Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

49th Annual Meeting and Exposition of the American Society of Hematology

Atlanta, Georgia / December 8-11, 2007

Editorial Panel:

Wendy Lam, MD, FRCPC Burnaby Hospital Regional Cancer Centre University of British Columbia Vancouver, British Columbia

Matthew C. Cheung, MD, FRCPC Sunnybrook Health Sciences Centre University of Toronto Toronto, Ontario

Pierre Laneuville, MD, FRCPC Division of Hematology MUHC-Royal Victoria Hospital Montreal, Quebec

Of the more than 10,000 patients diagnosed with a hematologic malignancy in Canada each year, about 60% are lymphomas. The incidence of non-Hodgkin’s lymphoma (NHL), which represents more than 85% of all lymphomas in Canada, has been increasing steadily. The reasons are unclear, but the incidence, paralleling reports from other countries, approximately doubled between the years 1970 and 1996 (Liu et al. Hematol Oncol 2003;21:57-66). Fortunately, the growth in the incidence of NHL is now being met with advances in treatment. This progress includes expanding indications for monoclonal antibodies (MABs) targeted at the CD20 protein which is expressed on the cells of a broad array of disorders arising from B-lymphocytes, particularly those associated with B-cell lymphomas.

The Role of MABs

MABs have extended patient survival when added to conventional cytotoxic chemotherapies for indications that include both indolent and aggressive NHL.

MABs targeted to the CD20 surface protein induce cancer cell death by multiple mechanisms, including complement-mediated and antibody-dependent cell-mediated cytotoxicity. There are also indirect effects that can contribute to cytotoxicity, including induction of structural changes, triggering of apoptosis, and sensitization of cancer cells to chemotherapy (Cerny et al. Anticancer Drugs 2002;13(suppl 2):S3-S10). The preponderance of clinical evidence with biologics targeting CD20 has been generated by studies with rituximab, although there is rapidly expanding evidence with other agents, such as alemtuzumab, epratuzumab, ibritumomab and tositumomab.

In this report, several important studies that explore the utility of biologics in the treatment of hematologic malignancies are critically evaluated to place their conclusions in the context of patient care. Some of these studies provide reassurance for practices that are already widespread, while others provide the basis for expanded indications. Although much of the data, particularly those documenting long-term safety and efficacy, continue to be generated by rituximab, the success with this agent has fuelled development of a growing number of MABs, including second generation humanized anti-CD20 MABs, and those that target other cell surface proteins such as CD52, CD40, HLA-DR, CD33 and CD19.

MABs in Indolent Lymphomas: Extending Benefit

The registration trial that provided rituximab with an indication for the first-line treatment of follicular CD20-positive, B-cell NHL was published more than two years ago (Marcus et al. Blood 2005;105:1417-23). In that study, the addition of rituximab to a combination of cyclophosphamide, vincristine and prednisone (R-CVP) more than doubled the median time to progression (TTP) vs. CVP (32 vs. 15 months; P<0.001). Although the majority of patients in both arms had progressed by three years, subsequent studies have indicated that maintenance rituximab may sustain remission. In a meta-analysis collating data from numerous studies of rituximab maintenance, new support has been provided for an approach already employed at many centres (Vidal et al. ASH 2007 Abs 3408).

The meta-analysis included five randomized, controlled trials with 1053 patients with follicular lymphoma evaluated on maintenance rituximab or in a comparator group. For effect on overall survival (OS), one study was omitted due to design issues. The hazard ratio (HR) for OS at last follow-up was 0.53 (95% CI, 0.39–0.73), signifying a 47% relative advantage (Figure 1). The advantage was achieved at an acceptable rate of adverse events. Although the relative risk for infectious complications was significantly increased (1.99; 95% CI, 1.21–3.27), these were considered manageable.

Figure 1. Rituximab as Maintenance Therapy for Patients with Follicular Lymphoma: Overall Survival

The results of this meta-analysis, which employed rigorous selection criteria to identify five studies from 266 trials evaluated, build on the evidence of the individual trials, most of which associated rituximab maintenance with an improvement in progression-free survival (PFS). Although PFS has been regarded at many centres as an acceptable surrogate for meaningful clinical benefit, the demonstration of an increase in OS in this meta-analysis, which was a collaboration among institutions in Germany, Switzerland and Israel, provides validation of an important outcome advantage achieved with an acceptable increased risk of adverse events.

In long-term follow-up of biologics as front-line therapy of indolent lymphomas, benefits continue to accrue. In new data, median follow-up of five years, from the FL2000 multicentre randomized study of rituximab in combination with cyclophosphamide, doxorubicin, etoposide and prednisone plus interferon alpha (R-CHVP+I) vs. CHVP+I, event-free survival (EFS) was 53% in the R-CHVP+I arm vs. 37% in the arm without rituximab (P=0.0004) (Salles et al. ASH 2007 Abs 792). Although the 84% rate of OS at five years in the R-CHVP+I arm was not statistically superior to the 79% OS in the CHVP+I arm, a multivariate regression analysis demonstrated differences in outcome when patients were stratified with the Follicular Lymphoma International Prognostic Index (FLIPI). In patients with a FLIPI score ³3, the addition of rituximab was associated with a significant improvement in both EFS (P=0.0002) and OS (P=0.025).

The authors concluded that results confirm that rituximab is particularly effective for the treatment of high-risk patients with follicular lymphoma. Although the relative tolerability of the two regimens was not discussed in the five-year outcome analysis, earlier reports indicated acceptable tolerability for the MAB regimen over the much abbreviated exposure period.

MABs in Aggressive NHL: Dose Intensification

In diffuse large B-cell lymphomas (DLBCL), there continues to be incremental progress in refining treatment to improve outcome even though the index study for the DLBCL indication for rituximab was published more than five years ago (Coiffier et al. N Engl J Med 2002;346:235-42). In that study, cyclophosphamide, doxorubicin, vincristine and prednisone plus rituximab (R-CHOP) was compared to CHOP alone. At the five-year follow-up (Feugier et al. J Clin Oncol 2005;23:4117-26), R-CHOP provided greater EFS (47% vs. 29%; P=0.00002) and OS (58% vs. 45%; P=0.0073). Subgroup analyses showed an advantage for R-CHOP in those with high or low age-adjusted International Prognostic Index (aaIPI) score.

In new data, a dose-dense R-CHOP-14 was found to produce a higher complete response (CR) rate (81% vs. 68%) and a greater EFS at one year (74% vs. 65%) than a conventional R-CHOP-14 regimen when administered to elderly patients (age >60) with a high aaIPI score at baseline (³3) (Pfreundschuh et al. ASH 2007 Abs 789) (Figure 2). The more intensive regimen was associated with greater toxicity in this phase II non-randomized study, but the potential for improvements in survival led the authors to recommend a multicentre study to test feasibility on a larger scale.

Figure
ial Survival Results

<img1307|center>

In this study, 100 elderly patients with aggressive CD20+ B-cell lymphoma received six cycles of CHOP every 14 days plus 12 doses of rituximab 375 mg/m2, administered on days 0, 1, 4, 8, 15, 22, 29, 45, 57, 71, 85 and 99. Radiotherapy was permitted for de-bulking and for extra-nodal involvement. Outcomes in this patient population were compared to 306 patients from the RICOVER-60 trial who received 6 x CHOP-14 combined with 8 x rituximab (results presented by Pfreundschuh et al. at ASH 2006).

The regimen proved to be challenging, producing three treatment-related deaths in the first 20 patients, but a change in the protocol to require levofloxacin, acyclovir and cotrimoxazole provided protection against further deaths due to infection. Complete remission rates were higher (83% vs. 78%) and progression rates on therapy were lower (5% vs. 7%), but an initial analysis of outcome did not suggest either an EFS or OS advantage for the 12-dose rituximab over the historical eight-dose rituximab R-CHOP-14. However, when patients were stratified by aaIPI, there was a more substantial difference for CR and EFS among patients receiving the more aggressive regimen.

A randomized study is needed to determine whether further dose intensification with a biologic is viable in high-risk patients, but the findings do suggest that increasing the exposure to MABs targeted at CD20 can independently influence response even in patients on maximally intensified chemotherapy. This provides a direction for clinical study, particularly when attempting to extend survival in individuals with poor prognostic predictors.

Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a far less common aggressive lymphoma that may also benefit from rituximab-containing regimens, according to two trials by the European MCL Network (Dreyling et al. ASH 2007 Abs 388). In one of the first-line trials, an elderly population was randomized to receive what was considered to be a standard of eight cycles of R-CHOP or an experimental regimen of six cycles of rituximab plus fludarabine and cyclophosphamide (R-FC). In those who achieved either a CR or partial response (PR), maintenance interferon was administered in the standard R-CHOP arm while maintenance rituximab was administered in the experimental arm. The second of the first-line trials was conducted in younger MCL patients. They were randomized to receive the standard induction of R-CHOP followed by a myeloablative consolidation therapy at 12 gray (Gy) total-body irradiation (TBI) and cyclophosphamide in two doses of 60 mg/kg or an experimental arm of R-CHOP plus high-dose cytarabine (ara-C) and then 10 gy TBI, ara-C in four doses of 1.5 mg/m2 and melphalan 140 mg/m2. Stem cell transplantation was not part of the study protocol.

Despite the fact that 66% of the elderly population had a high-risk IPI, the mainly hematological adverse events were considered manageable. The rate of grade 3 and 4 cytopenias was greater in the R-FC arm relative to the R-CHOP arm. However, infections were only observed in 19% of those taking R-CHOP and 23% of those taking R-FC, and febrile neutropenias were described as uncommon. The objective response (OR) rate reached 84% for both groups. The CR rate was 51%. The rate of PFS was 77% at 12 months. This rate of response compares favourably with previous PFS rates in MCL among elderly patients. Additional follow-up is needed to evaluate long-term response, including the role of rituximab maintenance.

In the study of younger patients comparing more aggressive regimens, the rates of grade 3 and 4 cytopenias were higher, exceeding 70% for thrombocytopenia and leukocytopenia in the arm treated with high-dose ara-C, but the rates of infection and febrile neutropenia were lower. Before consolidation, the overall OR in the two arms combined was 93% with a 60% CR rate. PFS at 12 months in the younger group was 90%, which exceeds that of most previously reported regimens. Due to the manageable toxicity in the study, the results support an approach in which a biologic is combined with aggressive chemotherapy.

Chronic Lymphocytic Leukemia

Biologics are being pursued in chronic lymphocytic leukemia (CLL) because of the presence of surface proteins which can be targeted, including CD20 and CD52. Promising results in initial single-centre clinical studies with rituximab, such as one carried out by the German CLL Study group (Huhn et al. Blood 2001; 98:1326-31), were the basis for several larger clinical trials with this and other biologics. The activity of biologics in CLL is now well established, but the relative benefit-to-risk ratio is an issue as clinical studies try to combine conventional chemotherapy with biologics to boost response with acceptable toxicity.

One of the issues is the risk of infection with the addition of biologics. In a review of a series of three sequential studies by the Cancer and Leukemia Group B (CALGB) study consortium, the risk of infection was found to increase significantly when fludarabine with a biologic was compared to fludarabine alone (Morrison et al. ASH 2007 Abs 756). The three studies evaluated were CALGB 9011, in which 188 previously untreated CLL patients received fludarabine alone; CALGB 9712, in which fludarabine was administered prior to or concurrently with rituximab in 104 patients; and CALGB 19901, in which 59 patients received fludarabine followed by alemtuzumab consolidation. When the rates of serious infection were compared, significant and potentially meaningful differences were observed. On protocol, 38% of patients receiving alemtuzumab plus fludarabine developed a serious infection, defined as an episode leading to hospitalization and/or parenteral antibiotics. Conversely, the rates were 23% in those receiving fludarabine alone and 20% in those receiving rituximab plus fludarabine (P=0.01 for alemtuzumab vs. fludarabine and P=0.0007 for alemtuzumab vs. rituximab).

When specific pathogens were analyzed, alemtuzumab was most closely associated with an increased risk of cytomegalovirus (CMV) infection. While the authors concluded that biologics do not appear to be interchangeable for relative risk of serious infection, they emphasized that these results may be useful for planning antimicrobial prophylaxis and monitoring.

In previously untreated CLL, preliminary results from a multicentre study evaluating a combination of rituximab, fludarabine, cyclophosphamide and mitoxantrone (R-FCM) followed by rituximab were characterized as promising (Bosch et al. ASH 2007 Abs 626). In this uncontrolled study, 69 patients younger than 70 years were treated with a regimen of rituximab 500 mg/m2 on day 1, fludarabine 25 mg/m2 on days 1 to 3, cyclophosphamide 200 mg/m2 on day 1 to 3, and mitoxantrone 6 mg/m2 on day 1. The regimen was repeated at four-week intervals for six cycles. All patients also received granulocyte colony-stimulating factor (G-CSF) and cotrimoxazole. If an OR was achieved, rituximab 375 mg/m2 was administered every three months for two years. At entry, 83% of patients were in an advanced clinical stage as defined by the Binet index.

Among evaluable patients, the overall OR rate has been 92% with 36% achieving a CR and 41% achieving minimal residual disease (MRD). Toxicity was characterized as manageable with grade 3/4 neutropenia observed in only 8% of patients (Figure 3). The most common serious adverse events have been infections, observed in 13% including one CMV reactivation. The OR rates, particularly the CR rates, are robust relative to previously studied regimens and have permitted almost all patients treated so far to proceed to rituximab maintenance. This OR rate predicts favourable long-term outcome, although prospective fol
nfirm sustained benefit.

Figure 3. R-FCM in CLL: Response Rates

<img1308|center>

In another phase II CLL study with a biologic, 42 evaluable patients with previously untreated disease were placed on a regimen called FCR-Lite (fludarabine 20 mg/m2 on days 1 to 3, cyclophosphamide 150 mg/m2 on days 1 to 3 and rituximab 500 mg/m2 on days 1 and 14 of a four-week cycle) administered for six cycles (Ahmad et al. ASH 2007 Abs 2037). Maintenance rituximab at a dose of 500 mg/m2 was administered every three months until progression. The OR rate, which was the primary end point, was 100% with 85% CRs and 15% PRs. MRD was tested by four-colour flow cytometry in eight patients at various points after achieving a CR. Seven had no MRD at follow-up ranging from seven to 30 months. MRD was detected in one patient at 12 months’ post-CR. Additional testing of MRD is underway.

In addition to an impressive OR rate, FCR-Lite was associated with a remarkably low rate of adverse events. Grade 3/4 neutropenia was only observed in 12% of patients, while grade 3/4 thrombocytopenia or anemia was documented in only 3% and 2.5%, respectively. The authors concluded that this regimen is at least as active as those tested previously but potentially better tolerated.

Expanded Uses for MABs

Two studies provide evidence that the roles of therapies that target CD20 remain incompletely defined. In one study, the efficacy of rituximab was evaluated in post-transplant lymphoproliferative disorders (PTLD) (Krishman et al. ASH 2007 Abs 1084). In the other, the same drug was tested in combination with dexamethasone for the treatment of idiopathic thrombocytopenic purpura (ITP) (Zaja et al. ASH 2007 Abs 567). Although both studies were modest in size, each suggested a degree of activity that would support larger and more definitive clinical trials.

In PTLD, the data were based on a pooled analysis of 17 reports with 308 patients. In all patients, rituximab was employed as a first-line therapy after immunosuppression withdrawal. Typically, patients were treated with weekly doses of rituximab 375 mg/m2 for four weeks with rituximab maintenance sometimes but not uniformly offered. The CR rate overall was 58%. In a minority of patients who received a hematopoietic cell transplant, the CR rate was 70%. The authors described side effects as minimal. Although long-term follow-up data were limited, a durable remission was reported in about one-third of the small group of patients followed for five years. The authors suggested that rituximab is a potential option in PTLD and is worthy of further analysis, although they cautioned that randomized prospective studies would be difficult to conduct in a relatively uncommon and heterogeneous disorder.

In the ITP trial, the study of rituximab in combination with dexamethasone was both prospective and randomized. The major inclusion criteria were age of 18 or older, no previous ITP treatment, and a platelet count £20 x 109/L. The participants were randomized to receive a single course of 40 mg dexamethasone on days 1, 2, 3 and 4 or the same regimen of dexamethasone with rituximab 375 mg/m2 on days 7, 14, 21 and 28. Patients in the dexamethasone-alone arm were permitted rescue with the combination therapy if they did not achieve a sustained response defined as a CR (platelet count >100 x 109/L) at six months, which was the primary end point. Although the study sample was a planned 198 patients, randomization was halted after 103 patients because of a pre-specified plan to close the trial if there was a 50% or greater difference in sustained response at any of the planned interim analyses. At the time that the study was closed, the sustained response rate was 81% in the arm that received rituximab vs. 29% in those receiving dexamethasone alone (P=0.0001). The rate of grade 3 or greater side effects did not differ substantially (8% for rituximab/dexamethasone vs. 12.5% for dexamethasone alone).

Summary

Biologics that target the CD20 protein are already well integrated into the management of hematologic malignancies for which they are indicated, but it is clear that their application remains a dynamic area of study. New data support a role for rituximab maintenance in at least some diseases where this agent is already employed for induction. Other data encourage definitive trials in malignancies where phase II and other exploratory studies have associated it with activity. Optimal dosing strategies of rituximab or the agents with which it is combined also remain incompletely defined, suggesting an opportunity to further optimize regimens. In Canada, where it has been available since 2001, rituximab has played an essential role in demonstrating the attributes of MABs. New data continue to refine their applications.