Introduction

Recent studies that were reported at the 45th annual meeting of the American Society of Hematology (ASH) in December 2003 demonstrated that antibody therapy combined with chemotherapy can be more effective than treatment with chemotherapy alone for patients with non-Hodgkin’s lymphoma (NHL). Rituxan® was used in many of the trials presented at ASH and results with Bexxar® and Zevalin® were also presented.

For indolent NHL, results indicate that the addition of antibody therapy to chemotherapy does improve outcomes over chemotherapy alone. Three studies suggested that the addition of Rituxan® to chemotherapy improves outcomes in follicular lymphoma. These studies utilized CHOP, CVP, and a Fludara®-containing regimen. A fourth study that combined Bexxar® with CHOP also found the combination to be more effective.

Results from a large US study suggested that the addition of Rituxan® to induction CHOP (R-CHOP) may not influence overall response rate or early progression (6 months) in patients with diffuse large B-cell lymphoma (DLBCL). The results from this study are inconsistent with a retrospective analysis from British Columbia that reported dramatic improvement in outcomes for DLBCL in patients treated with R-CHOP and with 2 previous trials that have led to R-CHOP becoming the standard initial treatment for intermediate/aggressive NHL.

Background

Monoclonal antibodies are a promising therapeutic advance because they kill tumor cells by a different mechanism than radiation or chemotherapy. Currently, there are three antibodies approved by the U.S. Food and Drug Administration (FDA) for malignancies of B cell lymphocytes.

Rituxan®, an anti-CD20 antibody, has been approved for the treatment of patients with NHL who have failed initial therapy. Rituxan® attaches to normal and abnormal lymphocytes and kills directly through immune mechanisms and apoptosis. Rituxan® has been used therapeutically since 1998 and there are numerous publications documenting the effectiveness of this agent for the treatment of low-grade and aggressive NHL, CLL, mantle cell NHL, cutaneous B-cell lymphoma, EBV-associated lymphoma and autoimmune diseases of B cells.

Zevalin® is comprised of the murine monoclonal antibody ibritumomab covalently bound to the metal chelator tiuxetan, which stably binds the pure ß-emitting radionuclide 90Y for therapy. The antibody homes to malignant cells and the radioactive isotope kills the cell. Isotope-antibody combinations are more toxic than antibody therapy alone, but are still more specific than external beam radiation therapy or brachytherapy and probably more effective than antibody therapy alone.

Bexxar®, which is an anti-B-cell antibody linked to iodine 131, was recently approved for the treatment of patients with CD20-positive, follicular NHL, with and without transformation, whose disease is refractory to Rituxan® and who have relapsed following chemotherapy.

Indolent NHL

Studies presented at ASH demonstrated that the addition of Rituxan® to chemotherapy improves patient outcomes compared to chemotherapy alone in patients with follicular lymphoma. The German Low Grade Lymphoma Study Group (GLSG) reported positive results with R-CHOP for the first-line treatment of follicular lymphoma. Furthermore, an international, multicenter, phase III trial showed that CVP plus Rituxan® produced superior results compared to CVP alone in stage III/IV follicular lymphoma. A third study showed that the addition of Bexxar® to CHOP produced more complete responses compared to historical data with CHOP alone.

CHOP vs. R-CHOP: The GLSG phase II study demonstrated that the addition of Rituxan® to CHOP chemotherapy resulted in a significant increase of time to treatment failure (TTF). The researchers suggested that this may represent the new standard therapeutic approach in the first-line treatment of follicular lymphoma.

A total of 606 patients with follicular lymphoma were randomly assigned to receive either 6 courses of standard CHOP chemotherapy or combined immuno-chemotherapy (CHOP plus Rituxan® 375 mg/m2 d1-5). In 394 currently evaluable patients, the addition of Rituxan® led only to a moderate improvement of CR rate (21% vs. 18%) and overall response (97% vs. 93%) in comparison to chemotherapy alone. However, TTF was significantly increased after combined R-CHOP (p<0.0007). Estimated median TTF was 2.6 years in the CHOP arm, whereas after a maximum follow-up of nearly three years, the TTF has not been reached for R-CHOP. Side effects in both treatment arms were similar with only a slight increase of grade III/IV neutropenia (42% vs. 37%) and allergy-like symptoms (4% vs. 0%) reported in the R-CHOP arm.¹

CVP plus Rituxan®: The result of a phase III trial comparing the combination of CVP plus Rituxan® (R-CVP) versus CVP alone showed a significantly higher overall response rate, longer time to treatment failure, and longer time to treatment progression for the R-CVP treated patients (see table 1). This study involved 322 patients with follicular small cell or follicular mixed NHL (90%), or follicular large cell NHL (9%). According to the FLIP index, 49% of patients had poor and 41% had intermediate prognosis disease. The median follow up was 18 months.

Table 1 Results of R-CVP vs. CVP on major efficacy endpoints

Both regimens were well tolerated. The incidence of acute events was similar in both groups except for Rituxan® infusion related reactions in the R-CVP group. There were no differences in infection rates between the treatment arms and no treatment related deaths.²

CHOP plus Bexxar®: The Southwest Oncology Group presented results (SWOG 9911) that suggest the addition of Bexxar® to 6 cycles of CHOP chemotherapy produced more complete responses than historical data with CHOP alone in patients with newly diagnosed follicular lymphoma. Furthermore, the 2-year PFS for the combination exceeded expectations based on historical experience with CHOP alone (see table 2). Preliminary results of the first 71 evaluable patients were presented at ASH, 2001 (abstract # 3504). The presentation at ASH 2003 included all 90 eligible patients followed for a median of 2.7 years after registration.

Six cycles of CHOP chemotherapy were administered at 3-week intervals followed by Bexxar® RIT. Four weeks after the completion of the last cycle of CHOP, patients with a partial (PR) or complete remission (CR) to chemotherapy underwent dosimetry with 450 mg of unlabeled Bexxar® antibody followed by 35 mg of Bexxar® trace-labeled with 5 mCi of Iodine-131. Based on the rate of clearance of this dosimetric infusion from the body, as assessed by gamma counting, patients were treated 1-2 weeks later with unlabeled Bexxar® followed by Bexxar® labeled with 48-115 mCi of I-131 (median 84.5 mCi) to deliver 75 cGy to the whole body (or 65 cGy if the platelet count was 100,000-149,999).

Table 2 Estimates of response to CHOP plus Bexxar® vs. historical data of CHOP alone

The addition of Bexxar® improved overall response in 28 patients (60%) and estimates of 2-year PFS exceeded historical data for CHOP alone (see table). The improved response rate with the addition of Bexxar® can be explained by a tendency to convert partial responses to an unconfirmed complete response (uCR) or CR (n=24) or from an uCR to a CR (n=4).

The researchers reported that 52% of patients experienced hematological toxicities, but these were predominantly moderate in severity. Secondary malignancies included one MDS and one breast cancer at 32 months. The researchers suggested that longer follow-up is necessary to better understand the possible risk of secondary malignancies with this regimen.³

SWOG and CALGB are currently conducting a prospective randomized study (S0016) comparing CHOP + Bexxar® to CHOP + Rituxan®.

U.S. researchers also reported that the Bexxar® regimen can be safely administered to patients greater than 60 years and even patients greater than 70 years of age, with no increased risk of hematologic toxicity compared with younger patients. Because NHL commonly occurs in elderly patients, these researchers analyzed the safety of the Bexxar® therapeutic regimen in patients 61-70 years of age (n=250) and >70 years of age (n=159) compared with younger patients (d60 years of age; n=586) involved in 5 core clinical trials.

Hematologic toxicity associated with the Bexxar® therapeutic regimen was similar across all age groups, except for a trend toward a higher incidence of grade 3/4 thrombocytopenia in patients d60 years of age and a longer duration of grade 3/4 thrombocytopenia in patients >70 years of age. Supportive care was similar across all age groups. Serious hemorrhagic events were reported in 1.3% of all patients and serious infections in 3.8%, but serious infections such as sepsis or pneumonia were seen more often in older patients.⁴

Intermediate/Aggressive NHL

Two past trials have shown that the addition of Rituxan® to CHOP chemotherapy improves outcomes over treatment with CHOP alone. An initial study presented at the ASH meeting in 2000 showed that one-year overall survival rate for patients receiving R-CHOP was 83% versus 68% for CHOP. Seventy-six percent of patients receiving R-CHOP achieved a complete or partial disappearance of their cancer compared to 60% of patients receiving CHOP alone.⁵ In a study presented at ASH in 2001 and later published in the New England Journal of Medicine in 2002, researchers reported better outcomes with R-CHOP than CHOP in previously untreated patients with diffuse large-B-cell NHL, 60 to 80 years old. There were 202 elderly patients involved in this study. The rate of complete response was significantly higher in the group that received R-CHOP compared to the group that received CHOP alone (76% versus 63%, p=0.005). With a median follow-up of two years, event-free and overall survival times were significantly higher in the R-CHOP group (p<0.001 and p=0.007, respectively).⁶

Results presented at ASH 2003 generated some confusion about the role of R-CHOP in DLBCL. In a plenary session, researchers from the US announced that the addition of Rituxan® to induction CHOP did not influence overall response rate or early progression (6 months) in patients with DLBCL. Furthermore, no statistically significant difference in overall survival was observed at this time. However, a retrospective analysis of outcomes in British Columbia reported dramatic improvement in outcome for DLBCL in patients treated with R-CHOP.

CHOP plus Rituxan®: The US, phase III trial involved 632 patients age 60 or greater with DLBCL who were randomized to R-CHOP (318 patients) or CHOP (314 patients). This study was not designed to directly compare R-CHOP with CHOP alone. Complete response or partial response patients underwent a second randomization to maintenance Rituxan® (Rituxan® 375 mg/m2) weekly time four repeated every six months times four) or observation.

With a median follow-up of 2.7 years, there was no difference in overall survival (p=0.25), but the TTF favored R-CHOP for induction (p=0.025). There was also no significant difference between R-CHOP and CHOP treated patients in overall response rate, progressive disease during treatment, or time to treatment failure 6 months prior to second randomization (see table 3).

Table 3 Major efficacy endpoints: R-CHOP vs. CHOP

The interaction between induction and maintenance was analyzed. For R-CHOP patients, there was no significant difference between maintenance Rituxan® (MR) or observation for time to treatment failure (p=0.83) or overall survival (p=0.33). By contrast, CHOP patients had a significantly longer time to treatment failure with MR (p=0.0001) but no statistically significant prolongation in overall survival (p=0.13) to date. R-CHOP plus MR significantly prolonged TTF in responders, but this advantage appeared limited to patients induced with CHOP alone.⁷

This was a difficult study to interpret. There was a loss of almost 100 patients from the original randomization (632 to 540 analyzed) and only 348 were evaluable from the randomization to Rituxan® maintenance vs. no maintenance. It was not clear what happened to the patients who were not evaluable. The study was also confusing because the authors stated that “the current study was not designed to directly compare R-CHOP alone with CHOP”. However, there was a group of patients who had R-CHOP and R-maintenance and a group that received CHOP and no maintenance. However the latter group probably received Rituxan® when they progressed. A lot of attendees at this talk were confused by the results as presented and it will probably take a detailed published report to sort out the facts.

Retrospective analysis of CHOP plus Rituxan®: The Canadian analysis compared outcomes of patients who were treated before versus those treated after the BC Cancer Agency implemented a new provincial policy on March 1, 2001 recommending the combination of CHOP and Rituxan® for all newly diagnosed patients with advanced stage DLBCL. This population-based analysis was conducted over a 3-year interval (Sept 1/99-Aug 31/02), 18 months prior to (Pre-Rituxan®) and 18 months following (Post-Rituxan®) policy change. Cases were identified from three sources; the BC Provincial Cancer Registry, the BC Cancer pharmacy records and the Lymphoma Clinical Database. There were 294 patients identified, 142 pre-Rituxan® and 152 post-Rituxan®. Median age was 63 years (range 19-86); IPI low (24%), low-intermediate (24%), high-intermediate (25%), high (27%); elevated LDH (65%), bulky disease>10cm (42%). There was no significant difference in age, IPI distribution, serum LDH, or presence of bulky disease between the Pre-Rituxan® and Post-Rituxan® groups.

Post-Rituxan® patients had significantly longer 2-year progression-free survival and overall survival rates, p=0.0009 and p=0.0001, respectively. The addition of Rituxan® to CHOP resulted in a dramatic improvement in outcome for DLBCL in patients of all ages, but was greatest for the elderly population. In multivariate analysis controlling for age, IPI score, and B-symptoms, Pre-Rituxan® /Post-Rituxan® era of treatment remained a strong, independent predictor of outcome (p=0.002).⁸

Zevalin® plus high-dose BEAM: A small pilot study (12 pts) presented by researchers from the City of Hope Comprehensive Cancer Center in Los Angeles showed that Zevalin® plus high-dose BEAM (carmustine, etoposide, cytarabine and melphalan) followed by AHCT is well tolerated and allows for targeted intensification of the conditioning regimen without increased transplant-related toxicity. The regimen was safely administered without dosimetric guidance for older patients with aggressive CD 20 +ve lymphoma. However, the researchers pointed out that longer follow-up is necessary, particularly considering the age and the refractory status of the patients.⁹

Recurrent NHL

The addition of Rituxan® to chemotherapy has also been demonstrated to be effective in the treatment of patients with relapsed disease. Studies presented at ASH suggest that the addition of Rituxan® to Fludara®-containing chemotherapy appears to be more effective than chemotherapy alone for the treatment of recurrent follicular lymphoma. Also, the addition of Rituxan® to Taxol®/Hycamtin® salvage therapy appeared to improve the overall and complete response rates in patients with NHL.

Fludara®-containing chemotherapy plus Rituxan®: Reported at ASH was the first prospective, randomized trial to demonstrate the superiority of combined immuno-chemotherapy over chemotherapy alone in patients with relapsed follicular and mantle cell lymphoma. Both response rate and survival were significantly improved for immuno-chemotherapy treated patients. Since most patients had received CHOP for first-line treatment, a Fludara®-containing regimen (FCM) was chosen for salvage therapy. This study involved 147 patients who were prospectively randomized to FCM alone or FCM plus Rituxan®.

The overall response rate for patients treated with FCM was 61% (14% CR, 47% PR). In the combined R-FCM arm, an overall response rate of 82% was obtained (37% CR, 46% PR; p<0.007). Similar improvement of remission rates were detected in follicular (94% vs. 74%) and mantle cell lymphoma (62% vs. 43%). In the total group, the R-FCM arm was significantly superior concerning progression-free (p<0.028) and overall survival (p<0.002). In a subgroup analysis of the R-FCM arm, a significantly longer progression-free survival was observed in follicular lymphomas (p<0.014), and significantly longer overall survival was observed in mantle cell lymphomas (p<0.005).¹⁰

Taxol®/Hycamtin® plus Rituxan®: Researchers from MD Anderson Cancer Center reported that the addition of Rituxan® to Taxol®/Hycamtin® salvage therapy improved the overall and complete response rates in patients with NHL over previously reported results with Taxol®/Hycamtin®.

The 71 evaluable patients had relapsed or refractory DLBCL, follicular large cell or transformed B-cell NHL and had failed prior CHOP-like or platinum-containing regimens. The median age was 55 and median number of prior treatments was 1. Treatment consisted of Taxol® (200 mg/m2 IV day 1 over 3 hours) and Hycamtin® (1 mg/m2 IV QD day 1-5), plus Rituxan® (375 mg/m2) which was given one day prior to starting each course of Taxol® plus Hycamtin®. All patients received prophylactic G-CSF support and courses were repeated every 3 weeks. Responding patients received a maximum of 6 courses or were offered stem cell transplantation after a minimum of 2 courses.

The addition of Rituxan® to Taxol®/Hycamtin® improved the overall response rate and complete response rate (see table 4). The Taxol®/Hycamtin® plus Rituxan® regimen induced a 45% response rate in patients who failed prior platinum-containing regimens.

Table 4 Response rates improved with the addition of Rituxan®

Treatment was reasonably well tolerated and most non-hematologic toxicities were of grade I and II. Grade IV neutropenic infection was observed in 3 patients. Neutrophil count of less than 500/ ml was observed after 31% of the cycles, and platelet count of less than 10,000/ ml was observed after 5% of the cycles.¹¹

Conclusion

Within the broad topic of antibody therapies for B-cell malignancies, the focus of much of the research reported at ASH this year was on immuno-chemotherapy regimens. Results continue to indicate that the combination may be more effective than chemotherapy alone in both first-line treatment and recurrent disease.

References

[1] Hiddemann W, Dreyling MH, Forstpointner R, Kneba M. Combined Immuno-Chemotherapy (R-CHOP) Significantly Improves Time To Treatment Failure in First Line Therapy of Follicular Lymphoma Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG). Proc Am Soc Hem, Blood 2003; 102(11):104a, Abstract #352.

[2] Marcus R, Imrie K, Andrew Belch A, Cunningham D, et al. An International Multi-Centre, Randomized, Open-Label, Phase III Trial Comparing Rituximab Added to CVP Chemotherapy to CVP Chemotherapy Alone in Untreated Stage III/IV Follicular Non-Hodgkins Lymphoma. Proc Am Soc Hem, Blood 2003; 102(11):28a, Abstract #87

[3] Press OW, Unger JM, Braziel RM, Maloney DM, et al. CHOP Followed by Tositumomab/Iodine I 131 Tositumomab (BEXXAR®.) for Treatment of Newly Diagnosed Follicular Non-Hodgkin s Lymphomas: A Phase II Trial of the Southwest Oncology Group (S9911). Proc Am Soc Hem, Blood 2003; 102(11):29a, Abstract #90

[4] Gregory SA, Zelenetz AD, Knox SJ, Vose JM, et al. The BEXXAR® Therapeutic Regimen (Tositumomab and Iodine I 131 Tositumomab) Can be Safely Administered to Patients over the Age of 70. Session Type: Poster Session 597-I. Poc Am Soc Hem. Blood 2003; 102(11):409a, Abstract #1485.

[5] Proceedings from the 42nd annual meeting of the American Society of Hematology, Vol 96, No 11, Abstract #950, pp 223a, 2000.

[6] Coiffier B, Lepage E, Briere J, Herbrecht R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. New England Journal of Medicine 2002; 346:235-242.

[7] Haberman TM, Weller EA, Morrison VA, Cassileth PA, et al. Phase III Trial of Rituximab-CHOP (R-CHOP) vs. CHOP with a Second Randomization to Maintenance Rituximab (MR) or Observation in Patients 60 Years of Age and Older with Diffuse Large B-Cell Lymphoma (DLBCL). Proc Am Soc Hem, Blood 2003; 102(11):6a, Abstract #8.

[8] Sehn LH, Donaldson J, Chhanabhai M, Fitzgerald C, et al. Introduction of Combined CHOP-Rituximab Therapy Dramatically Improved Outcome of Diffuse Large B-Cell Lymphoma (DLBC) in British Columbia (BC). Proc Am Soc Hem, Blood 2003; 102(11):29a, Abstract #88.

[9] Fung HC, Forman SJ, Nademanee A, Molina A, et al. A New Preparative Regimen for Older Patients with Aggressive CD 20-Positive B-Cell Lymphoma Utilizing Standard-Dose Yttrium-90 Ibritumomab Tiuxetan (Zevalin ) Radioimmunotherapy (RIT) Combined with High-Dose BEAM Followed by Autologous Hematopoietic Cell Transplantation (AHCT): Targeted Intensification without Increased Transplant-Related Toxicity. Proc Am Soc Hem, Blood 2003; 102(11):248a Abstract #870.

[10] Dreyling MH, Forstpointner R, Repp R, Hermann S, et al. Combined Immuno-Chemotherapy (R-FCM) Results in Superior Remission and Survival Rates in Recurrent Follicular and Mantle Cell Lymphoma Final Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG). Proc Am Soc Hem, Blood 2003; 102(11):103a, Abstract #351.

[11] Younes A, McLaughlin P, Romaguera J, Hagemeister F, et al. Taxol Plus Topotecan Plus Rituximab (TTR) with G-CSF Support: An Effective Salvage Program for the Treatment of Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma (NHL) Who Failed CHOP-Like and Platinum-Based Therapy. Proc Am Soc Hem, Blood 2003; 102(11):142a, Abstract #489.