NEW ORLEANSProlonged 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, Hodgkins disease, and non-Hodgkins 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.
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 dont 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
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 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-Hodgkinss
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.