By Jerald P. Radich, MD
2009-07-11
Dr. Radich indicated no relevant conflicts of interest.
Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944-50.
Goldstone AH, Richards SM, Lazarus HM, et al. In
adults with standard-risk acute lymphoblastic leukemia (ALL) the
greatest benefit is achieved from a matched sibling allogeneic
transplant in first complete remission (CR) and an autologous
transplant is less effective than conventional
consolidation/maintenance chemotherapy in ALL patients: final results
of the international ALL trial (MRC UKALL XII/ ECOG E2993). Blood. 2007. [Epub ahead of print]
The advance of therapy for pediatric ALL is a success story that
oncology can revel in; it also places the bar very high for the rest of
the oncology landscape. Whereas pediatric ALL therapy can cure upward
of 80 percent of patients, success in adult ALL is stuck at a rate of
~40 percent. Indeed, some pediatric trials are using risk
stratification to give less therapy to some cases. This is a mind-boggling luxury for those physicians who work in the adult arena.
Two recent papers have direct relevance to how we should be treating
adult ALL. The first, by Fielding, et al., examines the fate of adult
ALL cases that relapse after therapy. The paper is a clear,
illuminating, and utterly depressing read. The overall five-year
survival for cases who relapsed was only 7 percent. This bleak result
was not influenced by the type of therapy the patients initially
received (i.e., chemotherapy or transplantation). For those who
received chemotherapy following transplant, only 4 percent survived.
Patients who were "salvaged" with allogeneic transplant fared slightly
better, with a survival of 23 percent. The paper’s overwhelming
conclusion is that there is one good chance to cure patients, and that
more toxicity up front might be a reasonable tradeoff for a decreased
relapse rate.
The recent results of the MRC/ECOG trial of front-line therapy for
ALL suggest that allogeneic transplantation might offer the best chance
for cure. In this trial, patients who had a donor were eligible for
transplant in first CR; those without a donor were potentially
randomized to autologous or chemotherapy. Of the 1,929 patients
entering the trial, 1,031 were HLA typed, and 443 patients had an
HLA-matched related donor, while 588 did not. Analysis was performed
based on the donor status. The study suggests that, for
Ph-chromosome-negative patients, more intense therapy is associated
with greater success, with overall survival in allogeneic
>autologous> chemotherapy (~53 percent vs. 45 percent vs. 37
percent, respectively). The advantage of allogeneic transplantation did
not appear to be as strong in high-risk ALL, due to an unusual amount
of non-relapse mortality among the transplant recipients. There are, of
course, the usual caveats attached to such complex studies: worries
about dropout rate, differences in the percentages of patients
acceptable to randomization, analysis by "intent" rather than actual
treatment, etc.
A reasonable interpretation of the data would suggest:
- Adult ALL patients should
be offered a clinical trial whenever possible. The prevailing therapy
is not good enough to be a "standard" therapy.
- Allogeneic
transplantation should be considered in patients who are at good risk.
Given that, at many centers, unrelated transplant results are similar
to related, both avenues of donors should be considered.
- Physicians
should employ the most rigorous methods of minimal residual disease
detection, either flow cytometric or molecular (i.e., immunoglobulin
heavy-chain VDJ rearrangements). Physicians should demand that their
centers adopt technology that can detect at least one leukemic cell in
a background of >1,000 normal cells, since this level of detection
has been shown to reliably predict relapse.
- More
money needs to be spent studying the biology of ALL. Except for Ph+
ALL, the "targeted" therapeutic revolution has passed over ALL. Much
discovery is needed in adult ALL if we wish to ever approach the
success of our pediatric colleagues in this disease.
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