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Current Issues in Adult AML

Autologous BMT for AML

Brenner spacer
Malcolm Brenner, MD, PhD.
Director, Division of Bone Marrow Transplant and Cell and Gene Therapy Program, St. Jude Children's Research Hospital

Professor, Department of Pediatrics and Medicine, University of Tennessee

Many cancer centers in North America and Europe now offer autologous bone marrow transplantation (ABMT) to younger (<55 yrs) patients with AML in first remission, and almost all the remaining centers offer it as a therapeutic option in second remission.1 However, there have been few large-scale randomized studies to show that patients who receive BMT in either first or subsequent remission have a significantly higher survival rate than those treated with conventional chemotherapy alone. While most case or historically controlled studies have consistently shown that ABMT provides a modest improvement in the percentage of patients who are long-term survivors, a recent large randomized study by the UK Medical Research Council found no significant benefit for ABMT over a further course of chemotherapy.2-4

Overview of studies of autologous bone marrow transplantation in AML2-4
Therapy Survival rate
Chemotherapy 30-35%
Autologous bone marrow transplantation 40-60%

Autologous BMT compared with a further course of chemotherapy shows no significant benefit for BMT.4-6

A detailed study of the reason for failure after ABMT, however, suggests that these results do not mean that ABMT has no place in AML. While overall survival rates may be little different, the rate of relapse after ABMT is lower than after chemotherapy alone. However, this gain is offset by an increased toxicity from the pretransplant ablative regimen and from delayed hemopoietic recovery after marrow infusion. Since procedure related mortality begins to rise steeply after age 55, this effect is particularly evident in the older patient.1-5

Thus the aim is to develop autologous transplant protocols, which not only further reduce the risk of relapse, but also decrease procedure related morbidity and mortality. Several studies now address these issues.

Possible future routes to improved outcomes in AML

  • Maximize efficiency in eradicating leukemia during conditioning regimen with different drug combination.
  • Marrow purging technologies to remove tumorigenic cells from remission marrow.
  • Use of immunostimulatory agents post-transplant to induce destruction of minimal residual malignancy via cytotoxic effector mechanisms.
  • Genetic alteration of marrow stem cells to induce resistance to cytotoxic drugs, allowing further chemotherapy after ABMT to eradicate minimal residual disease.
  • Acceleration of hemopoietic recovery with new combinations of hemopoietic growth factors, including thrombopoietins to speed platelet recovery.
  • Acceleration of hemopoietic recovery through the addition of peripheral blood stem cells (PBSC) to marrow transplants.
  • Purging technologies to remove malignant progenitors, which may contaminate PBSC.

Conclusions

  • There is an increasing possibility that autologous bone marrow transplantation in younger patients (<55 yrs) with AML will ultimately reduce the risk of relapse.
  • There is steady improvement in our capacity to reduce the toxicities related to post-transplant aplasias. These trends may lead not only to a continued increase in the application of this methodology, but also to a higher success rate.

References

  1. Cassileth PA, Andersen J, Lazarus HM, et al. Autologous bone marrow transplant in acute myeloid leukemia in first remission. J Clin Oncol. 1993;11:314-319.
  2. Tiedemann K, Waters KD, Tauro GP, Tucker D, Ekert H. Results of intensive therapy in childhood acute myeloid leukemia, incorporating high-dose melphalan and autologous bone marrow transplantation in first complete remission. Blood. 1993;82:3730-3738.
  3. Petersen FB, Lynch MHE, Clift RA, et al. Autologous marrow transplantation for patients with acute myeloid leukemia in untreated first relapse or in second complete remission. J Clin Oncol. 1993;11:1353-1360.
  4. Sanz MA, de la Rubia J, Sanz GF, et al. Busulfan plus cyclophosphamide followed by autologous blood stem-cell transplantation for patients with acute myeloblastic leukemia in first complete remission: a report from a single institution. J Clin Oncol. 1993;11:1661-1667.
  5. Woods WG, Kobrinsky N, Buckley J, et al. Intensively timed induction therapy followed by autologous or allogeneic bone marrow transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: a Childrens Cancer Group pilot study. J Clin Oncol. 1993;11:1448-1457.
  6. Chao NJ, Stein AS, Long GD, et al. Busulfan/etoposide - initial experiences with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia. Blood. 1993;81:319-323.


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