Non-myeloablative Transplants

Non-myeloablative Transplants

 Dr. Marco Mielcarek explains how a reduced-intensity bone marrow transplant works for older patients or patients who were too ill and not eligible for a bone marrow transplant.

For years, people 60 or older and those with multiple health problems weren’t eligible for bone marrow transplants because conventional conditioning regimens were too toxic for them to withstand. Now non-myeloablative transplants (also called reduced-intensity or mini-transplants), which use reduced-dose conditioning regimens, are mild enough for many of these patients. Non-myeloablative transplantation was developed by researchers at Fred Hutchinson Cancer Research Center specifically for older and sicker patients.

Thanks to this option, there is no longer an absolute upper age limit for transplantation. Patients in their 60s, 70s, and 80s, as well as younger patients with additional medical conditions, now undergo non-myeloablative transplants at the Fred Hutchinson Transplant Program at Seattle Cancer Care Alliance. Some never have to be hospitalized during their transplant process; they complete their conditioning, transplant, and recovery as outpatients.

The Graft-Versus-Tumor Effect

Non-myeloablative transplants provide a graft-versus-tumor effect. First you receive reduced-dose conditioning to weaken your bone marrow and immune system, rather than high-dose conditioning to destroy it, so your body will accept the donor’s stem cells.

After conditioning, your transplant team infuses donated stem cells into your bloodstream through a central venous catheter (a small, flexible tube inserted into a large vein leading to the heart). The transplanted cells migrate to your bone marrow to grow and develop, a process called engraftment.

With reduced-dose conditioning, engraftment means a new immune system develops alongside your remaining, but weakened, immune system. So for a time, you have a mixed immune system. The goals are for the new, transplanted immune system (the graft) to attack cancer cells (the tumor) that may have survived conditioning and for the new immune system to take over completely as time goes on.

Research Results on Non-myeloablative Transplants

In November 2011, JAMA published the first study summarizing long-term results from a series of clinical studies of patients age 60 or older treated with non-myeloablative transplants developed at Fred Hutchinson Cancer Research Center.1 The authors concluded that age alone is no longer a consideration when determining whether an older patient with blood cancer is a candidate for transplantation.

On April 20, 2013, the Journal of Clinical Oncology published results with more definitive data from nearly 1,100 patients that showed increased medical problems unrelated to cancer (comorbidities) contribute significantly to poorer transplant outcomes.2 The study involved patients who were enrolled in prospective multi-center clinical trials between 1997 and 2009. All were age 60 or older; all were treated with the same non-myeloablative regimen, developed at the Hutch; and all had acute or chronic leukemia, lymphoma, multiple myeloma, myelodysplastic syndromes (which can progress to acute myeloid leukemia if not treated), or myeloproliferative diseases, such as chronic myelogenous leukemia.

Comorbidities and a higher degree of cancer aggressiveness both affected survival among these older patients. For example, patients who had fewer comorbidities and less aggressive cancer had a five-year survival rate of 60 percent, while patients with more comorbidities and more aggressive cancer had a survival rate of 30 percent, regardless of age.

Although survival rates of 30 to 60 percent may seem low, these patients all would have died of their diseases within a matter of months without a transplant. The majority of patients were referred for a transplant after they had exhausted all forms of conventional therapy.

While there is much room for improvement, particularly with regard to relapse, these results are encouraging given the poor outcomes with non-transplant treatments, especially for patients with high-risk acute myeloid leukemia, fludarabine-refractory chronic lymphocytic leukemia, or progressive lymphoma.

Work Goes on to Reduce Relapse Rates

In addition to survival and the impact of comorbid conditions, the 2013 study examined rates of relapse, hospitalization, acute and chronic graft-versus-host disease (GVHD), and the toxicity of the treatment to internal organs.

In one key finding, disease-relapse risks, not increasing age, were associated with worse outcomes. Other data showed that two-thirds of the surviving older patients who were affected by chronic GVHD had complete resolution of their symptoms and were able to discontinue immunosuppressive medications after a median time of two-and-a-half years from diagnosis. This was comparable to the results reported by previous studies on younger patients who were treated with high-dose radiation and chemotherapy. Half of the patients never required hospitalization after transplant.

These findings, together with the normal to near-normal performance status of surviving patients, should help allay reluctance to enter older patients with blood cancers on non-myeloablative transplant protocols. Additionally, the lack of a matched sibling donor also should no longer be a limitation given that transplants with matched unrelated donors have comparable outcomes.

Looking Forward

Hutch investigators continue to explore novel variations on the non-myeloablative–transplant theme to reduce relapse rates, particularly among patients with more aggressive blood cancers. New prospective clinical trials, with a focus on better GVHD prevention, are nearly underway. The goal is to eliminate toxic systemic conditioning.

One exciting trial is investigating whether the systemic chemotherapy and total body irradiation used in current transplant conditioning regimens can be replaced with an antibody against blood cells that has been coupled to a short-lived, alpha-emitting radionuclide. The alpha emitter is much more powerful than the beta-emitting radionuclides introduced in the 1980s. The targeted radiation possible with this radiolabeled antibody would greatly reduce the toxicities associated with current conditioning regimens.

The alpha-emitting radionuclide is an isotope called astatine-211. It is between 40 and 70 microns in size and has a half-life of seven hours. Made locally at the University of Washington, this isotope when coupled with an antibody will completely destroy the cell it hits without affecting any organs or bone marrow, eliminating the risk of any secondary cancers developing because of the treatment. The first animal study results have been published, and work on a grant required for the next phase of human testing is in process.

1Mohamed L Sorror et al, “Long-term Outcomes Among Older Patients Following Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation for Advanced Hematologic Malignancies,” JAMA 306 (2011): 1874-1883, accessed October 4, 2013, doi:10.1001/jama.2011.1558.

2Rainer Storb et al, “Graft-Versus-Host Disease and Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation,” Journal of Clinical Oncology 31 (2013): 1530-1538, accessed October 4, 2013, doi:10.1200/JCO.2012.45.0247.