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Michigan Oncology Journal Summer 1999

Low-Intensity Preparative Regimen and Allogeneic Peripheral Blood Stem Cell Transplantation

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

  1. 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.
  2. Patients with myelodysplastic syndromes who are transfusion-dependent.
  3. Patients with chronic myeloid leukemia who are in chronic or accelerated phase.
  4. Patient with acute lymphoid leukemia who are in complete remission or have less than 30% blasts in the marrow.
  5. 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.
  6. Patients with multiple myeloma, plasma cell neoplasms or Waldenstrom's macroglobulinemia.

Exclusion Criteria

  1. Cardiac disease of symptomatic nature; < 30% ejection fraction.
  2. Severe renal disease; creatinine > 2.O mg/dl or creatinine clearance < 40 ml/min (corrected for age).
  3. Severe pulmonary disease, < 60% normal (FEV1 & FVC).
  4. Severe hepatic disease; bilirubin >2.0, and/or transaminase > 3 x normal corrected for age.
  5. Performance status of 2 on the ECOG scale.
  6. Patients with evidence of HIV infection by western blot.
  7. 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

  1. 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.
  2. 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.
  3. 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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Please note: The articles listed in the Cancer Center's News Archive are here for historical purposes. The information and links may no longer be up-to-date.