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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.

ABSTRACTS in PERSPECTIVE based on presentations from the 10th International Conference on Malignant Lymphoma

Lugano, Switzerland / June 4-7, 2008

EDITORIAL OVERVIEW:

Joseph Connors, MD, ABIM, FRCPC

Chair, Lymphoma Tumour Group, BC Cancer Agency, Clinical Professor of Medicine, University of British Columbia, Vancouver, British Columbia

Follicular lymphoma (FL) represents the most common subtype of low-grade lymphoma in North America. Certain characteristics of the disease make it rather challenging to treat. For instance, the median age of presentation is 65 years, so most patients are elderly and therefore aggressive treatment may be unacceptably dangerous. In the early stages of the disease, patients are almost always asymptomatic and so—unless detected by chance—diagnosis is usually made when the disease is in advanced stages (stage III or IV). Currently, median survival in FL patients is more than seven to eight years, although individual disease courses may vary greatly, with some patients surviving for decades without symptoms or need for treatment, while others progress quickly and die within a couple of years of diagnosis despite treatment. Prognosis is particularly poor when the lymphoma undergoes transformation to an aggressive histological subtype resembling diffuse, large B-cell lymphoma (DLBCL). Conversion to aggressive disease occurs in approximately 3% of patients with indolent lymphoma each year. It should also be noted that most patients diagnosed with FL will eventually die from lymphoma and not other conditions. Overall survival (OS) in FL patients is improving with time, and the introduction of rituximab has been a major innovation, but there is still room for improvement. Continued refinements to rituximab-containing chemotherapy induction regimens and maintenance should be able to prolong survival still further. In the longer term, other new biological agents under development should eventually allow for more targeted therapies with improved efficacy and decreased toxicity.

FLIPI to Determine Risk

The FL International Prognostic Index (FLIPI) uses five factors (age, Ann Arbor stage, number of nodal sites, serum lactate dehydrogenase level, and hemoglobin level) to classify patients as low-risk (five- and 10-year survivals of 91% and 71%, respectively), intermediate-risk (five- and 10-year survivals of 78% and 51%, respectively) and high-risk (five- and 10-year survivals of 53% and 36%, respectively) (Curr Treat Options Oncol 2006;7:270-5).

While it is established that rituximab-containing regimens offer improved response rates and prolonged survival, a study by Hoster et al. investigated whether outcome might be influenced by FLIPI risk group.

Using data from a German Low Grade Lymphoma Study Group (GLSG) randomized trial, investigators analyzed outcome according to the FLIPI risk groups. The original trial compared overall response rates (ORR), time to treatment failure (TTF) and response duration (RD) for cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) vs. rituximab-CHOP (R-CHOP) induction therapy in patients with advanced-stage FL. There were 566 evaluable patients, of whom 70 (12%) were low-risk, 241 (43%) were intermediate-risk and 255 (45%) were high-risk. ORRs were over 90% for both CHOP and R-CHOP arms in all groups. The five-year TTF was 83% vs. 43% in the low-risk group, 74% vs. 38% in the intermediate-risk group and 50% vs. 20% in the high-risk group, respectively (P<0.005 in all cases). The study provides clear evidence that rituximab is beneficial in all patients regardless of their FLIPI scores.

Maintenance Therapy After Induction

Maintenance with rituximab in patients with FL has been shown to improve event-free survival and response duration in a clinical trial after CHOP induction with or without rituximab (Blood 2006;108:3295-301). The maintenance regimen was generally well tolerated in that trial; neutropenia was the only significant adverse event (10.8% in the rituximab maintenance arm vs. 5.4% in the observation arm) and probably contributed to the increased grade 3-4 infection rate. Nevertheless, fewer than 5% of the patients withdrew from rituximab maintenance treatment due to toxicity (four of the six due to infections). The question remains whether rituximab maintenance is also well tolerated after other induction regimens. This appears to be the case, according to the phase IIIb MAXIMA (Maintenance Rituximab in Follicular Lymphoma) trial reported by Wenger et al. MAXIMA was specifically powered to be able to detect rare events in patients with complete response (CR) or partial response (PR) after rituximab-containing induction therapy. The study also collected data on rapid infusions, a potentially useful strategy for reducing infusion costs. Data were presented for 349 patients with a median age of 56 years (809 infusions). No serious adverse events were recorded within 24 hours of maintenance infusion (including those who received rapid infusion). One patient with a history of cardiac arrhythmias died of unknown causes 13 days after the fourth infusion. Nine patients were found to have hematological toxicities, three of which were grade 3-4 neutropenia (one of which resulted in febrile neutropenia). These findings further support the safety of rituximab maintenance therapy in patients with FL even when given by rapid infusion.

Clinical Practice Perspective

Clinical trials are important in setting trends in clinical practice and treatment decisions should be based on the best available evidence at the time. Nevertheless, from the clinical practice point of view, it is also important to evaluate how the findings from clinical research actually work in practice. After all, the patients who are seen in the clinic may differ from those selected for clinical trials according to restrictive inclusion criteria. Data on patients from the British Columbia Cancer Agency (BCCA) do indeed reflect improvements in OS of patients with DLBCL when analyzed by era. The introduction of rituximab has undoubtedly improved survival in FL patients but it also brings with it the challenge of how best to integrate this agent into current treatment algorithms, not only to do what is best for the patient but also to optimize finite resources. The BCCA approach is to treat limited-stage (IA or IIA with low bulk, localized) FL with involved field radiation. Advanced-stage asymptomatic patients are observed and advanced-stage symptomatic patients receive eight cycles of R-cyclophosphamide/vincristine/prednisolone (CVP) and maintenance therapy with one dose of rituximab every three months for eight doses. After the first maintenance dose, all rituximab doses are given by rapid infusion lasting 90 minutes (20% of the dose in the first 30 minutes and then the remaining 80% in the next hour). Patients who convert to aggressive DLBCL receive R-CHOP and so doxorubicin is reserved until it is most needed. With this approach, resources are maximized while maintaining the positive impact of immunotherapy and ensuring as good a quality of life for the patient as possible.

Promising Treatment Strategy for Chronic Lymphocytic Leukemia

Like FL, chronic lymphocytic leukemia (CLL) is a low-grade malignancy that affects B lymphocytes. Although treatment algorithms have evolved substantially over recent decades, and high response rates have been obtained with fludarabine/cyclophosphamide/mitoxantrone (FCM), it has proved difficult to demonstrate changes in patient survival.

At the ICML meeting, Bosch et al. reported on a trial in which rituximab was added to FCM (six courses) for patients with CLL and responders then received rituximab maintenance. Of the 85 patients included in the study, CR was found in 94% (37% had CR with no minimal residual disease). Toxicity was manageable (12% of the patients had grade 3-4 neutropenia). Follow-up is still short and as yet, it remains to be seen whether these very promising results in the induction phase will be reflected in longer survival with maintenance treatment.

On the Horizon

While we still have much to learn in terms of the best induction and maintenance therapies with existing drugs, we must also be looking to develop new agents to further improve survival in patients with B-cell malignancies. Fortunately, a number of new agents are under development. GA101 is a fully humanized monoclonal antibody (MAb) that, like rituximab, targets CD20. Unlike rituximab, which binds to the type I epitope of this receptor, GA101 binds to the type II epitope. The implication is that such antibodies may have a greater cytotoxic potential. In a number of ex vivoand animal xenograft models, GA101 showed greater efficacy than rituximab and is currently entering clinical development. Another promising agent is SGN-40, an antibody that targets CD40, a member of the tumour necrosis factor receptor family that is expressed in malignant B cells.

Advani et al. reported a phase I trial of SGN-40 in 50 patients with relapsed/refractory B-cell NHL. The therapy was well tolerated and response was observed in six patients. CR was reported in 18% of the patients with large B-cell lymphoma. These patients had been heavily pretreated, so the response rates can be considered encouraging, particularly as the maximum tolerated dose was not reached. Further studies are ongoing or planned in which SGN-40 is used either as a single agent or in combination with other therapeutic agents.

Summary

Survival of patients with low-grade B-cell malignancies has been improving over the decades. The promising results with rituximab in clinical trials, both in induction therapy and maintenance, have been reflected in improved outcomes in clinical practice. In addition, innovations such as rapid infusions for maintenance therapy are reducing the burden on health services and improving patients’ quality of life. In the long term, new agents entering clinical development should help further improve survival.

330 The Addition of Rituximab to Frontline CHOP Significantly Improves Time to Treatment Failure and Response Duration in All FLIPI Risk Groups of Patients with Advanced-stage Follicular Lymphoma: Results of a Randomized Trial of the German Low-grade Lymphoma Study Group E. Hoster, M. Unterhalt, C. Buske, M. Dreyling, W. Hiddemann

Background: The addition of rituximab to frontline chemotherapy has been shown to improve response rates, response duration and time to treatment failure in advanced stage follicular lymphoma patients. We asked whether this benefit is seen in patient subgroups of different prognoses, as defined by the recently developed follicular lymphoma international prognostic index (FLIPI).

Methods: The data of a randomized GLSG trial recruiting advanced stage follicular lymphoma patients, who were in need of therapy, from May 2000 to August 2003 were used to compare overall response rates (ORR), time to treatment failure (TTF), and response duration (RD) after CHOP versus R-CHOP induction therapy according to FLIPI risk groups.

Results: Of 566 evaluable patients, 70 (12%) patients were classified as low risk (LR), 241 (43%) as intermediate risk (IR), and 255 (45%) as high risk (HR) according to FLIPI. Overall response rates for R-CHOP vs. CHOP were 97% vs. 87% (p=0.16) in the LR group, 97% vs. 92% (p=0.08) in the IR group and 96% vs. 91% (p=0.13) in the HR group. With a median follow-up of 4.3 years, the 5-years TTF was 83% vs. 43% (median not reached vs. 3.9 years, p=0.0019) in the LR group, 74% vs. 38% (median not reached vs. 3.4 years, p<0.0001) in the IR group, and 50% vs. 20% (median 5.0 vs. 2.3 years, p<0.0001) in the HR group. The 5-years RD was 86% vs. 50% (median not reached vs. 3.8 years, p=0.0093) in the LR group, 76% vs. 39% (median not reached vs. 3.4 years, p<0.0001) in the IR group, and 52% vs. 22% (median 5.0 vs. 2.3 years, p<0.0001) in the HR group.

Conclusions: The benefit of rituximab was clearly observed in all FLIPI risk groups justifying the use of combined immuno-chemotherapy in all patients with advanced stage follicular lymphoma in need of therapy.

Commentary on abstract 330

Although rituximab has been shown to improve response rates when added to front-line chemotherapy in the treatment of patients with advanced-stage FL, it is not clear whether the benefit is uniform across patients with different prognoses and tumour burdens. In this study, data from the randomized GLSG trial were retrospectively analyzed according to FLIPI score. Of the 566 patients included in the analysis, 12% were low risk, 43% were intermediate risk and 45% were high risk. Significant improvements were observed in five-year TTF in all risk groups, comparing R-CHOP to CHOP (83% vs. 43% in the low-risk group, 74% vs. 38% in the intermediate-risk group and 50% vs. 20% in the high-risk group). Differences in ORR, although favourable for the rituximab arm, were not statistically significant. This study provides support for the use of this agent in immunochemotherapy in all patients with advanced-stage FL, regardless of initial FLIPI risk.

Questions and answers with Eva Hoster, MSc, Institute of Medical Informatics, Biometry and Epidemiology, University of Munich, Germany

Q: The results of this study suggest that rituximab can be used in patients regardless of their FLIPI scores.

A: That is right. In terms of TTF, rituximab shows benefit in low-, medium- and high-risk groups. Another question is whether the FLIPI score can be used to determine which patients would benefit most from rituximab treatment. This study was not designed to answer that question.

Q: Why do you think that differences were not significant in terms of ORR?

A: The problem is that response rates were very high in both arms. The difference between responses rates was small and the study did not have sufficient power to detect such differences. In the TTF events, however, there were marked differences which could be readily detected by the study.

Q: Are there any results available for OS?

A: We are continuing with follow-up, but at present, there have been too few events to allow meaningful conclusions to be drawn.

430 Safety in Patients Receiving Maintenance Rituximab (MABTHERA) in Follicular Lymphoma: Results from the Phase IIIb MAXIMA Trial D. Thurley, L. Arcaini, R. Foa, A. Vranovský, V. Ivanova, G. Van Hazel, S. Kurtovic, S. Durán, E. Gamba, M. Wenger

Background: The benefit of improved PFS for rituximab (R) maintenance in follicular lymphoma (FL) has been first reported by Hainsworth et al. and was later confirmed in randomized trials by Ghielmini, van Oers, and others. The primary objective of the current study is to extend the safety database for rituximab maintenance following a wide range of induction therapies.

Methods: The sample size of this trial was calculated to detect at least one rare event with an incidence of 0.32% with 80% power. Patients with FL having achieved a CR or PR after R-containing induction therapy were eligible to receive standarddose R every 8 weeks for up to 2 years. Primary endpoint is safety, with standard secondary efficacy endpoints.

Results: 349 patients with FL have been enrolled at clinical cut-off for whom demographic data is available: Median age of the patient population is 56 years. 76% had their first lymphoma treatment prior to enrollment, while the remaining 24% had up to 4 previous treatments; 74% entered the study in CR/CRu. Data on a total of 809 infusions was available. Except for one patient who received R at standard infusion speed and suffered from a TIA no SAEs were recorded within 24h of the maintenance infusion, including those patients who received R via rapid infusion. Nine SAEs were recorded, all but one were considered unrelated. One patient with previously known cardiac arrythmias died 13 days after the 4th infusion of unknown causes. After clinical cut-off, another patient died of progressive lymphoma. Hematologic toxicity occurred in 9 patients, with three grade 3/4 events (neutropenia), one resulting in febrile neutropenia. Data on efficacy will be presented.

Conclusions: R maintenance q 8 weeks in FL after rituximab containing induction therapy can be safely administered. Rapid-infusion appears to be safe in this setting.

Commentary on abstract 430

Randomized clinical trials have confirmed the prolonged PFS is associated with rituximab maintenance therapy in FL. A wide range of induction therapies are now available. This study aimed to collect data on the safety of rituximab maintenance (including rapid infusion) following different types of induction. In particular, the study was powered to detect rare events. The median age of the 349 patients included in this analysis was 56. Data on a total of 809 infusions were available. No serious adverse events were recorded within 24 hours of administration of rituximab maintenance with the exception of a transient ischemic attack. Nine serious adverse events were reported in total but none were considered related to rituximab. One patient with an underlying heart condition died of unknown causes after the fourth infusion. Three cases of grade 3-4 neutropenia were recorded. These results support the safety of rituximab maintenance, including administration by rapid infusion.

Questions and Answers with Dr. Michael K. Wenger, Clinical Science Leader, Hoffmann-La Roche Ltd., Basel, Switzerland

Q: What percentage of the study population received the rapid infusion? Was there any difference in response to treatment between patients who received the rapid infusion vs. those who received standard administration of rituximab?

A: About 30% received rapid infusions, and there were no responses with regards to safety. Efficacy analysis for all patients, and subgroups, is pending, but no signal has been detected.

Q: You indicate that data on efficacy were presented at the meeting. Could you briefly summarize your efficacy findings so that we may include them in the introductory commentary that accompanies each abstract?

A: The Lugano meeting accepted the poster as publication only, so there was no way to present anything additionally. Unfortunately, the ASCO poster only contained very limited efficacy data (on the conversion rate of PRs to CRs), which was in the order of 10%. This is a standard finding in maintenance trials. No time-dependent end points were shown; it was too early, with roughly six months of follow-up.

Q: Are any subanalyses planned to compare the safety of maintenance rituximab after different rituximab-containing induction therapies?

A: We will do these analyses.

Q: What do you think are the main clinical implications of your study?

A: Maintenance rituximab appears to be safe, also when administered in a rapid-infusion way. This confirms the findings of controlled trials in a more community-type setting.

Induction and Maintenance Therapy for Follicular Lymphoma: My Clinical Practice Joseph Connors MD, University of British Columbia and Chair of Lymphoma Tumour Group, British Columbia Cancer Agency, Vancouver, BC, Canada

Background: Follicular lymphoma, the most common single type of lymphoma seen in North America, presents unique challenges in its management: (1) with a median age of presentation of 65 years, most patients are elderly; (2) 90% of patients harbour advanced-stage disease, requiring systemic intervention; (3) although a minority of asymptomatic patients do not require initial intervention, more than 80% of patients require treatment within 4-5 years; (4) although the median survival now exceeds 7-8 years, 10-20% of patients die in the first 2 years and most patients eventually succumb to lymphoma, not other conditions; (5) transformation to more aggressive diffuse large B-cell lymphoma occurs in 39% of patients every year and often proves rapidly fatal. Thee is a clear need for effective interventions.

Recent advances: In the past decade, several seminal observations about FL have been made: (1) the addition of rituximab to primary chemotherapy improves both progression-free survival (PFS) and overall survival (OS); (2) the addition of rituximab to second-line chemotherapy improves PFS and OS; (3) rituximab maintenance therapy improves PFS and OS when added to second-line immunochemotherapy and probably when added to primary immunochemotherapy; (4) rituximab can be given safely by rapid infusion, sparing treatment resources; (5) the addition of rituximab substantially improves treatment outcomes for transformed lymphoma. At the British Columbia Cancer Agency, we have built our primary and secondary treatment regimens on these observations.

Current BCCA approach: Previously untreated patients with symptomatic FL are treated with cyclophosphamide, vincristine, prednisolone and rituximab (R-CVP). Those with responsive disease (>90%) also receive rituximab maintenance therapy (375 mg/m2 iv over 90 min every 3 months for 2 years). Transformed lymphoma is treated with R-CVP plus doxorubicin (R-CHOP) followed by rituximab maintenance therapy. This approach reserves doxorubicin until it is crucially necessary, for transformed lymphoma, and maximises the impact of immunotherapy with rituximab while minimising the overall impact on resources (maintenance therapy with a total of only eight cycles of rituximab; rapid infusion for convenient outpatient treatment).

Conclusion: Recent advances in the treatment FL enable clinicians to treat this disease effectively, conveniently and with a substantial positive effect on progression-free and overall survival while minimising inconvenience and resource impact.

Commentary on Dr. Connors' abstract

Clinical trials such as the EORTC 20981 Intergroup phase III trial have demonstrated that the addition of rituximab to induction chemotherapy and rituximab maintenance can prolong PFS as well as OS in patients with relapsed/resistant FL (van Oers et al. Blood 2006;108:3295-301). Population-based data were derived from the BCCA experience. This characterization of clinical practice takes into account the wide variation in patient characteristics and disease course. In British Columbia, for patients with advanced stage FL a watchful waiting approach is taken with asymptomatic patients, while untreated patients receive eight cycles of RCVP and responders are given rituximab maintenance therapy. To facilitate the logistics of rituximab maintenance therapy, after the first dose, patients receive rituximab by rapid infusion lasting 90 minutes. This appears to be well tolerated and allows outpatient administration. Every year, in about 3% of patients, FL gives rise by transformation to DLBCL. When this happens, doxorubicin is added (R-CHOP), thereby reserving this agent for when it is really necessary and helping to optimize resources.

Questions and Answers with Dr. Joseph Connors, University of British Columbia, Vancouver

Q: An important aspect of the BCCA approach seems to be the rapid infusion of rituximab to optimize resources. How long have you been using rapid infusions and do you have any data comparing the safety of rapid infusion and conventional infusions?

A: In British Columbia we have been administering rituximab by rapid infusion when it is given in combination with corticosteroid-containing chemotherapy regimens or as single agent maintenance treatment for over five years, with cumulative experience with several thousand infusions. We have not seen any greater frequency of adverse reactions than we encountered prior to that change in infusion policy.

Q: Patients with asymptomatic advanced-stage disease are put on observation. In view of the fact that 90% eventually progress, do you envisage that this may change now that we are in the rituximab era and the results of more studies with this agent become available?

A: We now know that the integration of rituximab into treatment of symptomatic patients with advanced stage FL improves their overall survival. However, it will remain inappropriate to extrapolate and change treatment approaches for asymptomatic patients until we have supporting clinical trial evidence for these patients. I suspect it will be some time until such evidence is available and convincing.

Commentary on abstract 377

High response rates have been obtained in previously untreated patients with CLL who receive FCM. In this study, the authors hypothesized that addition of rituximab to the induction regimen followed by rituximab maintenance would be beneficial in such patients. This prospective trial included untreated patients with active CLL (85% were in Binet’s clinical stage B and C) younger than 70 years (median age 58 years). Patients received six cycles of R-FCM and those who had either CR or PR went on to receive rituximab maintenance. The ORR was 94% (CR with no minimal residual disease [MRD], 43%; CR with MRD, 37%). The main grade 3-4 hematological toxicity was neutropenia (12%) and 5% experienced nausea/vomiting. In general, though, these events were manageable. These results are interesting but two cautions are appropriate. First, the longterm results of this approach are not yet available. Second, without a randomized control it will remain impossible to determine if this novel approach genuinely improves outcome. This study has demonstrated that R-FCM is feasible. Randomized comparisons will be needed to prove it is more effective.

377 Interim Results of the Combination Rituximab, Fludarabine, Cyclophosphamide and Mitoxantrone (R-FCM) Followed by Rituximab Maintenance in Previously Untreated Chronic Lymphocytic Leukemia (CLL) F. Bosch, A. Muntañola, N. Villamor, M. Terol, E. Gonzalez-Barca, J. Ribera, M. Gonzalez, E. Abella, J. Delgado, F. Carbonell, J. Garcia Marco, L. Escoda, S. Ferrer, E. Monzo, Y. Gonzalez, J. de la Serna, P. Abrisqueta, E. Gine, O. Salamero, E. Montserrat

Immunochemotherapy is emerging as the new gold standard for CLL treatment. However, the best combination chemotherapy to be given along with rituximab has not yet been determined. In untreated CLL, FCM results in a response rate of 90%, including a high proportion of MRD-negative CRs.

Against this background, we have conducted a prospective clinical trial in which treatment-naïve CLL receive R-FCM followed by rituximab maintenance. We included pts younger than 70 yrs with active disease (NCI-WG criteria) and adequate performance status. R-FCM consists of rituximab 500 mg/m2 on day 1, fludarabine 25 mg/m2 on days 1 to 3, cyclophosphamide 200 mg/m2 on days 1 to 3, and mitoxantrone 6 mg/m2 on day 1, given at a 4-week intervals up to six courses. All pts receive G-CSF and cotrimoxazole. Pts achieving response (CR or PR) are subsequently treated with rituximab 375 mg/m2 every 3 months up to two years. Response is assessed 3 months after R-FCM treatment including MRD evaluation by flow cytometry. Out of 85 pts included in the study, 47 (65% male, median age 58 years) are evaluable for response to the first part of the treatment (R-FCM induction therapy). At study entry, 85% of the pts were in advanced (B and C) Binet’s clinical stage and 56% had increased (>20%) ZAP-70 expression. Ninety-one per cent of the pts have received the entire planed treatment. Overall response rate is 94%. MRD-negative CR is 37%, MRD-positive CR 37% (CR rate, 74%), nPR 7%, and PR 13%. Two out of 4 PR cases are MRD-negative. Toxicity has been manageable, with grade III–IV neutropenia being observed in 12% of the cases. In conclusion, R-FCM is a well tolerated regimen that induces a high CR rate, including a high proportion of MRD-negative CRs. Whether these already extremely promising results are improved by maintenance therapy with rituximab remains to be seen.

Commentary on abstracts 098 and 099

Although the introduction of rituximab and improvements in chemotherapy regimens have prolonged survival in patients with several B-cell neoplasms, there is still much room for improvement. Some promising new agents are entering clinical development. GA101 is a fully humanized MAb that recognizes a CD20 type II epitope. Whereas type I antibodies such as rituximab show limited antibody-dependent cellular cytotoxicity, this potentially more lethal mechanism is more prominent in type II antibodies. Indeed, GA101 showed greater B-cell depletion in whole blood assay, greater efficacy in several non-Hodgkin’s lymphoma (NHL) xenograft models and superior efficacy for tissue B-cell depletion in cynomolgus monkeys and huCD20 mice. The agent is currently in phase I clinical trials. While rituximab and GA101 target CD20, another promising new agent known as SGN-40 acts on CD40, a member of the TNF receptor family that is expressed on a number of cells, including malignant B cells, to induce cell death. The phase I trial reported here studied 50 patients with relapsed/refractory B-cell NHL with the objective of determining the toxicity profile and the maximum tolerated dose, characterizing the pharmacokinetics and assessing evidence of antitumour activity. Response was observed in six patients (CR rate of 18% in patients with DLBCL. Therapy was well tolerated and the maximum tolerated dose was not reached. In view of these encouraging results in heavily pretreated patients, further studies with SGN-40 are ongoing or planned, both as a single agent and in combination with other chemotherapeutic agents.

098 GA101, a Novel Therapeutic Type II CD20 Antibody with Outstanding Anti-tumor Efficacy on Non-Hodgkin Lymphoma Xenograpft Models and Superior B Cell Depletion P. Umana, E. Moessner, R. Grau, C. Gerdes, A. Nopora, C. Schmidt, P. Strein, S. Bauer, T. Friess, K. Dabbagh, J. DalPorto, C. Klein

GA101 is the first humanized, glycoengineered type II CD20 antibody. It is currently in Ph I clinical trials. GA101 was derived by humanization of the murine B-Ly1 antibody and is characterized by high binding affinity, type II mode of CD20 binding with reduced CDC and strong direct cell death induction compared to classical type I CD20 antibodies. The glycoengineered FC region binds with enhanced affinity to FcgRIIIa on immune effector cells leading to enhanced ADCC relative to rituximab.

We studied the effects of GA101 on the growth of s.c. NHL xenografts in SCID beige mice, a model primarily indicative of non-effector cell-mediated mechanisms. In different NHL models, GA101 demonstrated outstanding anti-tumor efficacy. Specifically, complete tumor remission was induced in SU-DHL4 DLBCL xenografts at 30 mg/kg weekly dose. By contrast, rituximab at higher doses was only able to slow down tumor progression. In addition, treatment with GA101 increased the medial and overall survival in an orthotopic disseminated Z138 MCL model compared to rituximab. In hCD20 transgenic mice, GA101 demonstrated superior depth of B cell depletion. The increased B cell depletion extended into the peripheral lymphoid compartments and to the range of B cell subsets targeted. Analogous findings were observed in cynomolgus monkeys where the efficacy of GA101 in depleting B cells in lymphoid tissues was compared with that of rituximab. Although ADCC plays an integral role, the enhanced depth of depletion observed with GA101 treatment is influenced by its unique binding mode and the induction of CD20-dependent cell death. In summary, the data demonstrate that GA101 represents a novel class of CD20 antibodies with outstanding efficacy compared to classical CD20 antibodies. It is anticipated that the combination of the type II epitope recognition with improved ADCC potency exclusive to GA101 will translate into superior clinical efficacy, establishing GA101 as best in class anti-CD20 therapy.

099 SGN-40 Shows Evidence of Activity in Patients with Relapsed Non-Hodgkin Lymphoma: Final Results of a Phase I Dose-escalation Study R. Advani, A. Forero-Torres, R.R. Furman, J.D. Rosenblatt, A. Younes, K. Harrop, N.C. Whiting, J.G. Drachman

Background: SGN-40 is a humanized monoclonal antibody that binds to CD40, triggers pro-apoptotic signal transduction and mediates effector cell function (ADCC/ADCP).

Methods: A multicenter, phase I, open-label, doseescalation study was conducted to assess the safety, MTD, PK profile, and preliminary antitumor activity of SGN-40 in patients with relapsed NHL. Cohorts of 3-6 patients received 6 IV infusions of SGN-40 (2-8 mg/kg) over 5 weeks (Cycle 1). Patients with SD or better were eligible to receive a second cycle. The dose escalation phase included 35 patients; 15 patients were added at the highest dose cohort to further evaluate SGN-40 safety and efficacy.

Results: Fifty patients (33 M, 17 F) with a median age of 62 yrs (range 24-86) participated at 5 sites. All patients who received at least 1 dose of SGN-40 were included in the analysis. Patients with multiple histological subtypes of NHL were enrolled, including DLBCL (21), FL (12), MCL (10), MZL (3), SLL (1) and other (3). Patients were heavily pretreated, with a median of 3 prior therapies (range 1-8). Treatment with SGN-40 was well tolerated and MTD was not reached. Two patients experienced dose limiting toxicity; conjunctivitis and transient loss of visual acuity (N=1) and Gr 3 ALT elevation (N=1). No dose related trends in adverse events were observed. PK demonstrated dose related increases in serum exposures. Six patients (12%) achieved an objective response (5 PRs and I CR) and 13 patients (26%) achieved SD. Three responses were ongoing at final clinical evaluation, up to 2 years after completing treatment. Two additional patients who discontinued SGN-40 due to toxicity achieved durable CRs after withdrawal from the study and without subsequent treatment. The median overall survival was 10.5 months (range 0.1-16.9).

Conclusions: Single-agent treatment with SGN-40 is well tolerated and shows promising antitumor activity in a heavily pretreated patient population.

EDITORIAL OVERVIEW:

Michael Crump, MD, FRCPC

Medical Oncology and Hematology, Princess Margaret Hospital, Associate Professor of Medicine, University of Toronto, Toronto, Ontario

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive histology lymphoma. As this lymphoma usually presents in patients over 60 years old, dose-intensified strategies such as stem-cell transplantation cannot be followed and there is a need for other effective treatments. The B-cell antigen, CD20, is expressed in the majority of DLBCLs and the combination of the anti-CD20 antibody rituximab with cyclophosphamide/doxorubicin/vincristine/prednisone chemotherapy (R-CHOP) as induction therapy has resulted in increased overall survival (OS) in pivotal trials. Although rituximab now forms a part of most therapies for DLBCL, work still has to be done to optimize these treatment regimens.

Avoiding Involved-field Radiation Therapy in Low-risk DLBCL Patients

In one of the standard approaches in the treatment of limited-stage DLBCL, i.e. stage I/II disease with no fever, weight loss and night sweats, and nodal mass <10 cm, patients received three cycles of CHOP and involved-field radiation therapy (IFRT) (Miller et al. N Engl J Med 1998;339(1):21-6). With the introduction of rituximab to the CHOP induction therapy, survival has been shown to be improved slightly, though the problem of late relapse outside of the radiation field still remains with abbreviated courses of chemotherapy in DLBCL (Persky et al. J Clin Oncol 2008; 26(14):2258-63). Controlled trials from France were carried out with CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients. A study by the Groupe d’Étude des Lymphomes de l’Adulte (Bonnet et al. J Clin Oncol 2007;25(7):787-92) suggest that the addition of IFRT, with its potential long-term toxicity, may not improve survival over chemotherapy alone. The value of IFRT, furthermore, has not been explored in the era of chemoimmunotherapy using rituximab.

This question was addressed by a study from the British Columbia Cancer Agency presented by Sehn et al. The investigators hypothesized that an FDG-PET scan would be able to identify those patients who had responded to immunochemotherapy and so would not benefit from IFRT. After three cycles of R-CHOP, patients with a positive FDG-PET scan received IFRT whereas those with negative PET findings received another cycle of R-CHOP. To date, this prospective cohort study has enrolled 65 patients (median age 67 years). Of the 49 patients (75%) who were PET-negative, 47 received the scheduled additional R-CHOP cycle. Encouragingly, after median follow-up of 17 months, only one of these patients has relapsed and estimated progression-free survival (PFS) and OS at two years are both 97%. Of the 16 patients (25%) who were PETpositive, all received IFRT. Three have relapsed (all out of field) and two of these patients have died. The estimated two-year PFS and OS were 83% and 76%, respectively, for those with a positive PET scan after three cycles of R-CHOP. The authors appropriately recommend caution in the interpretation of these results, since the number of patients treated is small and the follow-up of the cohort is still short.

Influence of Rituximab Serum Levels on Efficacy

The pharmacokinetics of rituximab has received relatively little attention. For one, it is not clear that the tenet of a dose-response relationship seen with many traditional cytotoxic drugs applies to monoclonal antibodies. Furthermore, the picture may be complicated by factors such as the potential impact of tumour burden on antibody penetration and kinetics. Nevertheless, the data available suggest that serum levels of rituximab build up slowly during standard three-weekly dosing. Outcomes in elderly patients with DLBCL improve by decreasing the interval between CHOP chemotherapy cycles from three weeks (CHOP-21) to two weeks (CHOP-14). Recently, in the RICOVER-60 (Rituximab with CHOP Over 60) trial, patients who received six or eight cycles of R-CHOP-14 fared significantly better than those who received CHOP-14 (Pfreundschuh et al. Lancet Oncol 2008;9(2):105-16). It may be hypothesized that some of this benefit could be attributed to achieving high serum levels of rituximab more quickly; if so, then more dose-dense regimens with this agent may be of further benefit.

This hypothesis is being put to the test in the Dense-R-CHOP- 14 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL), the 24-month results of which were presented by Pfreundschuh et al. Elderly patients received CHOP-14 therapy with 12 doses of rituximab on days 0, 1, 4, 8, 15, 22 and 29, then every two weeks up to day 99. Patients in the RICOVER-60 trial were used as a historical comparison. With this regimen, high serum levels of rituximab were quickly reached. An evaluation of the first 20 patients showed that grade 3-4 infections including cytomegalovirus were more common than anticipated. Subsequent patients received levofloxacin, acyclovir and co-trimoxazole prophylaxis, with an apparent reduction in infectious events. Although response rates were similar to the RICOVER-60 trial, the Dense-R-CHOP-14 trial included higher-risk patients. Stratification of the results by International Prognostic Index (IPI) group showed that IPI 3-5 patients had prolonged 24-month event-free survival compared to that observed with R-CHOP-14 (68% vs. 58%). Of course, any study with a historical control is subject to a number of caveats, but the results of this study do warrant a randomized trial to further investigate the benefits of dose-dense rituximab regimens, particularly in high-risk patients.

New Treatments in Other Aggressive B-cell Lymphomas

Mantle cell lymphoma (MCL) has historically been observed to be sensitive to initial therapy including an anthracycline and rituximab, but remission duration and survival have not improved with the same chemoimmunotherapy that has been successful in DLBCL. Dreyling et al. reported ongoing trials of initial therapy in MCL that compared standard R-CHOP regimens with rituximab, fludarabine and cyclophosphamide (R-FC), followed by either interferon or rituximab maintenance in patients aged >60 years; and standard R-CHOP followed by myeloablative consolidation cyclophosphamide and total body irradiation (TBI), compared to the incorporation of high-dose cytarabine in younger patients, using three cycles of R-dexamethasone/cisplatin/cytarabine (R-DHAP) during induction, and cytarabine, melphalan and TBI as the highdose regimen, supported by autologous stem cell transplantation.

In the case of the MCL elderlytrial, the results from the induction phase are still blinded, but show an overall response rate of 84%. Although the combined survival curves during the maintenance phase were lower than expected, those for the patients who achieved a complete response (CR) are extremely encouraging: only two patients have relapsed after 12 months of follow-up. Preliminary toxicity data from this trial indicate that R-FC may be associated with less myelosuppression and a lower incidence of febrile neutropenia than R-CHOP in this patient population. Reporting of response and PFS by study arm is anticipated. In the case of the MCL youngertrial (also still blinded), the CR rates and 12-month PFS were also very encouraging. R-DHAP appears to be associated with a higher rate of grade 3 and 4 anemia and thrombocytopenia, but the rate of febrile neutropenia was only modestly higher (18% vs. 11%). The follow-up of this trial is still short and results according to treatment arm have yet to be analyzed.

This year marks the 50th anniversary of the publication of the initial description of Burkitt’s lymphoma (BL) by Dr. Denis Burkitt, an Irish surgeon who spent several years studying diseases in African hospitals. BL is endemic in Africa, where triggers such as Epstein-Barr virus infection and malaria are believed to play a key role in its pathogenesis. In Western countries, BL often occurs in immunocompromised patients such as those with HIV infection. The disease is characterized by a relatively rapidly evolving clinical presentation, extensive stage disease and a characteristic histologic appearance, immunophenotype and cytogenetic abnormalities involving the c-Myc oncogene and the immunoglobulin heavy chain gene locus. Treatment strategies in adults have borrowed from the success of pediatric regimens that include short, intensive chemotherapy protocol including high-dose methotrexate and CNS prophylaxis. Instead of the traditional approach employing high doses of chemotherapy agents administered in rapid sequence, Dunleavy and co-investigators at the NIH tested the concept of continuous infusion chemotherapy using dose-adjusted etoposide, vincristine, and doxorubicin, with bolus cyclophosphamide, prednisone and rituximab (DA-EPOCH-R) (as described in Blood 2002;99:2685-93). The rationale for this approach is the potential benefit from continuous exposure to chemotherapy in a malignancy that has a proliferation fraction of >99% as assessed by immunohistochemical methods. They studied 24 previously untreated patients (16 HIV-negative, eight HIV-positive) who received six cycles of DA-EPOCH-R. Complete remission was achieved in all patients and OS and event-free survival at 28 months are 100% and 96%, respectively. Longer follow-up and independent confirmation of this novel approach—preferably by a direct comparison in a prospective randomized trial—are clearly needed.

New Cytotoxic Agents in B-cell Lymphomas

The purine-based alkylating agent bendamustine produces response rates of approximately 40% in patients with relapsed indolent non- Hodgkin’s lymphoma (NHL) when used as a single agent. In an effort to further improve outcomes, Mohren et al. studied a combination of bendamustine with rituximab in patients with CD20- positive “aggressive” NHL who experienced disease progression following anthracycline-based combination chemotherapy. The overall response rate in the 12 patients included in the study was 80% (four with CR, three of whom are still in CR after six to 33 months of follow-up). The toxicity of the therapy was acceptable with only one episode of grade 3 leukopenia as the only hematologic toxicity reported in 35 courses and no toxicity-related treatment delays or interruptions were reported. This is clearly a preliminary study, but the results are encouraging enough to warrant further evaluation of bendamustine in defined populations of patients with DLBCL and related subtypes of aggressive lymphoma.

Summary

Some promising new treatment options are being developed for aggressive B-cell lymphomas, building on the successful incorporation of rituximab into induction therapy. In the case of DLBCL, preliminary data indicate that FDG-PET may allow the identification of patients with limited stage disease for whom IFRT may not be necessary, while retaining its use in high-risk patients. In addition, innovative regimens such as dense-R-CHOP-14 suggest a way to explore the importance and toxicity of achieving higher rituximab serum levels early in the course of therapy, particularly in high-risk patients. In less common aggressive B-cell lymphomas, new regimens such as R-FC for MCL and DAEPOCH- R for Burkitt’s lymphoma are showing promise. Finally, new single chemotherapy agents such as bendamustine used in combination with rituximab have also produced some good preliminary results in patients with relapsed CD20-positive B-cell lymphoma. All of these new approaches should be tested in randomized phase III trials against the current standard treatments.

052 Limited-stage DLBCL Patients with a Negative PET Scan Following Three Cycles of R-CHOP Have an Excellent Outcome Following Abbreviated Immuno-chemotherapy Alone L.H. Sehn, K. Savage, P. Hoskins, R. Klasa, T. Shenkier, R.D. Gascoyne, N. Voss, D. Wilson, J. Connors

Introduction: One standard management of limited stage DLBCL combines 3 cycles of chemotherapy and involved-field radiation therapy (IFRT). Recently, four cycles of CHOP chemotherapy alone has been shown to be sufficient for low-risk elderly patients. FDG-PET scanning is an effective response assessment tool that may identify chemo-sensitive patients (regardless of clinical risk factors) who can be treated with abbreviated immuno-chemotherapy alone.

Patients: Since 2005, we have recommended that all patients with limited-stage DLBCL (stage I/II, no B-symptoms, mass <10cm) treated in British Columbia (BC) undergo a PET scan following 3 cycles of R-CHOP; PET-negative patients are then offered one additional cycle of R-CHOP, while PET positive patients receive IFRT. To date, 65 patients have been treated according to this algorithm with the following clinical characteristics: median age 67 y (range 31-88); 58% male; 58% stage I, 42% stage II; 5% PS>1; 8% elevated LDH; 57% at least 1 extranodal site. Stage-modified IPI risk factors (Miller et al): 21% 0; 71% 1-2; 8% 3-4. Median follow-up is 17 mos (range 3-30).

Results: 49 patients (75%) were PET-negative and 16 patients (25%) were PET-positive after 3 cycles of R-CHOP. No clinical factors were found to be predictive of PET status. Of the 49 PET-negative patients, 47 completed treatment with one additional cycle of chemotherapy, 1 received IFRT due to poor chemotherapy tolerance and 1 died of toxicity before receiving any more treatment. Only 1/49 PET-negative patients has relapsed (alive with lymphoma after salvage therapy). All 16 PET-positive patients received IFRT, with 3 relapses (all out-offield) and 2 deaths from lymphoma to date. The 2-year estimated progression-free survival is 93% overall (97% and 83% for PET-negative and PET-positive patients, respectively, p=0.04). The 2-year overall survival is 97% for PET-negative and 76% for PET-positive patients, p=0.12.

Conclusion: Patients with limited-stage DLBCL who are PET-negative after 3 cycles of RCHOP have an excellent outcome following 4 cycles of R-CHOP alone. Mid-treatment PET scanning can be used to identify patients who can be spared the long-term toxicity of radiation.

Commentary on abstract 052

Some standard treatment algorithms of limited-stage DLBCL use IFRT after initial chemotherapy. However, this therapy is associated with significant long-term toxicity such as secondary malignant disease. To that end, a treatment algorithm that avoids IFRT unless absolutely necessary was tested in this study. Patients with limited-stage DLBLC received three cycles of R-CHOP before undergoing an FDG-PET scan. Patients who had responded to treatment were given an additional cycle of R-CHOP whereas those with a positive scan received IFRT. In total, 49 patients (75%) were PET-negative and 47 received the scheduled additional R-CHOP cycle. Only one of these patients has relapsed (and is currently alive after salvage therapy). Sixteen patients (25%) were PET-positive and all received IFRT. To date, three relapses have occurred among these patients (all out of field) and two of these patients have died. The two-year PFS and overall survival were 97% and 97% for PET-negative patients and 83% and 76% for PET-positive patients, respectively.

Questions and Answers with Dr. Laurie H. Sehn, University of British Columbia, Vancouver

Q: What proportion of patients present with limited-stage DLBCL and who may therefore be eligible for this strategy?

A: I would say about one-quarter of all patients with DLBCL present in limited stage. Longer follow-up is clearly necessary to assess this approach, as we reported only preliminary results but so far, outcomes are very promising, and I would suggest this approach in limited-stage FDG-PET negative disease may be a reasonable strategy.

Q: Can you indicate which specific toxicities are seen with IFRT long-term and are there also additional or different short-term toxicities?

A: Certainly the toxicities of IFRT are well-documented and include secondary malignancies and coronary artery disease. Follow-up in our study is too short to document any long-term toxicities, but short-term toxicities really depend on the area that gets radiated. But if you can avoid the use of IFRT, you may be able to avoid the well-known toxicities associated with it.

Q: Where are you hoping to take this particular strategy next?

A: We are continuing our experience here using this strategy and ultimately it would be nice to test the strategy in the context of a randomized controlled trial.

428 Bendamustine/Mabthera in Patients with Relapsed or Refractory Aggressive CD20+ B-Cell-Lymphoma (OSHO #73) M. Mohren, M. Herold, K. Scheinpflug, G. Wilhelm, J. Uhlich, H. Schwarzbach, A. Franke

Introduction: Bendamustine has been extensively studied in patients with indolent B cell neoplasms showing high response rates and moderate mostly hematologic toxicity. However, only one small study of patients with relapsed non-Hodgkin’s lymphomas (NHL) treated with bendamustine as a single agent has been published to date showing a response rate of approximately 40%. To further improve treatment results we initiated the following study.

Patients and methods: Adult patients (>18 years) with relapsed or refractory aggressive CD20+ NHL, who had received at least one anthracycline based combination chemotherapy were eligible. The first course included mabthera 375 mg/m2 on days 1, 8, 15 and 22 and bendamustine 60 mg/m2 on days 1, 8 and 15 of a 4-week cycle. Bendamustine 60 mg/m2 days 1, 8 and 15 was given in cycles 2-4.

Results: Twelve patients aged 56 to 78 years (mean age 69,6 years) were included in this study. 10 patients had received one, 2 had had 2 prior therapies. 10 patients and 35 treatment courses are evaluable for response so far. Four patients had a complete, three a partial and one a minimal response. The overall response rate was 80%. Three of four patients are still in CR after 33, 18 and 6 months, respectively. One patient with a complete response had progressive disease after 2 months. Partial remission lasted for 2, 4 and 6 months in 3 patients. Two patients with high dose chemotherapy with autologous stem cell transplantation as first-line treatment had progressive disease after 1 and 2 courses, respectively. There was only one grade 3 leukopenia in one of 35 treatment courses and no further grade 3 or 4 hematologic toxicities. There were no toxicity-related treatment delays, interruptions or mortalities.

Conclusion: These preliminary results show that bendamustine/mabthera is a well tolerated regime with promising response rates also in patients with aggressive NHL. Larger patient numbers are needed to confirm our findings.

Commentary on abstract 428

A number of studies have shown the alkylating agent bendamustine to be beneficial in patients with indolent NHL, with the main toxicity noted being myelosuppression. Only one small study has investigated the agent as monotherapy in relapsed or refractory high-grade NHL, with promising results. In the study reported here, up to four cycles of bendamustine were administered along with rituximab to patients with refractory aggressive CD20-positive NHL who had failed anthracycline-based combination chemotherapy and ASCT in two cases. So far, of the 12 patients, results are available for 10 (35 cycles). The response rate was 80%, including four patients with CR, three of whom are still in CR after six to 33 months of follow-up. Importantly, the combination was well tolerated, the only grade 3-4 hematological toxicity reported was leukopenia. Although promising, these findings are preliminary and larger studies with a more rigorous design would be needed to allow firmer conclusions to be drawn.

Questions and answers with Dr. Martin Mohren, University Hospital Magdeburg, Germany

Q: Why was rituximab only administered during the first cycle?

A: Rituximab was administered only during the first course, since we wanted to give it in a dose-dense fashion and we still had little experience with rituximab. In view of the very poor prognosis of these patients, we were hesitant to add additional doses of rituximab.

Q: Are you aware of any larger studies that are planned or in progress to confirm the promising findings of your study?

A: There was another German study with the same combination using a four-weekly regimen that recruited poorly and was never published. The German study group is currently discussing a study in frail and elderly patients with rituximab and bendamustine as first-line treatment.

053 Improved Outcome of Elderly Patients with Poorprognosis Diffuse Large B-Cell Lymphoma (DLBCL) After Dose-dense Rituximab: Results of the Dense-R-CHOP-14 Trial of the German High-grade Non-Hodgkin Lymphoma Study Group (DSHNHL) M. Pfreundschuh, S. Zeynalova, V. Pöschel, M. Hänel, N. Schmitz, A.D. Ho, M. Reiser, M. Löffler, J. Schubert

Background: While 6 to 8 cycles of CHOP in combination with rituximab (R) are widely accepted as standard regimen of care for aggressive lymphomas, the optimal dose and number of R application have not yet been determined. In a previous pharmacokinetic study we had shown that the concomitant application of CHOP and R does not achieve a plateau of R trough levels until cycle 5 (Reiser, Blood 108, 778a, 2006). In order to achieve high R levels early, we increased the number of R applications.

Methods: 100 elderly pts. with aggressive CD20+ B-cell lymphoma received 6 cycles of biweekly CHOP-14 combined with 12x R (375 mg/m2) on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85, and 99. Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. The primary endpoint was event-free survival (EFS). 306 pts. treated within the RICOVER-60 trial (Pfreundschuh et al., Blood 64a, 2006) with 6xCHOP-14 and 8 applications of R served as control.

Results: 97/100 pts are evaluable for response. Plateau trough serum levels were achieved by day 1 of the first chemotherapy cycle and higher R levels were maintained throughout the treatment compared to 8 bi-weekly applications. Because 3 therapy associated deaths were observed among the first 20 pts treated, prophylaxis with levofloxacin, acyclovir and cotrimoxazol became mandatory for the following pts. Despite a less favorable study population DENSE-R-CHOP-14 resulted in a somewhat higher CR (83% vs. 78%) and lower progression under therapy rate (5% vs. 7%) rate, but event free and overall survival were not different compared to 8 biweekly applications of R. However, a subgroup analysis of pts according to IPI risk group showed that DENSER-DENSER R-CHOP-14 resulted in a higher CR-rate of pts with poor-prognosis (IPI:3-5) disease (81% vs. 68%) and in a better 1-year EFS-rate (74% vs. 65%) of these pts.

Conclusion: Densification of R results in higher serum levels and in higher CR and EFS-rates in elderly pts with poor-prognosis DLBCL. An update of the results of the completed trial with 125 pts will be presented.

Commentary on abstract 053

Serum levels of rituximab build up slowly even with bi-weekly dosing, and this may limit the potential benefit, particularly in patients with high-risk DLBCL. The present study was designed primarily to investigate the pharmacokinetics and safety of a dose-dense schedule of rituximab (bi-weekly CHOP-14 combined with 12 rituximab doses between days 0 and 99); secondary efficacy end points were also included. High serum levels were quickly reached in the 124 evaluable patients. After several grade 3-4 infections were reported in the first 20 patients, prophylaxis (levofloxacin, acyclovir and co-trimoxazole) was made mandatory and reduced infection rates by approximately half. CR with the dose-dense schedule was similar to the more conventional R-CHOP schedule of the RICOVER-60 trial, although the patients in the dose-dense trial tended to be higher-risk. Indeed, comparison of patients in IPI 3-5 risk groups showed greater benefit for the dose-dense regimen in terms of event-free survival. These promising results in high-risk DLBCL patients suggest that randomized trials are warranted to further investigate the dose-dense approach.

Questions and answers with Dr. Michael Pfreundschuh, Saarland University, Homburg, Germany

Q: Have you carried out any pharmacokinetic studies, and if so, to what extent are our traditional ideas about pharmacokinetics applicable?

A: Detailed pharmacokinetics was only studied in two centres and 20 patients. Of course, with antibodies, it is a different situation from cytotoxic drugs. However, if our observations can be confirmed—that is, that higher-risk patients have a better outcome with higher serum levels—this suggests that there might be a correlation between efficacy and serum levels, but this must await confirmation from other trials.

Q: Did you do carry out any genetic testing to see how this might affect the clinical outcome?

A: Not yet, but we have some tissue microarray assays which are being developed.

300 European Mantle Cell Lymphoma Network: An Update on Current First Line Trials M. Dreyling, E. Hoster, O. Hermine, H. Kluin-Nelemans, J. Walewski, M. Trneny, C. Geisler, M. Unterhalt, W. Hiddemann

Background: Conventional chemotherapy achieves only short term remission despite high initial response rates of 70%-80%. In the current study generation, the European MCL Network investigates the impact of various combined immuno-chemotherapy regimens. Additionally, in elderly patients the role of rituximab maintenance is being evaluated, whereas in younger patients dose-intensified regimens with implementation of high dose cytarabine are investigated based on the excellent results of the HyperCVAD regimen.

Methods: In MCL elderly, patients are initially randomized between 8 cycles of R-CHOP or 6 cycles of R-FC (experimental arm). Patients who achieve either a PR or CR, receive subsequently either interferon maintenance (standard arm) or a single rituximab dose every 2 months. In MCL younger, the standard arm (R-CHOP induction followed by myeloablative consolidation: 12 Gray TBI, 2x 60mg/kg cyclophosphamide) is compared to the implementation of high dose cytarabine into induction (R-CHOP/R-DHAP) and consolidation (10 Gray TBI, 4x1,5 g/m2 Ara-C, 140mg/m2 melphalan).

Results: In MCL elderly, 269 of 302 patients were evaluable based on the annual interim analysis. Median age was 70 years with 66% of patients displaying an intermediate high/high risk IPI. Induction was well tolerated with mainly hematological toxicity (grade III/IV in RCHOP/R-FC): Leukocytopenia 62/72%, thrombocytopenia 13%/40%, but only rare febrile neutropenia (23%/7%) or infections (19%/23%). Despite the poor risk profile, combined immuno-chemotherapy (total group) achieved a remarkable 84% response rate (52% CR/CRu). Although the impact of maintenance is not yet evaluable, both progression-free and overall survival were encouraging with 79% and 86% at 12 months, respectively. Interestingly, especially the CR patients showed a favorable clinical course with only 2 relapses in 28 patients (7%) observed so far. In MCL younger, 286 of 314 patients were evaluable. Again, toxicity (grade III/IV in R-CHOP/alternating R-DHAP) was mainly hematological: leukocytopenia 58/77%, thrombocytopenia 14%/74%, but only rare febrile neutropenia (11%/22%) or infections (5%/7%). Combined immuno-chemotherapy achieved a 91% response rate (56% CR/CRu) before subsequent high dose consolidation. Again, both progression-free and overall survival are remarkable with 82% and 88% at 12 months, respectively.

Discussion: Combined immuno-chemotherapy results in high response rates in two prospective international trials. Further recruitment and follow-up will determine the role of rituximab maintenance and high dose cytarabine in this distinct subtype of malignant lymphoma.

Commentary on abstract 300

In view of poor long-term outcomes of conventional chemotherapy despite high initial responses, the European Mantle Cell Lymphoma (EMCL) Network initiated trials to investigate different immunochemotherapy induction regimens with rituximab maintenance. The MCL-elderly (patients >60 years) compared one commonly used induction regimen (eight cycles of R-CHOP) with six cycles of R-FC. Patients with CR or PR then received either standard maintenance with interferon or rituximab every two months. The overall response rate of 84% during induction was extremely encouraging. Although it is still too early for solid data on maintenance, interestingly, of the patients who achieved CR, only two out of 28 patients (7%) have relapsed so far. The MCL-younger (patients <65 years) compared standard R-CHOP induction and consolidation using standard cytarabine-TBI and ASCT, to an induction regimen containing high-dose cytarabine using the DHAP regimen, with high-dose cytarabine also added to the transplant regimen. Once again, the response rate was high (91%) and 12-month PFS and OS were encouraging (82% and 88%, respectively). This latter study will determine the benefit of the addition of HD-ara-C in primary therapy of MCL, although it will not provide information about whether it is needed as induction or as part of the high-dose regimen, where it is likely to add toxicity.

Questions and answers with Dr. Martin Dreyling, Klinikum Großhadern, University of Munich, Germany

Q: In the MCL- elderlytrial, the results from the induction phase seem to be promising. Is it still too early to draw any conclusions about the maintenance phase?

A: Indeed, the results from the induction phase were very positive. The combined survival curves during the maintenance phase are somewhat disappointing. On the other hand, the survival curves for those patients achieving CR are encouraging, only two patients have relapsed so far. One of the problems with interpretation of the results of this study is that it is still blinded.

Q: When will the study be unblinded?

A: The study design is innovative and unblinding is to take place after a certain number of events have occurred, not after a predefined period of time. That said, we expect the study to be unblinded in one to two years.

Q: Do similar considerations apply to the MCL- youngertrial?

A: The MCL- youngeralso showed encouraging CR rates and 12-month PFS is also very promising, although of course, this study is also still unblinded. In this study, particularly striking were the good results after ASCT.

009 A Prospective Study of Dose-adjusted (DA) EPOCH with Rituximab in Adults with Newly Diagnosed Burkitt Lymphoma: A Regimen with High Efficacy and Low Toxicity K. Dunleavy, R. F. Little, S. Pittaluga, N. Grant, M. Shovlin, S. Steinberg, R. Yarchoan, J. Janik, E. S. Jaffe, W. H. Wilson

Background: Burkitt lymphoma (BL) is a rare and very aggressive lymphoma, characterized by a high tumour proliferative rate. “Standard” therapy of BL is highly effective but involves intensive, multi-agent chemotherapy that is associated with high treatment related toxicity and mortality, particularly in older patients. We hypothesized that the DA-EPOCH-R regimen may be effective in BL, given its established efficacy in DLBCL and its ability to overcome highly proliferative tumours.

Methods: We set out to investigate if DA-EPOCHR could maintain the high cure rates of standard therapy in BL while minimizing treatment related toxicity. Eligible patients had untreated BL and could be HIV negative or positive - HIV negative patients (n=15) received 6 cycles of DA-EPOCH (with Rituximab) as previously described (Blood 99: 2685, 2002) and HIV positive patients (n=8) received 3-6 cycles of DA-EPOCH-R for 1 cycle beyond CR for a minimum of 3 cycles (Blood 106: #930, 2005). All patients received intrathecal methotrexate prophylaxis and outpatient therapy was instituted where possible.

Results: Characteristics of 23 enrolled patients are: median age (range) 31 (18-66); male sex 18 (78%); median (range) ECOG PS 1 (1-3); stage III/IV 12 (52%); LDH >N 12 (52%); extranodal sites 17 (74%) and ileocecal disease 15 (65%). No patients had CNS involvement at diagnosis. Responses are CR/CRu in 100% with one patient receiving consolidative radiation to a site of residual disease. OS and PFS are both 100% and EFS 95% at a median potential follow-up of 27 months. Significant toxicities included tumour lysis syndrome (TLS) in one patient and fever/neutropenia in 16% of cycles. There were no treatment related deaths.

Conclusions: DA-EPOCH-R is a very effective and well tolerated regimen in the treatment of newly diagnosed BL and is associated with low toxicity and low rates of TLS compared to “standard” high dose regimens used in BL. This regimen may significantly advance the therapeutic index in the treatment of BL. Accrual continues.

Commentary on abstract 009

One of the characteristics of Burkitt’s lymphoma is rapid proliferation of tumour cells. Innovative schedules have therefore been based on the hypothesis that prolonged exposure in such situations can improve tumour cell kill. One such schedule, known as DA-EPOCH-R, has proved effective in DLBCL with high proliferation rates. In the study reported here, so far, 24 patients with Burkitt’s lymphoma (both HIV-positive and -negative) have received DA-EPOCH-R. The most frequent toxicity has been febrile neutropenia (reported in 16% of cycles) and there was one case of tumour lysis syndrome. All patients achieved CR and overall survival and event-free survival at 28 months are 100% and 96%, respectively. These promising results should encourage further larger trials with the DA-EPOCH-R regimen compared to start regimens such as CODOX-M in Burkitt’s lymphoma.

Question and answers with Dr. Kieron Dunleavy, National Cancer Institute, Bethesda, Maryland

Q: The study included both HIV-positive and -negative patients. Were there any differences in toxicity according to HIV status that would not be accounted for by differences in demographics of the two groups?

A: We did not observe any significant differences in terms of toxicity between the two groups of patients.

Q: The study you presented (and the extension of eligibility criteria in the future studies you mentioned) only considers untreated patients. Is there any intention to apply DA-EPOCH-R to patients who have failed other therapies, or will it remain a front-line treatment?

A: We are just interested in investigating DA-EPOCH-R in untreated patients with Burkitt’s lymphoma at the present time.

Q: The good overall and event-free survival is very high at 28 months. Presumably this means that maintenance therapy would not be beneficial with DA-EPOCH-R?

A: The results are excellent so far and there is no compelling rationale for maintenance therapy with this regimen in Burkitt’s lymphoma.