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Alert Number 13

Results of Phase - 2 Ontak in Relapsed CLL Patients

Date: April 15, 2004

We have just published a long article on the LMB-2 immunotoxin, and the recently announced Phase - II clinical trial using this compound. LMB-2 targets the CD25 marker on B-cells, and carries as a payload a fragment of the pseudomonas toxin to carry out the cell kill.

This Topics Alert is to bring you up to speed on another immunotoxin you may have heard of, Ontak. This drug also targets CD25 marker but instead of the pseudomonas toxin fragment it carries a fragment of diphtheria toxin. The logic is very similar. Below is an abstract of the results of a Phase II clinical trial that was conducted with mostly very late stage and certainly fludarabine relapsed and refractory patients. In other words, a tough crowd. Out of 18 patients recruited for the study, 12 were available for evaluation (I expect the other patients dropped out of the study before completion, possibly due to poor tolerance of the drug or progressive disease, something that happens frequently when one is dealing with advanced stage patients.)

11 out of the 12 showed reduction in blood CLL counts (remember, peripheral blood CLL cells are the easiest to kill, they are no more than the tip of the iceberg), 6 of these were more than 98% reduction in blood CLL counts. 7 out of 12 patients showed "some" reduction in lymph node size, the two star responders had 60% and 80% reduction respectively. I wish this was a little better, once again it is those dastardly lymph nodes that are the stumbling block. Using pre- and post bone marrow biopsies, 7 out of 11 patients had more than 50% reduction in bone marrow involvement, while 3 of them had more than 98% reduction. Pretty good for this refractory group of patients. Toxicities were not too bad, I am particularly pleased that there was no significant myelosuppression or immunosuppression. This is one area where immunotherapies such as this and LMB-2 have a big advantage over conventional chemotherapy. The progression free survival times may not seem like much, but given the nature of the patient group they are actually quite good. I am sure there will be new clinical trials of Ontak, with slightly different protocols and perhaps with immune boosters such as Cpg-ODN that we discussed in the LMB-2 article, or "Targretin" that appears to have a similar effect (see second abstract below), namely increasing the expression of CD25 marker on the target cancer cells. If you have relapsed or aggressive disease, and not a good candidate for bone marrow transplants because you do not have a well matched sibling donor, it might be worth your while to discuss immunotoxin therapy clinical trials with your doctor. Even people who are looking at a "MUD" (matched unrelated donor) transplant may wish to consider this type of therapy as an intermediate stage, since it does not seem to burn any bridges. Tough decisions to make, but it is better to have a couple more options than have your back against the wall, right?

If you want to read full text articles of either of the abstracts cited below, write to us and we will help you locate the PDFs.

Be well,



Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3555-61.

A phase II study of DT fusion protein denileukin diftitox in patients with fludarabine-refractory chronic lymphocytic leukemia

Frankel AE, Fleming DR, Hall PD, Powell BL, Black JH, Leftwich C, Gartenhaus R.

Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157

PURPOSE: Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. We tested the safety and efficacy in these patients of a diphtheria fusion protein DAB(389)IL2 (denileukin diftitox) directed against the interleukin 2 receptor that is expressed by CLL cells.
EXPERIMENTAL DESIGN: DAB(389)IL2 was administered by 60 min i.v. infusions for 5 days every 21 days at 9 or 18 micro g/kg/day for up to eight cycles.
RESULTS: Eighteen patients were treated. The mean age of the patients was 61.8 years. There were 14 males and 4 females. Two had Rai stage I, 6 had Rai stage II, and 10 had Rai stage IV. The mean number of prior treatments was 4.5 (range, 1-11). Responses were evaluated by peripheral CLL counts, computed tomography scans of all nodes and bone marrow biopsies. Twelve patients received greater than or equal to three cycles of DAB(389)IL2 and were evaluable for response. Eleven of 12 patients showed reductions of peripheral CLL cells, with 6 of 11 showing >95% reductions. Seven of 12 patients showed reductions of node diameters on exam and computed tomography scans, and 2 of 12 showed 60 and 80% shrinkage, respectively. Pre and postbone marrow biopsies showed a reduction in CLL marrow index in 11 patients. Seven of 11 patients had >50% reduction, including >98% reduction in 3 patients. DAB(389)IL2 produced 2 of 12 (17%) partial remission and 7 of 12 (58%) minimal responses. Progression-free intervals in the responders were 1, 1, 3+, 4, 9, 10, 10+, 14 and 19+ months. Toxicities were mild to moderate and included asymptomatic, transient transaminasemia, fever, asthenia, hypoalbuminemia, nausea, vomiting, myalgias, rash, anorexia, vascular leak syndrome, and elevated creatinine kinase. Antidiphtheria toxin antibody levels were variable and ranged from 0 to 9 micro g/ml (n = 5).
CONCLUSIONS: DAB(389)IL2 produced a rapid decrease of leukemic cells in the bone marrow and peripheral blood of most chemotherapy refractory CLL patients. Most patients also tolerated DAB(389)IL2 well, without significant myelosuppression and/or immunosuppression. The prolonged progression-free interval and subjectively observed quality-of-life in responders is intriguing. The results suggest DAB(389)IL2 has biological activity in patients with B-cell CLL. Follow-up studies of combinations or altered schedules or doses to improve the response rate are warranted.

PMID: 14506141

Editor's Note: "high-affinity IL-2R" is the same as CD25. Same marker, different way of saying it.

Blood. 2002 Aug 15;100(4):1399-403.

Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox.

Gorgun G, Foss F.

Department of Hematology Oncology and Experimental Therapeutics, Tufts New England Medical Center, Boston, MA 02111

Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10(-6) to 10(-10) M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R-targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.

PMID: 12149223

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