The role of rituximab and chemotherapy in aggressive B-cell lymphoma: A preliminary report of dose-adjusted EPOCH-R

The Role of Rituximab and Chemotherapy in Aggressive B-Cell Lymphoma: A Preliminary Report of Dose-Adjusted EPOCH-R Wyndham H. Wilson, Martin Gutierrez, Paula O’Connor, Stanley Frankel, Elaine Jaffe, Bruce A. Chabner, and Michael L. Grossbard Accumulating evidence suggests that the ability to activate apoptotic pathways may be an important determinant of chemotherapy sensitivity and presents a potentially important new therapeutic strategy. Monoclonal antibodies against the CD20 antigen directly induce apoptosis and may serve to modulate the threshold for chemotherapy-induced apoptosis. Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA), a monoclonal antibody against CD20, was combined with dose-adjusted EPOCH (infusional etoposide/vincristine/doxorubicin/bolus cyclophosphamide/prednisone) chemotherapy and tested in 38 untreated or relapsed poor-prognosis aggressive lymphomas. Twenty-three patients were untreated. Of these patients, all had large B-cell histologies, a median age of 52 years, Eastern Cooperative Oncology Group performance status > 2 in 30%, and high-intermediate or high International Prognostic Index scores in 61%. Fifteen patients had relapsed or refractory lymphomas. These patients had received a median of two (range, one to four) prior regimens, 67% had aggressive histologies, and 60% had high-intermediate or high International Prognostic Index scores. Complete remissions were achieved in 85% and 64% of untreated and previously treated patients, respectively; additionally 42% of patients with disease refractory before therapy achieved complete remission. At a median follow-up of 12 months, progressionfree and overall survival in the previously untreated group was 85% and 79%, respectively, and no patient in complete remission has relapsed. These results suggest that rituximab may modulate the sensitivity of B-cell lymphomas to chemotherapy. Semin Oncol 29 (suppl 2):41-47. This is a US government work. There are no restrictions on its use.

A

LTHOUGH lymphomas are highly responsive to chemotherapy, for most subtypes the persistence of drug-resistant cells leads to treatment failure.1-3 A variety of strategies aimed at overcoming specific drug-resistance mechanisms have been attempted with limited success, such as inhibition of cytoplasmic enzymes involved in detoxification (glutathione S-transferase) or membrane transport pumps (mdr-1).4-9 The rationale for these strategies is derived from classical concepts of drug resistance, which hypothesize the acquisition of drug-specific mechanisms, such as overexpression of membrane pumps, increased free radical scavengers, mutation(s) of intracellular targets, increased DNA repair activity, and limited Seminars in Oncology, Vol 29, No 1, Suppl 2 (February), 2002: pp 41-47

cytotoxic damage.10-14 However, accumulating evidence suggests that the important determinants of chemotherapy sensitivity may reside within the apoptotic pathways.15-17 Experimental studies show apoptosis to be a ubiquitous cell death pathway in lymphomas exposed to multiple therapeutic drug classes including conventional cytotoxics and protein kinase modulators.18,19 If the sensitivity to apoptosis is limited by imbalances in apoptotic signaling pathways, then strategies to modulate these pathways may profoundly enhance the efficacy of cytotoxic therapy.15-17 The monoclonal antibody rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA), targeting the CD20 antigen on B cells, directly induces apoptosis, in addition to acting through antibodydependent cellular cytotoxicity and complementmediated mechanisms, and may enhance the sensitivity of tumor cells to chemotherapy-induced apoptosis.20,21 Incubation of B cells with antiCD20 antibody has variable effects on cell cycle progression, and inhibits B-cell progression from G1 to the S/G2⫹M phases of the cell cycle following mitogen stimulation and/or drives resting G0 B cells into G1 but not S phase.22-24 Studies show that CD20 ligation is associated with transmembrane calcium conductance, which may inhibit cell cycle progression from G1 into S phase and/or induce apoptosis. These findings form the basis for the hypothesis that rituximab may functionally overcome clinical drug resistance by modulating sensitivity to chemotherapy-induced apoptosis.

From the Center for Cancer Research, National Cancer Institute, Bethesda, MD; the Department of Oncology, Massachusetts General Hospital, Boston, MA; Greenebaum Cancer Center, University of Maryland, Baltimore, MD; and the Department of Oncology, St Luke’s Roosevelt Hospital Center, New York, NY Address reprint requests to Wyndham H. Wilson, MD, PhD, National Cancer Institute, Building 10, Room 12N226, 9000 Rockville Pike, Bethesda, MD 20892. This is a US government work. There are no restrictions on its use. 0093-7754/02/2901-0107$0.00/0 doi:10.1053/sonc.2002.30151 41

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WILSON ET AL

Large B-cell lymphomas are an ideal subtype in which to test the hypothesis of chemosensitization by rituximab because, although potentially curable, up to 65% of patients fail treatment.25 Thus, significant synergy between rituximab and chemotherapy could be clinically assessed by the outcome measures of response and progression-free and overall survival, which may reflect an increase in the percent of curable patients. The generally aggressive natural history of these lymphomas also would lead to earlier conclusions, as compared with indolent lymphomas where differences in survival may not appear for many years. We were interested in assessing the efficacy and toxicity of dose-adjusted EPOCH (infusional etoposide/vincristine/doxorubicin/bolus cyclophosphamide/prednisone) and rituximab in large B-cell lymphomas.26 Previously, EPOCH was shown to be very active in both relapsed and previously untreated aggressive lymphomas.27,28 Herein, we present preliminary data of dose-adjusted EPOCHrituximab (EPOCH-R) in both relapsed and previously untreated aggressive B-cell lymphomas,

and show a high response rate with manageable toxicity.29 PATIENTS AND METHODS

Eligibility Between January 1999 and March 2001, 38 patients with previously untreated aggressive or relapsed/resistant CD20⫹ B-cell lymphomas received EPOCH-R at the National Cancer Institute (Bethesda, MD), Massachusetts General Hospital (Boston, MA), or the University of Maryland (Baltimore, MD). Eligibility requirements included measurable disease, a nonreactive test for human immunodeficiency virus, serum creatinine less than 1.5 mg/dL, serum bilirubin less than 2.5 mg/dL, absolute neutrophil count (ANC) ⱖ 1,000 cells/␮L, and platelet count ⱖ 100,000/␮L (unless caused by respective organ involvement with tumor). All patients gave written informed consent. Initial evaluation included a history and physical examination, standard blood tests, whole-body computed tomography, and bone marrow biopsies. Sites of disease were restaged every two cycles with computed tomography, gallium scan, and bone marrow aspirate and biopsy (if previously positive).

Chemotherapy A dose-adjusted EPOCH regimen was administered as outlined in Table 1. Based on in vitro studies showing that

Table 1. EPOCH Starting Dose Level Drug Rituximab Infused Agents* Etoposide Doxorubicin Vincristine† Bolus Agents Cyclophosphamide Prednisone G-CSF Next Cycle‡

Dose 375 mg/m2/d 50 mg/m2/d 10 mg/m2/d 0.4 mg/m2/d 750 mg/m2/d 60 mg/m2 twice a day 5 ␮g/kg/d

Route

Treatment Days

IV

1

CIV CIV CIV

1, 2, 3, 4 (96 hours) 1, 2, 3, 4 (96 hours) 1, 2, 3, 4 (96 hours)

IV PO SC

5 1, 2, 3, 4, 5 6 3 ANC ⬎ 5,000/␮L past nadir Day 21

Dose-adjustment paradigm Dose adjustments above starting dose level apply to etoposide, doxorubicin, and cyclophosphamide. Dose adjustments below starting dose level apply to cyclophosphamide only. Drug doses based on previous cycle ANC nadir§: If nadir ANC ⱖ 500/␮L on all measurements: increase 20% above last cycle If nadir ANC ⬍ 500/␮L on 1 or 2 measurements: same dose(s) as last cycle If nadir ANC ⬍ 500/␮L ⱖ 3 measurements: decrease 20% below last cycle Measurements of ANC nadir are based on twice-weekly CBC only. Abbreviations: G-CSF, granulocyte colony-stimulating factor; ANC, absolute neutrophil count; CBC, complete blood count; IV, intravenously; CIV, continuous intravenous (infusion); PO, orally; SC, subcutaneously. * Etoposide, doxorubicin, and vincristine can be admixed in the same solution. † Vincristine dose should never be routinely capped. ‡ Begin day 21 if ANC ⱖ 1,000/␮L and platelets ⱖ 100,000/␮L. § If nadir platelets ⬍ 25,000/␮L, decrease dose 20% below last cycle.

RITUXIMAB AND CHEMOTHERAPY IN LYMPHOMA

Table 2. Histology

Histology Large B-cell De novo Transformed HIV-associated lymphoma Mantle cell Follicular center cell Small lymphocytic LP-Hodgkin’s disease

Untreated N ⫽ 23

Relapse/Resistant N ⫽ 15

23

3 4 2 1 3 1 1

Abbreviations: HIV, human immunodeficiency virus; LP, lymphocyte predominant.

rituximab is most effective as a chemosensitizer when the lymphoma cells are primed before exposure to chemotherapy, rituximab is administered on the first day of treatment, immediately followed by EPOCH, to allow priming. All patients received granulocyte colony-stimulating factor beginning on day 6 and continued until an ANC greater than 5,000/␮L past the nadir; of note, granulocyte colony-stimulating factor was never stopped irrespective of ANC before recovery from the nadir. Cycles began every 21 days provided the ANC ⱖ 1,000/␮L and platelets ⱖ 100,000/␮L. Dose adjustments were a fundamental component of the EPOCH regimen. Adjustments above the starting dose level (termed level 1 or 100%) were always applied to etoposide, doxorubicin, and cyclophosphamide, and adjustments below the starting dose level were only applied to cyclophosphamide. The adjustment paradigm was based on the ANC nadir on the previous cycle as noted in Table 1. However, in the event of a platelet nadir of less than 25,000/␮L, doses were only reduced by 20%, irrespective of the ANC nadir. Of importance, the adjustment paradigm was based on twice-weekly complete blood count measurements at least 3 days apart and not during the total days of neutropenia. Deviations from the adjustment paradigm were made only in the event of a critical illness on the previous cycle, and not for uncomplicated infections. Vincristine was administered at a fixed dose of 1.6 mg/m2 (0.4 mg/m2/d) and was never capped. Vincristine was reduced 25% or 50% for grade 2 or 3 motor neuropathy, respectively, and reduced 50% for grade 3 sensory neuropathy. If neurologic toxicity improved to grade 1 or better, the dose was increased to previous levels. Patients received at least two cycles beyond best response with a minimum of six cycles. To prevent Pneumocystis carinii pneumonia, patients received trimethoprim-sulfamethasoxazole (double-strength) twice daily every Monday, Wednesday, and Friday during chemotherapy.

Definition of Response and Statistical Analysis Standard response definitions were used. (1) Complete response (CR): Disappearance of all detectable clinical and radiographic (⬍ 1.5 cm) evidence of disease. (2) CR/unconfirmed: Presence of lymph node/mass greater

43

than 1.5 cm that has regressed by more than 75% and is gallium negative. (3) Partial response: Fifty percent decrease in the sum of the products of the greatest bidimensional measurements. Survival time and time to any event (in months) were calculated from the date of study entry until death, relapse, and progression or last follow-up, as appropriate.

RESULTS

Patient Characteristics Of the 38 patients treated, 34 were evaluable for response and four patients are too early to evaluate. Of 23 previously untreated patients, all had aggressive histologies, median patient age was 52 years, 30% had an Eastern Cooperative Oncology Group performance status ⱖ 2, and 17% had involvement of the central nervous system (Tables 2 and 3). Other poor prognostic factors included advanced stage III or IV disease in 78%, elevated lactate dehydrogenase in 74%, and high-intermediate or high International Prognostic Index (IPI) scores in 61% of patients.30 Of 15 patients with relapsed or resistant lymphomas, 10 (67%) had aggressive histologies, which included four patients with transformed lymphomas (Table 2). High-risk IPI scores were present in 60% of these patients (Table 3), and all were extensively pretreated having received a median of two (range, one to four) regimens. Of the

Table 3. Patient Characteristics

Characteristics Median age (range) ECOG PS ⬎ 1 Extranodal site ⬎ 1 LDH ⬎ normal Stage III/IV International Prognostic Index Low/low-intermediate High-intermediate/high Chemotherapy Resistant* Sensitive†

Untreated N ⫽ 23 (%)

Relapsed/ Resistant N ⫽ 15 (%)

52 (21-81) 7 (30) 14 (61) 17 (74) 18 (78)

46 (14-72) 9 (60) 8 (53) 8 (53) 14 (93)

9 (39) 14 (61)

6 (40) 9 (60)

NA NA

7 (47) 7 (47)

Abbreviations: NA, not applicable; CR, complete response; PR, partial response; ECOG, Eastern Cooperative Oncology Group; PS, performance status; LDH, lactate dehydrogenase. *No response (CR/PR) to last chemotherapy. †At least PR to last chemotherapy.

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drugs present in the EPOCH regimen, 80% of previously treated patients had received at least four of the agents. Moreover, 47% of patients were resistant (refractory) to the last administered chemotherapy. Treatment Outcome Among 20 untreated patients evaluable for response, CR was achieved in 17 (85%) and three patients initially responded but subsequently progressed on treatment (Table 4). At a median follow-up of 12 months, progression-free and overall survival are 85% and 79%, respectively (Fig 1), and no patient who achieved a CR has relapsed (Fig 2). Three elderly patients died in remission; one from a fungal infection, one from central nervous system radiation-associated neurologic deterioration, and one from an unknown cause. Objective responses were achieved in 12 of 14 (85%) evaluable patients with previously treated lymphoma, including nine (64%) complete and three (21%) partial responses. To help provide information on the ability of EPOCH-R to overcome drug resistance, we assessed its activity under conditions where other regimens have failed. In this regard, we analyzed the response to EPOCH-R in patients who were resistant (ie, refractory disease) to their last combination regimen (Table 4), a group that generally has a low response to subsequent chemotherapy. Among seven such patients, five (71%) responded to EPOCH-R, including three (42%) complete responders. As expected, patients with chemotherapy-sensitive dis-

Fig 1. Analysis of progression-free and overall survival in untreated large B-cell lymphoma with a median 12-month follow-up. (A) Progression-free survival is 85% at more than 12 months. (B) Overall survival is 79% at more than 12 months.

ease had a higher overall response rate of 85%, with a 71% CR rate. While recognizing the premature nature of this data and the small sample of patients, the group has a progression-free survival of 60% at 5 months.

Table 4. Response Summary Response Patients

CR (%)

PR (%)

RR (%)

Untreated* (N ⫽ 20) Relapsed* (N ⫽ 14) Chemotherapy† Resistant‡ (N ⫽ 7) Sensitive§ (N ⫽ 7)

17 (85) 9 (64)

0 (0) 3 (21)

17 (85) 12 (85)

3 (42) 5 (71)

2 (29) 1 (14)

5 (71) 6 (85)

Abbreviations: CR, complete response; PR, partial response; RR, response rate. * Three patients too early to evaluate. † One patient received rituximab previously. ‡ No response (CR/PR) to last chemotherapy. § At least a PR to last chemotherapy.

Fig 2. Analysis of disease-free survival in 17 patients who achieved complete remissions, with a median 12-month followup. No patients have relapsed over a range of follow-up from 1 to 21 months.

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Table 5. Toxicity in Untreated Patients Variables

No.

No. of patients No. of cycles Hospitalization (% cycles) Fever and neutropenia Hematologic ANC ⬎ 500/mm3 Platelets ⬍ 50,000/mm3 Toxicity ⱖ grade 2 Gastrointestinal Neurologic (% patients) Deaths during remission (% patients)

23 93

% of Cycles

19

20

53 17

57 18

6 4 3

6 17 13

NOTE. National Cancer Institute common toxicity criteria used. Abbreviation: ANC, absolute neutrophil count.

Toxicity We report the toxicity of dose-adjusted EPOCH-R over 93 cycles administered to the 23 previously untreated patients (Table 5). The dose-adjusted paradigm targets a period of shallow neutropenia (ANC ⬍ 500/␮L for 1 to 4 days), and brief neutropenia (usually less than 4 days) was observed on 57% of cycles. Thrombocytopenia with platelets less than 50,000/␮L was observed in 18% of cycles, and admissions for fever with neutropenia occurred in 20% of cycles. There was one infectionrelated death from disseminated aspergillosis. Clinically significant gastrointestinal toxicity including mucositis and/or constipation (ⱖ grade 2) was uncommon, occurring in 6% of cycles, and significant sensory/motor neuropathy ⱖ grade 2 was only seen in three patients. There were no episodes of doxorubicin-related heart failure. DISCUSSION

This report reflects an interim summary of our results of dose-adjusted EPOCH-R in patients with aggressive CD20⫹ lymphomas.26,29 Although the results in untreated patients are early, the high CR rate of 85% (most CRs were achieved within two cycles of treatment) is encouraging. Furthermore, with a median follow-up of 12 months, no patient in remission has progressed, despite 60% of patients having high-intermediate or high-risk IPI. The disease-free survival of 100% observed in the present study is also markedly different from our results with dose-adjusted EPOCH in 50 patients

with large B-cell lymphomas, where we observed a 25% rate of relapse, of which two thirds occurred within the first year.28 Also suggestive of the benefit of rituximab with chemotherapy are the results of EPOCH-R in relapsed and resistant patients. Our experience with EPOCH alone as salvage treatment yielded a 74% response rate, including 24% CR, while the commonly used platinumbased regimen, ESHAP (etoposide/cisplatin/cytarabine/methylprednisolone), has an overall response rate of 64% with 28% CRs.27,31 Although the overall response rate of EPOCH-R, with 85% responses, is not dissimilar to that achieved with EPOCH, the CR rate of 42% in patients with resistant disease would not have been expected with EPOCH alone; indeed we only observed two CRs among 42 patients with resistant disease treated with EPOCH alone.27 In selected cases we have also observed the reversal of clinical resistance to EPOCH chemotherapy with the addition of rituximab.32 These preliminary results suggest that rituximab may help overcome clinical drug resistance, possibly by sensitizing tumor cells to the cytotoxic effects of chemotherapy. These results, albeit early, are consistent with results from two other studies that suggest a significant benefit of rituximab and chemotherapy.33,34 Coiffier et al33 recently reported preliminary results from a randomized study of CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) plus rituximab (CHOP-R) or without rituximab in elderly patients (ⱖ 60 years) with large B-cell lymphomas. In this study, rituximab was administered at 375 mg/m2 on day 1 of each cycle. An interim, intent-to-treat analysis of 328 patients showed a significant difference in CR and 12month event-free and overall survival, in favor of the rituximab-containing arm. Specifically, the outcome measure of event-free survival, which most accurately reflects the effect of a treatment regimen, was 69% and 49% for the CHOP-R and CHOP arms (P ⬍ .0005), respectively. Of note, there was no significant difference in toxicity between the two arms. Results from a phase II study of rituximab and CHOP in untreated aggressive B-cell lymphomas was also recently reported by Vose et al.34 In this study of 33 patients, 61% achieved CR and 90% of patients were progression-free with a median follow-up of 26 months. Although the progression-free survival rate in this study is similar to historical results for CHOP

46

alone, the 90% progression-free survival is unexpectedly high, even considering that 70% of patients in the series had low IPI-risk disease.25,30 Similar to the CHOP-R studies, the toxicity profile of dose-adjusted EPOCH-R is similar to that of dose-adjusted EPOCH, and is primarily hematologic, with infrequent significant gastrointestinal or neurologic toxicity.28 We believe these studies, in addition to our own, suggest that rituximab given in conjunction with chemotherapy can improve the outcome of aggressive B-cell lymphomas. It is worth noting, however, that the results from the CHOP-R studies may be confounded by the inclusion of patients with underlying indolent histologies. The randomized study of CHOP-R was restricted to elderly patients, where the incidence of indolent lymphomas is likely more prevalent than in younger patients, and in the phase II CHOP-R study, at least 39% of patients had translocation of the bcl-2 gene, which is more often associated with follicular center cell lymphomas. Because the natural history of transformed follicular lymphomas is different from de novo large B-cell lymphomas, stage for stage, such results cannot necessarily be extended to those obtained with de novo large cell lymphomas.35 This concern may be partially addressed by the present study, in which patients with evidence of indolent lymphoma, such as CD20-positive lymphoid aggregates in the marrow, were excluded. If the results of these trials maintain over time, the apparent magnitude of benefit suggests synergy between rituximab and chemotherapy, possibly through potentiation of cytotoxic effects. Indeed, as a single agent in recurrent aggressive lymphomas, rituximab produced a 33% overall response rate, of which only 10% were CRs.36 While recognizing these results are in relapsed patients, the low incidence of CR with rituximab alone indicates only modest activity as a single agent. The clinically relevant mechanisms of action for rituximab have theoretical if not practical implications for trial designs. When rituximab is used alone, both cellular-dependent and cellular-independent mechanisms of cell kill may be operable, whereas it is likely that cellular-dependent mechanisms would be impaired by the coincident use of chemotherapy. If rituximab sensitizes cells to chemotherapy, the resulting synergy would argue for combination

WILSON ET AL

treatments with rituximab and chemotherapy over sequential treatment approaches.37 In the absence of convincing scientific evidence for the important mechanisms of action, the clinical trial development plan for rituximab has taken an empirical approach with a broad array of combination and sequential trials designs. It is important to note, however, that the in vitro data and single-agent activity of rituximab argue against sequential trial designs leading to major breakthroughs in the cure of lymphomas. In contrast, in vitro evidence of potential synergy between chemotherapy and rituximab and the early results from combination trials suggest that this strategy may be optimal. In vitro, rituximab is most effective as a chemosensitizer when the lymphoma cells are primed before exposure to chemotherapy, suggesting that rituximab should be given before chemotherapy.37 This strategy was used in both studies of CHOP-R, as well as with dose-adjusted EPOCH-R, where rituximab was administered from 0 to 3 days before chemotherapy, thereby allowing time for priming. Further studies will be needed to assess the potential role of rituximab with chemotherapy, as well as to determine optimal rituximab and chemotherapy scheduling and the most effective chemotherapy platform. Although these results are encouraging, they must be interpreted with caution, not only because of the limited follow-up and patient numbers, but because of the potential eligibility bias for CD20-positive patients. Accrual continues to our trial of dose-adjusted EPOCH-R in previously untreated patients with aggressive CD20 lymphomas. REFERENCES 1. Wilson WH, Teruya-Feldstein J, Fest T, et al: Relationship of p53, bcl-2, and tumor proliferation to clinical drug resistance in non-Hodgkin’s lymphomas. Blood 89:601-609, 1997 2. Covelli A: Modulation of multidrug resistance (MDR) in hematological malignancies. Ann Oncol 10:53-59, 1999 (suppl 6) 3. Vossebeld PJ, Sonneveld P: Reversal of multidrug resistance in hematological malignancies. Blood Rev 13:67-78, 1999 4. Wilson WH, Bates SE, Fojo A, et al: Controlled trial of dexverapamil, a modulator of multidrug resistance, in lymphomas refractory to EPOCH chemotherapy. J Clin Oncol 13: 1995-2004, 1995 5. Bates SE, Wilson WH, Fojo AT, et al: Clinical reversal of multidrug resistance. Oncologist 1:269-275, 1996

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tyrosine and serine kinases with the B cell surface antigen CD20. Induction via CD20 of tyrosine phosphorylation and activation of phospholipase C-gamma 1 and PLC phospholipase C-gamma 2. J Immunol 151:4494-4504, 1993 25. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphomas. N Engl J Med 328:1002-1006, 1993 26. Gutierrez ME, Grossbard M, Jaffe E, et al: Dose-adjusted EPOCH-rituximab (EPOCH-R): An effective regimen in poor prognosis aggressive B-cell lymphoma. Biol Ther Lymphoma 4:10-13, 2001 27. Gutierrez M, Chabner BA, Pearson D, et al: The role of a doxorubicin-containing regimen in relapsed and resistant lymphomas: An 8 year follow-up study of EPOCH. J Clin Oncol 18:3633-3642, 2000 28. Wilson WH, Grossbard M, Pittaluga S, et al: Doseadjusted EPOCH chemotherapy in untreated large B-cell lymphomas: A novel pharmacodynamic-based regimen. Blood (submitted) 29. Wilson WH, Frankel SR, Drbohlav N, et al: Phase II study of dose-adjusted EPOCH-rituximab in untreated high risk large B-cell lymphomas. Proc Am Soc Clin Oncol 20:290a, 2001 (abstr 1158) 30. International Non-Hodgkin’s Lymphoma Prognostic Factors Project: A predictive model for aggressive nonHodgkin’s lymphoma. N Engl J Med 329:987-994, 1993 31. Valasquez WS, McLaughlin P, Tucker S, et al: ESHAPAn effective chemotherapy regimen in refractory and relapsing lymphoma: A 4-year follow-up study. J Clin Oncol 12:11691176, 1994 32. Little R, Gutierrez M, Wilson WH: Chemotherapy sensitization by rituximab: Presentation of two case studies. Case Stud Oncol 2:1-7, 2000 33. Coiffier B, Lepage E, Herbrecht R, et al: MabThera (rituximab) plus CHOP is superior to CHOP alone in elderly patients with diffuse large B-cell lymphomas (DLCL): Interim results of a randomized GELA trial. Blood 96:223a, 2000 (abstr 950) 34. Vose JM, Link BK, Grossbard ML, et al: Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated aggressive non-Hodgkin’s lymphoma. J Clin Oncol 19:389-397, 2001 35. Conlan MG, Bast M, Armitage JO, et al: Bone marrow involvement by non-Hodgkin’s lymphoma: The clinical significance of morphologic discordance between the lymph node and bone marrow. Nebraska Lymphoma Study Group. J Clin Oncol 8:1163-1172, 1990 36. Coiffier B, Haioun C, Ketterer N, et al: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 92:1927-1932, 1998 37. Demidem A, Lam T, Alas S, et al: Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother Radiopharm 12:177-186, 1997