Commentary (Pavletic): Nonmyeloablative Preparative Regimens for Allogeneic Hematopoietic Transplantation

During the past 5 years, many exciting clinical observations about nonmyeloablative allogeneic stem cell transplantation (alloNST) have been accumulating. The shift from the successful demonstration of mixed chimerism in large animal models to the clinical utilization of alloNST has been unusually rapid. According to the recent International Bone Marrow Transplant Registry analysis, 1,390 alloNST transplants have been registered since 1996 in North America, 92% of them between 1999 and 2001, with data for the years 2000 and 2001 still incomplete.

The age distribution of these patients has changed dramatically compared to conventional high-dose transplants, and about half of these patients are older than 50, many older than 60, and some older than 70 years of age. Clearly, with the advent of the alloNST, we are able to apply allogeneic stem cell therapy to new patient populations in whom toxicities otherwise would have been prohibitive. However, it is still unclear whether we are any closer to the ultimate goal of qualitatively better allogeneic stem cell therapy for human malignancy.

In this issue of ONCOLOGY, Champlin et al present an excellent review article on alloNST. They made an interesting historical change of the tone in their title, from a jubilant "Reinventing Bone Marrow Transplantation" in their first ONCOLOGY article on this topic in 1999,[1] to a much calmer "Biology and Current Indications" in the current issue, reflecting the maturation of this rapidly growing clinical field.

Clinical Biology of alloNST

A plethora of preparative regimens are currently used for alloNST; in general, they differ in dose intensity, ranging from highly myeloablative and immunoablative to true nonmyeloablative regimens that vary mainly in the degree of immunosuppression. The authors provide a useful working definition of a truly nonmyeloablative regimen and make an important distinction between more intensive regimens that should be more appropriately called "reduced intensity" and not truly nonmyeloablative. More intensive regimens, however, are required for engraftment in settings of greater genetic disparity such as unrelated- donor or HLA-nonidentical transplants.

The article fails to mention research trends in novel alloNST preparative regimens, especially the development of selective lymphoablative regimens such as monoclonal- antibody-based or nucleosideanalog- only-based regimens. The goal of selective lymphoablative regimens is to clinically produce states similar to those seen in patients with inherited combined immunodeficiencies, in whom donor engraftment can be accomplished without a preparative regimen.[2,3] The potential setting for such novel lymphocytotoxic protocols include nonmalignant diseases, some chemorefractory solid tumors, and lowgrade malignancies in minimal residual disease state.

The authors mention that among the advantages of alloNST transplants are a reduced incidence of acute graftvs- host disease (GVHD) and perhaps decreased incidence of infections. While this notion may be true in general, current clinical experience demonstrates that both acute GVHD and infections are still serious obstacles for successful alloNST. A large part of the problem is the fact that the alloNST patient population is much older than other patients and has a higher risk of GVHD and impaired immunologic reconstitution. The risk of chronic GVHD is not mentioned either, and the full magnitude of this long-term complication still needs to be determined. Among the potential disadvantages of true nonmyeloablative alloNST regimens, this review appropriately emphasizes their diminished cytoreductive potential, which may result in suboptimal disease control.

Results of Nonmyeloablative Allogeneic Transplants

Increased cytoreduction of a preparative regimen is very important in acute myelogenous leukema. Disease- free survival in refractory leukemia can be improved (from < 10% to 25%) with more intensive "reduced intensity" alloNST regimens. Based on the M. D. Anderson Cancer Center experience, alloNST results are particularly promising in low-grade lymphomas, mantle cell lymphoma, and chronic lymphocytic leukemia. Allogeneic transplantation-related mortality has been particularly prohibitive in patients with multiple myeloma. A novel strategy under study in multiple myeloma is the use of autologous transplant followed by nonmyeloablative allogeneic transplant- the so-called "tandem transplant" procedure.

Separation of Graft-vs-Malignancy From GVHD

As in every other article on the topic, the current review engages in the search for the "Holy Grail" of allogeneic hematopoietic stem cell transplantation: how to eliminate GVHD without adversely affecting the graft-vs-malignancy effect. The article cleverly emphasizes the importance of the GVHD-independent component of the allogeneic graftvs- tumor effect as a window of op-portunity that should be expanded and utilized for the enhanced success of alloNST. The authors propose different strategies, including graft engineering with a T-cell-depleted graft enriched with CD34-positive cells and posttransplant add-back of engineered T cells or NK cells directed at specific tumor targets.

Future of alloNST

This article appropriately concludes that indications for the alloNST procedure need to be better defined for each targeted malignancy. We appear to be witnessing the repeating story of a too-rapid spill of new technology into clinical practice. Controlled clinical trials are needed to compare nonmyeloablative regimens with alternative transplant and nontransplant approaches, to identify the best clinical strategies for a specific disease. The newly established Bone Marrow Transplantation National Clinical Trials Network should be an ideal mechanism for addressing such questions in a patient- specific and disease-specific manner.

By using alloNST, are we still reinventing hematopoietic stem cell transplantation? The answer is probably yes. Surprisingly, the most important qualitative innovation has occurred not at the clinical level but in our profound change in thinking about the biology of allogeneic hematopoietic engraftment. Nonetheless,many questions remain to be addressed by ongoing clinical research. Better strategies to eliminate GVHD are needed, and some of them may be on the horizon.[4] Less is probably not more, and relapse of the original malignancy will remain the ultimate enemy after alloNST. A host of novel anticancer molecules or cytokines could potentially be administrated during the transplant process to improve the therapeutic ratio of graft-vs tumor reactions.

Furthermore, alloNST technology has a high potential for the treatment of nonmalignant diseases or for achieving donor-specific tolerance in solid organ grafts.[5,6] AlloNST procedures are currently being performed with increasing success using stem cells obtained from unrelated volunteer donors and from unrelated-donor umbilical cord blood sources, adding to the further expansion of this procedure. That said, the relative absence of mechanistic and correlative research in this area is surprising, and without a combined clinical and laboratory effort, it will be difficult to accomplish authentic progress in clinical alloNST.

Finally, are the high-dose myeloablative allogeneic transplantation regimens "gone with the wind"? We do not know. The interplay of technologies may be competing, but it is also complementary. Much will depend on the development of more effective regimens for GVHD prophylaxis and control. For now, outside of clinical trials, high-dose regimens are still the standard of care in hematologic malignancy patients who, by age and function, are eligible for such protocols, especially if they are younger and have more aggressive disease.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1.

Champlin R, Khouri I, Komblau S, et al:Reinventing bone marrow transplantation. Oncology13:621-628, 1999.

2.

Rubocki RJ, Parsa JR, Hershfield MS,et al: Full hematopoietic engraftment after allogeneicbone marrow transplantation withoutcytoreduction in a child with severecombined immunodeficiency. Blood 97:809-811, 2001.

3.

Woolfrey AE, Nash RA, Frangoul HA, etal: Non-myeloablative transplant regimen usedfor induction of mutli-lineage allogeneic hematopoieticmixed donor-host chimerism inpatients with T-cell immunodeficiency. Blood92:520a, 1998.

4.

McSweeney P, Abhyankar S, Blunk B, etal: Tacrolimus and mycophenolate mofetil forGVHD prevention in adult hematopoietic allograftrecipients. Exp Hematol 30(suppl 1):119,2002.

5.

Burt R, Barr W, Oyama Y, et al: Futurestrategies in hematopoietic stem cell transplantationfor rheumatoid arthritis. J Rheumatol28(suppl 64):42-48, 2001.

6.

Spitzer TR, Delmonico F, Tolkoff-RubinN, et al: Combined histocompatibility leukocyteantigen-matched donor bone marrow andrenal transplantation for multiple myeloma withend stage renal disease: The induction of allografttolerance through mixed lymphohematopoieticchimerism. Transplantation 68:480-484,1999.