Saturday, June 25, 2011

Blinotumamab 3. Adult ALL

I want to concentrate on two papers which describe the treatment of acute lymphoblastic leukemia with blinatumomab. The first is published in J Clin Oncol this week (June 20th 2011) and descrbes a study of treatment of patients with minimal residual disease detected by PCR following their induction and consolidation treatment. These were all adult patients who carry a bad prognosis. I have a few remaining patients with this disease, but most have quite bad GVHD having required a transplant to salvage them. Most who have not have really bee young adults with what amounts to the same disease that occurs in childhood, which has a much better prognosis.

Although about 80% of adult ALLs have a CR after induction chemotherapy, 50% experience relapse and chemoresistant disease. In this trial patients were treated with Blinatumomab 15 microgm/sq m/24 hours by iv infusion for 4 weeks if they had MRD by PCR following the completion of their induction and consolidation treatment. In patients with an allogeneic donor transplant was offered at any time after the first course of blinatumomab. Responders were permitted to receive three further cycles of blinatumomab.

21 patients entered the trial of whom 20 were evaluable for response and 16 converted to MRD negative, all at the end of the first cycle of treatment. At a median of 405 days follow-up 16/20 patients eligible for follow up remained in ongoing hematological remission. 8 patients had allografts and remain in remission with no treatment associated mortality. 4 patients who did not have allografts have had a clinical relapse in the first 200 days post blinatumomab. In 2 cases the relapse was extramedullary (CSF, testis) and two had marrow relapse (one an initial responder to blinatumomab).

81% had transient grade 3 or 4 adverse events most commonly lymphopenia (this was really an intended event) and hypogammaglobulinemia. There were no drug associated deaths. There were 4 cases of infection. There was no cytokine storm and although there were transient increases in serum levels of some inflammatory cytokins, these increases were of short duration.

This was trial of patients with a more than 90% risk of relapse whose only chance of cure was an allograft (about a 30% success rate).

The second paper was an abstract presented at the recent meeting of EHA (abstract 552) This was a phase 2 study in adult patients with relapsed/refractory ALL of the same treatment detailed above for a first cohort of 5 patients and a second cohort had a dose reduction for the first 7 days to 5 microgm/sq m/24 hours, presumably while there were large numbers of circulating blasts.

Of the first 5 evaluable patients, 2 had CRs and 2 CRis within the first cycle. 3 had become MRD negative. One responder had an extramedullary relapse during cycle 3.

The commonest adverse events were fever and chills and one patient with a high leucocyte count had reversible cytokine storm. the second non-evaluable patient had a reversible event of encephalopathy and disorientation. Despite discontinuation of treatment, he reached MRD negativity. Recruitment of the second cohort is ongoing.

In essense this is the same study as the first, only given after relapse, not before it. I am sure there is a lot of impatience among CLL patients to see this drug used in CLL, but for now adult ALL, although less common, is a more urgent problem. The company involved here is Micromet Inc. of Munich and I guess if there were patient power to get this drug there might be a result.


~chris said...

Since Dr. M. Keating is an advisor to the Micromet's BiTE Antibody Scientific Advisory Board one would think that he could get a CLL clinical trial going?

"ICML brings together thousands of the world's leading specialists and researchers to present the latest advancements and insights in the treatment of malignant lymphomas," said Dr. Michael J. Keating, University of Texas MD Anderson Cancer Center professor of medicine, internist for the department of hematology, ICML advisory board member and a member of Micromet's BiTE Antibody Scientific Advisory Board. "The data on blinatumomab show that it holds the promise to become an effective therapy for a number of lymphomas and leukemias."

There must be more to this...

GClarke said...

Seems like Blinatumomab can do a good job removing the leukemia, and safely too. However the disease gradually returns after about two years. Longer term remissions seem to be strongly associated with stem cell transplants. Is it possible to have repeated treatments with Blinatumomab say every 18 months as required? And what are the likely costs and consequences?

Given that repeated treatments would apparently be quite safe, it would seem preferable, rather than risking a stem cell transplant.

Terry Hamblin said...

This may be the future. Repeated treatment may well be possible.