From Terry's Techniclone Terrace Nov. 17 1998 by golfdad97

My disclaimer concerning motivation for this summary is the same as for that given for Rituxan, in that this summary is meant to be for informational purposes only for those interested in discussing differences in the potential clinical outcomes of monoclonal antibody therapy of NHL. Again, the lack of paragraph distinction is regretted.

Bexxar: Anti-B1 antibody (Coulter). This is a different antibody targeted to the CD20 antigen of B-lymphocytes and is used as a radiolabel conjugate and is the direct correlate of radioimmunotherapy currently in use by TCLN and its Lym-1 antibody (to be described later). This form of therapy is championed by M. Kaminski and the group at Ann Arbor, Michigan and in my opinion, these people strongly believe in the clinical efficacy and approaches they use in treatment with this reagent. As you will see...they are willing to push the envelope in attempting to make this a front-line therapy for NHL.

Initial studies of Phase I focused upon the use of the I-131 (will confine remarks to iodine-based radiotherapy) conjugated to the B1 antibody and like all Phase I studies, they were limited to patients in dire need of further therapy with few alternatives. Studies defined the parameters of safety, dose and with this form of leukemia, one could look for therapeutic results. There are caveats to this form of therapy (radiolabel) not found with the use of naked antibodies...since we are delivering radiation to target sites in the body, and the toxicity will be limited by effects on normal tissue no different than observed for whole body irradiation, targeted beam radiotherapy or chemotherapy with toxic agents. Initial studies have to determine that the radiation uptake by areas of tumor is greater than that of normal organs and close monitoring of vital blood counts, effects on bone marrow, GI tract, central nervous system, etc is necessary. The logistics and expenses of this form of therapy can be extensive.
Pilot studies in 34 patients with NHL was performed several years ago and the dosimetry was established (conditions underwhich one could accurately estimate the amount of radiation being delivered to critical areas containing lymphoma). Hematologic toxicity was limiting and doses were escalated until about 750 rads (a measure of radiation being actually deposited in tissue) was found to be the upper limit, and represented about 50-75 mCi of radioactive material. A single dose of B1 (when I say B1, it is always radiolabeled with I131) was given as therapy, and of the 28 patients that could be evaluated, about 50% achieved a complete response (see earlier definitions) and a partial response (Bexxar studies usually use 50% reduction as partial) in 8 patients. The median duration of remission was about 16.5 months. These results could be broken down further in that of the 28 patients, 21 patients were low-grade or transformed NHL and of these patients, 19/21 responded and of the 7 intermediate-grade lymphoma patients, 3 responded. Hence, again, as with most therapies, better responses were observed in the low-grade lymphomas.

A comment on these initial studies is warranted. Radiotherapy with antibodies tends to unlease his hematologic effects due to resident time in the bone marrow...and if bulky disease or extensive bone marrow involvement is present, then non-specific toxicity will increase, just because of the targeting of the antibody. This is a common event in higher stage disease (say III and IV) because the bulk of the disease is not confined to discrete areas, such as lymph nodes. Hence, not only are there different risk factors than observed for the use of naked antibody, the whole system becomes complex in considering specific sites of disease and effects of the radiolabel...something to keep in mind.

These initial studies were reported a couple of years later (in a recent paper in Journal of Nuclear Medicine) and described results of 34 patients. The maximum tolerated dose was established as about 750 rads and in line with intuition, the patients who received higher doses of the therapy and responses were as described above. Some patients developed antimouse antibodies (since this antibody is mouse), with additional data that complete responses averaged about 13 months and the median duration of response for all patients who did respond about 11.5 months.

This group quickly took this form of therapy to the front line in several respects. First, the final Phase I/II results were reported this spring and invovled 59 patients (28 low grade, 14 transformed low-grade, and 16 intermediate and high grade lymphomas). The median number of prior chemotherapies was 4 and remember that these studies involve patients who are nonresponsive to further chemotherapy. Without intervening for bone marrow loss (for example, will discuss autologous bone marrow transplantation below), the therapeutic dose remained at about 750 rads. 24/28 of the low-grade patients responded and a complete response was observed in 46% of these patients. The mean tumor dose was about 14.5 times the whole body dose, meaning that localization to the tumor was good and much higher than that received by normal tissues, on the average. 15% of the patients developed antimouse reponses which can limit further therapy. To be honest, I could not calculate how the intermediate grade patients fared on this therapy, since the given numbers (ASCO) were confusing to my trained eye.

However, the power of clinical funding for this therapy is apparent. Also reported this spring are several other aggressive moves with B1 antibody. For example, the Michigan group showed that NHL patients who relapse from the initial B1 therapy (from the Phase I/II described above) can be retreated. 13 patients were retreated and of these 13, 12 responded to the initial therapy....described above. 11 of these patients were from the low-grade NHL group (suggesting that the intermediate grade patients above did not do well?) and of these 13, 8 responsed to re-treatment with a median duration of about 8 months. 4 of the 13 had a complete remission (second remission) of about 10 months. Again, it was noted that the higher the dose received (for whatever reason), the likelihood of response was greater...hence, this strategy was modestly successful, in that re-treatment of relapse patients can be attempted with some degree of confidence. But wait...there's more.

In collaboration with the O. Press group at University of Washington, the Coulter people have examined the effects of Bexxar therapy with chemotherapy....which we all know we are going to have to do. They described at ASCO, a Phase I/II trial of combining high-dose I131-B1 with chemotherapy (etoposide, cyclophosphamide) and autologous bone marrow transplantation in relapsed patients. Now what this means is as follows....they are going to adminster whopping doses of the radioactive material couple to the antibody, and they know it is going to wipe out the bone marrow...and they are going to give very potent and toxic chemotherapy, which they know is also myelosuppressive and they are going to "rescue" these patients from the myeloablative effects of these therapies by reinfusing their bone marrow stem cells that will give rise to new blood cells...and recovery from this massive attack on the lymphoma that will not go away. Very aggressive therapy, but cancer is an aggressive disease. They report treatment ranging up to 850 mCi (contrast that with perhaps 50-75 mCi of single dose administration) calculated to deliver up to nearly 3000 rads to critical organs. Of the 37 evaluable patients (26 with indolent, low-grade lymphoma and 12 with aggressive NHL originally enrolled in study), 33 are alive and 29 are progression free (not necessarily disease free) after 1.5 years. 4 patients have died. This study will continue...

In the meantime, the Coulter people have evaluated the with an independent review...the response to B1 antibody therapy in low-grade (or transformed low-grade) NHL...and this is the source of the artistic statistics that Berblady commented on a few days ago, with her astute and discerning fashion. Be that has it may...using the patients that were refractory to further chemotherapy, they examined whether treatment with B1 gave a remission duration or response that was "at least as good" as the last chemotherapy they received...which is an academic question of how are you going to approach treating the refractory patient...and can you do as good as chemotherapy. And wouldn't we rather have anything than chemotherapy, perhaps? But I will not digress at this late stage of information. To make a long analysis short...of the 45 patients evaluated, the question was asked how did they do compared to their last chemotherapy. The facts are: 11 patients did as good with either therapy...19 did better with B1 (at a design cutoff, I believe of at least 1 month median difference) and 11 did better with their last chemotherapy. I will leave it to all the statistic buffs to play with these results...but wait,...

They have at least got the ambition to take on first line therapy, since they now describe two other approaches involving the use of B1. First, there is a recent paper (J. Clin. Oncol. 16: 3270, 1998) in which they report the use again of massive doses of B1 therapy with bone marrow rescue (they purge the bone marrow of potential malignant cells as best they can by a variety of biological techniques) in patients who have relapsed from prior chemotherapy. Hence, this study is like that described above except they don't add the new chemotherapy. The therapy was administered to 29 patients (19 low grade and 10 high grade), most with stage III and IV disease which we would expect. Dosing ranged up to nearly 800 mCi. The results are not easy to interpret (always encounter this with the Press group, but no offense intended)...but as best as I can decipher...25/29 patients responded, and 23 of these were complete responses and the best responses were in the low-grade group (that is as good as I can see for the moment). 11 of 19 patients with indolent lymphoma remain in remission up to about 3-6 years and only 3 of the patients with aggressive disease remain in remission (27, 37 and 87 months). The overall survival rate for low-grade is 78% at 4 yerars...and the median time to treatment failure is about 3 years for low-grade and about 2 years for the high-grade group.

But it ain't over...they have described a study back at Michigan where this form of therapy has moved to first line with NO prior treatment of any kind in follicular lymphoma, a type that is amenable to this form of therapy (when you analyize all the groups). They received therapy up to the 750 rad limit and the intent is to enroll 60 patients...21 are now evaluable. Complete response in 71% and partial response in 29% (100% total) and of the complete responses, 2 patients have relapsed (median duration not yet reached at about 17 months) and 5 out of the 6 patients who had the partial response have relapsed...and so the intent is to back this treatment philosophy up until limits of success are reached.