Impact of Initial CSF Findings on Outcome Among Patients With National Cancer Institute Standard- and High-Risk B-Cell Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group

Abstract

Purpose To determine the prognostic significance of blasts, and of white and red blood cells, in CSF samples at diagnosis of acute lymphoblastic leukemia (ALL), a uniform CSF and risk group classification schema was incorporated into Children's Oncology Group B-cell ALL (B-ALL) clinical trials. Methods CSF status was designated as follows: CNS1, no blasts; CNS2a to 2c, < 5 WBCs/μL and blasts with/without ≥ 10 RBCs/μL or ≥ 5 WBCs/μL plus blasts, with WBCs ≥ 5 times the number of RBCs; CNS3a to 3c, ≥ 5 WBCs/μL plus blasts with/without ≥ 10 RBCs/μL or clinical signs of CNS disease. CNS2 status did not affect therapy; patients with CNS3 status received two extra intrathecal treatments during induction and augmented postinduction therapy with 18 Gy of cranial radiation. Results Among 8,379 evaluable patients enrolled from 2004 to 2010, 7,395 (88.3%) had CNS1 status; 857 (10.2%), CNS2; and 127 (1.5%), CNS3. The 5-year event-free and overall survival rates were, respectively, 85% and 92.7% for CNS1, 76% and 86.8% for CNS2, and 76% and 82.1% for CNS3 ( P < .001). In multivariable analysis that included age, race/ethnicity, initial WBC, and day-29 minimal residual disease < 0.1%, CSF blast, regardless of cell count, was an independent adverse predictor of outcome for patients with standard- or high-risk disease according to National Cancer Institute criteria. The EFS difference reflected a significant difference in the incidence of CNS, not marrow, relapse in patients with CNS1 versus CNS2 and/or CNS3 status. Conclusion Low levels of CNS leukemia, regardless of RBCs, predict inferior outcome and higher rates of CNS relapse. These data suggest that additional augmentation of CNS-directed therapy is warranted for CNS2 disease.

Fig 1.

Treatment schemas for Children’s Oncology Group protocols AALL0331 and AALL0232. (A) AALL0331: Patients with standard-risk–low disease had trisomies of chromosomes 4,10, and 17 or had an ETV6-RUNX1 fusion (ie, FAV genetics) with a day-15 (or day-8) M1 marrow and a day-29 minimal residual disease (MRD) level less than 0.1%; CNS1, no testicular disease, no very-high-risk (VHR) features. These patients were randomly assigned to standard therapy or standard therapy plus PEG-asparaginase (PEG). Patients with standard-risk–average disease did not have FAV genetics unless the status was CNS2 at diagnosis, and they had a day-15 (or day-8) M1 marrow and a day-29 MRD level less than 0.1%; no CNS3 or testicular disease; and no VHR features. These patients were randomly assigned according to a 2 × 2 factorial design to standard therapy with or without intensified consolidation (ie, intensive) or with or without intensified postconsolidation therapy with augmented interim maintenance (IM; ie, Aug IM1) and delayed intensification (DI; ie, Aug2 DI) until June 2008, when results of Children’s Cancer Group (CCG) trial CCG1991 demonstrated the superiority of escalated-dose intravenous (IV) methotrexate (MTX) compared with oral MTX. At that point, all patients received IV MTX, and the intensified postconsolidation comparison was closed. Patients with standard-risk–high disease had CNS3 disease at diagnosis, were pretreated with corticosteroids, had an MLL rearrangement, and were rapid early responders (RERs), or were slow early responders (SERs) without VHR features. After induction, these patients received intensive consolidation, two augmented IM phases, and two augmented DI phases before the maintenance phase. Patients with CNS3 status received cranial radiation during the second DI phase. The first IM phase was changed to high-dose MTX (HDMTX) in May 2011, when HDMTX proved superior to escalated-dose MTX in AALL0232. After induction, patients with t(9;22)(q34;q11); fewer than 44 chromosomes; and/or a DNA index less than 0.81, ≥ 1% MRD, or an M2 marrow after extended induction, MLL with SER status, and/or an M3 marrow on day 29 were not eligible to continue therapy in AALL0331 or AALL0232. Extended induction was administered to patients with an M2 marrow or a MRD level greater than 1% at the end of induction. Patients with an M1 marrow and less than 1% MRD at the end of extended induction continued with therapy as SERs. (B) AALL0232: As published, all patients except those with CNS3 or testicular disease at diagnosis or corticosteroid pretreatment were randomly assigned in a 2 × 2 factorial design to dexamethasone (Dex) or to prednisone during induction and to escalated-dose MTX or HDMTX during IM1 until June 2008, when the corticosteroid random assignment was restricted to patients younger than age 10 years at diagnosis because of excessive avascular necrosis in older patients who received dexamethasone. The MTX random assignment closed when HDMTX demonstrated greater efficacy (January 2011). Patients with either CNS3 or testicular disease at diagnosis, corticosteroid pretreatment, an MLL rearrangement, and RER status and patients who were SERs received two IM and two DI phases. Patients with CNS3 disease received 18 Gy cranial radiation, and SERs received 12 Gy. Extended induction was given to patients with an M2 marrow or greater than 1% MRD at the end of induction. Patients with an M1 marrow and less than 1% MRD at the end of extended induction continued to receive therapy as SERs. Ara-C, cytarabine; Cyclo, cyclophosphamide; D, day; Dauno, daunomycin; Doxo, doxorubicin; IT, intrathecal; TG, thioguanine; VCR, vincristine.

Fig 2.

The 5-year (A) event-free survival (EFS) and (B) overall survival (OS) for patients with standard- and high-risk disease according to National Cancer Institute criteria (combined risks) by CNS status at diagnosis. The 5-year EFS and OS rates for patients with CNS1 status were significantly better than for others: 85% (SE, 0.6%) and 92.7% (SE, 0.4%), respectively, versus 76% (SE, 2%) and 86.8% (SE, 1.6%), respectively, for CNS2 and 76% (SE, 5%) and 82.1% (SE, 4.7%), respectively, for CNS3 (P < .001 for EFS and OS).

Fig 3.

The 5-year (A) event-free survival (EFS) and (B) overall survival (OS) for patients with standard- and high-risk disease according to National Cancer Institute criteria with blasts with and without red blood cells in the diagnostic spinal fluid. The 5-year EFS and OS rates were not significantly different for patients with and without a traumatic lumbar puncture at diagnosis: 74.5% (SE, 2.6%) and 86.8% (SE, 2.0%), respectively, for CNS2a versus 79.8% (SE, 3.3%) and 86.9% (SE, 2.8%), respectively, for CNS2b and 72.2% (SE, 6.0%) and 86.2% (SE, 4.7%), respectively, for CNS2c.

Fig 4.

(A) The cumulative incidence of relapse (CIR) that involved the CNS among patients with standard- and high-risk disease according to National Cancer Institute criteria by CNS status at diagnosis. (B) The CIR rates for combined CNS relapses were 2.8% (SE, 0.2%), 7.7% (SE, 0.97%), and 5.1% (SE, 2.0%; P < .001), for patients with CNS1, CNS2, and CNS3 statuses, respectively. For isolated CNS relapse, the values were 2.0% (SE, 0.2%), 5.6% (SE, 1.8%), and 5.1% (SE, 2.0%; P < .001), for patients with CNS1, CNS2, and CNS3 statuses, respectively. (C) The cumulative incidence of isolated bone marrow relapse among patients with standard- and high-risk disease by CNS status at diagnosis. The cumulative incidence rates of isolated marrow relapse among patients with CNS1, CNS2, and CNS3 statuses at diagnosis were 5.7% (SE, 0.3%), 6.5% (SE, 0.9%), and 9.3% (SE, 2.9%), respectively (P = .0874).