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Voravit Ratanatharathorn, M.D.,
Associate Professor of Internal Medicine
There are two major limitations associated with the use of
high-dose therapy and allogeneic stem cell transplantation:
regimen-related toxicity and graft-versus-host disease (GVHD).
Both of these complications occur at greater frequency in
older patients. Therefore, in many centers, the upper age
limit of stem cell transplant candidates is arbitrarily set
at 55 years.
However, both complications can be reduced by decreasing the
intensity of the preparative regimen, provided that the immunosuppressive
activity of the preparative regimen is sufficiently maintained
to allow engraftment of allogeneic hemopoiesis. Traditionally,
preparative regimens used in allogeneic transplantation mainly
employ supralethal doses of alkylating agents and total body
irradiation, which impart both potent anti-tumor and immunosuppressive
effects. Immunosuppressive agents that are less toxic are
available, e.g., tacrolimus, mycophenolate mofetil (MMF),
antithymocyte globulin, total lymphoid irradiation (TLI),
fludarabine, etc. These agents can be combined with attenuated
doses of alkylating agents or lower doses of total body irradiation
to reduce the potential lethal toxicity from the regimen,
while engraftment can be consistently obtained. Engraftment
of allogeneic hemopoiesis per se is a potent adoptive immunotherapy
(1). Furthermore, it also provides the platform for further
adoptive immunotherapy by donor lymphocyte infusion (DLI).
Induction of durable remission with DLI in patients who relapse
after an allogeneic transplan-tation demonstrates the powerful
effect of immune-mediated graft-versus-tumor effect, and it
is most effective in patients with low tumor burden (2). Early
reports of non-myeloablative regimens (which provide excellent
immunosuppressive effects but minimal anti-tumor effect) in
allogeneic transplantation have uncovered the problems associated
with this approach. Early relapse following transplantation
is the most common cause of death. These findings underscore
the importance of the anti-tumor component of the preparative
regimen (3). If the anti-tumor component of the preparative
regimen is attenuated, we would expect that this approach
can only be used in patients with low tumor burden or an early
stage of malignancy. It is also important that donor-host
chimerism and tumor status are closely monitored, and that
DLI is appropriately applied in patients who show persistent
disease or early progression. With a lower-intensity regimen,
allograft recipients are likely to sustain a period of mixed
chimerism that may protect the host from severe acute GVHD,
and if necessary, may be induced into full chimerism with
graded increments of DLI, thus resulting in eradication of
residual malignant cells of host origin.
In 1998, we developed an innovative regimen (see Table 1)
using a low-intensity preparative regimen for allogeneic peripheral
blood stem cell transplantation in patients older than 55
years. The inclusion and exclusion criteria are as follows:
Inclusion Criteria
- Patients with acute myelogenous leukemia (AML) (M0 - M7 by FAB classification) who are in complete remission or have less than 30% blasts in the marrow.
- Patients with myelodysplastic syndromes who are transfusion-dependent.
- Patients with chronic myeloid leukemia who are in chronic or accelerated phase.
- Patient with acute lymphoid leukemia who are in complete remission or have less than 30% blasts in the marrow.
- Patients with Hodgkin's or non-Hodgkin's lymphoma who are not curable with conventional chemotherapy and do not have any tumor larger than 5 centimeters in diameter.
- Patients with multiple myeloma, plasma cell neoplasms or Waldenstrom's macroglobulinemia.
Exclusion Criteria
- Cardiac disease of symptomatic nature; < 30% ejection fraction.
- Severe renal disease; creatinine > 2.O mg/dl or creatinine clearance < 40 ml/min (corrected for age).
- Severe pulmonary disease, < 60% normal (FEV1 & FVC).
- Severe hepatic disease; bilirubin >2.0, and/or transaminase > 3 x normal corrected for age.
- Performance status of £ 2 on the ECOG scale.
- Patients with evidence of HIV infection by western blot.
- Patients who are to receive unrelated blood or marrow stem cell transplantation.
This regimen combines three powerful immunosuppressive agents
(tacrolimus, MMF and TLI) to eliminate the host's capability
to reject the allogeneic graft. The anti-tumor component of
this regimen is provided by busulfan at a dose that is reduced
by 50% from the conventional dose of 1 mg/kg, and cyclophosphamide
is not used. Anti-tumor activity remains substantial even
with a reduced dose of busulfan. However, the attenuated anti-tumor
dose of preparative regimen is expected to produce significantly
less regimen-related toxicity.
To date, three patients have been enrolled in this study.
Two patients had myelodysplastic syndrome (MDS), and one of
these patients had a transformation into acute myeloid leukemia.
This patient had received induction therapy with persistent
pancytopenia, but his marrow blast counts were less than 5%.
The third patient had chronic myeloid leukemia in chronic
phase. All three patients were older than 60 years of age.
None of these patients required antibiotics or parenteral
nutrition support during transplant admission. All recovered
their absolute neutrophil count to greater than 500/mL before
day 14 of transplantation. The tempo of hemopoietic recovery
in one of the patients is shown in Figure 1. Thus far, there
were no acute GVHD observed in any of these patients; mixed
chimerisms were documented in all three patients at 30 days
post-transplant.
Biologically, the interaction of various cellular lineage
from the host and recipient may be important in the development
of GVHD, engraftment and relapse. Longitudinal studies of
donor-host chimerism hopefully will aid us in determining
the timing of additional adoptive immunotherapy through DLI.
From a clinical point of view, this approach is an introduction
to a new paradigm of allogeneic transplantation. The past
focus of tumor eradication through the use of higher doses
of anti-tumor therapy has now shifted to exploit the adoptive
immunotherapeutic capability of allogeneic transplantation.
It is conceivable that this concept can be expanded to patients
with advanced malignancies by using sequential high-dose therapy
with autologous transplantation to effectively debulk the
tumor, followed by allogeneic transplantation after patients
are conditioned with a non-myeloablative regimen. The ultimate
objective is to make this procedure safer and more widely
applicable to the patients.
To refer a patient to protocol UMCC 9822, please call 800-865-1125.
References
- Sullivan KM, Storb R, Buckner CD, Fefer A, Fisher L,
Weiden PL, Witherspoon RP, Appelbaum FR, Banaji M, Hansen
J, et al. Graft-versus-host disease as adoptive immunotherapy
in patients with advanced hematologic neoplasms. N Engl
J Med. 320:828, 1989.
- Porter DL, Roth MS, McGarigle C, Ferrara JL, Antin JH.
Induction of graft-versus-host disease as immunotherapy
for relapsed chronic myeloid leukemia. N Engl J Med. 330:100,
1994.
- Giralt S, Estey E, Albitar M, van Besien K, Rondon G,
Anderlini P, O'Brien S, Khouri I, Gajewski J, Mehra R, Claxton
D, Andersson B, Beran M, Przepiorka D, Koller C, Kornblau
S, Korbling M, Keating M, Kantarjian H, Champlin R. Engraftment
of allogeneic hematopoietic progenitor cells with purine
analog-containing chemotherapy: harnessing graft-versus-leukemia
without myeloablative therapy. Blood. 89:4531, 1997.
Table 1: The schema of regimen UMCC 9822 is as follows:
Protocol Day Treatment Pre-transplant Intrathecal ara-C (optional)
-11 to -7 Fludarabine 25 mg/M2/day IV -6 to -3 Busulfan 0.5
mg/kg every 6 hours PO -6 to 0 Tacrolimus 0.06 mg/kg every
12 PO Mycophenolate 750-1,000 mg PO every 12 hours 0 Total
lymphoid irradiation 2 Gy Peripheral blood stem cell transplantation.
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