CNS involvement in AML is generally associated with a poor prognosis4,12,13
. However, little is known about the prognostic significance of CNS involvement with AML before transplantation, or how best to treat it. In this investigation, 12% of AML patients who presented for HCT had CNS+ disease, reflecting the importance of treatment options in this patient population. This retrospective study describes the largest number of adult AML patients with CNS+ disease in the HCT setting. Patients with CNS involvement before transplant experience a poorer transplant outcome compared to CNS− patients, as illustrated by the dismal 6% 5 yr OS of CNS+ITC patients. Encouragingly, however, the addition of cranial irradiation to intrathecal chemotherapy appears to mitigate the risk of CNS disease, at least to some extent. This last finding is consistent with a report by Castagnola et al.4
, which demonstrated improved survival in CNS+ patients treated with combined chemotherapy and cranial irradiation in the non transplant setting.
There is no current standard of care for CNS+ AML patients undergoing HCT. Our findings suggest a possible role for an irradiation boost as part of transplant conditioning regimens. In this study, the addition of RT showed a statistically significant DFS and OS benefit in patients with CNS involvement. The CNS+ITC patients had poor outcomes, with an estimated OS of 21% at 1 year, and 6% at 5 years. However, CNS+RT patients had overall 1 and 5 year OS rates of 53% and 42%, respectively. Furthermore, the addition of an irradiation boost was associated with RFS and OS comparable to CNS− patients. The OS mirrored the RFS for this patient cohort, which is not surprising in adult AML, as there are few salvage options available post transplantation.
Prognostic variables known to effect transplant outcome were examined. It has been established that patients in first remission have the most favorable prognosis15
. The CNS+ patients were more likely to have primary refractory disease or were transplanted while in relapse. The statistical analysis accounted for the disease status according to historical prognosis status post transplantation. The outcome differences found between the CNS−, CNS+ITC, and CNS+RT patients, remained statistically significant after adjusting for other prognostic factors such as age, sex, unrelated donor, or presence of total body irradiation in the conditioning regimen. Nevertheless, some uncertainty remains since it was not clear from the retrospective chart review why a given attending physician chose ITC alone and another chose ITC and a CNS irradiation boost.
We also examined the role of TBI in CNS disease, given that the 12 Gy dose of TBI treats the entire craniospinal axis. There were no differences in RFS or OS observed between TBI containing regimens in the CNS+ versus CNS− patients. Furthermore, there was a trend for worse OS in CNS+ patients who received a TBI containing regimen compared to those who did not. Given the small number of CNS+RT patients, we are unable to draw conclusions on the effect of TBI and dose to control CNS disease. However, this OS difference may be suggestive that patients with a TBI containing regimen who had CNS+ITC, a TBI dose of 12 Gy may be inadequate to control CNS disease.
To better understand the observed striking differences in RFS and OS between the three treatment groups, we investigated relapse and non relapse mortality rates of our patient populations. There appeared to be both a possible decrease in relapse rates as well as a decrease in non-relapse mortality associated with CNS irradiation. The non relapse mortality rate in the CNS+ITC was 48%, which may contribute to the observed RFS and OS differences between the CNS+RT and CNS+ITC groups. CNS+RT patients had equivalent non relapse mortality rates compared to the CNS− patients. Given the retrospective nature of this analysis, it is possible that cranial irradiation was selectively administered to patients who were more likely to survive HCT, and selectively withheld from patients perceived by physicians to be at higher risk. Although more patients in the CNS+RT group were transplanted in 2nd/3rd remission and relapse, their performance status could have been superior than those in the CNS+ITC group, thus leading to a difference in the non-relapse mortality observed.
Our study showed a trend for decreased systemic relapse in the CNS+RT patients compared to the CNS+ITC patients. The radiation boost in this study may have led to improved RFS and OS benefits via a decrease in CNS relapse. Furthermore, patients with CNS+ITC could harbor occult CNS disease leading to systemic and bone marrow relapses. It has been established in the literature that patients with CNS+ disease have an increased risk of CNS relapse post transplantation16
. This trend of decreased relapse in patients who are treated with CNS targeted therapy parallels relapse patterns in patients with CNS positive ALL treated with post transplant ITC 15
. In an earlier report by our institution, patients with CNS positive ALL in the HCT setting were found to have higher rates of post transplant CNS failure than those who did not have involvement of the CNS15
. Patients who had a history of, or active, CNS disease had a CNS relapse of 52% versus 17% if given post transplant ITC15
. In our study, patients were not routinely accessed by lumbar puncture for CNS relapse in the post transplant setting, and we are unable to definitively comment on the impact of a radiation boost on CNS relapse.
Our study prompts unresolved questions. Due to the small number of patients receiving craniospinal radiation, we are unable to clearly define which patients would benefit from craniospinal versus cranial radiation. In addition, patients who were CNS+ or CNS− did not routinely undergo post transplantation lumbar puncture, so we are unable to report CNS specific death in our study. Also, we were not able to examine the potential differences of dose rate effects, particularly the low dose rate TBI versus the high dose rate cranial radiation boost, on CNS disease.
Neurocognitive outcomes have not been reported in adult CNS+ AML. However, our group previously reported on CNS toxicity, specifically, leukoencephalopathy, associated with CNS directed therapy prior to HCT in AML (15). In this paper, we reported that 7 of the 415 patients who received allogeneic transplantation for acute leukemia experienced leukecoencephalopathy. There was no statistically significant relationship between a history of CNS disease prior to transplantation and the development of leukoencephalopathy. All seven cases were among the 201 patients treated with CNS directed therapy prior to HCT, with either ITC or RT. Five of the seven cases were among the 57 patients that received 6 or more doses of IT-methotrexate. None of the patients that received that received post transplantation ITC without prior CNS therapy developed leukcoencephalopathy. Therefore, CNS directed therapy should be administered with caution due to the increased risk of CNS morbidity post transplantation. In our current report, we are unable to comment on the neurocognitive outcome or CNS morbidity of the CNS+ patients, given the lack of detailed neurocogitive follow up in our population.
In conclusion, CNS+ AML is associated with a poor prognosis. This result augments our recently published investigation on disease status based risk stratification on the overall outcome of AML after HCT17
. The role of a CNS irradiation boost to standard ITC in HCT conditioning for CNS+ AML patients may potentially improve outcomes, but remains largely uncertain. Given the paucity of data in the literature regarding this subject, we recommend that if patients are to be treated with a radiation boost, it should precede HCT to allow for eradication of CNS disease prior to HCT. Whether there is a benefit to CSI over cranial RT in these patients remains unknown. Further, the cranial boost is given at a dose that is related to whether TBI is administered. With the addition of TBI, the majority of CNS+RT patients in this study were treated with a cranial boost to a total dose of 22-24 Gy. We are unable to further define the optimal cranial boost dose. Due to the added morbidity of CSI without data to support its inclusion in CNS+ AML, we recommend cranial irradiation instead of CSI.
Our study observed an improvement in RFS and OS with the addition of an irradiation boost, and a trend toward decreased relapse rates in the CNS positive patients who received a radiation boost. This investigation draws attention to CNS positive AML disease, and the role of a multimodality approach to CNS directed therapy. Furthermore, our study highlights the need for future prospective trials to further define optimal treatment strategies.