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How do transplants cure leukemia?
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Hematopoietic cell transplants are widely used to treat people with leukemia.
More than a half-million allogeneic transplants (allotransplants) have been performed worldwide.
Considerable data indicate these transplants have greater anti-leukemia efficacy than conventional therapies. Whether transplants result in better survival is controversial, but this benefit is clearest in people with leukemia who do not achieve remission with current nontransplant therapies.
The question arises: When successful, how do transplants cure leukemia? This question is the subject of this commentary.
Potential mechanisms of cure
There are many ways by which hematopoietic cell transplants might appear to cure leukemia. They include:
Let’s consider each mechanism (see Figure).
Image courtesy of Mine Harada, MD, PhD, and Robert Peter Gale, MD, PhD, DSc(hc), FACP, FRSM.
A substantial proportion — perhaps one-third — of those who receive a hematopoietic cell transplant in first remission were cured pretransplant. Their posttransplant freedom from relapse is unrelated to their receiving a transplant.
This situation arises because we are unable to accurately predict which people who achieve and remain in complete remission for 3 to 6 months are likely to relapse.
For example, in randomized clinical trials designed to compare postremission chemotherapy with transplants in people with acute myeloid leukemia in first remission, 25% to 50% in the chemotherapy cohort are cured. A similar proportion must operate in the transplant cohort.
Exactly who these people are is unknown. Tests such as cytogenetics, mutation analyses and measureable residual disease (MRD) testing are inaccurate predictors in people who are in remission at 3 to 6 months.
For example, MRD test results in people in complete remission after completion of postremission chemotherapy have about 30% false-negative and -positive results. The C-statistic derived from receiver operator characteristic curves for MRD test results in recent clinical trials is about 0.7, suggesting a high level of misassignment of cure (Estey E. Personal communication).
The only situation where we can be reasonably certain transplants are being done in those not already cured is in the setting of failure of conventional therapies. In this population, the cure rate is about 20%.
Immune-mediated effects
The early rationale for performing hematopoietic cell transplants was to allow the use of high-dose therapy, including drugs and radiation. We now know no dose of therapy we give completely destroys normal bone marrow function. However, infusing hematopoietic cells accelerates bone marrow recovery.
We can estimate the impact of high-dose therapy by comparing leukemia relapse rates in those who receive high-dose vs. reduced-intensity pretransplant therapy after adjusting for variables associated with leukemia relapse. In all settings, people who receive reduced-intensity pretransplant therapy have a greater likelihood of relapse than those who receive high-dose pretransplant therapy. The difference in relapse rates is 10% to 20%. These data indicate high-dose therapy is another way hematopoietic cell transplants cure leukemia.
Considerable data suggest immune-mediated anti-leukemia effects — sometimes referred to as graft-versus-leukemia — operate after allotransplants. For example, relapse risk is increased in people without acute or chronic graft-versus-host disease (GVHD), recipients of T-cell–depleted transplants and recipients of transplants from genetically identical twins. In contrast, relapse risk is decreased in those with acute and chronic GVHD (these are confounded).
These data suggest an immune-mediated anti-leukemia effect after allotransplants. This anti-leukemia effect is not proved leukemia specific and may simply be a result of alloreactivity — a form of GVHD — directed at disparate histocompatibility antigens (non-HLA antigens) rather than leukemia-specific antigens. Whether it operates in an autologous setting is unknown and unproved except in an artificial setting like genetically modified T cells, such as chimeric antigen receptor T cells.
Real cure vs. operational cure
We cure a substantial proportion of people with leukemia with conventional therapy. However, it is unclear how this is achieved. It is unlikely we eradicate all leukemia cells in each person.
Considerable data from atomic bomb survivors and other settings indicate, fortunately, it is unnecessary to eradicate every leukemia cell to cure leukemia. For example, the interval from the time BCR/ABL is formed to develop radiation-induced chronic myeloid leukemia in A-bomb survivors can take 40 years or longer. This means a person with a few residual leukemia cells may die of a competing cause before one or more of these residual leukemia cells undergo sufficient numbers of divisions to eventuate in clinical relapse. The process by which this occurs is called stochastic.
This stochastic effect should be distinguished from a fifth mechanism: misidentification of people as cured when they are not.
For example, most people with leukemia are old. Many destined to relapse may die of another event — eg, cardiovascular disease or another neoplasm — before their leukemia has sufficient time to relapse. The situation in these people is best termed operational cure to distinguish it from real cure (this distinction is important to the biologist but not to the person with leukemia).
The increased likelihood of cure in people who receive an allotransplant is the sum of these mechanisms. The proportional contribution of each mechanism likely will differ in different leukemias, different disease states and different people, including those with the same leukemia and disease state.
This complexity makes quantification of the impact of these mechanisms in a person difficult or impossible. Other mechanisms also may operate. Regardless of the mix of different mechanisms in different people with leukemia, the net result is a lower risk for leukemia relapse after allotransplants. Whether this benefit results in a survival advantage is controversial.
For more information:
Mine Harada, MD, PhD, is a member of the faculty of medicine at Kyushu University in Fukuoka, Japan.
Robert Peter Gale, MD, PhD, DSc(hc), FACP, FRSM, is a member of the Hematology Research Centre at Imperial College London. He also is a HemOnc Today Editorial Board member. He can be reached at Hematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, UK SW7 2AZ; email: robertpetergale@gmail.com.
Disclosure: Gale reports support from the National Institute of Health Research Biomedical Research Centre. Harada reports no relevant financial disclosures.
Perspective
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Elihu Estey, MD
In their paper, Harada and Gale provide an enlightening discussion of how allogeneic hematopoietic cell transplant (HCT) might cure leukemia. One way is by appearing to cure people already cured before HCT. To me, this highly likely possibility begs the question of the qualitative differences between HCT and chemotherapy. I will address this focusing on acute myeloid leukemia.At first glance, this question appears preposterous. Certainly, as described in Harada’s and Gale’s paper, receipt of donor cells is associated with immune-mediated anti-AML effects (graft-versus-leukemia, commonly called GVL). Perhaps the best example of this phenomenon is the reduction in AML seen following reinfusion of lymphocytes from the original donor in cases of post-HCT relapse. These donor lymphocyte infusions are unaccompanied by chemotherapy.
Although there is no GVL following chemotherapy, the same prognostic factors (imperfectly) associated with relapse after chemotherapy also predict relapse after HCT. Thus, although people with complex cytogenetic abnormalities appear less likely to relapse after HCT than after chemotherapy, people with complex cytogenetics are more likely to relapse after HCT than people with other cytogenetic findings — just as is the case with chemotherapy. The presence of aberrations in the FLT3 gene confers an increased risk for relapse with either HCT or chemotherapy, although the risk for relapse in FLT3-abnormal AML is greater after chemotherapy than HCT. The strongest predictor of relapse after HCT is the presence of measurable residual disease pre-HCT (ie, after completion of chemotherapy). Pre-HCT minimal residual disease denotes a relative failure of chemotherapy. Hence, unsuccessful chemotherapy begets unsuccessful HCT.
These data — together with Harada’s and Gale’s note that many of the people thought cured by HCT were already cured by chemotherapy — suggest HCT and chemotherapy have much in common mechanistically. One possibility is the existence of an immunologic analog of GVL in patients who never receive HCT. It might be productive to immunologically compare people cured by chemotherapy alone with people who relapse very quickly after chemotherapy. Better comprehension of the role of the native immune system in the cure of AML might eventually render HCT less necessary.
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