Weekly dose reduces targeted drug's side effects, but not its activity against ALL

December 11, 2012

ATLANTA - A potent chemotherapy agent wrapped within a monoclonal antibody selectively destroys the malignant cells responsible for acute lymphocytic leukemia (ALL) in either weekly or monthly dosing, researchers report at the 54th ASH Annual Meeting and Exposition.

This 'Trojan horse' assault on the cancer cells has significantly increased the response rate among patients with ALL, and now a clinical trial finds that weekly dosing works well and reduces side effects.

"The CD22 antigen is a specific marker for B-cell malignancies and is expressed in more than 90 percent of patients who have acute lymphocytic leukemia," said Susan O'Brien, M.D., professor in The University of Texas MD Anderson Department of Leukemia. "The antigen's specificity for B-cell cancers makes it a promising therapeutic target for intervention."

Bound to a potent toxin

The humanized antibody, known as inotuzumab ozogamicin, is attached to the toxin calicheamicin and binds to CD22. "After binding to the B cell, the antibody is internalized and the linker hydrolyzed, releasing the calicheamicin into only the malignant B cell," O'Brien said. "This enables us to bring in a very potent toxin that could not be given systemically and direct that toxin to the malignant B cell."

The experimental drug was first used in patients with B cell lymphoma. The main toxicity seen in the lymphoma trials was myelosuppression due primarily to deficiency of platelets.

"Myelosuppression is much less of an issue with acute leukemia, whether ALL or acute myelogenous leukemia, because you want to transiently wipe out the bone marrow to eradicate the leukemic cells," O'Brien said. "You expect to have myelosuppression as part of the therapy."

Toxicities manageable

For this study, the researchers used the dose defined as tolerable in the lymphoma trials-1.8 mg/m2-as a starting point.

"We observed very good activity in this relapse/refractory population and an overall response rate of 57 percent," O'Brien said. "The main toxicities were infusion reactions either during or shortly after infusion of the antibody. Patients developed fever sometimes associated with a drop in blood pressure. These were generally grade 1-2 so they were mild and easily treatable." The treatment was also associated with grade 1-2 elevations of transaminases, enzymes that reflect liver function, which had also occurred in the lymphoma trials.

Amended protocol

The researchers amended their protocol in an attempt to minimize toxicities. "We wondered whether we could reduce infusion reactions and liver function test elevations by giving the agent on a weekly basis instead of as a bolus every three to four weeks," O'Brien said. "The maximal plasma levels potentially would be lower, but the area under the curve might be the same because we would be giving the same total dose, just spread over three weeks."

Under the new protocol, the researchers gave the same total dose spread out over three weeks: .8 mg/m2 on Day 1 and .5 mg/m2 on Day 8 and Day 15. "We found exactly the same response rate with the weekly dose as with the monthly dose," O'Brien said. "But we did notice that the infusion reactions and the elevations in the transaminases were less frequent with the weekly schedule. This is probably because the side effects are most likely related to the peak concentrations of the drug, and when you spread it over three weeks the peak concentrations are not as high."

The Take-Away

"We observed impressive activity in a relapsed, refractory population," O'Brien said. "The toxicities were acceptable and were mainly grade 1-2 reactions to the drug itself, which is not uncommon because most antibodies are associated with mild infusion reactions. Transaminase elevations were predominately grade 1-2, and in the trial as a whole, fewer than five percent of the patients experienced grade 3-4 liver elevations."

O'Brien added that a new trial at MD Anderson is incorporating the antibody with low-dose chemotherapy as a frontline regimen for ALL in patients over age 65.

"One of the biggest complications in treating older patients with ALL is that the treatments cause myelosuppression, which makes patients more vulnerable to infection, and older patients are particularly susceptible to this and other complications," she said. "The idea is to take a very well-tolerated antibody and combine it with chemotherapy. That way we might not have to use full-dose chemo and can reduce side effects."
-end-
The clinical trial is funded by Pfizer, Inc., which developed inotuzumab.

Co-investigators with O'Brien are Deborah Thomas, M.D., Farhad Ravandi, M.D., Stefan Faderl, M.D., Jorge Cortes, M.D., Elias Jabbour, M.D., Hagop Kantarjian, M.D., Monica Kwari, B.S.N., Sergernne York, R.N., and Rebecca Garris, BSc, all of MD Anderson's Department of Leukemia; and Jeffrey Jorgensen, M.D., Ph.D., of MD Anderson's Department of Hemopathology; and Partow Kebriaei, M.D., of MD Anderson's Department of Stem Cell Transplantation and Cellular Therapy.

About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 41 comprehensive cancer centers designated by the National Cancer Institute. For nine of the past 11 years, including 2012, MD Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.

University of Texas M. D. Anderson Cancer Center

Related Chemotherapy Articles from Brightsurf:

Chemotherapy is used to treat less than 25% of people with localized sarcoma
UCLA researchers have found that chemotherapy is not commonly used when treating adults with localized sarcoma, a rare type of cancer of the soft tissues or bone.

Starved cancer cells became more sensitive to chemotherapy
By preventing sugar uptake, researchers succeeded in increasing the cancer cells' sensitivity to chemotherapeutic treatment.

Vitamin D could help mitigate chemotherapy side effects
New findings by University of South Australia researchers reveal that Vitamin D could potentially mitigate chemotherapy-induced gastrointestinal mucositis and provide relief to cancer patients.

Less chemotherapy may have more benefit in rectal cancer
GI Cancers Symposium: Colorado study of 48 patients with locally advanced rectal cancer receiving neoadjuvant chemotherapy, found that patients receiving lower-than-recommended doses in fact saw their tumors shrink more than patients receiving the full dose.

Male fertility after chemotherapy: New questions raised
Professor Delb├Ęs, who specializes in reproductive toxicology, conducted a pilot study in collaboration with oncologists and fertility specialists from the McGill University Health Centre (MUHC) on a cohort of 13 patients, all survivors of pediatric leukemia and lymphoma.

'Combo' nanoplatforms for chemotherapy
In a paper to be published in the forthcoming issue in NANO, researchers from Harbin Institute of Technology, China have systematically discussed the recent progresses, current challenges and future perspectives of smart graphene-based nanoplatforms for synergistic tumor therapy and bio-imaging.

Nanotechnology improves chemotherapy delivery
Michigan State University scientists have invented a new way to monitor chemotherapy concentrations, which is more effective in keeping patients' treatments within the crucial therapeutic window.

Novel anti-cancer nanomedicine for efficient chemotherapy
Researchers have developed a new anti-cancer nanomedicine for targeted cancer chemotherapy.

Ending needless chemotherapy for breast cancer
A diagnostic test developed at The University of Queensland might soon determine if a breast cancer patient requires chemotherapy or would receive no benefit from this gruelling treatment.

A homing beacon for chemotherapy drugs
Killing tumor cells while sparing their normal counterparts is a central challenge of cancer chemotherapy.

Read More: Chemotherapy News and Chemotherapy Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.