Breaking new ground: Richard Childs (left) and Ramaprasad Srinivasan, medically responsible investigator and principal investigator, respectively, of the first NIH study that involves transplantation on an outpatient basis

To borrow an old merchandising slogan, it's not your grandfather's allogeneic stem-cell transplantation.

It’s a formula for transplantation so different from the characteristically toxic standard myeloablative procedures, it can be done on an outpatient basis.

All that’s missing are the patients.

So far, one of a projected 58 patients has been enrolled in the "phase I/II study of HLA-matched mobilized peripheral blood hematopoietic stem cell transplantation for advanced mycosis fungoides [MF]/Sezary syndrome using nonmyeloablative conditioning with Campath-1H."

But the PIs—NCI’s Ramaprasad Srinivasan and NHLBI’s Richard Childs—are optimistic. The study is estimated to last for three to five years, and they expect that accrual will speed up once the anticipated favorable responses with the first few patients become known.

Already, this first patient is a standout: Not only the lead-off patient on the protocol, he’s the first patient on any NIH transplant protocol to have undergone the procedure as an outpatient. Considering only NHLBI and NCI, Childs estimated that between 600 and 700 patients have undergone transplantation on intramural NIH protocol over the last decade or so—all inpatient.

"This is a big step in the right direction," Childs observed.

"We’re doing something different," Srinivasan said. "In the old days, people going through allogeneic transplantation had to undergo intensive chemotherapy and/or radiotherapy that required hospitalization. They got very sick, couldn’t eat, threw up, got all kinds of infections, and were basically bedridden for the early part of the transplantation, anywhere between four and six weeks."

"About one in three patients died from the transplant itself," Childs added. Consequently, it was only when patients faced death from the disease—the usual fate within one to five years of the onset of advanced MF—that transplantation was considered.

The nonmyeloablative regimen of the current protocol is designed to eliminate the toxicity from an otherwise therapeutic, potentially curative approach. Not only does the pretransplant regimen prepare the host to accept the donor cells, it also has some inherent antitumor activity. The four-week preparative regimen includes escalating doses of Campath-1H, an anti-CD52 monoclonal antibody, on days 28 to 15 pretransplant, and fludarabine, an anticancer agent, for the last five days before transplant.

The investigators will conduct lab studies to document the effect of the preparatory regimen on the host immune system and the effect of donor immune cells on host tumor cells. They will look specifically at the following:

The roles of Campath-1H and fludarabine in the development of donor chimerism and the extent to which Campath-1H potentiates the depletion of donor T cells

The cell types and rate of donor cell repopulation post-transplant

The ability of cells of donor origin to battle the tumor, as demonstrated in a laboratory-based confrontation between isolated and expanded donor CD4 and CD8 cells and tumor cells

The ability of donor cells to recognize and presumably fight the patient’s tumor, as suggested by the presence (or absence) of cells of donor origin in skin-lesion biopsies

"If we don’t see a substantial number of patients engrafting, we would add another agent—cyclophosphamide—to the preparatory regimen in the next set of patients," Srinivasan said.

At more than 100 days post-transplant (at Catalyst press time), the patient, a 58-year-old African American man with a five-year history of progressive disease, was showing progressive donor engraftment and no signs of graft-vs-host disease. The first evidence of donor cells was spotted 15 days post-transplant, Srinivasan noted.

The investigators also saw evidence of antitumor activity but concluded that at that early stage the observed effects could be attributed entirely to the preparatory regimen. While transient, this effect is beneficial because it provides sufficient time for manipulation of the newly engrafted immune system to generate a durable immune response against the cancer. They plan to document laboratory correlates that indicate that donor immune cells are staving off disease over the long haul, as opposed to the short-term slaughter effected by the chemotherapy.

MF and its leukemic variant Sezary syndrome are the most prevalent forms of primary cutaneous T-cell lymphomas. The protocol is designed to see not only whether MF is successfully treated with this approach but also whether use of this relatively nontoxic agent—Campath-1H—is compatible with donor engraftment.

"If we can actually get a graft in this context, this approach could be applicable in a wide variety of conditions normally amenable to transplantation and the nonmyeloablative regimen, such as non-Hodgkins lymphoma," another condition in which the immunosuppressive regimen also has antitumor activity, Srinivasan said.

In general, patients with fast-growing, "out-of-control" disease do worse on nonmyeloablative regimens," Childs remarked.

In contrast, patients with slower growing disease or disease in remission before the procedure are more likely to benefit from the anticancer effects generated through engrafting donor T lymphocytes.

Moreover, Childs said, patients "with an immune system that is already beaten up" from prior chemotherapy before undergoing nonmyeloablative transplantation are more likely to achieve the rapid, sustained donor engraftment that is a prerequisite for the potentially curative donor-immune–mediated antimalignancy effects that occur after these types of transplants.

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