Acute Leukemias - Republican Scientific Medical Library

a 18.5 · Novel Transplant Approaches 233
(12 Gy) in 50 advanced leukemia patients, including 11
with ALL, undergoing allogeneic or autologous SCT.
All patients achieved primary engraftment. After a median
follow-up of 11 months, 28/50 (56%) patients were in
CR, nine (5%) patients relapsed, and 13 (7%) died from
treatment-related causes [29]. The ultimate benefits of
this approach with respect to safety and improvements
in survival will be defined by Phase II studies for patients
with ALL.
Nonradiation containing regimens, most commonly
busulfan and cyclophosphamide, have been investigated
in hopes of decreasing radiation-related complications.
Fractionated TBI/etoposide was tested against busulfan/cyclophosphamide
in a prospective, randomized
study conducted by the Southwest Oncology Group
(SWOG 8612). One hundred twenty-two patients with
leukemia beyond CR1 received either fractionated TBI/
etoposide or busulfan/cyclophosphamide in preparation
for SCT. One hundred fourteen (93%) proceeded to SCT.
All patients received cyclosporine and prednisone for
posttransplant immunosuppression. There was no significant
difference with respect to toxicity, incidence
of acute GVHD, overall survival, or DFS between the
two groups. The leading cause for treatment failure
was leukemic relapse (39%) [30]. Furthermore, retrospective
analysis of registry data from the International
Bone Marrow Transplant Registry (IBMTR) shows similar
rates for LFS and relapse when busulfan/cyclophosphamide
is compared to cyclophosphamide/TBI [31].
Careful comparisons of the incidence of second malignancies
with each of these regimens have not been made
but may have important consequences. Thus, a variety
of preparative regimens can be used, but leukemic relapse
remains the most significant factor affecting DFS.
18.4.3 Ex Vivo Purging
One major disadvantage of autologous SCT is autograft
contamination leading to an increased rate of relapse.
Ex vivo purging methods were developed to decrease
the residual leukemic burden of the graft. Pharmacological
agents include 4-hydroperoxycyclophosphamide (4-
HC), mafosfamide, and edelfosine. One major concern
regarding chemical purging is the potential toxic effect
on normal progenitor cells [32]. In efforts to overcome
this toxicity, some investigators have tested the simultaneous
administration of chemoprotectant agents such
as amifostine or adenosine triphosphate [33, 34].
Immunological methods of purging rely on MoAbs
combined with immunotoxins [35], exposed to complement
[27, 36–38], or combined with an iron-bound antibody
followed by a magnetic depletion [39]. It is difficult
to make any conclusions regarding the efficacy of
a particular purging method based on results from multiple,
single-center experiences using a variety of purging
methods. Generally, immunological purging methods
are able to eliminate 2–4.5 logs of leukemia cells.
Between 0 and 84% of mononuclear cells are lost during
the purging process; between 34 and 96% of CD34 cells
are recovered after purging [27]. Although purging with
monoclonal antibodies does not typically impair hematologic
recovery after transplant, some studies have
noted a delay in engraftment [40].
Ex vivo purging of the autograft with anti-sense oligodeoxynucleotide
(ODN) or ribonucleotide interference
(RNA-I) methods are still largely in preclinical
phases but have great potential for certain subtypes of
ALL. These methods target a specific mRNA or RNA sequence,
and can effectively block the production of a
protein; thus, they may be very effective therapy for leukemogenesis
that is driven by a specific protein, such as
in t(9;22)(q34;q11) ALL. Gewirtz et al. used ODN directed
against the c-myb proto-oncogene to purge autografts
of Philadelphia chromosome positive (Ph+)
chronic myelogenous leukemia (CML) patients who
were not eligible to receive allogeneic SCT (chronic
phase, n=20; accelerated phase, n=5) [41]. Autografts
were purged ex vivo with ODN for either 24 or 72 h.
After purging, Myb mRNA levels declined substantially
in approximately 50% of patients. However, cytogenetic
response post transplant was mixed in this small pilot
study, raising the issue of overall clinical efficacy. Still,
the study established the feasibility of ex vivo purging
with antisense ODN, and may lead to the development
of more effective antisense ODN targeted against a variety
of proteins.
18.5 Novel Transplant Approaches
18.5.1 Maintenance Therapy Post-SCT
Although the concept of maintenance therapy is established
for the chemotherapy treatment of ALL, its use
post transplant is not defined. Powles et al. reported
on the use of chemotherapy after autologous SCT to
prolong DFS. From July 1984 to December 1998, 77 adult