This coverage is supported by an educational grant from

Radioimmunotherapy in Patients with Non-Hodgkin's Lymphoma Refractory to Chemotherapy and Immunotherapy

 

 

Presented by Thomas E. Witzig, 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.

In 1998, after the initial Rituxan study was published, showing about a 50% response rate for the antibody, and results of the Phase I,II study of Zevalin were released, showing about an 80% response rate, questions arose as to what yttrium was really adding in Zevalin. This question was addressed in prospective trials by doing two separate trials.

The first trial was a randomized trial in which patients were randomized to receive either the Zevalin (yttrium conjugate) or rituximab. There were 134 patients in the study, which was closed in August 1999.

The second study looked at patients with Rituxan failure and then treated them with the yttrium-label antibody. Our hypothesis was that, indeed, the yttrium was adding something to the response rate. Patients received either the standard regimen of Rituxan (375mg/m2 every week for four doses) at that time, or the Zevalin regimen that was used in the preliminary trials.

The primary variable, the objective of the trial, was to look at the overall response rate. The study was blinded and all the scans were reviewed by a separate panel called the 'LEXCOR Panel,' which is a group of radiologists and lymphoma experts who looked at all the scans to further document the response rates, not knowing whether the patient had received Rituxan or Zevalin.

The secondary variable was to look at the duration of response and the time to progression, and also to again confirm where the dosimetry was needed for safety.

The inclusion criteria were very similar to those described for the early trials of Zevalin, i.e., good performance status, a CD20 positive lymphoma, platelet count of over 150,000, an absolute neutrophil count over 1500, and less than 25% marrow involvement. Participants could not have CLL or over 5,000 circulating malignant lymphocytes. Patients could not have a CNS lymphoma or HIV-related lymphoma. They had to have fairly normal liver and kidney function, and they could not have undergone any prior anti-CD20 therapy.

The patient characteristics were well-balanced, so that study participants were equally divided between the Zevalin and the rituximab arms. There was no difference in the age or gender between the two arms.

Looking at patient demographics a little more closely, it can be seen that patients up to age 80 were treated in both groups, with the median age being about 60. Most of them had received two prior chemotherapy regimens, and about half were resistant to their last chemotherapy. About 40% had bone marrow involvement. About half had bulky disease, depending on how you defined it, 50% of them greater than 5 cm.

So, the study participants were a fairly representative group of what clinicians see in their practices. About 60% had been resistant to any prior chemotherapy.

Remember, the goal of the study was to look at the response rate, and what was found was that the results were very similar to those previously published for Rituxan in the Phase III study, and in the Phase I,II study of Zevalin. Overall, it was shown that Zevalin therapy was associated with an 80% response rate, while rituximab was associated with a response rate of 50%. The complete response rates were 34% for Zevalin, and 20% for rituximab.

Statistically significantly greater clinical efficacy was found for Zevalin, compared to rituximab, in all of the different patient groups. In other words, if you looked at older patients versus younger or males versus females or patients that had bone marrow involvement or not, Zevalin was superior as far as the response rate.

Given that the last patients were added to this study only about one year ago, there are not a lot of data regarding time to progression and duration of response. In an abstract published at the 42nd annual meeting of the American Society of Hematology (December, 2000), it is mentioned that the time to progression at this point is not yet different between the two arms. However, if you look at the time to next anti-cancer therapy, in other words the time when the patient next required treatment, you can see that there does appear to be some difference.

Adverse effects in this trial were just what you would expect for Rituxan or Zevalin. There was really no major organ dysfunction. We have not seen any of that in any of the trials with Zevalin, as far as kidney, liver, heart, lung. The only toxicity has been hematologic. There were very low HAMA and HACA rates.

Hematologic toxicity associated with these agents is significant. Zevalin-treated patients had a platelet nadir of about 41,000 and ANC nadir of 900 neutrophils. They were also a little more anemic than those in the Rituxan arm. Only about 6% of patients had Grade IV toxicity of platelet counts less than 10,000.

Overall, the single-agent response rates in this trial appear to indicate a statistically significantly higher efficacy for Zevalin, compared to Rituxan.

About the same time as the study just discussed, another study was conducted to approach the question of whether yttrium was adding anything to standard therapy. This study took patients who had undergone Rituxan therapy but had failed it. Failure of Rituxan therapy was defined in two ways: a patient responded, but the response lasted less than six months, or a patient was simply refractory to the therapy.

This was a single-arm, multi-center, open-label trial. There were 57 patients involved in the trial, almost all of whom were diagnosed with follicular lymphomas. All these patients received the standard 0.4 mCu/kg dose of Zevalin. The trial closed also about a year ago.

The primary objective of this trial was to determine the overall response rate in this population, while the secondary goal was to compare the overall response rate and duration of response to what the patients had previously received with their last chemotherapy or their last dose of rituximab.

The response evaluation in this study was performed by the investigators at each site by looking at the scans, doing measurements, and coding the responses. The scans were then sent to the central LEXCOR panel for independent evaluation, which may have added a lot of work to the trial, but added a lot of validity in the sense that these investigators did not know what this patient was receiving and where they were in the treatment course.

The patient characteristics in this trial were actually a little different than in the other trials. They were about the same age group and most had follicular lymphomas, but they had undergone more prior therapies. A third of them had bone marrow involvement, and almost three-fourths of the patients had bulky disease, depending on how it is defined (here, greater than 5 cm). About 30% had had prior radiotherapy. And if you look at resistance to their previous chemotherapy, about 82% of the patients had shown some resistance to prior chemotherapy.

So, overall, the disease was more advanced in this group than in previous trials.

Using international workshop criteria that are now in place, an overall response rate of 74% was observed, with most responses being partial remissions. Overall response using IDEC criteria, which use a more strict 28-day confirmation, was 59%.

Median time to progression in this study was about nine months, although a few people have not yet relapsed.

Another question asked in this trial was, "How did the response to Zevalin compare with the prior response to chemotherapy?" What the investigators wanted to show was that the Zevalin response was at least as good as the patients' last chemotherapy. Data indicate about what you might expect: if patients were resistant to their last chemotherapy and then got Zevalin, they had a lower (47%) response rate; whereas if they had some chemotherapy response and then relapsed prior to this trial, their response rate was better (64%).

Looking at adverse events for this trial, there was an absolute neutrophil count nadir of about 700 k/ul. Nadirs for platelets and hemoglobin were about 33,000 k/ul and 9.9 gm/dl, respectively. It is interesting to note that the nadirs in this study all came out in about 50-60 days, compared to 10-14 days associated with chemotherapy-typical nadirs. This is a characteristic of radioimmunotherapy. It takes about 8-13 days to recover those counts. Usually it is a rather gentle drop, with not a lot of patient toxicity or needing to go in the hospital. Again, the adverse events were primarily hematologic. There was no major organ dysfunction. And the HACA rate in this trial was less than 2%.

There was, however, one case of acute myelogenous leukemia. This is something that we are going to need to watch. There have been other trials of other radiolabeled antibodies that have seen myelodysplastic syndromes occurring, and we must be very careful to monitor this as the years go by to see what the actual rate of these conditions is going to be in this patient population.

In summary this trial showed, again, an excellent overall response rate. The response rate associated with Zevalin was significantly greater than overall response rates to prior Rituxan therapy, and about the same as response rates to most recent chemotherapy.

It should also be pointed out that this treatment is quite easy to give. It is delivered over one week, which is certainly an advantage of this kind of treatment in the relapsed lymphoma patient.

These two trials, I believe, provide the evidence to the effect that adding the radioactive particle, the yttrium in this case, does seem to add efficacy beyond what cold, or non-labeled, antibody provides by itself. Of course, the long-term follow-up data are going to be very important in determining overall survival rates, times to progression, and durations of response.