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48th Annual Meeting and Exposition of the American Society of Hematology

Orlando, Florida / December 9-12, 2006

Several trials presented here at the American Society of Hematology (ASH) meeting have demonstrated incremental but important progress toward improving outcome in chronic lymphocytic leukemia (CLL). In CAM 307, a phase III study in progressive B-cell CLL, the monoclonal antibody (MAb) alemtuzumab as front-line therapy raised objective response rates by approximately 50% relative to chlorambucil but also demonstrated greater activity when patients were subgrouped by molecular and genetic markers associated with resistance. Minimal residual disease (MRD) negativity was achieved in only a small proportion of patients, all confined to the MAb arm. This latter outcome has been given new emphasis as efforts intensify to push past extended progression-free survival (PFS) to achieve the ultimate goal of disease cure.

Minimal Residual Disease Negativity

“Studies that have compared relapse rates have demonstrated very significant differences in risk in relapse for those who are MRD-negative relative to those who achieve a [MRD-positive] complete response [CR],” reported Dr. Steven E. Coutré, Division of Hematology, Stanford University School of Medicine, California. While “more data are needed to confirm that achieving MRD negativity is an appropriate end point with which to compare treatments or guide treatment intensification,” there are now numerous studies associating MRD negativity with improvement in outcome, including improved rates of overall survival.

In a multicentre phase III study carried out in treatment centres in 13 countries, 297 patients with previously untreated CLL requiring treatment due to progression were randomized to alemtuzumab or to chlorambucil, which has been widely employed as a first-line single-agent therapy in CLL. Alemtuzumab was delivered intravenously in a 30-mg dose three times a week for up to 12 weeks; chlorambucil was taken orally in a daily dose of 40 mg/m2 daily over 28-day cycles for up to 12 cycles.

After a median of three years of follow-up, the odds ratio of disease progression in the MAb group was 0.58 (95% CI, 0.43-0.77; P=0.0001) relative to those randomized to chlorambucil. This 42% increase in the likelihood of PFS was accompanied by substantial improvements in the rate of objective response, which was achieved in 83% of those receiving the MAb vs. 55% of those receiving chlorambucil. Of these objective responses, a CR was achieved in 24% vs. 2%, respectively.

The relative advantage in PFS for alemtuzumab was supported by numerous secondary end points. For example, the median time to initiating an alternative therapy was 23.3 months vs. 14.7 months (P=0.0001). Although a modest relative advantage for PFS in patients with trisomy 12 who received the MAb did not reach statistical significance (18.3 vs. 12.9 months; P=0.08), there was a distinct advantage in PFS for those with 17p deletion (10.7 vs. 2.2 months; P<0.02). PFS in patients with the 11q deletion was unchanged (8.5 months in both arms). Overall, patients randomized to alemtuzumab had a significantly longer period off treatment.

Prolonging the Interval Between Treatments

“The treatment-free interval was more than doubled in the alemtuzumab arm,” reported senior study author, Dr. Peter Hillmen, Department of Haematology, Leeds General Infirmary, UK. “The activity suggests that alemtuzumab should be considered in first-line combinations, expanding its current role in refractory disease and in high-risk patients.”

It is also notable that six MAb patients vs. none of those in the chlorambucil arm achieved MRD negativity. Although the proportion of patients achieving MRD negativity is small, it is an encouraging finding because of the likelihood that the agent will be increasingly combined with other potent anti-CLL agents in future studies. Several studies have previously associated it with MRD negativity using four-colour flow cytometry and other sampling techniques. In a study cited by Dr. Coutré that specifically evaluated MRD as a prognostic tool (Moreton et al. J Clin Oncol 2005;23:2971-9), six-year survival in relapsed CLL exceeded 80% in those who were MRD-negative while it fell below 40% (P<0.0001) in those who achieved a CR but remained MRD-positive. Many of the MRD-negative survivors remain disease-free, suggesting a possible cure despite having received treatment for refractory disease.

“Does MRD status make a difference? The data suggest that it does,” commented Dr. Coutré. He cautioned that additional studies are needed to establish the significance of MRD status as a clinical tool, particularly the necessity of using high-sensitivity techniques, such as polymerase chain reaction (PCR), vs. simpler but less sensitive four-colour flow cytometry. He indicated that it is the development of newer agents, such as alemtuzumab, that make it possible even to establish a negative MRD status.

Manageable and Predictable Side Effects

Adverse events with alemtuzumab in the phase III first-line study were characterized by Dr. Hillmen as “manageable and predictable.” The most common grade 3 or 4 events included lymphopenia (97% vs. 3%), pyrexia (8% vs. 0%), cytomegalovirus (CMV) events (8% vs. 0%), and chills (3% vs. 0%). There was no significant difference in the rate of febrile neutropenia despite the greater acute suppression of white cells. Patients did receive antimicrobial prophylaxis during the period of acute cytopenia that included trimethoprim/sulfamethoxazole and famciclovir. The prophylaxis was stopped when CD4+ cells climbed above 200 cells/mm3. In 21 of the 23 CMV infections identified on PCR, MAb treatment was at least temporarily discontinued, but 17 of these 21 restarted therapy when infection resolved.

The activity and tolerability of alemtuzumab as a front-line therapy in CLL is consistent with a large body of data that have associated it with a high degree of activity at later stages of disease. New data from a phase III trial evaluated it as a consolidation treatment in patients who achieved a CR or PR after induction therapy with fludarabine or fludarabine plus cyclophosphamide. Its addition substantially reduced the risk of progression relative to no further therapy. Accrual to this study was stopped after 21 patients were randomized because of a high rate of infections in the alemtuzumab arm, but follow-up in this group is now out to a median of 48 months.

“At 48 months, progression has been observed in 25% of patients who received alemtuzumab vs. 80% of those who were randomized to observation alone,” reported Dr. Carmen Schweighofer, Medical Clinic I, University Hospital, Cologne, Germany. While the median PFS in the observation arm was 20.6 months, median PFS has not yet been reached on active treatment. Despite the fact that randomization was ended prematurely, the MAb adverse events have been similar to those reported in other trials. There was only one possible late toxicity. Dr. Schweighofer indicated new strategies are in the process of being evaluated.

Optimal CLL Consolidation Regimen Sought

“The optimal alemtuzumab consolidation regimen has yet to be defined,” Dr. Schweighofer reported, but she indicated that the substantial activity observed in this study provides the basis for identifying a better tolerated regimen. She reviewed the design of a new study that will compare intravenous to subcutaneous alemtuzumab in a range of doses after fludarabine-based induction.

There are data to suggest that early recognition and treatment of infections on the MAb can substantially limit their impact. In the final report from a phase II trial of subcutaneous alemtuzumab plus fludarabine in fludarabine-refractory CLL, CMV reactivation was common but all resolved on antiviral therapy.

“The risk of infections was manageable as were other adverse events, and the rate of response was very encouraging in a poor-risk group,” reported Dr. Hazem A. Sayala, Leeds General Infirmary. In this study of 49 evaluable patients, treatment was initiated with alemtuzumab administered subcutaneously in a dose of 30 mg three times a week for up to 24 weeks. In those who did not achieve a response, oral fludarabine in a daily dose of 40 mg/m2 for three days every four weeks was added. On monotherapy, there were 22 objective responses, including MRD-negative CR in five, MRD-positive CR in two, and 15 PRs. Seventeen patients received fludarabine, which yielded one MRD-positive CR and one PR for a total response rate of 49% (24 in 49 patients). The median survival was 25 months for responders vs. 13 months for non-responders.

Another approach in high-risk CLL patients is the combination of alemtuzumab and rituximab, another MAb. While the former targets CD52 on the surface of B cells, the latter targets CD20. The potential for better malignant cell kill by employing both MAbs together is suggested by an interim analysis of a small trial projected to enrol 30 patients with early-stage, high-risk cancer identified by such molecular markers as the 17p13 deletion, the 11q22-3 deletion and ZAP-70 expression. In an analysis of the first 11 patients accrued, all achieved an objective response, including four MRD-negative CRs, one MRD-positive CR, and six PRs. There have been only two adverse events considered serious. One was a CMV reactivation that was responsive to treatment and the other was a febrile drug reaction to sulfamethoxazole/trimethoprim.

Defining High-risk Patients for Aggressive Therapy

“The standard of care for CLL is to treat only those patients with obvious clinical progression. However, the discovery of the molecular markers of more aggressive disease could change that paradigm,” observed the senior author of this study, Dr. Clive S. Zent, Assistant Professor of Medicine, Division of Hematology, Mayo Clinic College of Medicine, Rochester, Minnesota. “MAb therapies provide effective treatment with less toxicity than chemotherapy and are likely to be the most efficacious in early-stage CLL.”

The combination of alemtuzumab and rituximab is of particular interest because of the compatible mechanisms of action of these two agents, particularly the evidence that they are active even in patients with CLL considered high risk by its molecular profile. Partnering alemtuzumab with any of the other therapies associated with activity in CLL, including rituximab, purine analogs and alkylating agents, is attractive, because this agent, unlike the others, does not require an intact p53 pathway to provide anti-tumour effect.

“CLL with abnormalities of p53, which plays an important role in apoptosis, is problematic. Alemtuzumab is one of the few agents that demonstrates activity in this subtype of disease, although it is not effective in all patients. Combinations appear to be essential,” noted Dr. Ben Kennedy, consultant haematologist, University Hospitals of Leicester, UK. In citing evidence that CLL is an evolutionary disease that tends to acquire the genetic deletions that increase resistance to current therapies as it progresses, he is among several experts who foresees earlier intervention, including treatment in the absence of active progression.

Redefining Goals in CLL Treatment

There is now an assortment of treatments that can increase PFS, whether used as first-line or in patients relapsing after an initial therapy. However, the goalposts are being moved. Newer therapies show promise for increasing rates of CR, particularly MRD-negative CR. Relative to PFS, this end point may require earlier and more aggressive treatment in order to eradicate CLL cells when they are most vulnerable to therapy. Although aggressive therapy may be reserved for those determined to be at high risk by their molecular profile, it seems likely that conservative approaches, such as observation, will no longer be considered appropriate when treatments with acceptable safety can be administered to extend survival. Combinations are particularly promising for their potential to eradicate malignant cells by several independent mechanisms, but the optimal combinations are still being defined for first-line, consolidation and relapse treatment regimens.

“Agents with novel mechanisms of action may be particularly useful in improving activity against CLL in general and hematological malignancies overall,” commented Dr. Thomas S. Lin, Division of Hematology and Oncology, Ohio State University, Columbus. He told the audience that a number of promising phase I-II trials with such drugs as lenalidomide, flavopiridol, lumiliximab and ofatumumab provide the basis for suggesting that the recent progress in the treatment of CLL may continue. When combined with either traditional chemotherapies or newer agents, the improvements may not be limited to PFS or objective responses but to overall survival.

Summary

The recently released phase III results from CAM 307 comparing alemtuzumab to chlorambucil as front-line therapy in CLL have important clinical relevance. Most notably, objective response rates were raised by approximately 50% with the MAb compared to the alkylating agent, and the PFS was approximately doubled. Six patients in the study—all in the MAb arm—were rendered MRD-negative. In addition, response rates were higher among patients with cytogenetic abnormalities, particularly the 17p deletion. Although infections, including CMV, were more common on alemtuzumab, they were generally reversible with treatment and did not interfere with treatment efficacy. No treatment-related deaths were reported; anemia, thrombocytopenia, febrile neutropenia and symptomatic infections were similar to that seen with the alkylating agent. The study is indicative of the evolving regimens in early treatment of CLL with novel agents that appear to be more active and may permit strategies to be compared for overall survival rather than as an interval to progression. Regimens that combine traditional and novel therapies have the potential to build on these results.