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John Koreth, MBBS, DPhil
A drug that has become a mainstay of multiple myeloma treatment may
outperform alternative therapies in re-establishing the immune system of
patients who have received stem cell transplants from unrelated,
partially matched donors, according to early clinical trial results from
Dana-Farber Cancer Institute investigators.
The trial was designed to determine whether the drug bortezomib
(trade name Velcade®), when added to routine agents (tacrolimus,
methotrexate), can improve control of graft-versus-host disease (GVHD)
and improve immune system recovery following a transplant from a
GVHD is a common and potentially severe side effect of blood-forming
stem cell transplants, in which donor immune cells attack normal patient
cells and tissues. GVHD is more frequent in patients receiving
transplants from mismatched-unrelated donors (in comparison with
Based on bortezomib's effect in preclinical models, and in multiple
myeloma patients who have received donor stem cell transplants,
Dana-Farber's John Koreth, MBBS, DPhil, and colleagues theorized that it
could help control the overactivity of immune cells responsible for
GVHD in stem cell transplant patients.
Bortezomib inhibits the activity of antigen-presenting cells, which
help initiate the immune attack in GVHD, and reduces activity of an
important protein called nuclear factor-kB in T cells, which undertake
the immune attack.
In preclinical studies, bortezomib has been shown to selectively
deplete T cells that can target patients' normal cells. Mouse transplant
studies have shown that early administration of bortezomib protects
against GVHD without reducing the transplanted stem cells' ability to
settle in the bone marrow.
The new Phase I clinical trial involved 23 patients who received
bortezomib-based therapy (bortezomib, tacrolimus, and methotrexate)
after reduced-intensity stem cell transplants from mismatched-unrelated
Three dosage levels of bortezomib were tested. In updated results on
35 bortezomib-based, mismatched-unrelated patients, GVHD rates and
extent of immune system reconstitution were compared with patients who
had received sirolimus-based therapy (sirolimus, tacrolimus, and
methotrexate) after transplants from matched-related donors,
matched-unrelated donors, and mismatched-unrelated donors.
The results show that the bortezomib-based therapy was safe and had
little toxicity. Transplanted stem cells took root or "engrafted"
reliably, and the rate of GVHD in the bortezomib-based
mismatched-unrelated transplants was comparable to that in
sirolimus-based matched-related transplants.
Interestingly, immune cell reconstitution was significantly improved
in the bortezomib-based patients in the early post-transplant period
(3-6 months), compared with the sirolimus-based patients.
"Our results suggest that borezomib is a promising novel
immunomodulatory agent in donor stem-cell transplantation," Koreth says.
"A Phase II trial is now accruing patients to help determine its
The study's senior author is Dana-Farber's Edwin Alyea, MD.
Co-authors are Kristen Stevenson, Haesook Kim, PhD, Michael Garcia,
Vincent Ho, MD, Philippe Armand, MD, Corey Cutler, MD, Jerome Ritz, MD,
Joseph Antin, MD, and Robert Soiffer, MD, all of Dana-Farber.
The study was supported by Millennium Pharmaceuticals Inc. and the National Institutes of Health.