John F. DiPersio, MD, PhD
2010-01-01
There remains an embarrassing lack of data on the outcomes and characteristics
of patients with hematologic malignancies who relapse after allogeneic
transplantation. In addition, there is a dearth of effective therapies for these
patients. To address these concerns, the National Cancer Institute sponsored
an International Workshop on “Biology, Prevention, and Treatment of
Relapse After Allogeneic Hematopoietic Stem Cell Transplantation” this past November in
Bethesda, MD. The conference was co-chaired by Sergio Giralt, MD, from M. D. Anderson
and Michael Bishop, MD, from NCI and was attended by a diverse group of more than 230
scientists and clinicians.
Genetics was a dominant theme of discussion. Carlo Maley, PhD, from the Wistar Institute
suggested natural selection as a possible mechanism for the evolution of malignancies
as they relapse after allogeneic transplantation. There was agreement that universal and
standardized methods of data collection and specimen banking would have a transforming
effect on understanding the biology of natural selection or evolution of mutations. There
was also consensus that newer, cutting-edge genomic approaches are needed to answer
basic questions about the origins of mutations found at the time of relapse (via “natural
selection” or occurring in the peri-relapse period). Although the number of mutations may
appear daunting, only an aggressive and comprehensive approach to cataloging these
mutations at both the genetic and epigenetic levels would provide critical insights into the
dynamic changes that occur in the genome, transcriptome, and epigenome of malignancies
relapsing after transplantation.
There was spirited discussion on the value of identification of minimal-residual disease
in the post-transplant setting. For some diseases such as chronic lymphocytic leukemia
and follicular non-Hodgkin lymphoma, identification of persistent disease post-transplant
may, in fact, affect outcome, but for others, including the acute leukemias, early detection may not impact the therapeutic benefit of current interventions, including donor
lymphocyte infusions. Timing of relapse is also an important issue. Interventions may
have only limited impact on those patients who relapse early (vs. late). Although it is
reasonable to assume that early identification of minimal residual disease could result
in better outcomes, no such data exist. For some aggressive diseases, it may be akin
to watching an asteroid approach the Earth using the Hubble telescope or a hand-held
pair of binoculars. In spite of the fact that you can identify the asteroid (AML or ALL)
at an earlier point, there is no effective way to head off a catastrophe. Therefore, the
investment of time and money required to develop patient-specific polymerize chain
reaction (PCR) or next-generation sequencing assays to detect minimal residual disease
will be problematic, since these may benefit only those who relapse late after
transplant or who have indolent diseases. Again, there needs to be more basic understanding
of the genetics and genomics of these malignancies as they progress from
diagnosis to relapse after transplantation.
Among other interesting topics discussed were the pathways involved in the selfrenewal
of both normal and leukemic hematopoietic stem cells. In particular, Sonic
Hedgehog and β-catenin have emerged as potential targets in quiescent, therapy-resistant
leukemic stem cells. Additionally, extramedullary recurrence is being seen more
frequently and remains a major therapeutic problem.
So, even if we can see this asteroid approaching, there may be nothing we can do about
it for the next few years. But knowledge is power, and knowledge of the specific genetic
and phenotypic characteristics of these tumors as they evolve in patients under the
force of donor T cells or genetically modified and ex vivo activated T and NK cells will
provide important insights into future directions of study and more effective therapies.
We hope this will lead to improved patient outcomes.
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