New Nonmyeloablative Approach Can Extend Benefits of Stem Cell Transplant

NEW ORLEANS—Prolonged hospitalization and toxic effects have limited the use of peripheral blood stem cell transplants for hematologic malignancies to younger, fitter patients. But a new nonmyeloablative approach may allow otherwise-excluded patients to also benefit, according to two studies presented at the American Society of Hematology meeting.

A multicenter study from the Fred Hutchinson Cancer Research Center in Seattle, Stanford University in California, and the University of Leipzig in Germany used a minimally myelosuppressive and immunosuppresive conditioning regimen to markedly reduce the acute toxicity of allografting, thus allowing elderly patients to benefit. Although follow-up is short, this “mini-transplant” approach appears to induce graft-versus-tumor effects and can be performed in an ambulatory setting, reported Peter McSweeney, MD, now Associate Professor of Medicine at the University of Colorado in Denver.

The clinical trial included 45 patients with hematologic malignancies and ages ranging from 31 to 72. They had been precluded from having conventional stem cell transplant because of age, prior high-dose therapy, or organ dysfunction. The most common diagnoses were acute and chronic myelocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, Hodgkin’s disease, and non-Hodgkin’s lymphoma.

The patients received immunosuppressive conditioning with low-dose total body irradiation pre-transplant, and short-term (35 or 56 days) cyclosporine (Sandimmune, Neoral) and mycophenolate mofetil (Cellcept) post-transplant. Peripheral blood stem cells were transplanted from HLA-identical sibling donors.

Few Hospitalizations

This new approach necessitated few hospitalizations; more than 50% of the patients were never hospitalized at all. Graft rejection occurred in 20% of the patients and was nonfatal in each case. Acute graft-versus-host-disease (GVHD) grades II and III occurred in 47% of the patients with sustained engraftment, which was manageable with standard immunosuppressive therapy. Approximately 70% of the subjects developed some degree of GVHD over longer follow-up. Other adverse events were minimal, with no neutropenia, no severe nausea and vomiting, no mucositis, and no alopecia. Patients were very satisfied with quality of life during therapy, Dr. McSweeney observed.

Among the 29 patients with measurable disease who attained stable engraftment, 17 (59%) achieved a complete response after transplant and six (21%) achieved a partial response. Molecular remissions by polymerase chain reaction were attained in seven patients.

“The finding of molecular remissions is obviously very important. Although we don’t have long follow-up at this time, it raises the prospect that this is a curable form of therapy for some of these patients,” Dr. McSweeney proposed.

The Kaplan-Meier estimate for 1-year survival was 70% (33 of 45 patients). Transplant-related mortality was considered low at 7%.

More Good Results

Researchers from the National Heart Lung and Blood Institute (NHLBI) also reported excellent results with a different nonmyeloablative conditioning approach in both hematologic and solid tumors. The NHBLI team noted that the low toxicity of this modality allows it to be used for older and more debilitated patients. The researchers also found that powerful graft-versus-tumor effects can be generated by this novel approach.

Their study included 50 consecutive patients ranging in age from 23 to 68 years old. Half of the patients had hematologic malignancies and half had solid tumors, such as advanced renal cell carcinoma and melanoma. Patients underwent low-intensity conditioning with fludarabine (Fludara) and cyclophosphamide (Cytoxan, Neosar) followed by a G-CSF-mobilized stem cell transplant from an HLA-identical or 5/6 antigen-matched sibling donor and cyclosporine for GVHD prophylaxis (Figure 1).

Early donor engraftment was detected in 49 patients, and only 2 of the 50 patients rejected the allograft. At a median follow-up of 205 days (but ranging up to 645 days), the toxicity has been quite low, although GVHD was common. Several patients also developed pneumonitis engraftment syndrome, a side effect that appears unique to this regimen, but that rapidly responded to steroids. Transplant-related mortality was about 12%, reported Richard Childs, MD, NHBLI Senior Clinical Investigator.

Good response has been noted, including 56% of the hematologic patients (6 of 9 patients with lymphoid malignancy) and 40% of the solid tumor group.

Remarkable Responses

“Remarkable responses include one patient with chronic lymphocytic leukemia refractory to chemotherapy who is in molecular remission now at 8 months,” Dr. Childs reported. “Three remissions have also occurred in relapsed non-Hodgkins’s lymphoma patients who were refractory to chemotherapy.”

Several molecular remissions in patients with a variety of different hematological malignancies including chronic myelogenous leukemia (CML) have been sustained as far out as 20 months without evidence of recurrence.

Figure 2 shows the clinical outcome of a 56-year-old male with chronic myelomonocytic leukemia (CMML).

In the solid tumor group, one patient with metastatic renal cell carcinoma who failed prior interferon therapy had complete resolution of metastatic disease by day 110, and at 23 months has no evidence of recurrence, Dr. Childs added.