SAN FRANCISCOIn a phase II trial, recombinant human
keratinocyte growth factor (rHuKGF, or KGF) significantly reduced severe
mucositis and improved quality of life for patients with hematologic
malignancies who underwent autologous peripheral blood progenitor cell
Ricardo Spielberger, MD, of the City of Hope National Medical
Center, Duarte, California, presented the results at the 37th Annual Meeting of
the American Society of Clinical Oncology.
Dr. Spielberger said that about 80% of patients undergoing
transplantation for hematologic cancers using a conditioning regimen of total
body irradiation (TBI), etoposide (VePesid), and cyclophosphamide develop
severe (WHO grade 3-4) mucositis. Patients with grade 3 mucositis cannot
swallow solid food; at grade 4, alimentation is not possible, he said.
"Currently, there is no standard therapy available to prevent or reduce
severe oral mucositis," he added.
The trial drew upon in vitro data showing that KGF stimulates
the proliferation and differentiation of epithelial cells in animal models.
Eleven centers in the United States and Canada enrolled 129
patients; 80% had non-Hodgkin’s lymphoma or Hodgkin’s disease. The rest had
multiple myeloma, acute myelogenous leukemia, or acute lymphocytic leukemia.
All were in complete remission, Dr. Spielberger said.
All patients received the same conditioning regimen of 12 Gy of
TBI plus 60 mg/kg of etoposide and 75 or 100 mg/kg of cyclophosphamide. One
group received three doses of placebo for 3 days prior to TBI followed by three
more placebo doses after transplant. The second group had three daily doses of
KGF before TBI and three placebo doses after transplant. The third group
received three doses of KGF both pre-TBI and after transplant. Each dose was
administered intravenously at 60 µg/kg/d. The study period began 11 days prior
to transplant and continued 28 days afterward.
The mean number of days with severe mucositis was 7.7 for
patients who received only placebo and 5 for those who received KGF pre-TBI
followed by placebo after transplant (relative reduction of 35%). For the arm
that received KGF pre-TBI and post-transplant, the mean number of days with
severe mucositis was 4a relative reduction of 48%, compared with
The incidence of severe mucositis was also reduced, he said,
with the most impressive results registered for grade 4 mucositis. While half
of the patients in the placebo-only arm had grade 4 mucositis, incidence
declined to 33% in the group that received KGF followed by placebo and to 26%
in the group given KGF pre-TBI and post-transplant.
The KGF-only patients reported 36% less mouth and throat
soreness than the placebo-only group, Dr. Spielberger said. Use of opiate
analgesics was also lower (a mean of 8.3 days vs 12.1 days), as was use of
total parenteral nutrition (a mean of 7.7 days vs 11.3 days).
About one fourth of patients receiving KGF had adverse events,
including mild to moderate skin and oral erythema with or without edema, but
the regimen was described as well tolerated overall.
Phase III Trial Underway
A two-arm phase III trial is already underway to evaluate KGF’s
effect on duration of severe mucositis, Dr. Spielberger said. While the
investigation is primarily focused on supportive care, he suggested that KGF’s
effect on outcomes might also be evaluated. "Mucositis does have an impact
on morbidity and, if extremely severe, could have an impact on mortality,"
he said. Mucositis could increase the risk of other complications by becoming
"a port of entry for other infections."
Commentator Scott I. Bearman, MD, of the University of Colorado
Health Sciences Center, Denver, said the results suggest that KGF’s effect on
early regimen-related toxicity could make the regimen "easier, possibly
cheaper, and safer." He cautioned that whether the ability to escalate
doses further with cytoprotective agents leads to an improved antitumor effect
is unclear and needs to be studied.
Dr. Bearman also suggested that surrogate endpoints, such as
number of hospital days, hospital costs, and quality of life, be included in
future investigations. "I would suggest that improvement in these
surrogate endpoints alone would justify the routine use of cytoprotective
agents regardless of whether additional antitumor benefits result from further
dose escalation," he said.