Presented by Bruce D. Cheson, MD, at the Radioimmunotherapy of Non-Hodgkin's Lymphoma symposium held at the American Society of Hematology 42nd Annual Meeting, December 1, 2000, in San Francisco, California.

 

 

There are a number of radiolabelled antibodies currently being investigated for treatment of hematologic malignancies. Each has its advantages and drawbacks. The question that needs to be answered is: Which is the winner?

The first of these radioimmunoconjugates is I-131 tositumomab, an IGG-2A anti-CD20, the brand name of which is Bexxar. Although it has some beta emissions, it is primarily a gamma emitter. Unlike Zevalin, Bexxar is generally given with dosimetry. On day zero an unlabeled pre-dose is infused over the course of an hour, and then a dosimetric dose is used to determine patient-specific PK. On days 0, 2, 3, or 4, 6, or 7, three whole body counts are performed, and on days 7-14 a therapeutic dose of 450 mg of cold tositumomab is given, the millicurie dose of I-131 determined by the dosimetry.

In Bexxar clinical trials, 40% of patients had an elevated LDH, 40% had bulky disease, and the median number of prior chemotherapy regimens was three. These patients generally didn't respond to the last chemotherapy, with only 17% showing a complete response, and 30% a partial response that lasted just five months. After treatment with Bexxar, the 192 patients with low-grade lymphoma showed a response rate of 80%, which lasted a median of 11.7 months; complete response was 36%, lasting a median of five years. Of the transformed lymphomas, half responded, lasting about a year; 30% complete remissions, lasting almost two years. The 18 patients with intermediate grade lymphoma failed to respond.

Kaminski et al presented the findings of a tositumomab trial at ASCO 2000. That trial consisted of 76 previously untreated patients, 29% of whom had high tumor burden. The overall response rate was 97%. Three-quarters of those who started off PCR-positive became PCR-negative. At the time of that presentation, the median response duration had not yet been reached. Toxicities of this therapy included human anti-mouse (HAMA) in two-thirds of patients, and two-thirds of these developed flu-like symptoms which researchers attributed to the antibody. There was moderate reversal of myelosuppression, with nadirs at 4-7 weeks. No supportive care was needed, and the patients recovered totally after around 10-12 weeks.

There are some newer radiolabelled antibodies coming along. There is an ongoing Phase I trial of yttrium-labelled anti-CD22, which is epratuzumab. It includes different kinds of antibodies, and some patients have had prior autologous stem cell transplant, some have not, many patients have had prior rituximab therapy, some with partial remission. It is too early to give much data.

Another is Lym-1. It's another IGG-2A, which targets the beta chain of HLA-DR10. It works by the usual mechanisms. Its dose-limiting toxicity has been thrombocytopenia with some hypotension. A series of papers have been published, including 25 lymphomas and 5 CLLs who progressed after standard therapy. Tumor regression started quickly and they claim a 10% complete and 47% partial response rate. But the response criteria are not exactly what one would call conventional.

Those are not the only isotopes that can be used to treated lymphomas, and there are a few new ones which are less prevalent. Copper67 has a half life of 62 hours, a very short penetration, which for some situations might be good and for others might be bad. It has beta emissions comparable to I-131, but the gamma emissions are much more favorable, more like Bexxar, for imaging. It is nicely retained in tumors in vitro, and its hematologic toxicity is what is dose limiting.

In an article recently published in the British Journal of Cancer, 211-astatine was conjugated with rituximab, an alpha emitter this time. This radioimmunoconjugate was reported to have a very short half-life, short path length, and a very high tumor to normal cell toxicity ratio in vitro. It is expected to enter clinical trials soon.

Two of these radioimmunoconjugates may be on the market in the very near future. Can we increase their activity? When is the optimal time to give them? How best can we combine or sequence them with chemotherapy or with other monoclonal antibodies? Can we reduce the toxicities? And which is 'the winner'?

To increase the activity, one can consider increasing the dose, give repeated administrations, enhance antigen expression, augment effector cell function, and combine with other agents. There has been some important work done in increasing the dose of I-131 anti-B1, which is similar to Bexxar.

The first Phase I/II study of I-131 anti-B1 showed that when the patient was used as their own control, the probability of remaining free from failure was significantly longer than the patient's best prior chemotherapy response, and certainly their last chemotherapy response. In a recent paper that came out in Blood, the same radioimmunoconjugate was then combined with high doses of cyclophosphamide in patients with either low-grade or aggressive lymphoma. The results were compared with institutional data using the same chemotherapy without the radioimmunoconjugate. This comparative analysis suggested that with historical controls, a much better progression-free survival rate is attained when the radioimmunoconjugate is added than with the same preparative regimen, particularly for the indolent and aggressive lymphomas. The goal is to eventually replace total-body irradiation with a radioimmunoconjugate.

There are very limited data on repeated dosing with radioimmunoconjugates. Can it be done? In Kaminski's recent paper in Blood, seven of the 53 patients got a second dose in order to get a better response, but it didn't work. Only one patient went from stable disease to partial response. None of the other patients improved the quality of their response. However, there were 16 patients who progressed after getting the antibody and were re-treated. They had nine responses of the 16, including five complete remissions, with a median progression-free survival of 11 and a half months. So, yes, they can be re-administered.

What about hooking them to other forms of antibodies? There are a number of unconjugated antibodies that are candidates. Rituximab is generally given with Zevalin, Campath, epratuzimab HU1D10, and devacizumab. They do exist, and clinical trials in the future will probably combine one or more of these with the concept of targeting multiple antigens and attacking the lymphoma cell through multiple targets.

There are a number of ways to augment effector cell function. One option is to augment CD20 expression. This is an interesting concept that is in clinical trials and is based on the use of IL-12, which has a regulatory effect on T cells. It facilitates specific cytolytic T-cell responses, promotes the development of TH-1 cells, enhances antibody-dependent cellular cytotoxicity, enhances NK activity, and, importantly, induces gamma-interferon and TNF secretion by T-cells and NK-cells.

The concept is to hook the antibody to the lymphoma cell. It attracts, through ADCC, natural killer cells, T-cells, and macrophages, In the presence of IL-12 you get a virtual local explosion of gamma-interferon and TNF that further kills the tumor cells, as more and more T, NK, and macrophages are drawn into this network.

Well, when is the best time to use radioimmunoconjugates? Initial therapy is when they're likely to have their greatest activity, but the downside is that they may cause reduced tolerance to subsequent chemotherapy.

What about a salvage therapy? There has been a high response rate in chemotherapy and monoclonal antibody failures, but a lower response rate than with front-line. As shown both by Zevalin and Bexxar, there is increased myelosuppression and a greater risk of secondary myelodysplasia.

If you look at tositumomab I-131 by the amount of prior therapy, the response rate goes down, the median duration of response goes down from "not-reached" to a year, to seven months; the complete response rate goes down; and the median duration of those complete responses goes down dramatically. In addition, the toxicity goes up. The number of patients requiring platelet transfusion goes from zero up to 16; red cell from zero to 15. The patients requiring growth factor also increases.

It is difficult to increase radiolabeled antibody activity by combining them with chemotherapy because these are myelotoxic compounds. So you have a couple of options: you can sequence them, but which is the best direction, antibody first, chemotherapy after, or the converse? There are data which suggest that the antibody should be given first in vitro. They can possibly be combined using growth factors or with stem cell support.

One concept of sequencing them is in the Southwest Oncology Group trial, currently ongoing, in which CHOP is being compared in advance-stage indolent lymphomas with CHOP and Bexxar. Another sequencing concept is Czuczman's rituximab vs. CHOP, followed by Bexxar.

Is there life after radioimmunoconjugate therapy? Can you do something once the patient relapses? The answer is: I don't know.

Half of the patients in the tositumomab experiments received some chemotherapy, a quarter got radiation, and there were other treatments as well. However, the company did not follow those patients, so there is no record of response. But the possibility of autologous stem cell transplants can be considered in a very small number of patients. All 10 had successful harvests after I-131 and 8 of the 10 engrafted. So there is this potential.

In order to reduce toxicity, an effective dose can be lowered, particularly in the setting of thrombocytopenia. You have to protect normal target organs, as with I-131 tositumomab, where the thyroid must be protected. Secondary AML and MDS can be minimized, perhaps by selecting those patients ahead of time who haveclonal hematopoiesis or prior cytogenetic abnormalities, because those are the patients most likely to develop secondary MDS. You can conceivably reduce HAMA by pre-treatment with an immunosuppressant drug like fludarabine. In an institutional experience, three courses of fludarabine were given, followed later by Bexxar. The 14 evaluable untreated patients in this series showed a very high response rate. There were two complete remissions, 11 partials, and nobody developed HAMA, compared to 65% in the previous study. Remember that HAMA is only important if you plan on using the drug repeatedly.

So, which is the winner?

If you look at the data in these two studies of Y90 ibritumomab and I-131 tositumomab, the overall response rate and the complete remissions are almost identical, and the median response duration is exactly identical.

So, what happens when a patient fails rituximab? If a patient responded to rituximab and then relapsed, they have a 40% chance of responding again with an 11% complete remission and the responses lasting at least as long as the first response.

With either of these radioimmunoconjugates, the likelihood of getting a secondary response is in the range of 60%, and a complete response in the range of around 20%. Quite comparable, but they do tell you that they're quite effective, probably due to the radiolabeling.

Another way to pick the winner is its toxicity, including myelosuppression, organ damage, and secondary malignancies? And which is going to be the least toxic to the surrounding world, with regards to radiation exposure?

What may be the most critical point in deciding the winner is which will be the most convenient to administer and which will turn out to be the most cost-effective? If they both get on the market, this may be a rare example of when price gets driven by competition in this industry, and driven down.

We now have several highly active radioimmunoconjugates. Their use may vary with the clinical indication. There may be a role for both of these, as well as for a number of unconjugated antibodies. There is no room for single-agent comparisons. The most important goal for all investigators is to move the field forward; to find which one of these agents is the one that is best integrated into a multi-modality approach, combining or sequencing it with chemotherapy, combining it with other unconjugated antibodies, with cytokines, or followed with a vaccine.

More information about these trials can be obtained from local cancer centers, your local cooperative group, the pharmaceutical sponsors, or the National Cancer Institute.