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.

33rd Annual Meeting of the European Group for Blood and Marrow Transplantation

Lyon, France / March 25-28, 2007

Non-Hodgkin’s lymphoma (NHL) groups together a range of lymphoid malignancies, typically of B-cell origin, with diverse clinical presentations and prognoses. Therapeutic strategies vary greatly according to type of NHL. Researchers here discussed promising new approaches to treatment of follicular lymphoma (FL), risk stratification in chronic lymphocytic leukemia (CLL) and novel approaches to the management of chronic graft-versus-host disease (GVHD).

Inducing Tumour Remission in Follicular Lymphoma

According to Dr. Christian Buske, University Hospital Grosshadern, Munich, Germany, “In the pre-monoclonal antibody era, 35 years of intensive clinical research had achieved little by way of improved treatment outcomes.” But there has now been a paradigm shift and treatments are available that can improve overall survival in patients with advanced-stage FL. The therapeutic approach in such patients can be considered in three distinct stages. First, there is induction therapy with the goal of achieving optimal initial tumour reduction. Then there is a consolidation phase where the goal is to stabilize the remission the patient has achieved. Finally, in the long term, maintenance therapy can be offered with a view to postponing relapse as long as possible.

In first-line therapy, Dr. Buske was adamant. “The literature is quite clear; you should combine rituximab with a standard chemotherapy.” Thus, phase III studies that compared chemotherapy regimens with and without rituximab consistently showed treatment benefit in the rituximab arms. In one previously published study, researchers reported median time to progression of 15 months in patients with advanced FL (stage III or IV) for treatment with cyclophosphamide, vincristine and prednisolone (CVP) compared to 34 months for rituximab/CVP (R-CVP) (P<0.0001) (Marcus et al. Blood 2005;105(4):1417-23). Importantly, in that study, overall survival was also improved (81% for R-CVP vs. 71% for CVP after 53 months; P<0.03). Another study reported a comparison of rituximab added to a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with CHOP alone (Hiddemann et al. Blood 2005;106(12):3725-32). The median time to treatment failure was 31 months in the CHOP arm whereas the median was not reached in the R-CHOP arm. Importantly, the addition of rituximab to these regimens is well tolerated. Dr. Buske concluded his literature review by stating, “When we have a medically fit patient who can tolerate chemotherapy, which is of course important, this is the new standard in the first-line treatment of advanced-stage lymphoma.”

Consolidation and Maintenance in Follicular Lymphoma

Although an optimal strategy has yet to be determined, the one likely to predominate in the future was designed by the EORTC (European Organization for Research and Treatment of Cancer). In this schedule, doses of rituximab are given at three-month intervals for two years after the initiation phase.

An important question regarding maintenance therapy is whether the therapy received during the induction phase can influence the effectiveness of maintenance therapy with rituximab. A randomized phase III trial has attempted to answer that question (van Oers et al. Blood 2006;108(10):3295-301). During the induction phase, FL patients were randomized to R-CHOP or chemotherapy alone in a salvage situation. Patients who responded were then randomized a second time either to receive rituximab maintenance therapy or to a watch-and-wait approach.

After the initial randomization, overall response was achieved in 85.1% of the patients with R-CHOP compared to 72.3% with CHOP (P<0.001). After the second randomization, progression-free survival was 51.5 months in the maintenance arm compared to 14.9 months in the observation arm (P<0.001); overall survival after three years was 85% compared to 77%, respectively (P=0.011). Subgroup analysis of the maintenance phase suggested a trend towards better overall survival in patients pre-treated with rituximab, although the difference was not significant. Dr. Buske cautioned, “Maybe we need longer to be able to state clearly that overall survival improved in patients pre-treated with rituximab.”

Other Maintenance Strategies

Radioimmunotherapy is attractive as a consolidating tool. The RITZ (Randomization Intergroup Trial Zevalin) has been designed to test the efficacy and safety of ibritumomab consolidation followed by rituximab maintenance therapy in relapsing patients with advanced-stage FL responding to immunotherapy.

An alternative maintenance strategy consists of high-dose chemotherapy followed by autologous stem cell transplantation, but it is not clear how beneficial such approaches are. Three studies—GOELAMS (Groupe Ouest Est d’Étude des Leucémies et Autres Maladies du Sang), GELA (Le Groupe d’Étude des Lymphomes de l’Adulte) and GLSG (German Low Grade Lymphoma Study Group)—have produced contradictory findings in patients with unfavourable-prognosis FL.

In Vivo Purging

In the 1990s, ex vivo purging, that is, elimination of tumour cells from the graft, was shown to improve outcome after autologous bone marrow transplant in B-cell NHL (Gribben et al. N Engl J Med 1991;325(22):1525-33). Long-term follow-up suggests that the survival advantage has been maintained. In FL, B-cell purging of the stem-cell grafts did not show any benefit compared to unpurged grafts in terms of progression-free survival or overall survival (Schouten et al. J Clin Oncol 2003;21(21):3918-27). However, “Many groups have continued to believe that monoclonal antibodies given in vivo could replace our ex vivo manipulation of cells,” explained Prof. John Gribben, St. Bartholomew’s Hospital, University of London, UK. This has the added advantage that such antibodies can continue to be administered after transplantation.

Ongoing randomized studies are investigating the use of rituximab for in vivo purging after response to any high-dose therapy. The EBMT (European Group for Blood and Marrow Transplantation)-LYM1 trial in patients with relapsed or resistant FL has a first randomization to rituximab in vivo purging or no purging. In a second randomization, patients are assigned to maintenance therapy or watch-and-wait. “When we have the results of this study, we should be able to tease apart the contribution of using rituximab at the time of stem cell collection and after transplantation,” stated Prof. Gribben.

Progress over the Past Decade

In the past, few patients with CLL have achieved complete response and therapy has been palliative, but survival has improved over the last 10 years. Thus, in a recent single-arm study of the addition of rituximab to a fludarabine/cyclophosphamide combination, complete remission was achieved by 70% of the patients and the overall response was 95% (Keating et al. J Clin Oncol 2005;23(18):4079-88). According to Prof. Gribben, “The addition of rituximab to the therapeutic options seems to improve survival but data from randomized trials that confirm this improvement are still lacking.”

Stratifying Risk Through Biomarkers

In view of the side effects and dangers of transplantation, stratification of patients according to risk could be important to ensure that only patients most at risk of progression are exposed to the most aggressive therapy. As noted by Prof. Gribben, “It is time to move away from one-treatment-fits-all and adjust treatment according to risk as indicated by biomarkers.” Such an approach poses a number of questions, such as which biomarkers should be used, and whether therapy optimized for high-risk groups would overcome the poor risk factors or if these factors also indicate resistance to chemotherapy.

Molecular prognostic factors in CLL include cytogenetic abnormalities, mutational status of immunoglobulin genes, low expression of CD38 and expression of the tyrosine kinase ZAP-70. Genetic studies have been revolutionized by FISH (fluorescence in situ hybridization). With this technique, investigators detected chromosomal abnormalities in 82% of patients with CLL, the most common being 13q deletion (55%), although 11q deletion (18%), 12q trisomy (16%) and 17p deletion (7%) were also common (Dohner et al. N Engl J Med 2000;343(26):1910-6). According to subgroup survival analysis, patients with 17p clearly fared worse than other groups, whereas patients with 13q deletion had relatively good outcomes.

High-risk patients tend to have a poorer response to treatment according to the results of a retrospective analysis of two multicentre clinical trials: CALGB 9712 comparing a regimen of fludarabine followed by rituximab with fludarabine/rituximab and ECOG 2997 comparing fludarabine and fludarabine/cyclophosphamide). Patients with 11q and 17p deletions and those with unmutated IgVH gene had a worse outcome than other patients (Byrd et al. Blood 2005;105(1):49-53).

The Role of Transplantation

As pointed out by Prof. Gribben, “Unfortunately, we do not have randomized data looking at chemotherapy alone vs. chemotherapy plus transplantation.” Some studies have compared allogeneic and autologous stem cell transplantation, but the results are contradictory. Nevertheless, the EBMT has recently published consensus guidelines in an attempt to provide a framework for deciding when allogeneic stem cell transplantation might be appropriate. Thus, patients with 17p deletion and those who fail to respond or who relapse quickly after fludarabine combinations can be considered for transplant in first response (Dreger et al. Leukemia 2007;21(1):12-7), although researchers stressed that further clinical trials are necessary.

Chronic Graft-Versus-Host Disease

Chronic GVHD will develop in up to 80% of recipients from unrelated donors. Despite its importance, there is a lack of agreement on how to grade the disease and therapies remain unsatisfactory. According to Dr. Hans Messner, Princess Margaret Hospital, Toronto, Ontario, “While it is important to realize that the rate of secondary malignancies is greater in patients with GVHD, there is also a significant contribution of chronic GVHD to the control of underlying malignancies.” The onset of GVHD is delayed by weeks to months and is associated with inflammation, collagen production and fibrosis. The mechanisms are poorly understood but aspects such as alloreactivity, autoantibody production and B-cell expansion may play a role.

The incidence of chronic GVHD has increased in recent years because recipients (and donors) tend to be older. In addition, early survival after transplantation has improved, unrelated and partially matched donors are increasingly common and peripheral blood stem cells tend to be used instead of bone marrow stem cells for allografts. Outcome is dependent on the how the disease presents, thus progression from acute GVHD is associated with poor outcomes whereas an interrupted course is an indicator of a more promising outcome.

Administration of antithymocyte globulin has been shown to reduce the risk of developing chronic GVHD, particularly with lung involvement but unfortunately, survival has not actually improved (Bacigalupo et al. Biol Blood Marrow Transplant 2006;12(5):560-5). First-line treatment of established chronic GVHD usually comprises therapy such as cyclosporine and prednisone but outcomes are often unsatisfactory (Koc et al. Blood 2002;100(1):48-51). Given the poor results of first-line treatment, a number of salvage approaches have been attempted. Common salvage treatments include thalidomide and mycophenolate, although “the realization that B-cells may play an important role in GVHD means that rituximab may be useful in the management of this process,” said Dr. Messner.

The agent has been investigated in small studies, with overall response rates of 83.3% (Canninga-van Dijk et al. Blood 2004;104(8):2603-6) and 62.5% (Cutler et al. Blood 2006;108(2):756-62). Despite high overall responses, the number of patients achieving complete response is smaller.

In an effort to explain these results, Dr. Messner suggested, “Some of the interventions we have available may not address all of the manifestations of chronic GVHD, so there may be an opportunity to use different combinations to treat different organ involvements.”

Summary

Targeted therapies such as rituximab are finding a place in many different settings within the group of B-cell malignancies. Its addition to chemotherapy, induction regimens and maintenance therapy have shown promising results in patients with advanced FL. In vivo purging of stem-cell grafts with rituximab could help improve survival. In CLL, the agent may also prolong survival, although poor-risk groups generally appear to respond less satisfactorily to therapy.