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Radiolabeled Monoclonal Antibody Targets Bone Marrow in AML Transplant Patients

Radiolabeled Monoclonal Antibody Targets Bone Marrow in AML Transplant Patients

ORLANDO--A preparative regimen employing a radiolabeled monoclonal antibody (MoAb), coupled with busulfan (Myleran) and cyclophosphamide (Cytoxan, Neosar), yielded a low relapse rate in patients with acute myelogenous leukemia (AML) undergoing bone marrow transplantation (BMT) while in first remission.

"Although follow-up is short," Dana C. Matthews, MD, said in her presentation at the ASH meeting, "we are very encouraged by the low relapse rate."

Despite advances over the last two decades, AML patients undergoing BMT during first remission have shown no appreciable improvements in disease-free survival, said Dr. Matthews, of the Fred Hutchinson Cancer Research Center.

Increasing the radiation dose used in the preparative regimen lowers the relapse rate in these patients, according to previous studies conducted at Hutchin-son, but has no impact on overall disease-free survival, she said. Moreover, the higher radiation doses produce greater toxicity to normal organs, eg, the liver.

In contrast, use of an anti-CD45 murine MoAb labeled with iodine-131 enabled Dr. Matthews and her colleagues to safely deliver almost 11 Gy of radiation to marrow in 17 AML patients, ranging in age from 16 to 55 years, who were to receive a marrow graft from an HLA-matched, related donor.

In this phase I/II study, patients first received a trace dose of the radiolabeled MoAb followed by gamma camera imaging and a bone marrow biopsy to determine the estimated dose to target organs (spleen, bone marrow) and nontarget organs (liver, lung, kidney). These individualized radiation absorbed doses were used to calculate desired therapeutic doses of the MoAb, Dr. Matthews said.

Therapeutic Doses

The therapeutic doses were administered over 4 to 8 hours on the 14th day before transplantation and were followed by treatment with busulfan (16 mg/kg/day) on the eighth through fifth days prior to grafting and cyclophosphamide (120 mg/kg/day) on the third and second days preceding BMT.

She noted that no grade 3 or 4 regimen-related toxicity occurred in the first four patients, who received a lower radiation dose (105 to 152 mCi of iodine-131, which delivered an average of 3.5 Gy to the liver and 9.2 Gy to the marrow).

Use of a higher level of radiation (101 to 263 mCi of iodine-131, delivering an average of 5.25 Gy to the liver and 10 Gy to the marrow) in the next 13 patients resulted in three cases of grade 3 toxicity (mucositis) and one instance of grade 4 toxicity. The patient with grade 4 toxicity died of multiorgan failure, she added.

In the surviving 16 patients, no relapses have occurred over a median follow-up of 14 months. One patient is still alive 33 months after transplant. Although continued accrual and longer follow-up are needed to ascertain true toxicity rates and the durability of remissions, Dr. Matthews believes that the new therapy "should improve disease-free survival in AML patients in first remission."

 
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