Initial CNS Involvement Research Articles

CNS Irradiation in Adult De Novo B-Precursor ALL / Lbl: Results of the Randomized GMALL T rial 08/2013 Indicate Potential Antileukemic Efficacy

In the past decade outcome of adult ALL was improved significantly using pediatric-based chemotherapy. The GMALL Trial 08/2013 (NCT02881086) for patients (pts) aged 18-55 years (yrs) with newly diagnosed ALL/LBL is a pediatric based regimen with MRD based treatment stratification and risk adapted stem cell transplantation (SCT) (Gökbuget et al, ASH 2021). CNS prophylaxis consisted of three doses i.th. MTX during induction II, 11 doses of triple i.th. for standard risk (SR) in consolidation (C)/maintenance and 1 dose before SCT in high risk (HR); 7 vs 1 cycle of HDMTX (1.5 g/m 2 as 24h infusion) were scheduled in SR and HR resp. Prophylactic fractionated CNS irradiation (RAD) with 24 Gy during induction II (IP2) was part of all previous GMALL trials. The trial incorporated a randomization for Ph/BCR::ABL1 negative (Ph-) B-precursor ALL/LBL without initial CNS involvement and treated until C1 in order to compare standard IP2 with i.th. MTX with vs without CNS RAD. The key endpoint was the time from start of induction to start of C1 in CR pts, reasoning that less toxicities and treatment delays would occur without CNS RAD. Further endpoints were remission duration (RD), event-free survival (EFS) and cognitive disturbances (DemTect Test). The statistical assumption was that it is possible to detect a shortening of time to C1 from 74 to 69 days with a power of more than 90% with 215 pts per arm with a two-sided α-niveau of 5%. Between 8/2016-8/2022 1023 pts from 78 centers were included. 512 pts had Ph- B-precursor ALL/LBL (497/15). 31 pts had initial CNS involvement (N=20) or were not randomized due to other reasons (N=11). 241 pts were randomized in arm A (RAD) and 241 in arm B (NoRAD). The median age was 33.5 (18-55) yrs; c/pre B-ALL versus pro B-ALL was present in 83% vs 17%. 191 were HR vs 291 SR. No significant differences were observed between both arms. 477 pts were randomized (ITT population) and 422 were eligible (analysis population) since they achieved CR and were treated until C1. Reasons for non-eligibility were protocol violation (N=5), early death (ED) (N=15), withdrawal (N=12), no CR before C1 (N=18) and late withdrawals in CR before C1 (N=10). 207 pts in the RAD-arm (86%) vs 215 pts in the NoRAD-arm (89%) were eligible. In the analysis population treatment per randomization was 97% in NoRAD and 95% in RAD arm. CR rates before C1 (95% RAD vs 96% NoRAD), ED rates (5% vs 4%), rates of grade III/IV leukopenia in IP2 (14% vs 16%) and infections (29% vs 29%) were similar. The median time to C1 was similar too (75 vs 76 days; p=0.34). Relapse rates (RR) were lower in RAD (13%) vs NoRAD (18%) (p=0.14). Whereas CNS relapses were infrequent in both arms (N=1 vs N=3 i.e. 1% vs 1%; p=0.62), the rate of BM±other relapses (11% vs 15%; p=0.15) was lower in the RAD arm. The cumulative incidence of CNS relapse at 3 yrs was 1% vs 1% and of all relapses 14% vs 20% (p=0.13). The EFS at 3 yrs was higher for the RAD (79% [95%-CI: 72% - 85%]) vs NoRAD (72% [95%-CI: 65% - 78%])(p=0.10) in the analysis population and 74% vs 67% (p=0.13) in the ITT population. In the ITT population the impact was statistically significant (p=0.05) in SR pts whereas no difference was detected in HR (i.e. pts with indication for SCT) (figure 1); differences did not reach significance in the analysis population. We further analyzed the impact of randomization arm on cognitive function (analysis population). After C1 results were available in 264 pts. In the RAD vs NoRAD arm 2% vs 2% resp. had low scores (0-8) and 10% vs 8% intermediate scores (9-12) indicating a relevant or limited cognitive disturbance. At the end of therapy (week 130), results are available in 53 pts treated in SR arm. 0% vs 4% had low and 4% vs 4% intermediate scores. Thus, relevant cognitive limitations were present in both arms. The primary endpoint (time to C1) was not met. Pts with RAD did have a trend towards better EFS and RD. The CNS RR was overall low but CNS RAD might have an impact on the systemic relapse rate in SR pts. We recorded no significant negative impact of CNS RAD on DemTect results, but this requires further observation. Results must be interpreted in the context of adult pts with potentially lower risks for cognitive disturbances compared to children and - on the other hand - a relatively low dose of systemic HDMTX. Overall, no clear negative effects of CNS RAD were detected whereas a trend towards positive impact on EFS was observed. GMALL 08/2013 is an independent academic trial funded by the Deutsche Krebshilfe.

The value of bone marrow biopsy for staging of patients with primary CNS lymphoma.

BackgroundIn patients with presumed primary CNS lymphoma (PCNSL), a systemic manifestation is found only in a small minority. Although bone marrow biopsy (BMB) is recommended for staging, its diagnostic value is unclear.MethodsA retrospective analysis of 392 patients with presumed PCNSL from 3 university hospitals and 33 patients with secondary CNS lymphoma (SCNSL) and initial CNS involvement from a multicenter Germany-wide prospective registry was performed.ResultsA BMB was performed and documented in 320/392 patients with presumed PCNSL; 23 had pathologic results. One harbored the same lymphoma in the brain and bone marrow (BM), 22 showed findings in BM discordant to the histology of brain lymphoma; n = 12 harbored a low-grade lymphoma in the BM, the other showed B-cell proliferation but no proof of lymphoma (n = 5), monoclonal B cells (n = 3), or abnormalities not B-cell-associated (n = 2). In the group of SCNSL with initial CNS manifestation, 32/33 patients underwent BMB; 7 were documented with bone marrow involvement (BMI); 1 had concordant results in the brain and BM with no other systemic manifestation. Six had additional systemic lymphoma manifestations apart from the brain and BM.ConclusionsIn only 2 out of 352 (0.6%) patients with CNS lymphoma (320 presumed PCNSL and 32 SCNSL), BMB had an impact on diagnosis and treatment. While collected in a selected cohort, these findings challenge the value of BMB as part of routine staging in presumed PCNSL.

Prognostic significance of various 11q23/KMT2A rearrangements in infants with acute lymphoblastic leuekemia

The purpose of this work was evaluation of prognostic significance of 11q23/KMT2A rearrangements in infants (aged under 365 days) with B-cell precursor acute lymphoblastic leukemia (ALL) enrolled in Russian-Belarus multicenter trial MLLBaby. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Research Institute of Medical Cell Technologies (Ekaterinburg). Various 11q23/KMT2A rearrangements were revealed in 100 (72%) of 139 patients. Event-free survival (EFS) in the intermediate risk group of MLL-Baby trial was 35.1% (standard error (SE) 6.9%), in the high risk group – 38.3% (SE 7.1%) (p = 0.941). The most unfavorable prognosis had infants with translocation t(9;11)/KMT2A-MLLT3: EFS 18.8% (SE 9.8%), cumulative incidence of relapse (CIR) 75.0% (SE 9.7%). Intermediate results were obtained in patients with translocations t(4;11)/KMT2A-AFF1 and t(11;19)/KMT2A-MLLT1: EFS 36.9% (SE 7,2%) and 32,7% (SE 10.4%), respectively; CIR 46.3% (SE 7.8%) and 50.9% (SE 12.3%). The most favorable treatment outcome was achieved in infants carrying translocation t(10;11)(p12;q23)/KMT2A-MLLT10: EFS 83.3% (SE 15.2%), CIR 0,0%. In the multivariate analysis unfavorable outcome of KMT2A-rearranged infant ALL was associated with initial CNS involvement (p = 0.020), initial white blood cell count higher than 300 × 109 /L (p = 0.028), more than 5% blast cells on day 15 in bone marrow (p = 0.012) and presence of translocation t(11;19)/KMT2A-MLLT1 (p = 0.012).

Abstract OT3-10-02: A breast cancer trainees research collaborative group prospective study of treatment and outcomes related to central nervous system disease secondary to breast cancer in the United Kingdom

Abstract Introduction: Breast cancer brain metastasis (BCBM) is a particular feature of HER2-positive and triple negative breast cancer (BC) and is becoming more common. This reflects the improved survival of patients living with metastatic breast cancer as well as increased cross-sectional imaging of the central nervous system with magnetic resonance imaging (1). The development of BCBM on the background of adequately controlled extracranial disease is an increasingly prevalent clinical scenario. BCBM causes significant morbidity and mortality; unfortunately the efficacy of systemic treatment is extremely limited and, at present, no systemic therapies are specifically approved for the treatment of BCBM (2). Basic and translational research to understand the pathophysiology of BCBM remains limited by a lack of access to annotated clinical material. Such research is needed if preventative and novel treatment strategies are to be developed. Moreover, there is currently a lack of basic contemporaneous information regarding the incidence and management of BCBM in the UK, how it may vary across the country and its impact on patient outcomes. Finally, clinical studies have been hampered by a lack of a central resource to aid feasibility work and to identify potentially eligible patients. Study design: PRIMROSE will use the trainee collaborative model to establish an observational prospective UK cohort of newly diagnosed BCBM. Data collected will include routine clinico-pathological information, prior adjuvant and metastatic treatment as well as BCBM-related information including presentation, management and outcome. Anonymised data will be collated in a secure central REDCap database. All hospitals in the UK will be eligible to register patients driven by trainees from all specialties via the UK Breast Cancer Trainees Research Collaborative Group (BCTRCG) network. Eligibility criteria: Inclusion criteria: male or female patients aged >16 years of age, with histologically and/or cytologically confirmed BC with involvement of the brain parenchyma. There are no formal exclusion criteria. Patients with leptomeningeal disease will be registered, with data being collected in a separate project (PRIMROSE-LMD). Aims: The overarching objectives include defining the prevalence, management and outcome of BCBM in the UK. Endpoints: *Primary Endpoint: Overall survival from initial diagnosis of CNS involvement. Secondary Endpoints will include: 1. Time to initial CNS involvement from initial diagnosis of MBC; 2. Therapeutic interventions for management of CNS disease; 3. Time to intracranial tumour progression (for each line of therapy given for CNS disease); 4. Overall survival from MBC diagnosis; 5. Cause of death: progressive CNS disease versus progressive disease at other sites. *Information will be presented for the whole cohort as well as by breast cancer subtype Patient accrual: Patient accrual is due to commence in July 2019 and continue will for 2 years in the first instance. There is no predefined target accrual. Contact information: Study lead: Prof Carlo Palmieri; c.palmieri@liverpool.ac.uk

Clinical, Cytogenetic and Immunophenotype Distribution of Adult Acute Lymphoblastic Leukemia Among Latinos — a Report from a Large Single Institution Cohort in Southern California

Introduction:Acute Lymphoblastic Leukemia (ALL) is divided into Pre-B and T phenotypes depending on the progenitor cell giving rise to the malignant clone. This disease is the most common cancer in children while rare in adults. Interestingly, higher incidence rates and poorer outcomes have been reported in patients of Latin American ethnicity. This has been attributed to higher rates of Philadelphia-Like (Ph-like) ALL and increased incidence of high risk features such as absence of hyperdiploidy and absence of t(12;21). The current data among Latinos either exclusively looks at B cell precursor (BCP) ALL or does not distinguish between subtypes. Our study sets out to better define the phenotype of this subset of patients with traditionally poor outcomes.Methods:Our database consisted of 825 adult patients (ages 18-85 years) diagnosed with ALL from the City of Hope Comprehensive Cancer Center in Los Angeles, California. The population in Southern California has a particularly high number of Latinos due to its proximity to Mexico and Central America. According to the 2017 United States Census, 48.6% of the Los Angeles population is of Hispanic or Latino origin. Age at diagnosis, initial WBC count, CNS involvement, imumnophenotype, cytogenetics and rate of hematopoietic cell transplantation during therapy were assessed between ethnic groups. Multivariable Logistic Regression was done to determine the features that distinguish Latino patients for Non-Hispanic Whites.Results:57.4% of the patients were Latinos and 42.6% were Non-Hispanic Whites (NHWs), a distribution unique to the Los Angeles area and consistent with US census population data. BCP ALL was more common in Latinos when compared to NHWs with a Hazard Ratio of 5.13 (95% CI between 2.97-8.87). The presence of the t(9;22) or Philadelphia chromosome (Ph+) was more common in NHW patients. The Hazard Ratio for Ph+ ALL in NHWs was 0.53 (95% CI between 0.37-0.77) CNS involvement was more common in Latino patients and MLL was the only cytogenetic abnormality less common in NHWs. Normal Karyotype (NK), Complex and Others were all more common in Latino patients. No difference was found between WBC counts of Latinos and NHW. (Fig. 1).Discussion:ALL has been shown to have higher rates in the Latino population. Our results among adults ages 18-85 years old, demonstrated that this difference can be attributed to higher incidence of BCP ALL and not T-cell among Latinos. This is consistent with the previously reported higher rate of Ph-Like ALL and distinct molecular aberrations among Latinos. Our data shows that the rate of Ph+ ALL is higher in NHWs when compared to Latinos. This is a very interesting finding as the presence of Ph+ ALL and Ph-like ALL are mutually exclusive. Associations have been previously reported between Ph-like ALL and Latin American ethnicity. Although there are types of ALL that are neither Ph+ nor Ph-like this finding suggests a higher incidence of Ph-like ALL in Latinos. At the present time, standard cytogenetics do not include CRLF2, IKZF1 and other mutations found in Ph-like ALL. Complex cytogenetics and CNS involvement, both factors associated with poor prognosis, are most likely to present in a Latino patient. While the precise mechanism is unknown, our findings further support the hypothesis that a unique genetic fingerprint has led to development and outcomes of Ph-like ALL in Latinos. It is evident that this subset of unfavorable BCP ALL population needs special attention. More studies are imperative to further elucidate the mechanism behind Ph-like ALL and pinpoint the risk factors in the Latino population. [Display omitted] DisclosuresDouer:Spectrum: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Jazz Pharmaceuticals: Consultancy; Gilled Sciences, Inc: Consultancy; Shire: Membership on an entity's Board of Directors or advisory committees.

Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib

ObjectivesPatients with metastatic EGFR-mutant (mEGFRmt) NSCLC have favorable survival when treated with erlotinib. We hypothesized that treatment failure in most patients is limited to initial sites of disease, in which case incorporating local therapy such as radiation might further delay progression. We therefore analyzed patterns and predictors of failure in a large cohort of such patients. Materials and methodsWe reviewed 189 patients treated with erlotinib for mEGFRmt NSCLC. We classified first pattern of failure as involving initial sites only (ISF), new sites only (NSF), or the combination (CSF), and used competing-risks regression to identify factors associated with ISF, progression and overall survival (OS). We also separately analyzed intracranial and intrathoracic failure. ResultsOf 171 patients who progressed, 103 (60.2%) had ISF, 30 (17.5%) had NSF, and 38 (22.2%) had CSF. Younger age and lack of initial CNS involvement independently correlated with ISF, with a trend for higher T and N stage. Higher T and N stage was also a significant predictor of progression. Factors predicting shorter OS were female gender, weight loss, initial intracranial involvement, and ≥4 extracranial metastases. Intrathoracic progression was a component of first failure in 61%, and three-year cumulative incidence of brain metastasis was 30%. ConclusionThe main pattern of progression in mEGFRmt NSCLC on erlotinib is in the initial sites of disease. Younger patients and those without brain involvement are particularly likely to develop ISF. This suggests a role for incorporating local therapy into treatment of selected patients with mEGFRmt NSCLC.

Infant Lymphoblastic Leukemia: A Single Center Experience

Infantacute lymphoblastic leukemia (ALL) is a rare disease and consist of 4-5% of all childhood ALL. Despite improved survival rates of childhood ALL, infants with ALL have a worse prognosis . There were 206 patients diagnosed with ALL at Hacettepe University, Pediatric Hematology Department between 1 January 2008 and 31 December 2016, 11 out of 206 (5.3%) were diagnosed as infant ALL. We aimed to evaluate clinical findings, laboratory results and treatment outcome of our infant ALL patients retrospectively. There were 9 boys and two girls with a median age of 8 months (range 1-12 months) and nine out of 11 (82%) were older than 6 months of age at the initial diagnosis. Interestingly 2 of 3 siblings born from spontaneous triplet pregnancy diagnosed at the same time when they were 7 months old while the other sibling diagnosed 4 months later when he was 11 months old. Physical examination revealed hepatosplenomegaly in 10 out of 11 patients and 1 patient had extramedullary involvement with subcutaneous nodules on the forehead. On admission median WBC count was found 202x10-9/L (range 37.4-739x10-9/L) with a median hemoglobin level 9 g/dL (range 2.6-12.9 g/dL) and median platelet count 81x10-9/L (range10- 314x10-9/L). Immunophenotyping revealed CALLA+ B cell leukemia in 3 patients, CALLA- B cell in 6 patients and T cell leukemia in 2 patients. Cytogenetic analysis showed t(4;11) positivity in 4 patients and 3 of them were spontaneous triplets. Initial CNS involvement were positive in 2 of the patients. Eight patients (73%) were treated with Interfant protocols (Interfant 99 (n=4), Interfant 06 (n=4)) and 3 patients received Modified St. Jude Total XV protocol. Relapse were observed in 2 patients (one had both CNS and bone marrow relapse one year after the completion of chemotherapy and the other experienced an early bone marrow relapse at the 7thmonth of the treatment). Hematopoetic stem cell transplantation (HSCT) was performed in five patients from matched related donor (n=2), unmatched related donor(n=1), and matched unrelated donor(n=2). Moreover, relapse after HSCT was observed in 2 patients 3 and 4 months later; one received second transplantation and survived while the other died because of progressive disease. Four of the five patients who had HSCT survived 74 months, 45, 18 and 13 months after the initial diagnosis, respectively. After a median of 18 months (range 4- 74 months ) follow-up period 6 patients are alive (45 %) and on remission 4 after HSCT and 2 with only chemotherapy. Infant leukemia usually presents with high hyperleucocytosis and extramedullary involvement. The prognosis is poor and international colloborative studies reprorted that 4 year -event free survival rates were between 28-54%. Our results suggest that bone marrow transplantation seems to be a good and efficient choice of treatment. However there is still a big issue to decide which patient should go under transplantation and more studies are needed to reevaluate the eligibility criteria for HSCT in this group of patients. Moreover to the best of our knowledge infant leukemia in triplets without monozygocity were first time reported. DisclosuresNo relevant conflicts of interest to declare.

The Nationwide Study of Erdheim-Chester Disease in Japan

Background: Erdheim-Chester disease (ECD) is a subtype of non-Langerhans histiocytic disorder that is shown to be driven by hyperactivation of MAPK pathway (most frequently caused by BRAFV600E mutation) and characterized by generalized organ dysfunction with infiltration of CD68-positive, CD1a-negative histiocytes. However, ECD is a rare entity and therefore very little is known about epidemiology of this disorder.Methods: We underwent a postal questionnaire-based, multi-center retrospective study to clarify the clinical features of ECD patients. We first sent 3850 questionnaires to various departments including orthopedics, respiratory medicine, dermatology, hematology, and pathology to cover as many ECD patients as possible, and identified 71 ECD patients in Japan. We further collected detailed clinical information and patients' samples if available. All cases were pathologically proven and the diagnoses of ECD were self-reported by each institute. DNA was extracted from each clinical sample and Sanger sequencing or allele-specific polymerase chain reaction (PCR) for BRAFV600E mutation were underwent with specific primers.Results: Among 71 patients with ECD, detailed clinical information about 38 patients were collected. The median age was 51 years old (range: 25-76 years old) and there was a male predominance (1.9:1). Major affected lesions were the bone (84 %), central nervous system (CNS; 50 %), cardiovascular lesion (37 %), skin (37 %), retroperitoneum (37 %), endocrines (37 %), lung (24 %), and digestive organ (12 %). C-reactive protein at onset was higher than upper normal limit in 24 of 29 patients (median 23.8 mg/L). The median time from the onset to diagnosis was 17 months and median survival from initial onset was 10.9 years. In the univariate analyses, age older than 60 years old at initial onset (hazard ratio [HR], 30.2; 95% CI, 5.7-159; p < 0.001), weight loss (HR, 5.4; 95% CI, 1.4-20.8; p = 0.014), CNS involvement (HR, 25.2; 95% CI, 3.1-203; p = 0.0024), cardiovascular lesion (HR, 3.6; 95% CI, 1.2-10.8; p = 0.021) and digestive organ disease (HR, 5.6; 95% CI, 1.6-20.2; p = 0.0085) were associated with poor prognosis. Interestingly, the bone involvement was associated with better outcome (HR, 0.20; 95% CI, 0.065-0.63; p = 0.0052). Multivariate analysis revealed that older age was an independent poor prognostic factor (HR, 18.9; 95% CI, 2.12-169; p = 0.0085). In addition, patients with CNS involvement were significantly older than patients without CNS disease (median, 63.7 vs 44.0 years old; p < 0.001). We also analyzed the BRAF V600E mutation status in seven cases. Allele-specific PCR identified that three of seven patients had BRAFV600E mutation.Conclusion: Our nationwide survey revealed that older age was associated with CNS involvement and poor prognosis in ECD patients. In addition, the bone, cardiovascular, CNS and digestive organ involvement might also affect clinical outcome. It is of note that the bone lesion was associated with better survival in the univariate analysis. However, larger and prospective studies are warranted. Regional disparity such as percentage of bone lesions should be also investigated. DisclosuresOgura:Payment for lectures including service on speakers bureaus: Speakers Bureau.

Dose-Intensity Impacts On Survival of Adolescents and Young Adults with Acute Lymphoblastic Leukemia Treated in Adult Departments by a Pediatric Protocol (FRALLE 2000BT)

AbstractAbstract ▪3561▪This icon denotes a clinically relevant abstract Background:Adolescents (15–19y) with acute lymphoblastic leukemia (ALL) markedly benefit from pediatric rather than adult chemotherapy regimens, as highlighted by many retrospective studies (Boissel et al., JCO 2001). In young adults with ALL, there are now strong evidences that pediatric or pediatric-inspired protocols may also improve long-term outcome (Huguet et al., JCO 2009). However, whether care environment (adult vs pediatric unit) may impact this outcome remains an open issue. To address this question, we explored the outcome of adolescents and young adults (AYA, 15–29y) treated in adult hematology departments by the pediatric FRALLE 2000-BT protocol. Methods:From February 2001 to June 2011, 89 AYAs with Ph-negative ALL including 60 adolescents (15–19y) and 29 YAs (20–29y) were treated according to the pediatric FRALLE 2000-BT protocol in 13 French and Belgian adult hematology units (median follow-up, 5 years). After a prednisone prephase and a four-drug induction (prednisone, daunorubicin, vincristine and L-asparaginase), patients achieving CR received four 8-week phases of treatment: consolidation, 1st delayed intensification (DI), interphase, 2nd DI, and maintenance. According to FRALLE protocol recommendations, each phase should begin after hematological recovery of previous phase (ANC>1 G/L, Platelets>100 G/L). Twenty-five patients (18 adolescents and 7 YAs) underwent allogeneic transplantation after consolidation phase or 1stDI. Results:Apart age (median age, 18 vs 23y; p<.0001), adolescent and YAs cohorts had similar characteristics, including WBC, B/T lineage distribution, and high-risk karyotype (t(4;11)/MLL-AF4, hypodiploidy)), except for initial CNS involvement (1/60 vs 4/29 respectively, p=.02). Initial peripheral response to prednisone (PDN) at D7 and bone marrow response to chemotherapy at D21 were better in the adolescent subgroup, without reaching significance (slow PDN-responders: 30% vs 38%, p=.42; slow chemo-responders: 13% vs 21%, p=.37). Overall CR rate was 99% and did not differ between both cohorts (98% in adolescents, 100% in YAs). 5y-OS and 5y-EFS were estimated respectively at 66% and 61%. Despite similar CR rates, 5-year EFS was significantly shorter in adolescents than in YAs (47% vs 79%, p=.02). A non significant shorter 5y-OS was also observed in adolescents (58% vs 81%, p=.11). To explain this difference, we looked at dose-intensity disparities between both subgroups. During induction phase, no differences in drug cumulative doses were observed. To further explore potent difficulties to respect protocol schedules in younger patients, we compared intervals from induction D1 to start of different trial phases between both subgroups. In comparison to YAs, intervals from induction D1 to consolidation, 1st DI, 2nd DI and maintenance phases were progressively delayed in adolescents: 4 days for consolidation (p=.24), 6 days for 1st DI (p=.19), 9 days for 2nd DI (p=.005), and finally 25 days for maintenance phase (p=.0002). In univariate analysis, among age (adolescents vs YAs), B/T lineage, WBC, cytogenetics, and time to 1st DI, only age and time to 1st DI significantly affected EFS (p=.05 and p=.001 respectively). In bivariate analysis, age and time to 1st DI were identified as independent prognostic factors for EFS (p=.03 and p=.004, respectively). The same observation was done with interval time to 2ndDI. Conclusion:The outcome of AYAs treated in adult units with the pediatric FRALLE 2000 protocol is encouraging, particularly in YAs. The poorer outcome observed in adolescents may be related to increasing intervals from initial induction to the different phases of treatment. Prospective trials are required to register individual reasons that lead physicians and patients to progressively delay therapy. This study suggests that trial itself is not sufficient to improve the outcome in adolescents with cancer and that AYA programs are needed to explore the difficulties encountered by patients and care teams to adhere to therapy. Disclosures:No relevant conflicts of interest to declare.

Excellent Outcome In Infants below One Year of Age with AML – Results of Studies AML-BFM -98 and -2004

AbstractAbstract 17Infants <1 year of age with AML are very vulnerable patients who may not tolerate intensive treatment, which is however required to achieve complete remission (CR) and long-term survival. In several pediatric AML studies, outcome of this age group is described as unfavorable. Here we report the improved outcome of 108 infants with AML (Down syndromes excluded) who were treated within the studies AML-BFM 98 and -2004 until end of 2008. Treatment regimensof study AML-BFM 98 (see Creutzig, J Clin Oncol 24, 2006) and AML-BFM 2004 were largely similar. AML-BFM 2004: Induction with AIE (cytarabine, idarubicin and etoposide) or ADxE (Dx=liposomal daunorubicin) - exclusively in high-risk (HR) patients supplemented by HAM (high-dose cytarabine [HD-Ara-C] and mitoxantrone) - continued by two short therapy cycles with medium and HD-Ara-C and anthracyclines, followed by intensification with HAE (HD-Ara-C and etoposide) and maintenance. Allogeneic stem cell-transplantation (SCT) in 1st CR from a family donor was restricted to HR patients. Drug dosage was generally calculated according to bodyweight instead of bodysurface in this age cohort; HD-Ara-C was dose adjusted for age (from 20% in the <3-month- to 60% in >11-month-olds). Patients'age was 0.6 years in median (interquartile range 0.3 –0.7 years) and white blood cell count 26,000μ /L (interquartile range 8,500 – 106,250μ /L). Most infants (103/108) were HR patients according to morphology, cytogenetics, molecular genetics, and therapy response. Four of the 5 standard risk patients had favorable cytogenetics with inv(16) and t(15;17); 47/90 (52%) patients with data showed a MLL rearrangement. Resultsin this cohort of infants were similar compared to older HR patients. Early death rate was higher by trend compared to 1–3 year old patients: 6/108 (5.6%) vs. 3/156 (1.9%), px2 0.12; non-response rates were similar: 11/108 (10.2%) vs. 14/154 (9.1%), px2 0.77. Overall survival (OS) in the total group (n=108) was 68%+5%. OS improved from study -98 to -2004 from 60%+6% (n=59) to 78%+6% (n=49), plogrank 0.07. Event-free survival (EFS) in the total group was 45%+5%; EFS results in study -98 vs. -2004 were similar: 43%+7% vs. 47%+8%, plogrank 0.98. There was no difference in OS, EFS and cumulative incidence for relapse in infants aged 1–3, 4–6, 7–9 or 10–12 months, regardless of whether presenting with or without initial CNS involvement, MLL rearrangement or other molecular-/cytogenetic features (the number of patients with favorable cytogenetic was too low). Results for HR infants (95% of the patients) were similar to those in older age groups (1-2 or 2–10 year olds, plogrank 0.75). All 8 patients receiving allogeneic (SCT) in 1st remission survived although 2 children relapsed. Five of 10 patients transplanted after initial non-/partial response and 19/30 patients transplanted after relapse are still alive. Survival after relapse (n=37) was 50±8%. The rate of grade III/IV toxicities after induction was highest in infants <1 year of age and decreased in the age groups of 1–2 and 2–3 years (general condition 52% vs. 44% vs. 30%, (px2 <1 vs. 2–3 years 0.07); infection 47% vs.49% vs. 23% (px2 <1 vs. 2–3 year olds 0.06); lung problems, e.g. artificial respirator needed 31% vs. 18% vs. 0% (px2 <1 vs. 2–3 years 0.01); whereas the treatment related death rate was in the same range as in older patients (4%). Conclusion:Our data show that intensive AML treatment is feasible in infants. Toxicities can be managed, and outcome is excellent, which is partly due to salvage therapy after relapse, with a present 5-year OS rate of 78%.*Supported by the Deutsche Krebshilfe e.V. Disclosures:Off Label Use: liposomal daunorubicin is used, which is off label for pediatric AML. It was used because it offers a possibility to increase cumulative dosages of anthracyclines with lower cardiotoxicity.

Preventive CNS Irradiation with 12 Gy Compared to 18 Gy: Results of Studies AML-BFM 98 and 2004.

Abstract 483The importance of preventive CNS irradiation (CNS-RT) for disease control in childhood acute myeloid leukemia (AML) is unclear. Results of study AML-BFM 87 revealed an increased risk for relapse when CNS-RT was omitted in CNS negative patients (Creutzig, J Clin Oncol 11, 1993). With the aim to reduce the risk for late effects associated with CNS-RT, we evaluated a dose reduction for CNS-RT by comparing the effect of a reduction of the standard dose of 18 Gy to 12 Gy in a randomized prospective way in the AML-BFM 98 and 2004 trials. Methods:To achieve a power of 80% for non-inferiority (range 11%) 240 patients per group were required, which could only be achieved by randomization over two study periods (7/1998 - 4/2009). Patients:Out of a total number of 1,202 study patients, 471 were not eligible for randomization (126 patients with Down syndrome, 138 patients who did not achieve remission or died/relapsed during the first 140 days before irradiation, 97 patients with initial CNS involvement and 110 patients who were assigned to stem cell transplantation [SCT]). Out of the 731 eligible patients, 241 refused randomization. Thus, a total of 490 children and adolescents <18 years with de novo AML were randomized to receive 12 Gy (n = 248) or 18 Gy (patients between 15 and 24 months: 15 Gy) (n = 242). Eighteen of the randomized patients did not receive radiotherapy. Four of the patients randomized to 12 Gy were treated with 18 Gy, and 15 patients randomized to 12 Gy received 18 Gy. Since this was a non-inferiority study, the analysis was performed for patients as treated (12 Gy n=251, 18 Gy n=221). Therapy:Treatment regimens of study AML-BFM 98 (see Creutzig, J Clin Oncol 24, 2006) and AML-BFM 2004 were largely similar. AML-BFM 2004: AIE (cytarabine, idarubicin and etoposide) or ADxE (Dx = liposomal daunorubicine) followed by HAM (high-dose cytarabine and mitoxantrone) and subsequently, two short therapy cycles with medium and high-dose cytarabine and anthracyclines. Intensification and maintenance were as in study -98. Allogeneic SCT from a family donor was restricted to high-risk patients. Intrathecal cytarabine was given 12 times in addition to CNS-RT. Results:The patient characteristics were similar in both randomized groups. Five-year survival (OS), event-free survival (EFS) and relapse rate (cumulative incidence) were similar in patients who received 12 Gy or 18 Gy (80%±3% vs. 77%±3%, 68%±3% vs. 60%±4%, 30%±3% vs. 36%±4%, respectively. The lower limit of the one-sided confidence interval for the difference in 5-years pEFS (7%) was 0.004. There were 7 relapses with CNS involvement (1 in the 12 Gy group, incidence 0.4% and 6 in the 18Gy group, incidence 3%, p=0.04). Secondary leukemias occurred in 1 and 3 patients, respectively. The analysis for patients treated as randomized (12 Gy n=229, 18 Gy n=216) was comparable. Conclusion:Our results demonstrate that there is no disadvantage for patients irradiated with a reduced CNS dose of 12 Gy regarding OS, EFS and rate of relapse. Due to intensification of chemotherapy, results in the AML-BFM studies improved considerably since study -87. Since the results of other international pediatric AML studies indicate that prophylactic CNS-RT does not improve outcome in the context of current chemotherapy regimen and because intensified chemotherapy elements with improved CNS efficiency such as high-dose cytarabine and liposomal daunorubicin have been introduced in our treatment schedule after study -87, we intend to replace CNS-RT by inclusion of triple intrathecal therapy in the next trial in order to reduce irradiation related long-term sequelae. Disclosures:No relevant conflicts of interest to declare.

Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997–2004)

A population-based cohort of children aged 1-18 years with acute lymphoblastic leukaemia (ALL) was treated with a dexamethasone-based protocol (Dutch Childhood Oncology Group [DCOG] ALL-9). We aimed to confirm the results of the most effective DCOG ALL protocol for non-high-risk (NHR) patients to date (ALL-6), compare results with ALL-7 and ALL-8, and study prognostic factors in a non-randomised setting. From Jan 1, 1997, until Nov 1, 2004, patients with ALL were treated according to the ALL-9 protocol in eight Dutch academic centres with their affiliated peripheral hospitals. Patients were stratified into NHR and high risk (HR) groups. HR criteria were white-blood-cell count of 50,000 cells per microL or more, T-cell phenotype, mediastinal mass, CNS or testicular involvement, and Philadelphia chromosome or MLL rearrangement; patients who did not fulfil these criteria were deemed to be NHR. The NHR group was treated with a three-drug induction (dexamethasone, vincristine, and asparaginase) for 6 weeks, medium-dose methotrexate for 3 weeks, then maintenance therapy. HR patients received a four-drug induction (as for the NHR patients plus daunorubicin) for 6 weeks, high-dose methotrexate for 8 weeks, and two intensification courses before receiving maintenance therapy. Triple intrathecal medication was given 13 times in NHR patients, 15 times in HR patients (17 times for patients with initial CNS involvement). No patient received cranial irradiation. Maintenance therapy was given until 109 weeks for all patients and consisted of mercaptopurine and methotrexate for 5 weeks, alternated with dexamethasone and vincristine for 2 weeks. Kaplan-Meier analysis was done on an intention-to-treat basis with event-free survival as the primary endpoint. This trial is registered at trialregister.nl, number NTR460/SNWLK-ALL-9. 859 patients were recruited to the study. Complete remission was achieved in 592 (98.5%) of the 601 patients in the NHR group and 250 (96.9%) of the 258 in the HR group. Five patients in the NHR group and four in the HR group died during induction. Median follow-up for patients alive was 72.2 (range 4.8-132.7) months as of August, 2008. 5-year event-free survival was 81% (SE 1%) in all patients: 84% (2%) in NHR patients, and 72% (3%) in HR patients. Isolated CNS relapses occurred in 22 (2.6%) of 842 patients. In a multivariate analysis, DNA index was the strongest predictor of outcome (<1.16 vs >or=1.16; relative risk 0.42, 95% CI 0.22-0.78), followed by age (1-9 vs >or=10 years; 2.23, 1.60-3.11) and white-blood-cell count (<50,000 vs >or=50,000 cells per microL; 1.60, 1.13-2.26). The overall results of the dexamethasone-based DCOG ALL-9 protocol are better than those of our previous Berlin-Frankfurt-Münster-based protocols ALL-7 and ALL-8. The results for NHR patients were achieved with high cumulative doses of dexamethasone and vincristine, but without the use of anthracyclines, etoposide, cyclophosphamide, or cranial irradiation, therefore minimising the risk of side-effects. Dutch Health Insurers.

Contribution of All-Trans Retinoic Acid to Improved Early Relapse-Free Outcome in Infant Acute Lymphoblastic Leukemia Comparing to the Chemotherapy Alone.

The efficacy of conventional and intensified chemotherapy in infant acute lymphoblastic leukemia (ALL) is limited worldwide particularly because of the high early relapses and treatment related mortality. We hypothesized that all-trans retinoid acid (ATRA) may participate in the differentiation of infant leukemic cells to normal progenitors with a consequent loss of malignant features and enhanced antiproliferative effects of chemotherapy. Our prospective multicenter non-randomized MLL-Baby/ALL-MB 2002 trial evaluated whether the novel recently developed ATRA based regimen, MLL-Baby is safe and more effective in the prevention of very early relapses comparing to ALL-MB 2002 - a well established protocol in Russia and Belarus. The trial was approved by Ethics Committees and parents' informed consent was signed in all cases. The decision to receive MLL-Baby or ALL-MB 2002 was judged by the treating physician. The major difference between the 2 treatment approaches was the addition of ATRA in the MLL-Baby protocol. Patients were equally distributed of patients (pts.) between the two groups according to risk: only pts. with t(4;11) and/or MLL/AF-4 or without complete remission (CR) achieved on days 36/43 were subjects for the high risk group (HRG). The remaining pts were stratified to an intermediate risk group (IRG). Treatment schedules were also similar in both regimens except for CNS-disease prophylaxis: in MLL-Baby, cranial irradiation 12 Gy was retained only for HRG pts with initial CNS involvement who were older than 12 months and substituted by 5 additional intrathecal treatments, while all pts. allocated to ALL-MB 2002 1year of age underwent cranial irradiation 12 Gy, regardless of their initial CNS status and risk group. In MLL-Baby pts, the initial ATRA pulse in daily dose 25 mg/m2 was given after debulking of the main tumor from day 36 to day 43, followed by 12 in IRG and 16 in HRG 2-weeks of ATRA courses alternating with chemotherapy. Between September 2003 and November 2006, 40 pts. aged 1–12 months were enrolled onto MLL-Baby (n=19) and ALL-MB 2002 (n=21) protocols. Both groups were balanced for median age 8 (1–12) and 6 (2–12) months, p=0.47; initial WBC 115,5 (1,2–450) and 105,5 (2.6–350) per microliter, p=0.76; initial CNS disease 3 vs. 5, p=0.5; 11q23/MLL translocations 12 vs. 10 pts., including t(4;11) - 6 vs. 7 pts, p=0.74 and BI phenotype 9 and 4 cases correspondingly, p=0.37, respectively. No significant differences were observed between MLL-Baby and ALL-MB 2002 with respect to rates of induction deaths: 1 vs. 3 cases, CR rates 94.7% vs. 85.7%, deaths in CR 1 vs. 0; whereas the early relapse rate was higher with ALL-MB 2002 compared to MLL-Baby: RFS was 0.24±0.13 vs. 0.94±0.05 (p=0.02) with a median of follow-up 20 months (1–55). EFS differed significantly: 0.21±0.11 vs. 0.84±0.08 (p=0.03). Most relapses on ALL-MB 2002 (n=11) and MLL-Baby (n=1) developed very early: 7 of 11 pts. and 1 of 1 pt. respectively and were localized only to bone marrow in most cases: 6 of 11 pts. and 1 of 1 pt. correspondingly. Our data indicate that ATRA administration contributes positively towards early relapse-free outcome in infants with ALL. A prospective randomized clinical trial with longer follow-up is needed to confirm these results.

Central Nervous System (CNS) Relapse in Adult Patients with Acute Lymphoblastic Leukemia (ALL): Frequency and Prognosis in 467 Patients without Cranial Irradiation for CNS Prophylaxis.

Background. Recurrence of ALL in CNS in adults is considered a poor prognostic feature but few studies have analyzed this issue. The objective of this study was to analyze the frequency, prognosis and predictive factors of CNS involvement and recurrence in adult patients with ALL treated with 4 PETHEMA protocols not including cranial irradiation for CNS prophylaxis.Methods. From June 1989 to December 2003, 467 adult patients (≥ 15-years-old) diagnosed with ALL were treated with one of the four consecutive protocols of PETHEMA group: ALL-89 (standard and high risk, n=108), ALL-93 (high risk, n=222), ALL-96 (standard risk, n=84), and ALL-97 (Burkitt's leukemia, n=53). CNS prophylaxis consisted of intrathecal (IT) injection of methotrexate (12 mg), cytarabine (30 mg) and hydrocortisone (20 mg), for 12–14 courses, together with high-dose systemic methotrexate and cytarabine during the early intensification phase. Cranial or craniospinal irradiation was not used in any case.Results. The median (SD) age was 33 (16) years and 272 (58%) were males. ALL type according to the FAB classification was: L1 28%, L2 61%, L3 11%. Immunological subtypes were: early-pre-B 15%, common 45%, pre-B 5%, mature B 11% and T 24%. CNS involvement at diagnosis was observed in 18 (3.9%) patients. Predictive factors for CNS involvement at diagnosis were: L3/mature B ALL (p<0.0001) and testicular involvement (p=0.006). Overall, complete remission (CR) was achieved in 381 (81%) of the patients, of whom 159 (42%) relapsed: 137 (36%) in bone marrow (BM) and 22 (5.8%) in CNS (14 isolated and 8 combined CNS and BM). The median (range) CR duration prior to CNS recurrence was 1.06 yr (95%CI0.11–2.01) for isolated CNS relapse, 0.6 yr (95%CI o.30–0.89) for combined relapse and 0.93 (95%CI 0.78–1.07) for BM relapse (p=0.76). No correlation was found between initial CNS involvement and CNS relapse. An initial LDH value > 1,000 U/L was the only factor associated with higher risk of CNS relapse (p<0.001). Treatment of CNS relapse consisted of systemic and IT therapy in the 22 cases (cranial irradiation was added to one) and CR was attained in 7 (32%) out of 22 of these patients. Stem cell transplantation was performed in 4 patients and 3 patients developed a second CNS recurrence. The median overall survival (OS) after recurrence was 0.7 yr for isolated CNS relapse, 0.13 yr for combined relapse and 0.41 yr for BM relapse (p=0.11).Conclusions. The frequency of CNS relapse in adult ALL patients receiving IT and systemic therapy for CNS prophylaxis is similar to that observed in protocols including cranial irradiation. An initial LDH value > 1,000 U/L was the only factor associated with higher risk of CNS relapse. Adult patients with CNS recurrence have a poor prognosis, although it is not different from that observed in BM relapses.

Neuropsychological sequelae in children with AML treated with or without prophylactic CNS-irradiation

In study AML-BFM 87 the relapse rate was lower in patients receiving cranial irradiation (CRT). However, CRT has always been associated with adverse cognitive side effects. Therefore, the impact of CRT on neuropsychological function in children with AML was retrospectively evaluated. We tested 53 children (30 boys, 23 girls) treated according to the AML-BFM-87 protocol (median age at diagnosis: 8.5 years, range 0.3 - 17.5; median time since diagnosis: 5.7 yrs, 3.8 - 10.7 yrs). To avoid any bias from additional therapy elements, patients with relapse or initial CNS involvement and transplanted patients were excluded (n=32). Our cohort was representative of the total group of 104 long term survivors of study AML-BFM 87. CNS prophylaxis consisted of ARA-C i.th., high dose ARA-C i. v. and either no CRT (n=15) or CRT (n=38) at a dose of 12 - 18 Gy depending on age. Neuropsychological function was evaluated by psychological tests of attention and concentration (test d2 by Brickenkamp) and an intelligence test (Progressive Matrices by Raven). In addition, patients and their parents were interviewed about the occurrence of learning problems, subjective deficits in concentration and physical impairment. In the total group, no significant differences were seen between irradiated and non-irradiated patients regarding the psychological tests. However, the irradiated patients scored below the non-irradiated control group in test "d2" (concentration: 41st vs. 59th percentile). In the interview, irradiated patients tended to report more learning problems (lp) (10/36 vs. 1/14; p=0.15) and subjective deficits in concentration (con). In irradiated girls (con: 6/15 vs. 0/8; p=0.06; lp: 5/15 vs. 0/8; p=0.12) and younger patients (0 - 5 years at diagnosis; con: 7/12 vs. 2/9; p=0.18; lp 3/10 vs. 1/9; p=0.18) this trend was even more pronounced. Children with AML and CRT had no significant intellectual impairment in standardized tests when compared to non-irradiated patients. However, more irradiated patients reported learning problems and subjective concentration deficits.

Results of the LMT81 protocol, a modified LSA2L2 protocol with high dose methotrexate, on 84 children with non‐B‐cell (lymphoblastic) lymphoma

From May 1981 to June 1989, 84 children with non-B-cell lymphoma (82 lymphoblastic, 1 T-cell immunoblastic, 1 unclassified diffuse lymphoma) were treated in the pediatric department of the Institut Gustave Roussy according to a protocol called LMT81, which was derived from the LSA2L2 protocol of Wollner and modified by the adjunction of 10 courses of high dose methotrexate to improve the CNS prophylaxis. No planned irradiation was performed except in cases of initial tests (2 patients) or CNS (5 patients) involvement and residual mass (2 patients). Sixty patients had mediastinal involvement; for the others, primaries were in the head and neck (7), nodes (2), (sub)cutaneous (4), bone (7), and elsewhere (2). According to Murphy's staging system, there were 2 stage I, 6 stage II, 33 stage III, and 43 stage IV. Among the stage IV patients, 41 had bone marrow involvement, 24 of them with more than 25% blast cells in bone marrow and 19 with blast cells in blood; 7 had CNS involvement. Three patients did not achieve complete remission, 4 died in remission (two measles, one post-transfusion AIDS, one unexplained definitive aplasia) and 13 relapsed at 2 to 29 months (median-13 months). Among the 77 patients without initial CNS involvement, there was only one isolated CNS relapse. With a median follow-up of 57 months (10-106 months), the event-free survival is 75% (SE 2.5) for the 84 patients with a plateau at 29 months, 73% (SE 8) for stage I and II patients, 79% (SE 4) for stage III, and 72% (SE 4) for stage IV patients. Survival was similar in each stage group. Reasons for failure of treatment, however, were different, being toxic deaths in stage II; initial therapy resistance, early relapses, and toxic deaths in stage III; and tumor failures in stage IV. In conclusion, this protocol is efficacious on T and non-T, non-B childhood lymphoma with a low incidence of CNS relapse. A future study will seek to diminish toxicity and long-term sequellae while at least maintaining the same cure rate of patients.

CNS involvement in small noncleaved-cell lymphoma: is CNS disease per se a poor prognostic sign?

Of 120 patients with small noncleaved-cell lymphoma who were entered sequentially on four National Cancer Institute (NCI) protocols, 29 (24%) had CNS involvement at some time in their clinical course. Seventeen had initial CNS involvement, and 12 developed CNS involvement at the time of first relapse. All 29 patients had extensive disease at presentation. The median serum lactate dehydrogenase (LDH) levels at presentation were 1,150 IU/L for patients with initial CNS involvement and 1,083 IU/L for patients with CNS involvement at relapse. CNS disease was significantly associated with serum LDH levels (P less than .0001), bone marrow involvement (P less than .0001), and jaw involvement (P = .018), but not involvement of the abdomen. There were nine long-term survivors among the 29 patients (31%). CNS disease did not appear to confer a worse prognosis on these patients than on patients without CNS involvement who had similar degrees of serum LDH elevation or who had bone marrow involvement, suggesting that extensive disease rather than CNS involvement was responsible for the poor prognosis. Event-free survival for patients with serum LDH levels above 500 IU/L was not different whether CNS disease was present or not (P = .29), nor was event-free survival different for patients with stage IV disease, whether CNS disease was present or not (P = .92). Although some patients had CNS radiation, there was no evidence that this was of therapeutic benefit. Intrathecal (IT) chemoprophylaxis effectively prevented spread to the CNS in patients without initial CNS involvement. Five of 18 patients (28%) who received no IT prophylaxis had CNS relapse (four isolated to the CNS), but only seven of the 85 patients (8%) who received IT prophylaxis had CNS relapse (two isolated to the CNS). The differences in overall and isolated CNS relapse rates were statistically significant (P = .034 and P = .008, respectively).

Allogeneic bone marrow transplantation in adults with Burkitt's lymphoma or acute lymphoblastic leukemia in first complete remission.

The prognosis of adults with Burkitt's lymphoma is very poor and depends on initial CNS and/or bone marrow involvement. We report results in nine adult patients with CNS (n = 9) and/or bone marrow involvement (n = 7) treated in first complete remission (CR) with allogeneic bone marrow transplantation (BMT). CNS treatment before the conditioning regimen consisted of cranial irradiation at 15 Gy (n = 8) and intrathecal chemotherapy (n = 9). The conditioning regimen included cyclophosphamide and total body irradiation (TBI) in a single dose. No postgraft CNS prophylaxis was administered. At the present time, seven patients are alive and disease-free at 18, 23, 44, 47, 54, 54, and 59 months. Two patients died at 14 and 7 months from transfusion-related acquired immune deficiency syndrome and bacterial septicemia and were disease-free at the time of their death. These preliminary results should encourage the use of BMT. A prospective randomized trial is warranted to further specify and investigate the advantages of allogeneic BMT versus conventional chemotherapy.

Improved treatment results for lymphoblastic lymphoma in adolescents and adults using a doxorubicin-based (APO) protocol.

A multi-drug chemotherapy (APO) protocol incorporating doxorubicin was used to treat 12 patients (median age 19 years) with lymphoblastic lymphoma. The APO protocol consisted of intensive induction and consolidation phases, prophylactic CNS treatment, and 24 months of maintenance therapy. Eleven patients had an anterior mediastinal mass, while T cell markers were found on the lymphoma cells in eight of the nine cases tested. Two patients had initial CNS involvement, with one also having bone marrow replacement. Complete remission was obtained in all patients, with no deaths due to treatment toxicity. There have been four relapses, one in the patient with initial CNS and leukemic disease, two in abdominal sites, and in the mediastinum in one patient. With a median follow-up time of 30 months from diagnosis, 67% of patients remain alive in first remission. These results indicate that the APO protocol provides a highly effective approach to the management of this high grade lymphoma in adolescents and adults.

Effective multiagent chemotherapy in children with advanced B-cell lymphoma: who remains the high risk patient?

Between 1981 and 1985, 50 patients, mainly children and adolescents, with advanced B-cell lymphoma were entered on a protocol comprising eight drugs: cyclophosphamide, vincristine, prednisolone, high dose methotrexate, adriamycin, BCNU, cytosine arabinoside and thioguanine. Treatment to the central nervous system consisted of intrathecal methotrexate and cytosine-arabinoside in association with high dose methotrexate without irradiation. Data was collected prospectively with regard to response rate, treatment related complications and survival. Histology was reviewed in all referred cases and in 21 there was supportive evidence from immunological and cytogenetic studies. The overall complete response rate was 86%: 31/36 stage III and 12/14 stage IV. There were four treatment related deaths. The overall disease-free survival is 75% with a median follow up of 32 months. In the group of stage IV patients 5/7 with only marrow involvement, 2/4 with isolated CNS involvement and 1/3 with combined CNS and marrow infiltration survive. All the patients with CNS involvement at presentation underwent consolidation treatment with high dose chemotherapy and bone marrow transplant. These results demonstrate the very high curability of B-cell lymphoma using intensive multiagent therapy even with advanced abdominal disease. Bone marrow infiltration does not appear to be an adverse prognostic factor in isolation from bulk disease or CNS involvement. There remain, however, two groups of patients in whom further intensification of therapy is indicated, namely, those with initial CNS involvement, especially in combination with marrow infiltration, and those with extensive multiorgan involvement at presentation who fail to achieve remission with initial therapy. For the other patients, the large majority, a reduction in the intensity and duration of therapy is currently under study.