CNS3 Patients Research Articles

Impact of Central Nervous System (CNS) Leukemia Status-Based Therapeutic Protocol Change on the Incidence of CNS2 Diagnosis in Pediatric B-Lymphoblastic Acute Leukemia

B-lymphoblastic acute leukemia (B-ALL) is the most prevalent cancer among children, and prophylactic central nervous system (CNS) therapy has significantly contributed to high cure rates for the past 50 years. However, relapses in bone marrow and/or CNS continue to pose challenges to achieving cure for all patients, especially in those with high-risk disease. CNS status at diagnosis, defined as CNS1 (no blasts present), CNS2 (blasts with <5 total white blood cells [WBC] per mm 3 in a cerebrospinal fluid [CSF] sample), and CNS3 (blasts with ≥5 total WBC per mm 3 or grossly traumatic), plays a crucial role in determining treatment stratification. In the past, patients with CNS1 and CNS2 received similar therapy, but evidence suggested that those with CNS2 were at a higher risk for marrow and/or CNS relapse. As a result, the Children's Oncology Group (COG) frontline trials AALL1131 and AALL0932 implemented additional CNS therapy for CNS2 patients beginning in 2012 and 2016, respectively, specifically twice weekly intrathecal chemotherapy until CSF cleared of disease 3 consecutive times. This change highlighted the necessity for accurate identification of CNS2. Based on anecdotal observation, we hypothesized that the incidence of CNS2 among pediatric B-ALL patients at diagnosis was higher after this therapeutic change due to pathologist awareness of its implications for patient management. The electronic medical records of all consecutive pediatric patients diagnosed with B-ALL at Children's Hospital Los Angeles (CHLA) from September 2008 to December 2019 were reviewed. CSF WBC count and blast involvement were used to calculate CNS status. Blast involvement was determined by one or more pathologists per case by morphologic review of cytocentrifuged CSF material. The patients were divided into two cohorts, one before (cohort A) and one after (cohort B) the COG AALL0932 protocol change (May 20, 2016). Differences between cohorts were evaluated via Fisher's exact test and Wilcoxon rank sum test. All tests were two-sided, except for CNS2 status, and significance level was set a priori at 0.05. During the study period, 391 patients were diagnosed with B-ALL at CHLA. These included 192 patients prior to the CNS status-based therapeutic change (cohort A) and 199 patients after the therapeutic change (cohort B). The incidence of CNS2 status was higher in cohort B (20%) than in cohort A (13%) (p=0.052). Conversely, the incidence of CNS1 status was lower in cohort B (77%) than in cohort A (85%), while the incidence of CNS3 was similar before (5%) and after (4%) the protocol change. There were no differences between the cohorts in patient age at diagnosis [cohort A: mean age 8.91 years (SD 5.67 years) vs. cohort B: mean age 8.10 (SD 5.62 years); p=0.20], sex (cohort A: 59.9% male vs. cohort B: 58.8% male; p=0.80), or ethnicity (cohort A: 76.0% Hispanic vs. cohort B: 67.7% Hispanic; p=0.09). These data suggest that the incidence of CNS2 status in pediatric patients with B-ALL at our institution was higher after (20%) than before (13%) the COG protocol changes that began treating CNS2 patients more intensively than CNS1 patients. In addition to increased frequency of intrathecal chemotherapy, in the ongoing frontline COG standard-risk ALL trial, patients with CNS2 status and neutral cytogenetics are upstaged to higher-risk therapy irrespective of end-induction response. A limitation of this study is that pathologist reviewers of CSF cytospin morphology at the time of CNS assignment differed during the two time periods, such that an observational bias cannot be entirely excluded. Notably, flow cytometry - a more sensitive methodology than cytospin morphology for detection of leukemic cells in CSF material - was not used in these cohorts, but increasingly widespread adoption of such techniques may further increase the incidence of CNS2, including in patients who would otherwise have been diagnosed with CNS1 disease (by cytospin morphology) and as such may be overtreated. Future directions of our study include examination of clinical outcome as well as recent (2021-present) patterns of flow cytometry use in CSF specimens and associated diagnoses of CNS disease in pediatric patients with B-ALL at diagnosis.

Clinical Features and Therapeutic Evaluation of Central Nervous System Involvement in Pediatric Anaplastic Large Cell Lymphoma

Objective：To analyze the clinical features of central nervous system involvement (CNS3) in pediatric anaplastic large cell lymphoma (ALCL) and evaluate the efficacy of CNCL-ALCL-2017 protocol for the treatment of CNS3. Methods：The clinical data of 215 pediatric ALCL patients ≤18 years old enrolled in the Chinese Children's Cancer Group (CNCL) between April 2017 and March 2023 were collected sequentially. All enrolled patients staging and CNS layering were according to the IPNHLSS staging system and treated with CNCL-ALCL-2017 protocol (modified BFM-ALCL99 protocol). The clinical features at diagnosis and treatment outcomes of CNS3 patients were analyzed. All patients were followed up until June 30, 2023. Data were collected using a unified information platform. Associations between patient characteristics were analyzed with Chi-squared or Fisher's exact tests. Eventfree survival (EFS) and overall survival (OS) curves were estimated according to the KaplanMeier method and compared by Logrank test. Furthermore, statistical analysis was performed using SPSS 22.0 software. P<0.05 was considered statistically significant. Results: Among the 215 ALCL pediatric patients, 17 (7.9%) had CNS3, including 13 males and 4 females with median age of 8.0 (range 1.0-14.0) years. In this patients, brain parenchyma and spinal cord involvement were found in 58.8% (10/17) patients on imaging, with space-occupying lesions in 7 cases and abnormal signals on MRI in 4 cases. Concurrent space-occupying lesions and abnormal signals on MRI was detected in 1 case. Cerebrospinal fluid (CSF) positivity was detected in 35.3% (6/17) patients, including 2 cases with positive ALK gene and 5 cases with positive flow cytometry, with 1 case positive for both. Cranial nerve deficits such as facial nerve palsy, visual or hearing impairment were observed in 23.5% (4/17) patients. Concurrent CSF, imaging and cranial nerve abnormalities were present in 5.9% (1/17), while two of this were present in 29.4% (5/17). Isolated CSF positivity without other abnormalities was detected in 23.5% (4/17). Pathological subtypes included common type (76.5%, 13/17), histiocyte-rich variant (5.9%, 1/17), small cell variant (5.9%, 1/17), others (11.8%, 2/17). Immunohistochemistry showed ALK + in 94.1% (16/17) and CD3 + in 76.5% (13/17). Concurrent ALK gene positivity in both peripheral blood and bone marrow was detected in 64.7% (11/17), with 58.8% (10/17) positive in both samples. The median follow-up of all patients was 35.4 months (range 0.5-74.9). All CNS3 patients had stage IV disease and were treated with regimen D (with 5 g/m 2 methotrexate). The 3-year OS was 94.3%, 98.2% and 93.3% for CNS1 (144, 67.0%), CNS2 (54, 25.1%) and CNS3 (17, 7.9%) patients, respectively; the 3-year EFS was 85.6%, 90.3% and 86.7%, respectively. No significant differences were found among the three groups. The 3-year OS and EFS for the whole cohort were 95.1% and 84.7%, respectively, also with no significant differences from the CNS3 group. Of the CNS3 patients, 1 was lost to follow-up after the first course, 1 died during treatment, and the interim CR rate was 75.0% (12/16). CSF conversion was achieved in 3/6 (50%) CSF-positive patients. 6.25% (1/16) patient had CSF ALK gene re-positivity during maintenance and persistent positivity despite additional ALK inhibitor alectinib and intrathecal therapy. In the CNS1 group, 2 cases were lost to follow-up and 4 cases died. The relapse rate was 11.4% (16/140), and the rate of central nervous system relapse was 2.1% (3/140). Additionally, the rate of CNS1 relapse was slightly higher but not statistically significantly different for CNS2. Conclusions: CNS involvement is relatively rare in pediatric ALCL. Detection rate of CNS3 can be improved by CSF flow cytometry and gene screening. The prognosis of CNS3 was significantly improved with CNCL-ALCL-2017 protocol, which may be related to the increased dose of methotrexate in the protocol. The short follow-up time and the small number of cases in this group may affect the results. Furthermore, CNS relapse rate of CNS2 was not markedly higher compared to CNS1. Keywords: Anaplastic large cell lymphoma; Pediatric; Central nervous system; Clinical features; Prognosis

Outcomes following brexucabtagene autoleucel administered as an FDA-approved therapy for adults with relapsed/refractory B-ALL.

7001 Background: In October 2021, brexucabtagene autoleucel (brexu-cel) became the first CAR-T cell therapy to receive FDA approval for adults (≥18 yrs) with relapsed/refractory (r/r) B-ALL. Approval was based on Phase II results of ZUMA-3, a single-arm, open-label, multicenter trial which reported on 55 treated patients with CR/CRi achieved in 71%; cytokine release syndrome (CRS) and neurologic toxicities occurred in 89% (grade 3-4, 24%) and 60% (grade 3-4, 25%), respectively. Here, we report outcomes of 76 adults with r/r B-ALL treated with post-approval brexu-cel at 13 U.S. centers. Methods: Retrospective data were collected across centers participating in a real-world outcomes collaborative of CAR-T in ALL (ROCCA). Descriptive statistics, Kaplan-Meier methodologies and cumulative incidence functions were used to summarize outcomes. Results: Among 76 patients infused, median age was 44 yrs (range, 18-81); 54% were male, 57% were non-Hispanic White (25% Hispanic), and 71% had Ph-neg disease. Median number of previous lines of therapy was 3.5 (range, 1-9) including blinatumomab in 53% and inotuzumab in 37%; 46% had relapsed post-transplant. Prior to apheresis, 69% of patients had active disease ( > 5% marrow blasts or presence of extramedullary disease), including 8 patients with CNS3 disease, 19% had detectable measurable residual disease (MRD) only, and 12% were MRD-neg. Median time from apheresis to infusion was 31 days. Lymphodepletion was predominantly with flu/cy (88%); 5 received cy/cladribine, and one patient each received single agent cy, single agent cladribine, and single agent bendamustine. Among 65 patients at least 28 days post-CAR-T with response assessed, 90.8% achieved CR/CRi, of whom 83% were MRD-neg, including CNS disease clearance in 7/8 CNS3 patients. CRS and ICANS (ASTCT criteria) occurred in 81.6% (grade 3-4, 6.6%) and 59% (grade 3-4, 38.6%), respectively. Median follow-up for survivors was 196.5 days (IQR 135.5-284.5). At last follow-up, 21 patients progressed/relapsed and 13 had died (7 of B-ALL; 6 of neurotoxicity/infection). Cumulative incidence of relapse and death in remission at 180 days were 31.5% (95% CI: 19.7%-44.1%) and 8.9% (95% CI: 3.5%-17.5%), respectively, while six-month PFS and OS were 58.8% (95% CI: 44.6%-70.5%) and 86.7% (95% CI: 75.8%-92.9%), respectively. Eleven patients underwent allogeneic transplant in CR/CRi after brexu-cel; all of whom remain in remission at last follow-up. Conclusions: These data are the first to demonstrate post-approval efficacy and toxicity rates of brexu-cel in adults with r/r B-ALL. Unlike the ZUMA-3 population, 31% of patients infused in this real-world cohort lacked morphologically detectable disease and 8 had CNS3 prior to apheresis. Our data confirm high response rates associated with brexu-cel in adult ALL, but also highlight the need for interventions to reduce associated toxicities.

Patterns and Prognostic Impact of CNS Infiltration in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia

Acute lymphoid leukemia (ALL) is a subtype of acute leukemia which portends a high risk of central nervous system (CNS) infiltration. At the diagnosis, 5-10% of ALL patients have CNS involvement, which has been demonstrated to decrease overall survival (OS). Based on pediatric trials, conventional cytology (CC) has been the standard for CNS disease assessment, although, more recently, flow cytometry (FC) has gained space across several centers. In this study, we intend to: i) access the impact of CNS involvement (defined by CC or FC) on OS, event-free survival (EFS) and relapse of ALL patients treated in a public health center; ii) find variables associated with CNS infiltration in this cohort. Methods: This retrospective study encompassed 105 cases of ALL newly diagnosed at Instituto do Cancer de Sao Paulo (ICESP). Clinical data were collected from Leukemia clinic database, already approved by Local Ethics Committee. Variables related to cerebrospinal fluid (CSF) were collected from the first lumbar puncture (LP). Traumatic LP was defined as more than 10 red blood cells/µL. CNS status was assessed through the COG's classification and divided into positive/negative for analysis purposes. Patients were treated with different regimens, but intensive intrathecal chemotherapy was given in CNS2 or 3 cases, while cranial irradiation was scheduled for CNS3 patients, only. Results: A total of 105 cases were diagnosed from 2014 to 2020. Only one was excluded (death before the first LP). Median age at diagnosis was 37 years (range, 15-79) with a male majority (58%). Most cases had a B-cell phenotype (76%), followed by T (19%) and ambiguous (5%). Philadelphia chromosome was found in 39%. Eighty-nine percent received corticosteroid at the time of LP with a median time of 7 days. Traumatic LP was reported in 50%. CSF resulted positive for disease in 15% (16/104) and 26% (19/72), by CC and FC, respectively. Among those with a positive CC, 56% (9/16) had a traumatic LP. By COG's classification, CNS1, CNS2 and CNS3 were found in 84%, 14% and 2% of cases, respectively. At the time of PL, 44% of patients presented blasts in peripheral blood. By comparing CC and FC, we noticed only one case with CCpos/FCneg whereas 9/19 with FCpos did not have CCpos. Sensitivity and specificity of CC for CNS disease were 53% and 98%. Traumatic LP and positive CC were not statistically correlated (p=0.8) and prior chemotherapy was associated to higher traumatic LP rates (56 vs 31%, p=0.019). Higher white-blood cell (WBC) counts were found in subjects with positive CC or FC (Mann-Whitney test, p=0.007 for CC). Furthermore, the blast percentage was also relevant for CNS positivity (p=0.027). Genetic subgroup, age, CD34 expression and phenotype were not correlated with CNS invasion, among others. Most patients received adapted versions of BFM (n=43), GRAAPH (n=24) and GRAALL-Elderly (n=18) regimens. Five patients received cranial irradiation. Median OS for the whole cohort was 16.4 months, with a 3y OS of 42.5% (95% CI 33.5-54). For BFM subset (Philadelhpia-negative, below 50 years-old), OS and EFS were 53.5% and 37.3%. We did not find correlation between CNS disease with OS or EFS in univariate analysis. Three-year relapse rate was 38.5% (95% CI 29-49) whereas non-relapse mortality (NRM) was 33%. In multivariate analysis, a positive CC increased relapse rate (HR= 2.3 [95% CI 1.1-4.9, p 0.029]). Initial WBC was also correlated with relapse in our cohort. Among relapses, only one was isolated in CNS, while 13 had concomitant bone marrow and CNS involvement. Eighteen patients proceeded to allo-stem cell transplantation so far. Conclusion: Several studies have demonstrated correlation between CNS infiltration and shorter OS in ALL, even though it relies on how these patients are managed and how CNS is assessed upfront. Our data showed that those who had a positive CSF cytology had a higher risk of relapse, whereas FC was not able to discriminate this risk. Survival rates seem to be increasing over the last years by the adoption of a stratified risk strategy. CSF contamination do not represent a major concern according to our report, as it did not increase CNS involvement or relapse rates. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PATTERNS AND PROGNOSTIC IMPACT OF CNS INFILTRATION IN ADULTS WITH NEWLY DIAGNOSED ACUTE LYMPHOBLASTIC LEUKEMIA

Acute lymphoid leukemia (ALL) is a subtype of acute leukemia which portends a high risk of central nervous system (CNS) infiltration, which decreases overall survival (OS). Conventional cytology (CC) has been the standard for CNS disease assessment, although flow cytometry (FC) has gained space across several centers. In this study, we intend to: i) access the impact of CNS involvement (defined by CC or FC) on OS, event-free survival (EFS) and relapse of ALL patients treated in a public health center; ii) find variables associated with CNS infiltration. This retrospective study encompassed 105 cases of newly diagnosed ALL at Instituto do Cancer de São Paulo. Data were collected from Leukemia clinic database, approved by Local Ethics Committee. Variables related to cerebrospinal fluid (CSF) were collected from the first lumbar puncture (LP). Traumatic LP was defined as more than 10 red blood cells/μL. CNS status was assessed through the COG's classification and divided into positive/negative. Intensive intrathecal chemotherapy was given in CNS2 or 3 cases, while cranial irradiation was scheduled for CNS3 patients. A total of 105 cases were diagnosed from 2014 to 2020. Median age at diagnosis was 37 years (range, 15-79) with a male majority (58%). Most cases had a B-cell phenotype (76%), followed by T (19%) and ambiguous (5%). Philadelphia chromosome was found in 39%. Eighty-nine percent received corticosteroid at the time of LP with a median time of 7 days. Traumatic LP was reported in 50%. CSF was positive for disease in 15% (16/104) and 26% (19/72),by CC and FC, respectively. Among those with a positive CC, 56% (9/16) had a traumatic LP,but they were not statistically correlated (p = 0.8). Prior chemotherapy was associated to higher traumatic LP rates (56 vs 31%, p = 0.019). CNS1, CNS2 and CNS3 were found in 84%, 14% and 2% of cases, respectively. At the time of PL,44% of patients presented blasts in peripheral blood. By comparing CC and FC, we found one case with CC pos /FC neg whereas 9/19 with FC pos did not have CC pos . Sensitivity and specificity of CC for CNS disease were 53% and 98%. Higher white-blood cell (WBC) counts were found in subjects with positive CC or FC (Mann-Whitney test, p = 0.007 for CC). Also, the blast percentage was relevant for CNS positivity (p = 0.027). Genetic subgroup, age, CD34 expression and phenotype were not correlated with CNS invasion. Most patients received adapted versions of BFM (n = 43), GRAAPH (n = 24) and GRAALL-Elderly (n = 18) regimens. Median OS for the whole cohort was 16.4 months, with a 3y OS of 42.5% (95% CI 33.5-54). For BFM subset, OS and EFS were 53.5% and 37.3%. We did not find correlation between CNS disease with OS or EFS in univariate analysis. Three-year relapse rate was 38.5% (95% CI 29-49) whereas non-relapse mortality (NRM) was 33%. In multivariate analysis, a positive CC increased relapse rate (HR = 2.3 [95% CI 1.1-4.9, p 0.029]), aswell as initial WBC. Among relapses, only one was isolated in CNS and 13 had also concomitant bone marrow involvement. Several studies have demonstrated correlation between CNS infiltration and shorter OS in ALL, even though it relies on how these patients are managed and how CNS is assessed upfront. Our data showed that those with a positive CSF cytology had a higher risk of relapse, whereas FC was not able to discriminate this risk. Survival rates are increasing over the last years by the adoption of a stratified risk strategy. CSF contamination did not increase CNS involvement or relapse rates.

Outcomes Based on CNS Disease Status in Pediatric Acute Myeloid Leukemia and the Role of Peripheral Blood Contamination in Diagnostic Lumbar Punctures; A Report from the Children's Oncology Group Studies AAML0531 and AAML1031

The diagnosis and treatment of CNS leukemia in AML differs between pediatric and adult oncology. Adult AML patients generally receive no prophylactic intrathecal (IT) treatment. Here we evaluate an approach utilized on 2 recent Children's Oncology Group (COG) clinical trials for pediatric AML which included CNS prophylaxis and a low threshold to initiate CNS leukemia directed therapy.A total of 2119 patients with de novo AML were evaluable from COG trials AAML0531 and AAML1031. Patients with FLT3/ITD on AAML1031 are excluded as that cohort remains eligible for ongoing accrual. The median (range) follow-up time was 7.1 (0 - 10.5) years for AAML0531 and 2.5 (0 - 5.7) years for AAML1031. All patients received IT cytarabine once with each induction and intensification cycle (except for one of the intensification cycles with high dose cytarabine). An LP to determine CNS status was performed at start of induction therapy. CNS positive (CNSpos) leukemia was treated with twice weekly IT cytarabine until 2 negative CSF samples were obtained (minimum 4 and maximum 6 ITs). CNSpos was defined similarly on both trials (Table 1). In order to understand the role of traumatic LP in CNS status and outcomes, CNS status in this analysis was further classified according to criteria used for ALL (Table 1). Comparing the ALL criteria to the AML CNS definition, CNS1 patients are CNS negative (CNSneg) and CNS3 patients are CNSpos, however among patients with CNS2 by ALL criteria, the AML CNS definition does not take into account the number of CSF WBCs in an atraumatic LP and also uses a higher CSF RBC number (100 versus 10) to require use of the Steinherz/Bleyer algorithm.The rate of CNS relapse (isolated CNS and combined CNS and bone marrow) was evaluated separately on each trial since the protocols differed in number of chemotherapy courses and SCT allocation. On AAML0531, the 5 year CNS relapse rate was lower for CNS1 (4.5 ± 1.7%) compared to CNS2 (9.1 ± 4.5%) or CNS3 (17.7 ±9.4%), P<0.001. This finding was replicated in the AAML1031 outcomes; CNS relapse rates were 4.9 ± 1.8% (CNS1), 11.7 ± 5.0% (CNS2) and 19.3 ±8.8% (CNS3), P<0.001. Patients who were CNSpos had a higher 5 year CNS relapse rate on both studies (CNSpos 13.2 ± 5.1% vs. CNSneg 4.9 ± 1.7% on AAML0531, P<0.001; CNSpos 12.9 ± 4.3 % vs. CNSneg 5.6 ± 1.8% on AAML1031, P<0.001). Event free survival (combined AAML0531 and AAML1031) differed by CNS category (CNS1 51.2%, CNS2 43.5%, CNS3 37.7%, P<0.001) and AML CNS group (CNSneg 41.2%, CNSpos 49.9%, P<0.001), but overall survival did not differ significantly.We evaluated the role of peripheral blood contamination. For patients with CSF RBC ≥100, the majority of patients were classified by ALL criteria as CNS2 or CNS3, and the rate of CNS3 disease increased approximately two fold compared to those with CSF RBC <100 (Fig 1a). When considering the COG AML definition, CNSpos rate was substantially higher among those with CSF RBC 10-99 (41%) compared to those with CSF RBC <10 (24%) or RBC ≥100 (27%; Fig 1b). This difference is likely due to the presence of peripheral blood blasts without “correction” for this blood contamination because the Steinherz/Bleyer algorithm was not used to determine CNSpos when CSF RBC <100.The median blood WBC count was significantly lower in patients with CNS1 (14,650; 95% CI 13,200-15,900) compared to CNS2 (46,200; 95% CI 40,500-53,700) or CNS3 (32,400; 95% CI 21,900-43,500). Further, when this analysis was restricted to patients with an atraumatic tap (CSF RBC <10), those with CNS1 still had significantly lower WBC compared to those with CNS2 or CNS3 (median WBC [95% CI]: CNS1 15,100 [13,400-16,800]; CNS2 53,700 [45,800-62,000]; CNS3 35,500 [21,000-50,100]). This suggests that the biologic drivers resulting in leukocytosis may also increase the risk of CNS leukemia.This analysis demonstrates that CNS disease in AML is associated with a higher CNS relapse risk but caution must be used in interpreting disease status at diagnosis. Due to the worse prognosis associated with CNS disease, we advocate continued use of diagnostic lumbar punctures and intensified treatment for pediatric patients with CNS disease. However, we also speculate that deferring the initial diagnostic lumbar puncture until clearance of peripheral blasts (which usually occurs by day 5-8 of induction) may minimize the risk of false positive diagnosis of CNS disease resulting from high peripheral WBC and blast contamination of CSF samples. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic Impact of CNS-2 status in T-ALL: A report from the Children’s Oncology Group.

10003 Background: In B-acute lymphoblastic leukemia (B-ALL), CNS2 was associated with inferior 5-year (yr) event-free and overall survival (EFS/OS) in recent trials. Here, we report the impact of CNS2 in T-ALL on AALL0434 and AALL1231, recently completed consecutive randomized phase 3 trials for children and young adults with T-ALL and T Lymphoblastic Lymphoma. This report is limited to T-ALL. Both trials used augmented Berlin Frankfurt Münster regimens. AALL0434 compared Capizzi escalating methotrexate+pegaspargase (C-MTX) vs High Dose MTX (HDMTX) +/- six nelarabine (Nel) courses; outcomes improved with CMTX and Nel. CNS1/CNS2 patients, except those defined as low risk (LR) received 12Gy cranial radiation (CRT); CNS3 patients received 18Gy CRT. AALL1231 randomized patients to +/- bortezomib (Bort). AALL1231 changed the AALL0434 backbone, using dexamethasone instead of prednisone throughout. CRT was given only to patients with CNS3 disease (18Gy) and those defined as very high risk (VHR) (12Gy). CNS2 patients could not be classified as LR on AALL0434 or standard risk (SR) on AALL1231. CNS1/CNS2 patients received the same intrathecal therapy frequency on both studies. Methods: CNS status was assigned at diagnosis. CNS2 defined as: presence of &lt; 5/ μL WBCs and cytospin positive for blasts or ≥ 5/μLWBCs with negative Steinherz Bleyer algorithm. Outcomes by CNS status were compared between AALL0434 and AALL1231. Results: From 2007-2014, AALL0434 enrolled 1562 evaluable T-ALL patients, including 1128 (72.8%) CNS1, 306 (19.7%) CNS2 and 116 (7.5%) CNS3. 90.8% received CRT, including 90.4% of CNS1 patients. 5yr EFS rates for CNS1, 2, and 3 were 85.2±1.3%, 83.1±2.6%, and 71.4±5.2% (p = 0.0007); OS rates were 90.4±1.1%, 89.2±2.1%, and 83.1±4.3% (p = 0.0438). There were no differences in 5yr disease free survival (DFS) between CNS1 and CNS2 treated with CMTX (89.7% vs. 92.9%, p = 0.17) or CMTX+Nel (91.8% vs. 89.9%; p = 0.62). AALL1231 accrued 614 evaluable T-ALL patients [CNS1 437 (71.1%), CNS2 134 (21.8%), CNS3 43 (7.0%)] from 2014 to early closure in 2017. Of these, only 12% were scheduled to receive CRT. 3yr EFS rates for CNS1, 2 and 3 were 84.1±2.1%, 84.6±3.8% and 78.6±7.9% (p = 0.50). 3yr OS was: CNS1 87.5±1.9%, CNS2 92.2±2.8%, CNS3 78.5±7.9% (p = 0.017) . 3yr EFS was not statistically distinct without Bort in CNS1, 2 or 3 (85.3±2.9%, 81.4±5.6%, 71.9±13.4%) (p = 0.10) or with Bort (82.9±3.0%, 88.3±4.9%, 83.3±9,4%; p = 0.43). Intermediate risk (IR) CNS1 and CNS2 patients received identical therapy and had similar 3yr EFS (88.8±2.8% vs 88.8±3.5%, p = 0.98). Conclusions: Unlike in B-ALL, EFS/OS was similar for CNS1 and CNS2 on AALL0434 (with CRT) and AALL1231 (without CRT). Further, IR CNS1 and CNS2 on AALL1231 had similar outcomes with identical therapy. Thus, CNS2 status is non-prognostic in T-ALL on these contemporary COG regimens. CNS3 patients have poor outcomes in T-ALL despite CRT and intensive chemotherapy, novel approaches are needed. Clinical trial information: NCT00408005, NCT02112916.

Children's Oncology Group (COG) AALL0434: Successful Disease Control without Cranial Radiation in Newly Diagnosed T Lymphoblastic Lymphoma (T-LL)

Background: COG AALL0434 evaluated the safety and efficacy of a multi agent chemotherapy backbone containing Capizzi based methotrexate/pegaspargase in newly diagnosed T-LL patients. High-risk patients were randomized to receive the COG augmented BFM (ABFM) regimen with or without Nelarabine. This was part of a larger trial including T-Lymphoblastic Leukemia (T-ALL) patients featuring a 2 x 2 pseudo-factorial randomization at the end of induction using the COG ABFM regimen with a randomization of Capizzi MTX/pegaspargase (C-MTX) verses high dose MTX and a randomization with or without Nelarabine (Nel).Methods: AALL0434 enrolled 277 patients with T-LL (2010-2014). Patients were assigned to two risk categories based upon the degree of bone marrow involvement at diagnosis: (≥1%, High Risk, <1% Standard Risk), and the ability to achieve at least a partial response at the end of induction. Patients with prior steroid treatment were assigned to the high risk group. Both groups were treated using the ABFM C-MTX regimen. High-risk patients were randomized to receive or not receive six, 5-day courses of Nel 650 mg/m2/day. No patients received prophylactic cranial radiation and CNS3 patients were ineligible. Response criteria included, Complete Response (CR): disappearance, Complete Response unconfirmed (CRu): >75% reduction, Partial Response (PR): >50% reduction, of all measurable disease, all without new lesions.Results: At the end of induction, 98.9% of the evaluable patients achieved at least a partial response (30.7% CR, 34.7% CRu, 33.5% PR). For all T-LL patients, the 4-year event free survival (EFS) and overall survival (OS) were 87.0 +/- 2.1% and 90.0+/-1.8%. The 4-year Disease Free Survival (DFS) from end of induction was 90.0+/- 2.1%. There was no difference in DFS observed between the high risk and standard risk groups, (p=0.25) or by treatment regimen (p=0.31). Nel did not show an advantage for high-risk T-LL patients, with 4-year DFS 85.0 +/- 5.6% with Nel (N=60) vs 89.0 +/- 4.7% without Nel (N=58) (p=0.28). Neither stage nor tumor response at the end of four weeks of induction therapy resulted in differences in EFS (p= 0.34 and p= 0.22, respectively). Minimal detectable disease (MDD) of the bone marrow at diagnosis (<0.1%, 0.1-0.99%, >1.0%), used to establish the risk assignment for this trial, failed to demonstrate thresholds at diagnosis that resulted in differences in EFS (p=0.27). Relapse involving the CNS only occurred in 4 patients (1.4%). Overall toxicity and neurotoxicity was acceptable and not significantly different than that experienced from the ALL cohort. There was one observed second malignancy and 5 deaths not from progressive disease.Conclusion: COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provides excellent disease control regardless of stage, or the degree of disease involvement of the bone marrow at diagnosis. Nelarabine did not show an improvement in the outcome, although the trial was underpowered to address this specific question. DisclosuresTeachey:Amgen: Consultancy; La Roche: Consultancy. Bollard:Torque: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Neximmune: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Central nervous system disease in pediatric acute myeloid leukemia.

Central nervous system disease in pediatric acute myeloid leukemia.

The Effect of Traumatic Diagnostic Lumbar Puncture in De Novo Pediatric Acute Myeloid Leukemia - a Report from the Children's Oncology Group

Background - In many adult protocols for acute myeloid leukemia (AML), the standard of care is to perform a lumbar puncture (LP) at the time of diagnosis only if there are central nervous system (CNS) symptoms present, and if absent, the LP is performed after a period of systemic therapy in order to avoid contamination of the cerebrospinal fluid (CSF) with circulating blasts in the case of a traumatic LP, or is not done at all. This differs from the practice in pediatric AML protocols where LP is performed as part of the diagnostic workup and intrathecal (IT) cytarabine given at the time of the diagnostic LP, as well as during therapy, similar to the pediatric ALL approach. We sought to determine the effect of an initial traumatic LP in a large cohort of pediatric patients with de novo AML.Methods - Treatment protocols COG AAML03P1 and AAML0531 enrolled 1344 patients with diagnostic LP and outcome data available. In these protocols, patients identified to be CNS2 (0-5 WBC with blasts present) or CNS3 (>5 WBC with blasts or CNS symptoms at diagnosis) prior to systemic therapy received additional IT therapy, while CNS1 (no blasts) patients received IT therapy only at the beginning of most courses of chemotherapy. Patients were analyzed for CNS status as well as diagnostic LP red cell count. A diagnostic LP with greater than 100 red blood cells was considered traumatic. The effect of traumatic LP on outcome was analyzed.Results - Among these patients, 949 were CNS1, 217 were CNS2 and 178 were CNS3. In looking at percentage of patients with more than 100 RBC in the CSF, there were 52 (5.48%) CNS1, 12 (5.53%) CNS2 and 55 (30.9%) CNS3 (three group comparison, p<0.001). As well, in patients with 6 to 100 RBC in the CSF in each CNS group there was a significant difference with 150 (15.81%) CNS1, 64 (29.49%) CNS2 and 45 (25.28%) CNS3 patients, (p<0.001). Figure 1 shows the number of patients in each CNS group with number of RBC in the diagnostic LP. The number of RBC in the CSF did not correlate with the degree of peripheral blood hyperleukocytosis.The outcomes of patients with traumatic initial LP showed that patients who had a traumatic initial LP did not have a significantly different OS (HR 1.14, p=0.405) or EFS (HR 1.22, p=0.132) from study entry, nor RR (HR 1.06, p=0.769) or TRM (HR 1.30, p=0.510) compared to those with an atraumatic LP. This was similarly seen in the subgroups, CNS1, CNS2, and CNS3. In examining patients with 0 RBC in their initial CSF, OS was similar among the CNS1, CNS2 and CNS3 patients (62.6%, 62.7% and 66.4% respectively, p=0.974). The OS was also similar for patients with <100 RBC (64.5% ± 2.8%) and >100 RBC (63.0% ±9.1%). In examining outcomes of CNS3 patients with a traumatic tap, there were no significant differences in OS, EFS, or RR among those with traumatic tap and those without. Overall though, multivariable analyses showed that CNS3 patients had significantly worse EFS from study entry compared to CNS1 and CNS2 patients (HR 1.58, p<0.001) due to a higher RR (HR 1.64, p=0.003). The CNS3 patients with traumatic LP had similar OS and EFS compared to those without traumatic LP (OS 63.5% ± 15.2% vs 60.8% ± 11.4% respectively, and EFS 43.4% ± 15.3% vs 35.5% ± 10.9% respectively).Conclusion - There were significantly more CNS3 patients with >100 RBC in the CSF than in the other 2 CNS groups. Outcome for these patients with traumatic LP vs those with atraumatic LP however were not different for EFS, OS or RR for all 3 CNS groups. It is likely that more than half of the CNS3 patients received extra IT therapy due to traumatic LP. In the majority of cases these IT therapies were given with sedation, potentially unnecessarily. The concern though that a traumatic initial LP contributes to worse outcome in CNS3 patients is not warranted. Delaying initial LP to align with adult practice, when peripheral blasts are cleared, would not change prognosis, but may lessen the number of patients who need additional IT therapy from traumatic LPs, thus sparing a significant proportion of children unnecessary procedures and CNS directed chemotherapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Assessment of Central Nervous System Involvement in Pediatric Acute Lymphoblastic Leukemia Patients Using Next-Generation Sequencing Method

Background: Successful outcome in childhood acute lymphoblastic leukemia (ALL) relies upon appropriate central nervous system (CNS)-directed therapy for treatment of subclinical or overt CNS leukemia. Patients with leukemia blasts detected in the cerebrospinal fluid (CSF) at diagnosis have poorer survival compared with patients without blasts in the CSF and require intensified intrathecal therapy to avert a higher rate of relapse. Traditionally, CSF assessment is performed by morphological analysis of CSF smears and the blasts confirmed by immunohistochemistry or flow cytometry. The confirmation tests are done at few institutions and rely on subjective operator judgment for identification of leukemic blasts. A precise definition of CNS involvement is necessary to avoid over- or under- treatment. Next-generation sequencing (NGS) is currently being used for minimal residual disease (MRD) assessment in lymphoid malignancies (Faham et al., Blood 2012). In this study, we assessed whether the NGS method could be used to detect leukemic clonotypes in CSF samples from 89 newly diagnosed pediatric ALL patients.Methods: Diagnostic bone marrow samples and paired CSF samples were obtained from 89 patients. CSF samples were collected in one tube and fractionated for Wright stained cytospins (1ml), TdT immunohistochemistry (1ml), and the remainder (3-5ml) for NGS-based MRD studies (Adaptive Biotechnologies, South San Francisco, CA). Briefly, using universal primer sets, we amplified variable, diversity, and joining gene segments from immunoglobulin (Ig) heavy chain (IGH), Ig kappa chain (IGK), and T-cell receptor beta (TRB), delta (TRD) and gamma (TRG) loci from genomic DNA. Amplified products were sequenced and analyzed using standardized algorithms for clonotype determination. Tumor-specific clonotypes were identified for each patient based on their high-frequency within the B-cell repertoire. The presence of the tumor-specific clonotype was then quantitated in CSF (cell pellet and supernatant) samples obtained at diagnosis. A quantitative and standardized measure of leukemic clonotype level per million leukocytes in each follow-up sample was determined.Results: Diagnostic bone marrow samples from 89 pediatric ALL patients were used to identify the tumor-specific clonotypes. At least one tumor-specific clonotype was identified in 86/89 (97%) of the patients. The IGH-VDJ assay was the most frequent gene rearrangement: at least one IGH-VDJ clonal rearrangement was detected in 66 of the diagnostic ALL samples. TRD was the second most informative receptor with a clonal rearrangement found in 43 patients, followed by TRG in 38 patients, IGK in 31 patients, TCB in 16 patients and IGH-DJ in 13 patients. The level of tumor burden associated with each leukemic clonotype was then assessed in CSF samples drawn at diagnosis from each of the 86 patients. All 40 CNS1 patients had no detectable or minimal (<10) leukemic cell equivalents. Of the 24 patients with CNS2 but TDT negative status, only 2 had >10 leukemic cell equivalents in the CSF. By contrast, 8 of 20 (40%) patients with CNS2 and TDT positive status and both patients with CNS3 had CSF with >10 leukemic cell equivalents (Figure 1).Conclusions: This study demonstrates that the NGS-based method can be used to assess CNS involvement in pediatric patients with ALL. Based on these results, NGS-based CNS assessment will be used for patient stratification in future clinical trials for pediatric ALL. [Display omitted] DisclosuresZheng:Adaptive Biotechnologies Corp.: Employment, Equity Ownership. Carlton:Adaptive Biotechnologies Corp.: Employment, Equity Ownership. Faham:Adaptive Biotechnologies Corp.: Employment, Other: Stockholder.

Does the early intensification of intrathecal therapy improve outcomes in pediatric acute lymphoblastic leukemia patients with CNS2/TLP+ status at diagnosis?

ObjectivesWe aimed to determine whether the addition of two extra intrathecal methotrexate (ITM) doses during induction in acute lymphoblastic leukemia (ALL) patients eliminate the prognostic significance of CNS2/TLP+ status.MethodsWe retrospectively analyzed 224 patients according to the central nervous system (CNS) involvement at diagnosis: CNS1, CNS2, or CNS3. Patients with CNS2/TLP+ received two additional ITM doses during induction. Patients were treated according to the Children's Cancer Group (CCG)-1991/1961 protocols between January 2001 and December 2007.ResultsThe 5-year relapse-free survival (RFS) rates for the ALL patients in the CNS1, CNS2, and CNS3 groups were 80.4 ± 3.0, 100, and 73.5 ± 11.3%, respectively; a non-significant difference was observed between the groups (P = 0.063). However, the patients with CNS2 had significantly better survival compared with the CNS3 patients (P = 0.03). The 5-year cumulative incidence of relapse (CIR) rates for the three groups were 17 (95% confidence interval (CI): 11.9–22.9), 0, and 18.8% (95% CI: 4.3–41.1), respectively; (P = 0.214) and those of isolated or combined CNS relapse were 9.6 (95% CI: 5.8–14.5), 0 and 6.3% (95% CI: 0.3–25.8), respectively (P = 0.424).ConclusionsThis study shows that the intensification of ITM therapy during induction improves outcomes in patients with CNS2/TLP+ status and eliminates its prognostic significance. This suggests that early intensification using CNS-directed therapy is beneficial in controlling minimal CNS disease.

Identifying causes of variability in outcomes in children with acute lymphoblastic leukemia treated in a resource-rich developing country.

The outcome of children with acute lymphoblastic leukemia (ALL) in developing countries is less favorable than in developed countries, primarily due to resource constraints. However, it is unknown whether the therapeutic results differ. Thus, we hypothesized that outcomes in resource-rich developing countries would be similar to those in industrialized regions. We performed a retrospective analysis of 224 consecutive children with ALL, who were treated according to the Children's Cancer Group (CCG) protocols between January 2001 and December 2007. High-risk (HR) and standard-risk (SR) patients were treated with modified CCG-1961 and CCG-1991 protocols, respectively. Modifications included substitution of dexamethasone for prednisone in HR patients and addition of two intrathecal methotrexate treatments for CNS2 patients during induction. All patients received double delayed intensification with two interim maintenance phases. Five-year overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) were 84.7 ± 2.4%, 77.0 ± 2.9%, and 81.4 ± 2.7%, respectively. Remission was achieved in 98.1% of the patients. Induction failure and relapse rates were 1.9% and 15.1%, respectively. Death as the first event occurred in 6.4% of cases, of which 2.7% and 3.7% involved deaths in induction and remission, respectively. Interestingly, a significant reduction in induction deaths was observed over time. Despite the encouraging results observed in the present study, our patients displayed significantly lower survival outcomes compared to subjects treated in major clinical trials conducted by leading leukemia cooperative groups. Furthermore, this work underscores the need for targeted interventions to reduce death as the first event in developing regions.

An Analysis of CNS2 Patients with AML: Do They Require Additional Intrathecal Therapy? a Report from Children’s Oncology Group Protocols AAML0531 and 03P1 and St Jude Children’s Research Hospital Protocol AML02

Introduction: Pediatric patients with acute myeloid leukemia (AML) require central nervous system (CNS) directed chemotherapy to minimize CNS relapse. Patients with AML who have CNS disease at diagnosis, defined as >5 white blood cells (WBC) with positive blast in cytospin, require more intensive CNS directed therapy to clear CNS disease and prevent CNS relapse. Those with <5 WBC but with a positive cytospin are designated as CNS2 disease. Those without any blast (negative cytospin) are designated as CNS1. The need for extra CNS therapy for CNS2 patients varies among treatment protocols, and consensus has not been reached as to the best CNS directed therapy for these patients. We studied the impact of intensive vs. standard management of CNS2 patients by comparing patients treated on the two most recent Children’s Oncology Group (COG) trials to those treated on the St Jude Children’s Research Hospital AML02 trial, where COG trials managed those with CNS2 disease more intensively, similar to CNS3, and AML02 treated such patients similar to CNS1. Both trials used a similar MRC-based chemotherapy backbone. This backbone gave intrathecal (IT) cytarabine at the beginning of each cycle of therapy except Capizzi II therapy, and on the AML02 protocol most patients received IT triple therapy. On both backbones, patients with CNS3 disease, and those on COG trials with CNS2 disease, received twice weekly IT cytarabine until the CSF was clear of blasts plus 2 additional treatments with a minimum of 4 IT treatments given. Thus, this analysis is the first comparison of outcome of CNS2 patients examining the variable of additional CNS directed therapy.Methods: Disease characteristics and clinical outcome for children who were CNS2 treated with intensive or standard intrathecal chemotherapy were compared across COG and SJCRH studies and compared to those who were CNS1 or CNS3.Results: Among the 1361 eligible patients enrolled on AAML03P1 and AAML0531 with available data for CNS status, 247 had CNS2 status. Of the 200 eligible patients enrolled on AML02, 47 patients had CNS2 status. On all protocols, patients with CNS2 status had a significantly higher incidence of Inv(16) compared to CNS1 patients (p<0.001 for both protocols). As well, patients with CNS2 status had a higher incidence of M4 FAB classification compared to CNS1 patients (p<0.001 for COG protocols and p=0.002 for AML02). On both protocols, patients who were CNS2 had similar incidence of Inv(16) compared to patients who were CNS3. In contrast, on the COG protocols the incidence of M4 FAB was similar among CNS2 and CNS3 patients, while on the AML02 protocol the incidence of M4 FAB was significantly higher in CNS2 compared to CNS3.The event free survival (EFS) for patients treated on COG protocols showed significant differences according to CNS status, with CNS1 patients having superior EFS compared to CNS2 and CNS3 patients (p=0.005), while on AML02, the EFS for CNS2 patients was significantly higher than CNS3 patients (p=0.04) and higher, but not significantly, than CNS1 patients (p=0.06). The overall survival (OS) for CNS2 patients treated on COG protocols was not significantly different from that of CNS1 and CNS3 patients (p=0.32), while on AML02, the OS was significantly higher for CNS2 patients compared to CNS1 (p=0.05) and CNS3 patients (p=0.02)(Figures 1 and 2). However, for the AML02 protocol, the Cox analysis showed that CNS status was not independently associated with EFS, OS, or cumulative incidence of relapseOn the COG protocols there were 101 patients with relapse involving CNS, of which 34 were CNS1, 32 CNS2 and 34 CNS3 with a 5 year CNS refractory/relapse rate of 4%, 13% and 28% respectively (p<0.001). One patient with CNS relapse was unknown for CNS group. Of the 101 patients who relapsed involving CNS: 34% were CNS1, 32% were CNS2, and 34% were CNS3.Conclusions: Patients with AML who have <5 white cells with blasts present in the cerebrospinal fluid at diagnosis may not require extra IT therapy but may be able to be treated in the same fashion as patients with no blasts in the CSF at diagnosis. Additional analyses will assist in determining which, if any, CNS2 patients require extra IT therapy. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Superior outcome of pediatric acute myeloid leukemia patients with orbital and CNS myeloid sarcoma: A report from the Children's Oncology Group

Extramedullary leukemia (EML) is common in pediatric acute myeloid leukemia (AML) and occurs as leukemia cells within the cerebrospinal fluid (CSF) or as a solid tumor (myeloid sarcoma-MS). The effect of MS on survival is unknown. Patients on CCG protocols 2861, 2891, 2941, and 2961 being treated for AML with intensive-timing chemotherapy were classified for the presence of EML (CSF leukemia, CNS-MS, orbital-MS, or non-CNS MS). CSF leukemia was classified as CNS3 (>5 WBC in the CSF with blasts) and non-CSF leukemia as CNS1/2 (<5 WBC in the CSF with or without blasts). Characteristics and outcomes of these patients were compared. Of the 1,459 total patients, 1,206 (82%) had no EML, 154 (11%) had CSF leukemia, 19 (1%) had CNS-MS, 23 (2%) had orbital-MS, and 57 (4%) had non-CNS MS. The CR rate was significantly higher in patients with orbital-MS and CNS-MS than in those with non-MS and non-CNS MS (96% and 95% vs. 78% and 78%, P = 0.034). Patients with orbital-MS and CNS-MS had significantly higher overall survival than patients with non-CNS MS (92% and 73% vs. 38%, P < 0.001), CNS3 patients (92% and 73% vs. 51, P < 0.001), and CNS1/2 patients (92% and 73% vs. 50%, P < 0.001). Patients with orbital-MS had a significantly lower relapse rate. Patients with MS involving orbital and CNS sites had a significantly better survival than patients with non-CNS MS, with CSF leukemia, or with no EML.

Pediatric Patients with Extramedullary Leukemia Involving the Central Nervous System Have a Superior Outcome.

Purpose: Extramedullary leukemia (EML), formally known as chloroma, is discrete collections of leukemia cells outside of the bone marrow. EML is often seen within the central nervous system (CNS) and these are often treated in a similar fashion as leukemia cells within the cerebral spinal fluid (CSF). We previously demonstrated that the presence of leukemia cells within the CSF (CNS leukemia) does not affect overall survival. We sought to determine the outcome of patients with central nervous system EML and compare these patients with those with CNS disease and non CNS EML.Methods: Patients enrolled on Children's Cancer Group protocols 2861, 2891, 2941 and 2961 being treated for de novo acute myeloid leukemia (AML) with intensive timing chemotherapy were classified for the presence of CNS disease as CNS1 (<5 wbc in the CSF without blasts), CNS2 (<5 wbc in the CSF with blasts), or CNS3 (≥ 5 wbc in the CSF with blasts), as well as EML in the CNS (eg orbit, brain, etc) or non-CNS EML (eg skin, lung, etc). These patient's outcomes were then analyzed.Results: A total of 1459 patients treated with intensive timing chemotherapy were analyzed in this study. At diagnosis, 1113 (76%) were CNS1, 143 (13%) CNS2, 154 (11%) CNS3, 48 (3%) had CNS EML, 57 (4%) had a non-CNS EML, and only 6 patients (0.4%) with CNS EML had CNS3 status. Patients with CNS EML had a significantly higher overall survival from study entry compared to patients with non-CNS EML (83% vs 38%, p<0.001), and compared to CNS3 patients (83% vs 50%, p<0.001). The patients with CNS EML also had a significantly higher event free survival compared to patients with non-CNS EML (65% vs 34%, p<0.001), and compared to CNS3 patients (65% vs 34%, p<0.001). There was no significant difference in relapse risk, bone marrow relapse, isolated CNS relapse, or EML relapse comparing patients with CNS EML and non-CNS EML. CNS EML patients had a significantly lower relapse risk compared to CNS3 patients (29% vs 49%, p=0.025). There was not a significant difference in bone marrow relapse, isolated CNS relapse, or EML relapse comparing these 2 groups of patients.Conclusion: Patients with extramedullary leukemia involving the CNS had a significantly better survival than patients with non-CNS EML or patients with CNS leukemia at diagnosis. This should reassure clinicians caring for these often challenging patients.

Dexamethasone in Induction Can Eliminate One Third of All Relapses in Childhood Acute Lymphoblastic Leukemia (ALL): Results of An International Randomized Trial in 3655 Patients (Trial AIEOP-BFM ALL 2000)

From 07/2000 to 06/2006, 4741 eligible pts with ALL (age range 1–17 years) were enrolled in the trial AIEOP-BFM ALL 2000 (registered at http://clinicaltrials.gov with identifiers NCT 00430118 (BFM) and NCT 00613457 (AIEOP)). 3655 patients from Germany, Italy, Austria, and Switzerland entered the randomized comparison of dexamethasone (DEX) at 10 mg/m2/d vs prednisone (PDN) at 60 mg/m2/d (both given daily from d8 to d29 of induction plus 9 days tapering after a 7d prednisone prophase). Induction therapy also comprised vincristine (1.5 mg/m2) and daunorubicine (30 mg/m2) both given on d8, 15, 22, 29, as well as L-asparaginase given at 5,000 IU/m2 x8 q3d from d12. I.T. methotrexate was given thrice (in CNS-2 and CNS-3 patients for 5 times) in induction. Post-induction therapy was derived from trial ALL-BFM 95 (A. Möricke et al, BLOOD 2008) but stratification and subsequent treatment intensity was based on early response as measured by prednisone response (on d8) and MRD quantification on d33 and d78. With a median follow-up of 4.4 years, 6-year event-free survival (6y-EFS) was 84.1% (SE 1%) and 79.1% (1%) for patients randomized to receive DEX or PDN, respectively (log-rank p=0.0083). The 6-year cumulative incidence (CI) of relapse was 11% (1%) and 18% (1%) for patients randomized to receive DEX or PDN, respectively (Gray p<0.001). The difference between the two groups was observed for isolated BM relapses (8% vs 12%), CNS-relapses (2% vs 4%) and other relapses (2% vs 3%). Higher toxicity was observed in patients treated with DEX: CI for death in induction was 2.0% for DEX and 0.9% for PDN (p=0.003). The latter value was similar to that of study ALL-BFM 95 (0.7%). CI for death in remission was similar being 2.0% and 1.6% for DEX and PDN groups. In each arm, only 0.2% did not achieve CR after intensive consolidation. Severe toxicities, mainly infections, were recorded for DEX treated patients more frequently. Three years into the trial, the DSMC and the TSC decided to halt the randomization for patients aged 10 years or older. CI for relapse/death in induction in this age group is now at 15%/4.5% for DEX, and 20%/2.4% for PDN (p=0.09/0.13). In patients less than 10 years of age, the CI for relapse/death in induction was 11%/1.4% if treated with DEX, and 18%/0.5% if treated with PDN (p<0.001/0.01). If specific biological subgroups were analyzed, a significantly lower CI of relapse for patients randomized to receive DEX was observed in T-ALL as well as TEL/AML1 positive and negative pcB-ALL patients. The reduction was most pronounced in T-ALL patients with good prednisone response after the prophase: CI for relapse in DEX treated patients (n=135) was only 6% (SE 2%) as compared to 20% (SE 4%) in PDN treated patients (n=138; p=0.003). Four patients died in the DEX arm, 3 in the PDN arm for toxicity. In TEL/AML1-positive patients with good prednisone response, the CI for relapse was 4% (SE 1%) in the DEX group and 13% (SE 2%) for PDN treated patients (p<0.001). This large difference became most evident only more than 2 years from diagnosis. The percentage of patients found negative for MRD at d33 was very similar between the randomized groups: It was 47.9% for patients treated with DEX, and 45% for patients treated with PDN. Interestingly, patients with pcB-ALL found MRD negative at d33 had significantly less subsequent relapses if treated with DEX in induction (p(Gray)=0.012). In conclusion, the use of DEX at the same dosage as applied in delayed intensification (10 mg/m2/d for 3 weeks) although associated with a greater risk of severe toxicity leads to a marked reduction of the risk of relapse, translating this into a significant benefit in terms of EFS. This was most evident in patients with in vivo sensitivity to the prednisone prephase, while the efficacy of DEX in poor responding patients was not convincing. In the future, more intensive clinical monitoring and early anti-infective interventions could render the advantage of using DEX even more evident. Moreover, other potentially toxic agents such as anthracyclines may be limited in induction for carefully selected subgroups of patients with the aim of limiting early or late toxicities.

The Presence of Central Nervous System Disease at Diagnosis in Pediatric Acute Myeloid Leukemia Does Not Affect Outcome.

Introduction: The presence of disease in the central nervous system (CNS) in pediatric acute myeloid leukemia (AML) is often thought to confer a worse prognosis. This study examined the outcome of children with AML who had CNS disease at diagnosis.Methods: Patients enrolled on Children's Oncology Group protocols 2891 (N=836)and 2961 (N=901) being treated for de novo AML were classified for the presence of CNS disease at diagnosis as: CNS1 (less than 5 WBC in the CSF with no blasts), CNS2 (less than 5 WBC in the CSF with blasts) or CNS3 (5 or more WBC in the CSF with blasts). CNS disease at diagnosis was then analysed for survival, patient characteristics and outcome using univariate analysis. Patients on these protocols were treated with intrathecal chemotherapy and not radiation therapy for their CNS disease.Results: For both AML protocols, the overall survival and event free survival were highest in patients with CNS2 disease but this was not significantly different from the survival of the CNS1 and CNS3 patients. [Display omitted] [Display omitted] Patients with CNS 2 and 3 disease were of significantly lower median age than CNS1 patients (p=0.001 in 2891 and p=0.005 in 2961). There was a significantly higher WBC count at diagnosis (p=0.001 in both studies), presence of hepatomegaly (p=0.001 in both studies), presence of splenomegaly (p=0.003 in 2891 and p=0.001 in 2961), FAB M2 morphology (p=0.001 in both studies) and FAB M4 morphology (p=0.001 in both studies) in patients with CNS2 and 3 disease compared to CNS 1 patients. Also, CNS2 and 3 patients had a significantly higher incidence of abnormal chromosome 16 (p=0.002 in 2891 and p=0.001 in 2961). In protocol 2891 significantly more CNS2 and 3 patients had hyperdiploid cytogenetics compared to CNS1 patients (p=0.016), and in protocol 2961 there were significantly more patients with t(8;21) in the CNS1 group (p=0.007). In terms of overall outcome, there was a significantly higher incidence of isolated CNS relapse in patients with CNS3 disease at diagnosis in the 2891 protocol (p=0.001), and in patients with both CNS2 and 3 disease at diagnosis in the 2961 protocol (p=0.001).Conclusion: Patients with CNS disease at diagnosis have similar survival to those without CNS disease, although they have an increased incidence of isolated CNS relapse. More aggressive CNS directed therapy may be warranted in this patient population.

Dexamethasone-Based Treatment and the Risk of CNS-Relapse in Acute Lymphoblastic Leukemia: Results from DCOG Protocol ALL-9.

Several groups recently reported on the significance of small numbers of blasts (CNS2; WBC ≤5×106/l with morphological blasts) in the cerebrospinal fluid (CSF), as well as on traumatic lumbar puncture (TLP+; >10 eyrthrocytes ×106/l, with blasts). In general, CNS2 does not have poor prognostic significance, whereas TLP+ does. We retrospectively analysed the prognostic influence of CSF involvement in DCOG ALL-9, which was highly dexamathasone (DEX) driven. The induction consisted of 3 drugs with DEX 6 mg/m2, followed by 3 MTX courses 2 g/m2 (4 × 3 gr/m2 for high-risk (HR) patients), and maintenance with DEX/vincristine and 6-MP/MTX blocks. 13 intrathecal triples (ITH) were given as CNS-prophylaxis. HR-patients (29%) received anthracyclines in induction and 2 extra intensification courses. CNS3 patients (WBC >5×106 with blasts) received additional ITH, and in case of persistent blasts after 4 ITH also irradiation. CSF at diagnosis was sent on culture medium to the DCOG for analysis. Classification was based on morphology, or TdT for CNS1 (WBC ≤5×106/l and no blasts) and CNS2. 859 patients (1–18 years) were enrolled; of 139 no CSF was received; hence we report on 720 patients. Median age was 5 years; WBC 10.4×109/l; 61% boys; 83% B-cell precursor ALL, 10% T-ALL, 7% unknown; 1.6% BCR-ABL, 0.1% MLL-AF4, 21% TEL-AML, 22% hyperdiploid. Based on morphology, 43% was CNS1, 41% CNS2, 1.9% CNS3, 11.3% TLP+ and 2.6% TLP−(ery's>10×106/l without blasts). Frequencies with TdT were similar, but of the 201 patients with morphological CNS1, 30 (15%) were TdT positive; and of 259 patients with morphological CNS2, 121 (47%) were TdT positive (p<0.001). Median follow-up was 4 years. 5-year pEFS (morph.) was: CNS1 84%, CNS2 80%, CNS3 71%, TLP+ 70% and TLP− 100% (p=0.008), with a trend for pOS (p=0.07). With longer follow-up the difference between CNS1 and -2 became larger (8-yr. pEFS 82 vs. 71%; p=0.08). The 5-yr. cumulative incidence of relapses (CIR) were 12%, 16%, 22%, 21% and 0%, respectively (p=0.067). However, if only CNS-relapses (isolated or combined) were considered, CIR rates were 2%, 4%, 15%, 7% and 0% (p=0.025), whereas CIR rates did not differ for other relapses (p=0.48). At multivariate analysis (including sex, age, RG, IPT, cytogenetics, CNS3 and TLP+), TLP+ was an independent risk-factor with a RR of 1.65 (1.01–2.69; p=0.035) for pEFS, and 1.75 (1.01–3.05, p=0.046) for pOS. When WBC was added to the model, TLP+ lost its significance, but the RR remained similar (RR1.48; p=0.11). TLP+ patients had higher WBC than other patients (WBC >50×109/l: 34 vs 21%; p=0.014). pEFS for CNS1 and -2 utilizing TdT-staining did not differ (82 vs. 80%, p=0.87), nor did the CIR. Combined morphology and TdT-data did not have prognostic significance (p=0.53). In conclusion: a) TLP+ is an independent risk factor, even on a highly DEX based regimen, and is related to high WBC; b) the incidence of CNS2 in this study was relatively high; c) there was a trend for poor outcome for CNS2 with longer follow-up; d) there is a discrepancy between morphological and TdT-based CSF classification for CNS1 and -2, but morphology seems superior for prognostification. Poor outcome for TLP+ patients has now been documented in several studies using different treatment regimens. Future studies should show whether intensified CNS-directed treatment is able to reduce the 7% CIR involving the CNS in TLP+ patients.

Prognostic Significance of Blasts in the Cerebrospinal Fluid Without Pleiocytosis or a Traumatic Lumbar Puncture in Children With Acute Lymphoblastic Leukemia: Experience of the Dutch Childhood Oncology Group

To determine the significance of blasts in the CSF without pleiocytosis and a traumatic lumbar puncture in children with acute lymphoblastic leukemia (ALL). We retrospectively studied a cohort of 526 patients treated in accordance with the virtually identical Dutch protocols ALL-7 and ALL-8. Patients were classified into five groups: CNS1, no blasts in the CSF cytospin; CNS2, blasts present in the cytospin, but leukocytes less than 5/microL; CNS3, blasts present and leukocytes more than 5/microL. Patients with a traumatic lumbar puncture (TLP; > 10 erythrocytes/mL) were classified as TLP+ (blasts present in the cytospin) or TLP- (no blasts). Median duration of follow-up was 13.2 years (range, 6.9 to 15.5 years). Event-free survival (EFS) was 72.6% (SE, 2.5%) for CNS1 patients (n = 304), 70.3% (SE, 4.7%) for CNS2 patients (n = 111), and 66.7% (SE, 19%) for CNS3 patients (n = 10; no significant difference in EFS between the groups). EFS was 58% (SE, 7.6%) for TLP+ patients (n = 62) and 82% (SE, 5.2%) for TLP- patients (n = 39; P < .01). Cox regression analysis identified TLP+ status as an independent prognostic factor (risk ratio, 3.5; 95% CI, 1.4 to 8.8; P = .007). Cumulative incidence of CNS relapses was 0.05 and 0.07 in CNS1 and CNS2 patients, respectively (not statistically significant). In our experience, the presence of a low number of blasts in the CSF without pleiocytosis has no prognostic significance. In contrast, a traumatic lumbar puncture with blasts in the CSF specimen is associated with an inferior outcome.