Discussion
Reduction of CNS radiation ALL patients with iCNS-R continues to be a
challenge, yet remains an important goal given the late effects of CNS
radiation and limited options for treatment following subsequent
relapse. Excellent outcomes reported in POG 9061/9412 in patients with
late CNS-R were attributed to a treatment approach reliant on the use of
effective anti-leukemia agents with good CNS activity facilitated by a
delay in delivery of CNS radiation that had previously limited
chemotherapy delivery because of prolonged myelosuppression.
Specifically, POG 9061 delayed CNS radiation for six months after
relapse and POG 9412 then intensified the chemotherapy, delayed CNS
radiation for 12 months after relapse and reduced the dose of CRT from
2400 to 1800 cGy. COG AALL02P2 was designed to test one year of further
intensified systemic therapy, followed by CRT at a reduced dose of 1200
cGy. AALL02P2 encountered a number of challenges with lower than
expected enrollment given continued success with frontline therapies and
decreasing CNS-R rates, as well as a large number of enrolled patients
who did not complete protocol-prescribed therapy. The study was closed
before reaching planned accrual when an interim analysis crossed
predefined monitoring boundaries and showed inferior EFS compared to POG
9412.
With respect to overall survival, this treatment strategy with COG
AALL02P2 did prove as effective for patients with late relapse and NCI
SR ALL as the predecessor POG 9412 study, however, EFS was markedly
inferior for this cohort compared to the prior trial. NCI HR patients
fared equally poorly on both trials, without meaningful differences in
outcomes.
As in POG 9412, COG AALL02P2 continued to show a difference in outcomes
between the NCI HR and SR ALL groups. The overall survival showed a
trend towards better survival in the NCI SR group. Similar results are
seen in this recent trial with EFS for NCI HR vs SR. Barredo et al,
previously reported in POG 9412 that NCI SR ALL status was an
independent favorable prognostic factor in addition to length of CR1
suggesting that the NCI/Rome criteria serve as a clinical surrogate for
inherent biological differences.20 There were 11
relapses with 8 attributable to CNS relapse in POG 9412, suggesting a
need for further improvement in CNS (and marrow) control. Interestingly,
in AALL02P2, NCI SR ALL patients fared far worse with respect to EFS
than the similar cohort in POG 9412. This may be related to several
factors including differences in frontline treatments with more
intensified therapies thereby rendering these patients more difficult to
treat as well as a large number of patients on COG AALL02P2 who did not
receive the protocol-prescribed radiation. These patients (26% of the
total enrolled) that did not follow the protocol-directed therapy
included 10 patients who had events prior to the timing of radiation, as
well as a patients, and/or clinicians, who chose not to continue with
the protocol post amendment.
Novel therapies to reduce the risk of second relapse and treatment
providing safer and less toxic CNS directed therapy are needed.
Consideration of other factors in addition to CNS penetration of drugs
is needed; the CNS is thought to be an immunologic sanctuary not just a
physical barrier.40 Subclinical seeding of the CNS
from other sites, particularly the BM, is implicated in subsequent BM
relapse and improved methods of eradicating disease systemically are
needed. While delay of CNS irradiation has proven to be an important
part of relapse therapy, this study emphasizes the necessity of ensuring
adequate delivery of CRT. The results of AALL02P2 suggest that cranial
radiation is a critical and necessary component of relapse therapy for
iCNS-R of B-ALL in the context of chemotherapy-driven regimens.
Nevertheless, emerging data using immunotherapy (chimeric antigen
receptor T-cells) in the setting of extramedullary disease at diagnosis
or relapse of ALL may provide an alternative strategy to decrease or
eliminate CNS irradiation.41-44
While baseline bone marrow MRD data were only available from 64%
(76/118) patients, MRD analysis was not predictive of either EFS or OS.
Within the sensitivity of 0.01%, 19.7% of patients were MRD-positive,
though it is certainly possible that rates would be higher with more
sensitive MRD technologies.
The incidence of isolated CNS relapse has decreased with contemporary
strategies, and several trials have shown that cranial irradiation can
be omitted in newly diagnosed ALL patients.14,21,23,24 However, the individual trials conducted
to date have included relatively few patients with overt CNS disease. A
large study from the Ponte de Legno group aggregated data from 16,623
children (<18 years) with ALL treated by 10 cooperative groups
between 1996 and 2007.24 In that study, cranial
radiotherapy was associated with a reduced risk of CNS relapse only in
the small subgroup of 406 patients with CNS3 status, and the overall
event rate did not differ between those that did or did not receive
radiotherapy. In parallel to newly diagnosed ALL, there is great
interest in reducing radiotherapy dose, or eliminating it entirely, in
patients with CNS-R due to the long-term adverse impact of cranial
irradiation on CNS outcomes, secondary brain tumors, and quality of
life.9,30,45-47 Toward this end, earlier studies from
the POG and others demonstrated that it was possible to preserve
outcomes in patients with late CNS-R by intensifying systemic
chemotherapy while reducing radiation dose and limiting it to the
cranial fossa (eliminating spinal irradiation). However, despite further
intensification of systemic chemotherapy, COG AALL02P2 showed inferior
EFS compared to POG 9412 when the cranial radiation dose was reduced to
1200 cGy, intended to be delivered at 12 months from onset of
recurrence. Limitations in the current study included a small sample
size due to increasing rarity of iCNS-R, early study closure and a
substantial number of patients, 34/118 (29%), who did not receive
protocol directed radiation either due to early relapse prior to 1 year
or decision to not follow the treatment plan. It is also possible that
cranial irradiation may need to be administered earlier after relapse,
and that further intensifying systemic cytotoxic therapy is
counterproductive.
The overall goal to limit cranial radiotherapy in patients with iCNS-R
remains important. Future studies might also incorporate newer
immunotherapies or more sensitive marrow MRD technologies and/or CNS
response measures to attempt to identify which patients with iCNS-R
might be cured without irradiation, and whether different subgroups
might require lower or higher doses of radiotherapy. To gain adequate
power to address these questions, future trials will likely require
international collaboration.
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authors and does not necessarily represent the official views of the
National Institutes of Health.