patients treated with ProMACE-MOPP had no treatment delays, one had one delay of 9 days, three had two delays of 1 to 2 weeks, and two had four delays ranging from 1 to 3 weeks. Both..... patients with four delays achieved and remain in complete I A A i9 2 remission. For ProMACE-CytaBOM-treated patients, two had no delays, three had one delay of 1 week or less, two had two delays of 1 to 2 weeks, and one had three delays of 1 week. On the other hand, the delivered doseintensities of five of the six agents common to both regimens were significantly (21% to 41%) higher for patients */ who received ProMACE-CytaBOM (Table 4) Fig 2. (A) Kaplan-Meier plot of disease-free survival of all 27 patients who achieved a complete response to primary therapy. Curve plateau is at 8%. (*) 5 of 22 relapsed. (B) Same as (A), broken down by stage. (*) Stage I, of 8 relapsed; () stages II to IV, 5 of 19 relapsed. P 2 =. 1. survival, and overall survival rates; however, the number of patients with a high LDH level was small (n = 6). The only factor that significantly affected survival of advanced-stage patients was the treatment regimen used. All patients with localized disease achieved a complete response and none have relapsed from the initial remission. All patients with advanced-stage disease treated with ProMACE-CytaBOM also achieved a complete response, and only one patient has relapsed. The patient relapsed in the CNS and underwent successful salvage treatment with systemic chemotherapy plus CNS radiation therapy. She has been in her second remission for more than 2 years. In contrast, patients treated with ProMACE/MOPP flexitherapy or ProMACE-MOPP did not fare as well. We have previously demonstrated that ProMACE/MOPP flexitherapy and ProMACE-MOPP are comparably effective regimens in advanced-stage aggressive-histology lymphoma." If we consider patients treated with these two regimens together, their overall survival (35% at 15 DISCUSSION When we identify a particular tumor as a diffuse small noncleaved-cell non-burkitt's lymphoma, we are not necessarily naming a discrete clinicopathologic entity. Unlike Burkitt's lymphoma, which has a molecular signature (ie, translocation of chromosome 8), diffuse small noncleaved-cell non-burkitt's lymphoma may not be a single disease entity. Diffuse small noncleaved-cell non-burkitt's lymphoma is a rare form of aggressive-histology lymphoma in adults with immunodeficiency disorders. Furthermore, it is not recognized in the Kiel scheme; such cases in Europe are generally considered within the spectrum of centroblastic lymphoma. Its rarity makes it difficult to discern whether its natural history and response to treatment resembles diffuse large-cell lymphoma or Burkitt's lymphoma. In the past, this distribution might have been considered moot because of the difficulty of morphologically distinguishing Burkitt's and non-burkitt's lymphoma. However, the genetic differences suggest that the disorders are different. Furthermore, the use of more complex and more toxic pediatric lymphoma-like regimens may be necessary for one but not the other. In general, adult patients treated with regimens used in diffuse large-cell lymphoma have fared poorly compared with children treated with more aggressive combination chemotherapy programs. Indeed, pilot experiences with high-dose regimens in adults with diffuse small noncleaved-cell non-burkitt's lymphoma have shown promising results in patients without HIV infection. Here we report the National Cancer Institute experience over the last 15 years using ProMACE-based chemother-

5 DIFFUSE SMALL NONCLEAVED-CELL NON-BURKITT'S LYMPHOMA 2157 Table 3. Response by Prognostic Factors CR Rate Relapse Rate Died Variable No. % No. % No. % DFS OS All patients 27/ 82 5/ / Sex Male Female PS Good Poor (<7%) B symptoms Yes No Stage I II III IV Stage I Il-IV LDH (U/mL) < 5 > 5 14/18 13/15 25/29 2/4 23/27 4/6 6/9 6/6 7/1 19/ /14 2/13 5/25 /2 4/23 1/4 /8 1/6 2/7 /8 5/19 4/24 1/ /18 4/15 1/29 3/4 9/27 4/6 5/9 5/1 12/ No. of extranodal sites Mass > 1 cm No large mass > 1 cm Flexitherapy ProMACE-MOPP ProMACE-CytaBOM Stage I Flexitherapy + ProMACE-MOPP ProMACE-CytaBOM 24/27 (P 2 =.2) 9/9 18/24 21/26 5/7 5/8 6/9 11/17 1 3/9 75 2/ /21 /5 2/5 /8 65 4/ /27 5 5/6 (P 2 =.5) (P 2 =.3) 4/ / /26 2/7 6/8 5/9 Abbreviations: PS, performance status; CR, complete response; DFS, disease-free survival; OS, overall survival (P 2 =.2) (P 2 =.2) 36 11/ (P 2 = (P 2 =.4) apy in patients with diffuse small noncleaved-cell non- Burkitt's lymphoma. Modified ProMACE-MOPP plus involved-field radiation therapy is extremely effective treatment for patients with stage I or IE disease. All eight such patients achieved a complete response, none relapsed, and the only death was a woman who died perioperatively during her second coronary artery bypass procedure several years after completing lymphoma treatment. ProMACE/MOPP flexitherapy and ProMACE-MOPP achieve reasonable complete remission rates (65%) in patients with advanced-stage disease, although the overall survival rate is poor (35% at 15 years). However, the eight patients with advanced-stage disease treated with ProMACE-CytaBOM all achieved a complete response; one patient has relapsed (but survives in second remission) and one patient has died (of Pneumocystis pneumonia). The major unresolved question is whether the results in this small trial can be extrapolated to the general population of adult patients with diffuse small noncleavedcell non-burkitt's lymphoma. Although all eight patients treated with ProMACE-CytaBOM achieved a complete response, few of the patients had high LDH levels and other poor prognostic factors; thus, it remains unclear whether ProMACE-CytaBOM is equally effective in high-risk patients. The 95% confidence limits on the 1% complete response rate for ProMACE-CytaBOM with such a small number of patients is large (63% to 1%). However, if the true complete response rate were

6 2158 7%, there is only a 5.7% chance that we would have obtained eight of eight complete responses. Thus, it is likely that the true complete response rate is greater than 7%. ProMACE-CytaBOM has the distinct advantage of being deliverable in the outpatient clinic and, with the use of co-trimoxazole prophylaxis, we have had no treatmentrelated mortality in the last 65 treated patients. The toxicity of ProMACE-CytaBOM is acceptable. The recent Intergroup Study of CHOP; methotrexate with leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-bacod); methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B); and ProMACE- CytaBOM found that ProMACE-CytaBOM was comparable to CHOP in incidence of life-threatening and fatal toxicity. 24 In contrast, more aggressive high-dose combination chemotherapy programs designed like the pediatric regimens have been reported to produce excellent results, although with more severe, but tolerable toxicity.' 2 '13 McMaster et all 3 used brief intense therapy that included cyclophosphamide 1.5 g/m 2 on days 1 and 2, etoposide 4 mg/m 2 /d on days 1 to 3, vincristine 1.4 mg/m 2 on days 8 and 22, bleomycin 1 U/m 2 on days 8 and 22, highdose methotrexate (2 mg/m 2 on day 15) with leucovorin rescue, and prednisone 6 mg/m 2 /d for the first 7 days. In 19 patients with diffuse small noncleaved-cell non- Burkitt's lymphoma (including three with HIV-associated lymphoma), complete responses were obtained in 17, and 13 had durable responses. There were two toxic deaths. Furthermore, four additional patients had therapy delayed or abbreviated due to life-threatening toxicity. z CD H 7. UCD cr Fig 3. Kaplan-Meier plot of overall survival of 25 advanced-stage patients as a function of primary treatment: ProMACE/MOPP flexitherapy and ProMACE-MOPP (*; 11 of 18 died) v ProMACE-CytaBOM (; 1 of 8 died). Curve plateau of ProMACE/MOPP flexitherapy plus ProMACE-MOPP is at 35%; for ProMACE-CytaBOM, at 88% (P 2 =.4). Table 4. Delivered Dose-Intensity: ProMACE-MOPP Versus ProMACE-CytaBOM Delivered Dose-Intensity (mg/m 2 /wk) LONGO ET AL Agent ProMACE-MOPP ProMACE-CytaBOM Cyclophosphamide Doxorubicin Etoposide Vincristine Methotrexate Prednisone Mechlorethamine Procarbazine Cytarabine Bleomycin 1.4 Other studies suggest that more typical adult lymphoma regimens might be effective in these patients. Bernstein et a1' 2 used a regimen that included cyclophosphamide 1,2 mg/m 2 on day 1, doxorubicin 4 mg/m 2 on day 1, vincristine 2 mg on day 1, prednisone 4 mg/m2 orally on days 1 to 5, and methotrexate 3 g/m 2 on day 1 with leucovorin rescue. They treated 1 patients with diffuse small noncleaved-cell non-burkitt's lymphoma, including four patients with stage I or IE disease, one with stage IIE disease, two with stage III disease, and three with stage IV disease. Six of seven assessable patients had a complete response, and eight of 1 patients had durable remissions. The regimen reported by Bernstein et a1' 2 is only moderately more aggressive than the usual lymphoma regimens and produces excellent results. Lopez et a1 25 used several lymphoma-intensity regimens in 23 patients with diffuse small noncleaved-cell non-burkitt's lymphoma. Patients with stage I to III disease had an overall survival rate of nearly 9% in this series; patients with stage IV disease had a less than 3% overall survival rate. It seems unlikely that a prospective study comparing a childhood lymphoma-like regimen with an adult lymphoma regimen will be undertaken in this rare lymphoma. Given the safety and efficacy of modified ProMACE-MOPP with involved-field radiation therapy in patients with localized disease and ProMACE-Cyta- BOM in patients with advanced-stage disease, we believe the use of these regimens is a reasonable treatment choice for adults with diffuse small noncleaved-cell non-burkitt's lymphoma. ACKNOWLEDGMENT We are grateful to Terry Phillips for outstanding editorial services.

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