Non-Myeloablative Chemotherapy Followed by HLA-Matched Related Allogeneic Stem Cell Transplantation for Hematologic Malignancies

Trial Information

Non-Myeloablative Chemotherapy Followed by HLA-Matched Related Allogeneic Stem Cell Transplantation for Hematologic Malignancies

Allogeneic bone marrow transplantation (BMT) became feasible in the 1960s after elucidation
of the Human Leukocyte Antigen (HLA) complex. Since then, the therapy has evolved into an
effective treatment for many hematologic disorders. Otherwise incurable malignancies are
frequently cured by this approach, with the likelihood of cure ranging from 10% to 85%,
depending on the disease and the disease status. The treatment strategy incorporates very
large doses of chemotherapy and often radiation to eliminate cancer cells and to
immunosuppress the recipient to allow the engraftment of donor cells. Donor cells give rise
to hematopoiesis within two to three weeks, rescuing the patient from the effects of high
dose therapy. In the ideal situation, immune recovery and recipient-specific tolerance
occurs over the following 6-18 months, and the patient is cured of their underlying
malignancy, off immunosuppression, with a functionally intact donor-derived immune system.
However, complications are common and include fatal organ damage from the effects of high
dose chemotherapy, infection, hemorrhage, and, in particular, graft-versus-host disease
(GvHD). A realistic estimate of transplant-related mortality in the standard HLA-matched
sibling setting is approximately 25%. The risk of treatment-related mortality limits the
success and certainly precludes its use in older patients. Thus, new strategies in
transplantation are needed.

With the growing understanding that much of the curative potential of allogeneic bone marrow
or stem cell transplant (SCT) is from an immune anti-tumor effect of donor cells, known as
graft-versus-leukemia (GvL) or graft-versus-tumor (GvT), a new strategy is being employed
that shifts the emphasis from high-dose chemo-radiotherapy to donor-derived, immune-mediated
anti-tumor therapy. In this approach, patients receive preparative regimens that, while
having some anti-tumor activity, are mainly designed to be immunosuppressive enough to allow
engraftment of donor stem cells and lymphocytes. Engrafted lymphocytes then mediate a GvL
effect; if the GvL effect of the initial transplant is not sufficient, then additional
lymphocytes may be infused (achievement of engraftment allows additional lymphocytes to
"take" in the recipient without requiring any additional conditioning of the recipient). The
lower intensity of the preparative regimen lessens the overall toxicity by minimizing the
doses of chemo-radiotherapy. In addition, less intensive preparative regimens may be
associated with less GvHD, as much evidence suggests that high-dose therapy contributes to
the syndrome of GvHD by causing tissue damage, leading to a cytokine milieu which enhances
activation of graft-versus-host (GvH) effector cells. Thus, such an approach may allow the
safer use of allogeneic transplants in standard populations and may allow extension of
allogeneic transplantation to patients who could not receive standard (myeloablative)
transplants because of age or co-morbidities. This protocol investigates a non-myeloablative
transplant approach, using fludarabine and cyclophosphamide, to allow engraftment of
allogeneic cells, which may then mediate anti-tumor effects.