Safer Curative-intent Therapy for Low-grade B-cell Malignancies
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a) Allo-HSCT involves administration of intensive chemotherapy (ovals), often combined with total body irradiation (lightning bolts), before the cells are transplanted (day 0).
b) During non-myeloablative conditioning, fludarabine combined with reduced-intensity chemotherapy or low-dose total-body irradiation are administered to the patient before hematopoietic stem cells are transplanted. This less intensive conditioning is not myeloablative but is sufficiently immunosuppressive to allow engraftment of donor stem cells.
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Low-grade B-cell malignancies, including nodular lymphomas, chronic lymphocytic leukemia, and multiple myeloma, remain essentially incurable. "Even high doses of chemotherapy with autologous hematopoietic stem cell transplantation cannot cure these malignancies, perhaps because the cell of origin is too similar to the normal stem cell," says UAB hematologist and oncologist William P. Vaughan, MD, MBA, director of UAB's Bone Marrow Transplantation and Cell Therapy Program.
Myeloablative allogenic bone marrow transplantation (allo-HSCT) has curative potential for various leukemias and lymphomas, including low-grade B-cell malignancies and a number of other malignant and nonmalignant disorders. After massive myeloablative chemotherapy to kill the majority of malignant stem cells, donor stem cells restore normal marrow function and the donor immune system can control residual leukemia or lymphoma in the recipient. However, older adults and other persons at high risk for complications cannot withstand the rigorous chemotherapy—with or without radiation—and immune suppression used to condition patients for this type of allo-HSCT.
Nonmyeloablative allo-HSCT transplant achieves the same immunological advantage—the graft-versus-malignancy effect—of myeloablative allo-HSCT with less-aggressive chemotherapy or irradiation. "Recent studies of nonmyeloablative HSCT have demonstrated a powerful graft-versus-malignancy effect against myeloma and other B-cell malignancies when the transplant is performed for low-grade, low-volume disease," Vaughan says. The treatment requires only 2 gray of total body irradiation to paralyze the recipient's immune system, permitting the donor stem cells to gradually replace the recipient's bone marrow stem cells and initiate the graft-versus-tumor effect. "The malignancy just slips away," he says.
Morbidity and mortality associated with the nonmyeloablative regimen is significantly reduced compared with traditional allo-HSCT. Myeloablative transplant patients are hospitalized for 6 weeks or more, and 10% to 15% of even young, low-risk patients may not survive hospitalization. For 2 to 3 weeks recipients have no marrow function and receive a massive chemotherapy preparative regimen along with immunosuppression. The risk for graft-versus-host disease (GVHD) is high, and patients aged 45 to 60 years have 20% to 30% mortality at 4 months. A significant fraction require intensive care, and readmissions are common.
Patients receive nonmyeloablative treatment in an outpatient setting and ≥75% never need hospitalization. Those who do usually require only brief hospitalization for complications. GVHD risk is lower and disease tends to be less severe.
"Based on hundreds of patients who have undergone the treatment, long-term survival rates range from 30% to 40%," Vaughan says. In multiple myeloma, 2-year all-cause mortality is about 20% with a 40% possible cure rate, compared with 60% mortality and a 20% cure rate with traditional ablative allo-HSCT.
Nonmyeloablative allo-HSCT is becoming the standard of care for many patients with low-grade B-cell malignancies and a matched related donor. Some research has shown success with nonmyeloablative allo-HSCT with matched unrelated donors. "We have a protocol for B-cell malignancies that allows us to treat sicker, older patients [≤70 years] and use matched unrelated donors," he says. "Exciting advances are occurring in the application of sophisticated cell therapy. Nonmyeloablative allo-HSCT is the first potentially curative therapy for these malignancies and a very attractive alternative compared to continuous and progressively toxic traditional palliative treatments."
For more information call Dr. William Vaughan at 1-800-UAB-MIST or email at mist@uabmc.edu.