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Treatment of hematological malignancies with nonmyeloablative, HLA-haploidentical bone marrow transplantation and high dose, post-transplantation cyclophosphamide

https://doi.org/10.1016/j.beha.2011.05.001Get rights and content

Hematopoietic stem cell transplantation provides the only potential curative option in many patients with hematological malignancies. Finding a suitably matched donor in a timely manner is often difficult. However, most patients have a partially HLA-mismatched (HLA-haploidentical) first-degree relative readily available. Historically, HLA-haploidentical bone marrow transplantation (BMT) has been considered extremely high risk due to high rates of life-threatening graft-versus-host disease (GVHD) and non-relapse mortality (NRM). Modifications of the stem cell graft, such as T-cell depletion, have resulted in poor rates of engraftment. We have recently completed a phase II clinical trial of nonmyeloablative HLA-haploidentical hematopoietic BMT followed by post-transplantation high-cyclophosphamide. High-dose cyclophosphamide has been shown to create immunogenic tolerance by specifically killing activated mature T-cells. As a result, alloreactive T-cells in the donor graft are selectively destroyed thereby decreasing the incidence of severe GVHD. As well, host-versus-graft reactive T-cells are also selectively eliminated thereby increasing rates of engraftment. Among 210 patients with hematological malignancies receiving nonmyeloablative, HLA-haploidentical BMT with post-transplantation cyclophosphamide, the rate of sustained donor cell engraftment has been 87%. The cumulative incidence of grade 2–4 acute GVHD is 27%, grade 3–4 acute GVHD is 5% and chronic GVHD is 15%. Interestingly, increasing HLA disparity between donor and recipient was not associated with increasing incidence of GVHD or decreased event-free survival. Nonmyeloablative haploidentical stem cell transplantation with post-transplantation cyclophosphamide seems to be a promising, potentially curative, option for patients with hematological malignancies who either lack an HLA-matched related or unrelated donor, or in whom a myeloablative preparative regimen is contraindicated due to significant co-morbidities or history of extensive pre-treatment.

Introduction

Allogeneic stem cell transplantation, or alloSCT, is a potentially curative option for many patients with hematological malignancies, particularly those with cytogenetically standard or poor risk acute leukemia in remission [1]. Historically the curative potential of alloSCT was ascribed to the eradication of the malignancy by lethal doses of chemotherapy with or without radiation, and the bone marrow infusion “rescued” the patient from otherwise fatal marrow aplasia. However it is now quite apparent that an important mechanism of cure in alloSCT is the graft-versus-leukemia, or GVL, effect [2]. Donor T-cells contained in the graft are likely responsible for the GVL effect. Unfortunately, donor T-cells also play a significant role in graft-versus-host disease (GVHD), a major contributor to non-relapse mortality (NRM). The goal in alloSCT is to develop a way to maximize the graft-versus-tumor (GVT) effect while minimizing GVHD, graft failure, NRM, and relapse. We continue to search for the best combination of donor, conditioning regimen, and post-transplantation immunosuppression to achieve those goals.

Section snippets

Nonmyeloablative conditioning regimens

There has been increasing experience with the use of nonmyeloablative conditioning regimens prior to alloSCT. These regimens typically incorporate highly immunosuppressive but moderately myelosuppressive chemotherapy followed by high stem cell doses and post-transplantation pharmacologic immunosuppression. The principles underlying the use of nonmyeloablative conditioning [3] are: (1) immunosuppression should be sufficient to allow donor engraftment; (2) a high dose of donor stem cells

HLA-haploidentical stem cell transplantation

Most experience with alloSCT has been with matched sibling donors. However, only about 30% of patients have a matched sibling making it necessary to identify alternative donors. The National Marrow Donor Program (NMDP) was initiated in 1986 to create a network “to facilitate successful transplants of hematopoietic stem cells from volunteer unrelated donors as lifesaving therapy for patients of all racial and socioeconomic backgrounds.” Finding potential matched unrelated donors has proven to

Drug-induced immunological tolerance

The idea of giving post-transplantation cyclophosphamide came from studies that have shown that a properly timed, high dose of cyclophosphamide induces immunological tolerance. Drug-induced immunological tolerance is not a new concept. It was initially reported in 1959 when it was shown that giving rabbits 6-mercaptopurine prevented their ability to produce antibodies against human serum albumin [30].

Through a progression of studies it was found that cyclophosphamide given one to three days

Phase I trial of nonmyeloablative, HLA-haploidentical BMT with high dose, post-transplantation cyclophosphamide

Based on the results of our mouse data we completed a phase I clinical trial to determine the minimal conditioning, including post-transplantation cyclophosphamide which permitted stable engraftment of partially HLA-mismatched marrow from first-degree relatives [43]. All patients had high-risk hematological malignancies and were not eligible for standard alloSCT. The preparative regimen initially consisted of fludarabine and total body irradiation (TBI). GVHD prophylaxis consisted of high-dose

Phase II trial of nonmyeloablative, HLA-haploidentical BMT with high dose post-transplantation cyclophosphamide

Because of the encouraging results of our phase I clinical trial we designed a phase II clinical trial. We provide here an update on data that have previously been reported *[44], *[45]. As of September 14, 2010, 210 consecutive patients received nonmyeloablative, HLA-haploidentical transplantation with high-dose, post-transplantation cyclophosphamide and had at least one year of follow-up. Details concerning criteria for eligibility, HLA typing, transplantation procedure, and outcomes

Discussion

Our data suggest that nonmyeloablative, HLA-haploidentical bone marrow transplantation with high dose, post-transplantation cyclophosphamide is a safe alternative for patients with hematological malignancies without suitable donors or with co-morbidites that would preclude them from receiving a myeloablative transplant. It allows for transplantation to occur more quickly in patients in whom the disease is too advanced or aggressive to wait for a suitable matched unrelated donor to be found.

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgments

Supported by P01 CA15396 from the National Cancer Institute.

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