Zevalin

Over the last thirty years, the yearly incidence of non-Hodgkin's lymphomas (NHL) has almost doubled to about 20 new cases per 100,000 people. The cause is mostly attributed to the more frequent use of organophosphate and thiazine pesticides in agriculture. Since 1995, this impressive increase has fortunately leveled off.

The classification of NHL has evolved markedly from the original Rappaport and Kiel classifications, based mostly on morphology, to the recent WHO-REAL classification using both morphology and cell surface phenotype to characterize each group. These groups can then be organized according to their clinical behavior. (Table 1)

Each of these newly defined entities has been further characterized by molecular biology and a specific gene translocation was defined for most of them. This is summarized in Figure 1.

For the last thirty years, the CHOP (cyclophosphamide (Cytoxan(R)), hydroxydaunorubicin (Adriamycin(R)), Oncovin(R) (vincristine), and prednisone) regimen has been the first line of chemotherapy. In a landmark, intergroup, randomized study, three third-generation regimens challenged CHOP and were found to provide no additional disease-free or overall survival benefit than CHOP, but more toxicity.1

Thus, despite unsatisfactory long-term remission rates, CHOP remains me only recognized treatment for advanced NHL.

MONOCLONAL ANTIBODIES2

Most B-cell lymphomas express CD20 on their membrane. A monoclonal antibody specific for CD20 was initially recognized to induce apoptosis in vitro and allow specific elimination by cytotoxic T-cells in vivo.3 A humanized anti-CD20, rituximab (Rituxan(R)), is now in clinical use. As a single agent in advanced relapsed NHL, riuximab produces a 30% overall (complete plus partial) response rate lasting for several months with very minimal toxicity.4 In combination with CHOP rituximab improved relapse free survival and overall survival in de novo NHL.5 A recent, randomized study of 400 patients showed a significant advantage for CHOP plus rituximab compared to CHOP alone.6 A clear advantage was seen for event free survival (61% vs 43%) and overall survival (70% vs 57%) at 2 years follow-up. Furthermore, patients treated initially with CHOP plus rituximab, who relapse later, are still responsive to CHOP plus rituximab in 93% of the cases.7 Conceptually, rituximab should be even more efficacious in the setting of minimal residual disease such as that attained after high dose therapy followed by autologous stem cell transplantation.

RITUXIMAB AND TRANSPLANTATION

The use of autologous stem cell transplantation (ASCT) as a curative approach for the treatment of relapsed or poorly responsive NHL is debated, but many studies provide convincing data to support ASCT for NHL. Despite many successes, relapse, which may be viewed as failure to eliminate minimal residual disease (MRD) in the patient by high dose chemotherapy given prior to ASCT, is all too frequent and often occurs in areas of former bulk disease. Studies using gene marking techniques have demonstrated that the autologous bone marrow graft itself may participate in relapse.8,9 Despite reducing the level of contaminating tumor cells, in vitro "purging" of the stem cell graft is unable to eliminate all contaminating malignant cells, leaving a small number in the purged graft.10 Thus, the post transplant patient should be considered likely to have not only persistent MRD but engrafted tumor cells as well. Hence, the full eradication of lymphoma cells can only be achieved using a "consolidation" approach after ASCT. Unfortunately, at this time in the patients' treatment, additional chemotherapy is toxic and, to a minor extent, might increase the risk of secondary malignancies. Many groups have used anti-CD20 to perform an in vivo purging of the graft just before collection and high dose therapy followed by autologous stem cell reinfusion (ASCR).

At the Roger Williams Medical Center, a similar approach was studied using rituximab in the setting of MRD. Due to the concern of increasing infectious complications by using rituximab before transplant we chose a consolidation approach. We hypothesized that immune consolidation given immediately after ASCT would improve the outcome of NHL patients because it would treat MRD due to both disease remaining in the patient after high dose chemotherapy as well as tumor cells contaminating the graft. We began a pilot, phase II study of ASCT for NHL with immune consolidation using rituximab. The results were compared to our most recent historical controls receiving the same treatment through ASCT.

Between November 1994 and September 2001, 21 consecutive patients received an ASCL for advanced or relapsed NHL. The first 10 patients received a standard ASCT; the later 11 received rituximab consolidation following ASCT. (Table 2) The high dose chemotherapy used prior to autologous blood stem cell infusion was CTCb11 consisting of cyclophosphamide (6000 mg/m^sup 2^ total dose), thioTEPA (500mg/m^sup 2^ total dose) and carboplatin (800 mg/m^sup 2^ total dose) chosen for its relatively decreased toxicity compared to other transplant regimens12 and its known activity in a broad range of lymphomas.13 In the consolidation group, all patients were given rituximab starting during the second or third month after transplant at a dose of 375 mg/m^sup 2^ weekly for four weeks, given every six months for five cycles.

The frequencies of serious or life-threatening toxicity during the early post transplant period (days 0 to 100) were similar in both treatment groups. Rituximab was well tolerated with minimal side effects. One rituximab patient presented with a C. albicans pneumonia (confirmed by open lung biopsy) 14 months post-transplant but was effectively treated with a long course of fluconazole. The patient remains in complete remission at 32 months of follow-up.

Analysis of freedom from relapse (FFR) to estimate the relapse rate was performed at a median follow-up of 24 months with a minimum follow-up of 16 months. The actuarial 30-month relapse rate was 28% for the consolidation group and 50% for the controls. Overall, 4 relapses were registered in the treatment group and 6 relapses in the control group. The potential advantage observed for the consolidation group was not mathematically significant (two tailed P=0.17) with this small sample size and short follow-up. However, the median time to relapse was 7 months for the historical group and 31 months for the consolidation group.

At the time of this analysis, 10 patients have died, 3 in the consolidation group and 7 in the control group. Four deaths were due to antibiotic resistant opportunistic infections (2), toxicity (mucositis and respiratory failure; 1), or intercurrent events (sudden death at home; 1). Six deaths were due to recurrent disease. The actuarial overall survival (OS) rate at 30 months was 70% and 40% for the consolidation and control groups, respectively (two tailed P=0.056. (Figure 2) The data are suggestive of an advantage for the rituximab treated group. Further, the median time to death was 8 months for the historical controls but not yet reached for the consolidated group.

The analysis of event free survival (EFS) confirmed an advantage for the consolidation group over the controls. The projected EFS rate at 30 months was 63% and 30%, respectively (two tailed P=0.056). Further, the median time to relapse or death was 4 months for the historical controls and 31 months for the consolidated group. In both the consolidation and control groups, one patient each is alive but in relapse.

These results support the hypothesis that minimal residual disease persisting after high dose chemotherapy and autologous stem cell infusion may be controlled by immunotherapy with rituximab for NHL. It is feasible, non-toxic and appears to provide a major advantage compared to non-consolidated historical controls. Other investigators are exploring the use of rituximab peri-transplant as well.14-17,19 We cannot assess the long-term risk of secondary malignancies due to rituximab in these studies.

EMERGING THERAPEUTIC TOOLS

Alemtuzumab:

Alemtuzumab (CAMPATH-1H) is a humanized monoclonal antibody targetting CD52, a surface antigen present on most normal and malignant T and B-cells with a high level of expression. Alemtuzumab has been studied in relapsed or refractory B-CLL18, 19 in T-cell prolymphocytic leukemia and cutaneous T-cell lymphomas20 with reasonable success. The effect on relapsed indolent NHL has been disappointing.21 Table 3 compares and summarizes the information known on rituximab and alemtuzumab.

Anti-CD22 and anti-HLA-DR:

Based on the success of the monoclonal antibody approach, new targets are currently in development. Epratuzumab is a monoclonal antibody against the CD22 antigen present on 75% of B-lymphocytes and has been used in phase II clinical trials with a 20-40% overall response rate. In combination with rituximab, the response rate was 67%.22 Another target is HLA-DR expressed on normal and malignant B cells. Apolizumab (Hu1d10) is a monoclonal antibody directed against HLA-DR inducing in vitro lysis of lymphoma cell lines. Although preliminary, a phase one trial showed some durable responses in follicular lymphoma patients.

Radioimmunotherapy:

Indolent lymphomas are highly radiosensitive. Radioconjugated monoclonal antibodies against CD20 have the advantages of acting on CD20 negative malignant neighbouring cells, in poorly vascularized tissue. Zevalin(R), a murine anti-CD20 (ibritumomab) conjugated with ytrium 90 is a high energy pure [beta]-emitter and can be administered on an outpatient basis. In a phase III trial, the overall response for the radioimmunoconjugate was 80% versus 44% for rituximab.23 Bexxar(R) (tositumomab) is an anti-CD20 monoclonal antibody of murine origin linked with iodine131 which requires a prolonged stay in a specialised inpatient setting but yields a high rate of prolonged complete remissions in pretreated NHL patients.24 Bone marrow toxicity is dose limiting for both radioimmunoconjugates. The most ideal setting for radioimmunoconjugates is after conventional therapy and stem cell collection but before high dose therapy as additional cytoreductive therapy pre-transplant.

CONCLUSION

The end of the 20th century was marked by the first therapeutic use of targeted specific immune treatments for management of NHL. These monoclonal antibodies are both safe and much less toxic than chemotherapy. They can be combined with chemotherapy, tagged with radioactive elements, or used in the setting of high dose therapy followed by ASCT. New agents are under evaluation. Unfortunately, these are very expensive.

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Jean-Francois F. Lambert, MD and Gerald J. Elfenbein, MD

Jean-Francois Lambert, MD, is Senior Registrar, Division of Hematology, University Hospitals of Geneva.

CORRESPONDENCE:

Jean-Francois Lambert, MD

Division of Hematology

University Hospitals of Geneva

CH 1211, Geneve 14, Switzerland.

phone:+4122 372 39 33

fax:+41 22 372 72 88

e-mail: jean-francois.lambert@hcuge.ch

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