Abstract
There is limited knowledge of the rate of central nervous system (CNS) involvement and risk factors for its development in acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic cell transplantation (HCT). In this study we retrospectively evaluated CNS involvement in 327 patients who underwent myeloablative HCT in our institute, where all patients have CSF examined by morphology or flow cytometry prior to HCT. Twenty-two patients (7%) had CNS AML involvement at pre-HCT evaluation. Covariates associated with such involvement were higher WBC at diagnosis, prior CNS or other extramedullary disease (EMD), and evidence of systemic disease at pre-HCT evaluation. History of prior CNS disease and disease status at pre-HCT evaluation allowed stratification of patients into three risk groups (i) 35% (20 patients), (ii) 16% (51 patients) and (iii) 3% (254 patients) rates of pre-HCT CNS involvement. Treatment of pre-HCT CNS disease was uniformly successful regardless of whether cranial XRT was employed. Perhaps as a result, presence of CNS pre-HCT had no independent influence on post-CT outcome, which was primarily influenced by status of systemic disease at time of HCT.
Keywords: Acute myeloid leukemia (AML), Central Nerve System (CNS), Hematopoietic cell transplantation (HCT)
Introduction
The exact incidence of central nervous system (CNS) involvement in adults with acute myeloid leukemia (AML) is unknown, but considered uncommon (<5%) (1-3). Therefore cerebrospinal fluid CSF evaluation is usually performed only in patients with neurological symptoms, and, unlike in acute lymphoblastic leukemia (ALL), prophylactic therapy is not indicated (4). Risk factors associated with CNS AML are higher pre-treatment levels of LDH and WBC , chromosome 16 inversion and chromosome 11 abnormalities, FAB subgroup M4 and M5, and younger age (5, 6). Although high dose cytarabine (HiDAC), intrathecal chemotherapy, and cranial irradiation are effective treatments, relapse rate is high and CNS involvement is considered poor prognostic factor (2, 7-9).
Allogeneic hematopoietic cell transplantation (HCT) can be curative in AML (10, 11). However, despite advances in therapy, relapse remains the major cause of post-HCT mortality (12, 13). The incidence of CNS disease before and after transplant and the effect of CNS disease on transplant outcome is uncertain (3). In our institution all AML patients considered candidates for allogeneic HCT undergo routine CSF examination as part of pre-transplant evaluation, allowing a relatively unbiased look at the incidence of AML in CSF pre-HCT. Therefore the primary objectives of this study were to assess the rate of CNS involvement in AML patients undergoing HCT, evaluate potential risk factors for CNS disease, and examine the effect of CNS involvement on transplant outcome.
Patients and Methods
Patient Population
We retrospectively evaluated 327 adults (age ≥18) with AML who underwent myeloablative HCT at the Fred Hutchinson Cancer Research Center (FHCRC) between January 2007 and December 2012. Per standard practice at our institution all patients underwent routine evaluation for CNS AML involvement at the time of pre-HCT evaluation by morphologic or multiparameter flow cytometric evaluation of cytospun CSF. AML CNS involvement was defined as unequivocal morphologic or immunophenotypic evidence of leukemic blasts in the CSF, or, in symptomatic patients by abnormal findings on computed tomography (CT) or magnetic resonance imaging (MRI).
All patients with evidence of CNS involvement at pre-HCT evaluation were treated by intrathecal/intraventricular chemotherapy (+/−cranial radiation), and entered transplant with no evidence of CNS disease. Transplant conditioning regimens have included Busulfan/Cyclophosphamide (n=84), Treosulfan/Fludarabine/+/−low dose TBI (n=79), Busulfan/Fludarabine (n=54), Cyclophosphamide/high dose TBI (n=37), Fludarabine/I131 anti-CD45 Ab/+/−Cyclophosphamide (n=35), Cyclophosphamide/Fludarabine/high dose TBI (n=33), and others (n=5). All patients provided informed consent for treatment approved by the institutional review board. Separate institutional approval was obtained to gather data from patient records and databases for this retrospective study.
CSF Evaluation
Cytomorphological evidence of CNS involvement was defined by microscopic counting of myeloblasts in cytospin CSF preparation stained with May-Grunwald-Giemsa. Cytomorphological analysis performed on cytospin preparation is highly specific (>95%), but has lower sensitivity of approximately 80% (14). In most cases CSF was also evaluated by multiparametric flow cytometry, which has a diagnostic value that is more than twice of cytomorphology (15). Flow cytometry analysis was performed on a modified 4-laser, 10-color Becton Dickinson LSRII flow cytometer (BD Biosciences, San Jose, CA) as previously described (16).
Statistical Methods
Wilcoxon rank sum tests were used to compare quantitative variables and Fisher’s exact test was used to compare categorical variables in patients with and without CNS involvement. Overall survival (OS) after transplant was measured from date of transplant to date of death due to any cause, with patients last known to be alive censored at the date of last contact. Relapse-free survival (RFS) after transplant was measured from the date of transplant to the date of first relapse or death from any cause, with patients last known to be alive in CR censored at the date of last contact. Time to relapse (TTR) after transplant was measured from date of transplant to date of relapses, with deaths in CR considered a competing event. OS and RFS were estimated with the Kaplan-Meier method and TTR was estimated using cumulative incidence curves. Cox regression models were used to assess OS and RFS, and proportional hazards models for the subdistribution of a competing risk were used to assess TTR. Multivariable analyses for CNS involvement at time of transplant included history of CNS involvement and other extramedullary disease, remission status, cytogenetics, prior high dose cytarabine (≥ 500mg/m2 per dose), and the quantitative covariates white blood cell count and age. Classification and regression tree (CART) analysis was used to define subgroups at differing risk of CNS disease at time of HCT.
Results
Patient characteristics
327 adults with AML who underwent myeloablative HCT were retrospectively evaluated. Median age was 49 (range 19-73). Twenty-eight (9%) patients had favorable karyotype (SWOG criteria), 215 (66%) had intermediate-risk karyotype, and 84 (26%) had unfavorable karyotype at diagnosis. 209 patients had received high dose cytarabine. At time of CNS evaluation pre-HCT, 166 patients were in CR without minimal residual disease, 65 had CR with MRD, 41 had CRp or CRi, and 54 had overt systemic relapse (>5% blasts in marrow). Twenty patients had a prior history of CNS disease. Median follow-up time among patients censored for OS was 3.1 years (1130 days). Characteristics of patients are presented in Table 1.
Table 1.
Patient Characteristics
| Median (range) or N (%) | |||
|---|---|---|---|
| Factor | No CNS involvement at pre-HCT evaluation (N = 305) |
CNS involvement at pre-HCT evaluation (N = 22) |
P-value |
| Age at HCT | 49 (19, 73) | 50 (22, 69) | 0.49 |
| Gender - Male - Female |
160 (52) 145 (48) |
19 (45) 12 (55) |
0.66 |
| WBC at diagnosis (×103/μL) | 5 (0, 800) | 34 (2, 269) | <0.001 |
| Risk group1
- Unfavorable - Favorable - Intermediate-I - Intermediate-II |
79 (26) 23 (8) 128 (42) 75 (25) |
5 (23) 5 (23) 7 (32) 5 (23) |
0.15 |
| Prior CNS involvement - Yes - No |
13 (4) 290 (96) |
7 (32) 15 (68) |
<0.001 |
| Prior EMD (no CNS) - Yes - No |
25 (8) 280 (92) |
5 (23) 17 (77) |
0.04 |
| Prior HDAC treatment - Yes - No |
195 (64) 108 (36) |
14 (67) 7 (33) |
1.0 |
| Disease status at pre-HCT evaluation CR no MRD CRp/CRi CR-MRD No CR |
162 (53) 38 (12) 60 (20) 44 (14) |
4 (18) 3 (14) 5 (23) 10 (45) |
0.0015 |
| CR status at pre-HCT evaluation CR1 CR2 CR≥3 No CR |
185 (61) 70 (23) 6 (2) 44 (14) |
3 (14) 4 (18) 5 (23) 10 (45) |
|
| HCT allotype HLA Matched-Related HLA Matched-Unrelated HLA Mismatched-Related HLA Mismatched-Unrelated |
102 (33) 118 (39) 8 (3) 55 (18) |
10 (45) 7 (32) 2 (9) 3 (14) |
0.23 |
| Graft Source Bone Marrow Peripheral blood Cord Blood |
58 (19) 208 (68) 38 (12) |
8 (36) 13 (59) 1 (5) |
0.19 |
Based on ELN risk classification (4) (20)
Predictors of CNS relapse
35 patients (11%) had AML CNS involvement at any time pre-HCT, among them 22 (7%) had CNS AML involvement at their pre-HCT evaluation. Five of these 22 patients had had prior (treated) CNS AML, three had had prior EMD not involving the CNS, and 2 had had both prior CNS and other EMD (Figure 1). The incidence of CNS AML at pre-HCT evaluation was 7/20 (35%) in patients with past CNS involvement versus 15/305 (5%) in patients without history of CNS disease (p <0.001), and was 5/30 (17%) in patients with a history of other EMD versus 17/297 (6%) (p = 0.04) in patients with no prior EMD. Other covariates associated with CNS AML at pre-HCT evaluation were (i) higher WBC at diagnosis (p <0.001, medians of 34,000 in those with versus 5,000 in those without CNS disease) and (ii) disease status at time of CNS evaluation pre-HCT (p<0.001) with only 2% of patients in CR without MRD having CNS involvement versus 9% of those with CR with MRD, 7% of those with CRp or CRi, and 19% of those with overt relapse. Age, karyotype, and receipt of high dose cytarabine were not associated with CNS involvement pre-HCT in univariate analysis (Table 1).
Figure 1.
Prior CNS and extramedullary disease among 327 AML patients undergoing myeloablative HCT
Seven of the 22 patients with CNS involvement at pre-HCT evaluation had normal karyotype. Of these 22 patients seven patients had molecular studies performed and among them one patient had FLT3 ITD mutation and one patient had FLT3 ITD mutation and NPM1 mutation (both with normal karyotype). Among the 13 patients who had CNS involvement prior to arrival to transplant but with negative CNS on pre-HCT evaluation three had normal karyotype. Six of those patients had molecular studies performed and all were negative. Among the 35 patients with CNS disease at any time prior to transplant seven had normal karyotype.
Classification and regression tree (CART) analysis identified 3 risk groups for pre-HCT CNS disease: (1) high = prior CNS disease (20 patients, 35% with CNS involvement at pre-HCT evaluation), (2) intermediate = no prior CNS involvement but with systemic relapse at time of pre-HCT evaluation (51 patients, 16% with CSF involvement at pre-HCT evaluation), (3) low = no prior CNS disease and systemic CR at time of pre-HCT evaluation (254 patients, 3% with CSF involvement).
No routine imaging was performed for evaluation of AML CNS disease, but brain or spine imaging were performed only if patients presented with neurological or other concerning symptoms, independent of CSF involvement. Nine of the 22 patients found to have positive CSF disease during pre-HCT evaluation underwent brain or spine imaging Abnormalities were identified in two cases; thoracic spine chloroma was identified in a patient presented with paresthesia, and left temporal chloroma was identified in a patient presented with headache and diplopia. In both cases patients also found to have abnormal blasts in CSF evaluation.
An additional 50 patients arrived on the transplant service during this period of time but did not undergo transplant, primarily due to refractory disease. 33 of these 50 patients underwent lumbar puncture (LP) as part of pre-HCT evaluation and seven (21%) were found to have CNS disease. Six of these seven patients had concurrent marrow involvement. Two of the 50 patients had had evidence of CNS involvement prior to arrival for pre-transplant evaluation; however the majority of the patients did not have CNS evaluation prior to arrival to transplant.
Effect of pre-transplant CNS involvement on post-transplant CNS involvement and transplant outcome
All 22 patients with CNS involvement at pre-HCT evaluation received CNS-directed treatment with intrathecal methotrexate (usually) or cytarabine. Median number of intrathecal therapies was 3 (range 2-9), with clearance of CSF after median of 2 doses (range 1-5). Twelve patients also received craniospinal irradiation with median cranial dose of 2400 cGy and median spinal dose of 1800 cGy in fractions of 200 cGy (Table 2). Eighteen patients also received CNS-directed therapy after HCT (between 1-6 intrathecal treatments). Nine and 8 patients with prior history of CNS disease, but with no evidence of CNS involvement at time of pre-HCT evaluation received CNS-directed therapy before and after transplant respectively. Eight of the 35 patients with history of CNS disease pre-HCT received high dose TBI as part of their transplant conditioning, and 9 patients received cranial irradiation. Two of the 35 patients (6%) with CNS disease at any time pre-HCT had documented CNS disease after transplant. Patients with no evidence of CNS disease before HCT did not receive CNS prophylactic therapy before or after transplant.
Table 2.
CNS directed therapy for 22 patients with CNS disease at pre-HCT evaluation
| Patient | Intrathecal therapy | Cranial irradiation (cGy) |
Spinal irradiation (cGy) |
|---|---|---|---|
| 1 | IT Methotrexate (×6); CSF cleared after 2 doses |
2400 | 1800 |
| 2 |
IT Methotrexate (×2); CSF cleared after 1 dose |
1800 | 1260 |
| 3 | IT Methotrexate (×2); CSF cleared after 1 dose |
2200 | none |
| 4 | IT Methotrexate (×4); CSF cleared after 3 doses |
2340 | 1800 |
| 5 | IT Methotrexate (×3); CSF cleared after 3 doses |
2400 | 2400 |
| 6 | IT Methotrexate (×3); CSF cleared after 1 dose |
2400 | 2400 |
| 7 | IT Methotrexate (×5); CSF cleared after 4 doses |
2400 | 2400 |
| 8 | IT Methotrexate & Cytarabine (×3); CSF cleared after 2 doses |
2400 | 2400 |
| 9 | IT Methotrexate (×5); CSF cleared after 4 doses |
2400 | 1800 |
| 10 | IT Methotrexate (×2); CSF cleared after 1 dose |
none | none |
| 11 | IT Methotrexate (×3); CSF cleared after 2 doses |
2400 | 2400 |
| 12 | IT Methotrexate & Cytarabine (×3); CSF cleared after 2 doses |
none | none |
| 13 | IT Methotrexate (×4) CSF cleared after 3 doses |
1080 | 1080 |
| 14 | IT Methotrexate (×2); CSF cleared after 1 dose |
none | none |
| 15 | IT Methotrexate (×3); CSF cleared after 2 doses |
none | none |
| 16 | IT Methotrexate & Cytarabine (×3); CSF cleared after 1 dose |
none | none |
| 17 | IT Methotrexate (×4); CSF cleared after 3 doses |
none | none |
| 18 | IT Methotrexate (×3); CSF cleared after 3 doses |
none | none |
| 19 | IT Methotrexate (×3); CSF cleared after 2 doses |
none | none |
| 20 | IT Methotrexate (×2); CSF cleared after 2 doses |
1200 | 1200 |
| 21 | IT - MTX (×4; cleaer after 3) | none | none |
| 22 | Intraventricular (via Ommaya reservoir) Methotrexate (×5) followed by Cytarabine (×4); CSF cleared after 5 Methotrexate doses |
none | none |
On univariate analysis patients with CNS involvement at pre-HCT evaluation had shorter post-HCT overall survival (OS) (p = 0.002). However, multivariable analysis indicated that this reflected the association of CNS disease with poorer systemic response to pre-transplant therapy and evidence of systemic disease at time of transplant; specifically, the multivariable hazard ratio (HR) was 1.48 for CNS involvement versus no CNS involvement (p = 0.17) in contrast with HR of 3.62 for CR with MRD versus CR without MRD (p <0.001) and 3.78 for no CR versus CR without MRD (p <0.001). Tests for interactions indicated that the relatively small effect of CNS disease on survival was similar in patients with CR + MRD, CRp or CRi or neither CR nor CRp/CRi (Table 3). Similar results were shown for RFS (Table 4). High dose TBI or cranial irradiation as part of the transplant conditioning regimen did not affect time to relapse, RFS and OS of the 35 patients with history of CNS disease pre-HCT (Figure 2).
Table 3.
Multivariate analysis for overall survival after transplant
| Covariate | HR | 95% CI | P-value |
|---|---|---|---|
| CNS disease at time pre-HCT evaluation (ref = no CNS disease) |
1.35 | (0.32, 5.8) | 0.68 |
| Prior CNS (ref = No prior CNS) | 1.23 | (0.59, 2.54) | 0.58 |
| CR-MRD at time of HCT (ref = CR no MRD) | 3.77 | (2.4, 5.92) | <0.001 |
| CRp/CRi (ref = CR no MRD) | 1.49 | (0.81, 2.74) | 0.19 |
| No CR (ref = CR no MRD) | 3.74 | (2.32, 6.03) | <0.001 |
| WBC at time of diagnosis | 1 | (1, 1) | 0.54 |
| Favorable cytogenetics (ref = Unfavorable) | 0.67 | (0.32, 1.4) | 0.28 |
| Intermediate-I cytogenetics (ref = Unfavorable) | 0.99 | (0.65, 1.5) | 0.96 |
| Intermediate-II cytogenetics (ref = Unfavorable) | 0.73 | (0.45, 1.17) | 0.19 |
| EMD (ref = no EMD) | 1.22 | (0.67, 2.2) | 0.52 |
| Age (years) | 1 | (0.99, 1.02) | 0.9 |
| Prior HDAC (ref -No prior HDAC) | 1.19 | (0.81, 1.74) | 0.37 |
| CNS*CR-MRD (ref = No CNS and CR no MRD) | 0.74 | (0.12, 4.55) | 0.74 |
| CNS*CRp/CRi (ref = No CNS and CR no MRD) | 2.55 | (0.31, 20.67) | 0.38 |
| CNS*No CR (ref = No CNS and CR no MRD) | 1.22 | (0.22, 6.64) | 0.82 |
Table 4.
Multivariate analysis for relapse-free survival after transplant
| Covariate | HR | 95% CI | P-value |
|---|---|---|---|
| CNS disease at time of pre-HCT evaluation (ref = no CNS disease) |
1.38 | (0.33, 5.89) | 0.66 |
| Prior CNS (ref = No prior CNS) | 1.16 | (0.59, 2.31) | 0.66 |
| CR-MRD (ref = CR no MRD) | 4.49 | (2.93, 6.89) | <0.001 |
| CRp/CRi (ref = CR no MRD) | 1.59 | (0.9, 2.81) | 0.11 |
| No CR (ref = CR no MRD) | 4.32 | (2.72, 6.84) | <0.001 |
| WBC at time of diagnosis | 1 | (1, 1) | 0.14 |
| Favorable cytogenetics (ref = Unfavorable) | 0.82 | (0.41, 1.63) | 0.57 |
| Intermediate-I cytogenetics (ref = Unfavorable) | 1 | (0.67, 1.49) | 0.99 |
| Intermediate-II cytogenetics (ref = Unfavorable) | 0.69 | (0.44, 1.09) | 0.11 |
| EMD (ref = no EMD) | 1.48 | (0.87, 2.53) | 0.15 |
| Age (years) | 1 | (0.99, 1.01) | 0.76 |
| Prior HDAC (ref -No prior HDAC) | 1.05 | (0.73, 1.5) | 0.8 |
| CNS*CR-MRD (ref = No CNS and CR no MRD) | 0.47 | (0.08, 2.88) | 0.42 |
| CNS*CRp/CRi (ref = No CNS and CR no MRD) | 1.75 | (0.22, 13.9) | 0.6 |
| CNS*No CR (ref = No CNS and CR no MRD) | 0.89 | (0.16, 4.76) | 0.89 |
Figure 2.
Transplant outcome of 35 patients with history of AML CNS involvement prior to HCT, stratified by TBI dose (Left) and cranial irradiation (Right).
A. OS, B. RFS, C. Cumulative incidence of relapse
Discussion
CNS involvement is considered rare in adults with AML. Therefore, in contrast to ALL where CSF is routinely evaluated at diagnosis, in AML CSF is typically examined only in patients with CNS symptoms. In our institution all AML patients considered candidates for allogeneic HCT undergo routine CSF examination as part of pre-transplant evaluation, allowing a relatively unbiased look at the incidence of AML in CNS pre-HCT. Our retrospective analysis of 327 patients revealed an 11% rate of CNS involvement at any time prior to HCT. This rate is higher than historically appreciated (1), but lower than the 19% AML CNS involvement recently reported in newly diagnosed AML patients who underwent routine CSF evaluation (17). Potential explanation to the lower rate of CNS disease detected in our cohort compared to the rate detected by Rozovski et al. is the difrences in the patient population included in thses two studies. For example, Rozovski et al. found that CNS involvement was more common in young patients and among African-American patients. Our chort included older patients (median 49 versus 41) and had lower rate of African-Americans (1.5% versus 8%), which could affect the rate of CNS disease detected in these two studies. Another explanation could be a selection bias among the 42 patients included in the investigational study reported by Rozovski et al, while our study included all 327 patients underwent HCT at our center.
By using history of prior CNS disease and systemic disease status at time of pre-HCT evaluation we identified three risk groups for CNS involvement at the time of pre-HCT evaluation. Although the rate of CNS involvement in the low risk group (no prior history of CNS disease and no evidence of systemic disease at time of transplant) was lower compared to the high risk group (3% versus 35%), the low rate of complications after LP leads us to recommend diagnostic LP for all AML patients pre-HCT. This approach is supported by the availability of effective strategies to control CNS disease, as demonstrated by clearing of CNS disease prior to HCT in all patients with CNS disease in our cohort, with documentation of CNS disease post-transplant in only two of the 35 patients (6%) with documented CNS disease at any time pre-HCT.
Thompson et al. retrospectively evaluated the risk of CNS relapse and leukoencephalopathy in patients who received bone marrow transplant for ALL (n=198) and AML (n=217) (18). Similar to our findings they reported small risk of CNS-AML relapse after transplant, with only three patients (all transplanted in marrow relapse) developed CNS-AML relapse after transplant, and with no clear association between CNS disease pre-HCT and CNS relapse post-HCT. In addition to supporting Thompson’s findings in a more recent and larger cohort, our study also demonstrated that high dose TBI or cranial irradiation as part of the transplant conditioning regimen did not affect time to relapse, RFS and OS of patients with history of CNS disease pre-HCT. Additionally, our study found risk factors for CNS disease pre-HCT including prior history CNS or other extramedullary disease, high WBC count at diagnosis and systemic relapse at time of transplant.
CNS toxicity post-transplant was beyond of the scope of our study. However other have reported risk of leukoencephalopathy post-transplant when pre- and post-HCT CNS directed therapy was applied; Thompson et al reported 3% risk in AML adult patients (18), and Johnson et al reported 17% in ALL pediatric patients who received pre-transplant CNS prophylaxis and at least six doses of IT-MTX post-transplant (19). Based on the relatively low risk of CNS-AML relapse post-HCT shown in our and Thompson’s studies, and the potential risk for CNS toxicity with CNS directed therapy, no prophylactic CNS therapy is recommended for AML patients undergoing HCT. However as our finding of no association between CNS disease pre-transplant and post-transplant survival is based on a population of patients who cleared their CNS disease pre-HCT, our recommendation is to treat and clear CNS disease before transplant. Similar to our findings Aoki et al. recently demonstrated that AML CNS disease is not an independent factor in determining survival after HCT (3). As all patients in our cohort had cleared their CNS disease pre-transplant, we were unable to evaluate the effect of untreated CNS disease on transplant outcome. However our results indicate that CNS AML is associated with unsuccessfully treated systemic AML, which by itself is associated with poor outcome after HCT.
This study has several limitations. The data were collected retrospectively, the patient population was heterogeneous, patients were treated according to a variety of protocols with different treatment strategies, and methods and timing of follow-up were not standardized. Despite those limitations, we believe that this study gives reliable estimate of the rate of AML CNS involvement at time of HCT, identifies risk factors for such involvement, and evaluates its effect on transplant outcome.
Our results suggest that AML CNS disease pre-HCT is not uncommon (7%), is primarily associated with a history of prior CNS disease, and when treated is not an independent factor in determining survival after HCT. Based on our findings and considering the relative low risk of lumbar puncture, our recommendations are to perform routine CSF evaluation to all AML patients prior to HCT, add imaging as indicated based on clinical manifestation, and treat any CNS disease prior to transplant.
Acknowledgments
We thank the patients who participated. We thank members of the research and clinical staff at the FHCRC and referring physicians for their contribution to the care of our patients after hematopoietic cell transplantation.
Footnotes
Financial Disclosure: The authors declare no competing financial interests
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