Author: John  Barrett MD, FRCP, FRC Path., Chief, Stem Cell Allotransplanation Unit, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

The application of allogeneic stem cell transplants (allo SCT) to treat and cure malignant disease has followed two guiding principles: (1) use of transplanted stem cells to permit dose intensified treatment of malignancy by circumventing dose-limitation from marrow failure (2) use of the allograft to provide an immunological graft-versus-malignancy effect. While it is clear that increasing treatment intensity pre-transplant can achieve more cures in some hematologic malignancies, there are many malignancies that do not respond to dose intensification. Furthermore, increased cure rates are only bought at the expense of increased transplant-related mortality (TRM) due to damage to non-hematopoietic tissue. In the 1990s, following the demonstration that donor lymphocytes could induce durable remissions in leukemia patients relapsing after BMT, confidence grew in the ability of the graft-versus-leukemia (GVL) effect to eliminate and cure malignant disease.^1-3

 

This experience set the stage for testing the potential of the alloimmune transplant itself to eliminate malignancy without recourse to dose-intensive preparative regimens. Such transplants required a different approach to the preparative regimen, with the main focus being to ensure engraftment using powerful immunosuppression but with no primary intention of disease control. This altered approach brought some potential advantages:(1) reducing the intensity of the regimen opened up the possibility of safely transplanting patients hitherto considered unsuitable because of a high risk of TRM (eg, patients over 60 years, patients debilitated by co-morbidities and prior intensive therapy including autologous stem cell transplantation (auto SCT); (2) the graft-versus-malignancy (GVM) effect could be logically explored in diseases such as metastatic cancers where dose-intensive treatments had proved ineffective; (3) reduced intensity preparative regimens were seen by some transplant teams as a means to control engraftment by initially achieving a balance between host and donor immune systems (mixed chimerism) and then introducing donor lymphocytes to treat the malignancy. Clearly there were limitations to abandoning intensive anti-malignancy treatment prior to transplant since patients with rapidly progressing malignancy would not survive long enough to benefit from the slower-acting GVM effect. Furthermore, it was not clear whether the GVM effect could work effectively against a heavy tumor load.

 

The development of reduced intensity allotransplants thus proceeded along several lines in several pioneering centers, notably the MD Anderson Cancer Center in Houston (emphasis on decreasing TRM in older or debilitated patients),⁴ the Hadassah Hospital in Jerusalem (emphasis on treating debilitated patients and obtaining balanced chimerism),⁵ the Fred Hutchinson Cancer Institute in Seattle (emphasis on treating older patients and obtaining balanced chimerism),⁶ San Martino Hospital Genova (treatment of ASCT failures)⁷ and the National Institutes of Health, Bethesda (emphasis on GVM in metastatic solid tumors).⁸ Today, reduced intensity transplants are being increasingly used worldwide to treat an ever-widening spectrum of diseases. Transplantation techniques differ as widely as the names ascribed to them, which include non-myeloablative stem cell transplants (NST), reduced intensity conditioning (RIC) transplants and minitransplants. The International Bone Marrow Transplant Registry reports indicate that about 1 in 10 transplants for malignant disease now use reduced intensity conditioning.

Table 1 lists the common indications for NST. The most widely accepted indications are indolent diseases such as chronic lymphocytic leukemia (CLL), multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL), and selected patients with myelodysplastic syndromes (MDS) and chronic myeloid leukemia (CML). More experimentally reduced intensity transplants are being explored in treatment of metastatic cancers. Transplants have successfully been performed on patients in their 70s, but upper age limits are determined as much by biological age and the risk/benefit ratio for the individual. Transplants have proved to be well tolerated in younger but debilitated patients with a prior history of fungal infection or who have failed an auto SCT. Thus it appears reduced intensity transplants can be applied to a wider spectrum of individuals than hitherto.

 

Table 1. Indications for reduced intensity stem cell allotransplants for malignant disease

 INSERT TABLE 1, TEXT and TABLE 2

 

Patients generally tolerate the low intensity regimens extremely well, with some protocols being well-suited to be performed entirely in an outpatient setting. The regimens characteristically produce very brief and mild post-transplant cytopenias. Patients frequently require no transfusion support and neutropenic fevers are less common with some regimens. Immediate toxicity is predictably low. Notably, mucositis is absent and veno-occlusive disease of the liver is seen only infrequently and exclusively in busulphan-containing regimens. There is as yet no data on the late effects of NST regimens. The incidence of secondary malignancies should be lower than with standard transplants, and deleterious effects on growth, development and gonadal function are anticipated to be minimal. Acute GVHD is the most common complication and is the main cause of TRM. Chronic GVHD has generally been less problematic, but an accurate estimate of the risk is not yet possible because of the short follow-up. While it is clear that reduced intensity transplants are better tolerated, survival following transplant is dictated by the success or lack of it in controlling the original malignancy. Thus, patients with chronic leukemias, lymphomas, leukemia in remission, and early stages of MDS have quite favorable outcomes with (where measurable) sustained molecular cures. In contrast advanced leukemias and rapidly progressing malignancies have a high probability of treatment failure.

Myeloid leukemias: Early and sustained cytogenetic and molecular remissions of CML following reduced intensity transplants are possible.^5,9 Giralt, et al, reported brief responses, probably regimen-related, in 5/13 relapsed or refractory AML patients.10 There is some evidence for a GVL effect in MDS but nonresponses have been seen, primarily in patients with secondary MDS.^11,12

Lymphoid malignancies: Complete remissions were seen in three of eight patients with CLL and five of seven patients with NHL.¹³ Durable responses are possible in heavily pretreated and chemo-refractory patients. Promising results are also reported in patients with multiple myeloma.¹⁴

Metastatic cancers: The most dramatic effects of low intensity stem cell transplants have been reported in metastatic renal cell cancer. In a series of 19 patients, four obtained durable complete remissions and a further six had partial responses.⁸ More limited reports identify responses in breast cancer and ovarian cancer. In contrast, no responses have been seen in patients with metastatic melanoma.

Conclusions 

Reduced intensity transplants are a promising new approach to the treatment of malignant diseases. Their introduction into clinical practice has widened the indications for allogeneic stem cell transplants by extending the procedure to older and debilitated individuals and by increasing the range of diseases found to be susceptible to a GVM effect. However, the procedure should still be regarded as being at an early phase of development best suited to be performed as part of a controlled clinical study. There is as yet no standard of practice to clearly indicate which patients should be considered for this type of transplant and no consensus on the best regimen.

REFERENCES

1. Barrett AJ and Malkovska V: Graft-versus-leukaemia: understanding and using the alloimmune response to treat haematological malignancies. British Journal of Haematology. 1996;93:754-761

 

2. Horowitz MM, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990; 75:555-565.

 

3. Kolb H-J, Schattenberg A, Goldman JM, et al: Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995;86:2041-2047

 

4. Champlin R, Khouri I, Kornblau S, et al: Reinventing bone marrow transplantation: reducing toxicity using nonmyeloablative preparative regimens and induction of graft-versus-malignancy. Current Opinion in Oncology. 1999;11:87-95.

 

5. Slavin S, Nagler A, Naparstek E, ET AL: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic disease. Blood. 1998;91:756-63.

 

6. Storb R: Non-myeloablative preparative regimens: theory and practice. In: McArthur JR, Schechter GP, Schrier SL, Bajus JL eds: American Society of Hematology, Educational Program Book, Bone marrow transplantation in malignant disease. Published by the American Society of Hematology, Washington DC, USA. 1998, pp 342-470.

 

7. Carella A, Lerma E, Corsetti MT, et al: Evidence of cytogenetic and molecular remission by allogeneic cells after immunosuppressive therapy alone. British Journal of Haematology. 1998;103:565-567.

 

8. Childs R and Barrett J: Nonmyeloablative stem cell transplantation for solid tumors: Expanding the application of allogeneic immunotherapy. Semin Hematol. 2002;39:63-71.

 

9. Keleman, E, Masszi T, Remenyi P, et al: Reduction in the frequency of transplant-related complications in patients with chronic myeloid leukemia undergoing BMT preconditioned with a new non-myeloablative drug combination. Bone Marrow Transplantation. 1998;21:747-749.

 

10. Giralt S, Estey E, Albitar M, et al: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood. 1997;89:12-20.

 

11. Battiwalla M and Barrett J: Allogeneic transplantation using non-myeloablative transplant regimens. Best Pract Res Clin Haematol. 2001;14:701-22.

 

12. McSweeney PA, Niederwieser D, Shizuru JA, et al: Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97:3390-400.

 

13. Khouri IF, Keating M, Korbling M, et al: Transplant-lite: Induction of graft-versus-malignancy using a fludarabine-based nonablative chemotherapy and allogeneic blood progenitor transplantation as treatment for lymphoid malignancy. Journal of Clinical Oncology. 1998;8:2817-2824.

 

14. Vesole DH, Simic A and Lazarus HM: Controversy in multiple myeloma transplants: tandem autotransplants and mini-allografts. Bone Marrow Transplant. 2001;28:725-35.