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

Abstract Abstract 3561 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.

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A Pediatric Treatment of Ph-Negative Acute Lymphoblastic Leukemia (ALL) Is Effective and Safe In Adolescents and Young Adults (AYAs) until 29 Years of Age

Blood ◽

10.1182/blood.v116.21.2125.2125 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2125-2125

Author(s):

Thomas Cluzeau ◽

Nathalie Dhedin ◽

Françoise Huguet ◽

Emmanuel Raffoux ◽

Sebastien Maury ◽

...

Keyword(s):

Young Adults ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Central Nervous System Involvement ◽

Early Response ◽

Continuous Variable ◽

Response To Therapy ◽

Younger Adults ◽

Response To Chemotherapy

Abstract Abstract 2125 Background: Over the last three decades, progress in the treatment of childhood acute lymphoblastic leukemia (ALL) has considerably improved the outcome of children, leading to 5-year OS of more than 80%. Numerous comparisons, including the French LALA/FRALLE (Boissel et al. JCO 2001), have reported a better outcome in teenagers treated with pediatric as compared to standard historical adult ALL protocols. Even if modern pediatric-inspired adult ALL protocols have recently reported impressive improvements, especially in younger patients (Huguet et al. JCO 2009), the issue of whether younger adults (YAs) should be treated according to pediatric or adult protocols remains an open one. The aim of this study was first to evaluate the feasibility and the results of a non-modified pediatric protocol (the French FRALLE 2000) in adolescents and younger adults (AYAs, aged 15–29 years) treated in adult departments. Methods: From February 2001 to June 2010, 72 AYAs with Ph-negative ALL were treated according to the pediatric FRALLE 2000-BT protocol in 12 adult hematology units in France and Belgium. After a prednisone prephase and a four-drug induction (prednisone, daunorubicin, vincristine and L-asparaginase), patients in CR received a consolidation, a 1st delayed intensification, an interphase, a 2nd delayed intensification, and a maintenance chemotherapy during two years. Results: The median age was 19 years (range, 15–29 years). The cohort was separated in 2 subgroups: 44 adolescents aged 15–19 years and 28 young adults (YAs) aged 20–29 years. There were no significant differences between the adolescent and the YA populations in term of sex ratio, white blood cell count (WBC), central nervous system involvement, and phenotype (BCP- vs T-ALL). As expected, few recurrent cytogenetical abnormalities were identified in this population and did not differed between both subgroups. In the adolescent group, we identified 2 patients with t(4;11), 1 patient with t(1;19), and 3 patients with hypodiploïdy and/or neartriploïdy, whereas this repartition was 2/2/1 in YAs. Rates of good early response to prednisone were in 68% in adolescents and 61% in YAs (p=.52), while rates of good early response to chemotherapy were 80% and 86%, respectively (p=.51). No patient died during induction. Complete remission (CR) rate did not differ between subgroups (98% vs 100%, p=.42). With a median follow up of 4.8 years, 5-year EFS was 57% (41% in adolescents vs 79% in YAs, p=.03) and 5-year OS was 67% (56% and 82% respectively, p=.09). In patients with BCP-ALL, 5-year EFS was 60% (43% in adolescents vs 91% in YAs, p=.02) and 55% in T-ALL (57% vs 50% respectively, p=.81). Twelve patients (17%) received an allogeneic stem cell transplantation (SCT) in first CR (5 adolescents and 7 YAs). Four patients died in first CR, all after SCT, (2 adolescents and 2 YAs). In univariate analysis, a high WBC (continuous variable, p=.02) and a poor early response to chemotherapy (33% vs 63%, p=.02), but not phenotype or poor early response to prednisone, were significantly associated with a shorter EFS. In multivariate analysis, age (adolescents vs YA, p=.04), WBC (continuous variable, p=.0005), and poor early response to chemotherapy (p=.006) had still an impact on EFS. The poor outcome of adolescents compared to YAs, also observed in the French adult GRAALL protocol (not published), was not explained by differences in ALL characteristics, early response to therapy, or treatment-related toxicity. Conclusion: The pediatric protocol FRALLE 2000 is effective and safe for the treatment of selected AYAs with Ph-negative ALL referred to adult departments. The results observed in the YA population are promising, warranting prospective comparisons with the more recent pediatric-inspired adult protocols. The unexpected poorer outcome of adolescents deserves further investigations to explore a potential impact of the quality of care delivered in an adult environment. Disclosures: No relevant conflicts of interest to declare.

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Augmented Berlin-Frankfurt-Muenster Based Therapy For Young Adults With Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood.v122.21.1400.1400 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1400-1400 ◽

Cited By ~ 1

Author(s):

Michael E. Rytting ◽

Deborah A. Thomas ◽

Susan O'Brien ◽

Kurt Schroeder ◽

Rebecca Garris ◽

...

Keyword(s):

Young Adults ◽

Acute Lymphoblastic Leukemia ◽

De Novo ◽

Conflicts Of Interest ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Philadelphia Chromosome ◽

Significant Difference ◽

Grade Iii

Abstract Pediatric-based therapy of acute lymphoblastic leukemia (ALL) has been proposed as superior treatment for teen-agers and young adults with ALL. Several trials report improved survival rates in young adult ALL patients (pts) when treated with pediatric-based regimens. Augmented Berlin-Frankfurt-Muenster (ABFM) treatment is effective treatment for ALL in adolescents up to age 21. In an attempt to improve cure rates in AYA pts with ALL, we administered ABFM therapy to pts age 12 to 40 in a prospective, single institution trial. Results were then retrospectively compared to the HYPER CVAD regimen, the historical adult ALL regimen used at our institution. 85 pts with de novo Philadelphia chromosome negative ALL have completed at least 6 months of therapy. There are 69 (81%) pts with pre-B ALL and 16 (18%) pts with T-cell ALL/lymphoma. The age range is 13-39 with a median of 21. The median WBC at diagnosis is WBC=14 thousand/microliter (range 0.4-494). 80/85 (94%) pts entered remission (<5% blasts on day 29 marrow morphology). 1 patient died during induction. 61(72%) pts attained remission at day 15 of induction. 29 (22%) did not have morphological remission by day 15 of induction. At the end of induction, 46(58%) pts were minimal residual disease (MRD) negative by flow cytometry (<0.01% blasts). 25(31%) were positive for MRD and 6(7%) were not available or equivocal. By approximately day 84 of treatment, 55(69%) pts were negative for MRD and 13(16%) were positive or suspicious. Toxicities encountered include severe allergy to PEG-asparaginase in 17 (20%) pts, thrombosis in 18 (21%), hyperbilirubinemia grade III-IV in 31 (36%), elevated ALT grade III-IV in 28 (33%), hypofibrinogen grade III-IV in 30 (35%), pancreatitis in 9(11%), and avascular necrosis in 9 (11%). Grade III-IV hepatic toxicity is frequent but resolves within two weeks in almost all pts. For the entire cohort, the estimated 3 year overall survival (OS) is 75% and 3 year complete remission duration (CRD) is 71%. In univariate analysis, negative MRD at day 29 was associated with improved OS and day 84 negative MRD was associated with improved CRD. The presenting WBC was associated with OS and CRD. On multivariate analysis, only WBC over 50k/microliter maintained significance for OS and CRD. In comparing ABFM to HYPER CVAD, there is no significant difference in OS or CRD between the two regimens (fig. 1 and 2). This lack of difference in OS and CRD persists when patients are stratified for age > or </= 21 years, for presenting WBC over 50 thousand, and for MRD at the end of induction. In our hands, pediatric based therapy has significant though tolerable toxicity. Outcomes in AYA pts are similar but not superior to results obtained with historical ALL therapy. Disclosures: No relevant conflicts of interest to declare.

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Outcome Among Adolescents and Young Adults with Acute Myeloid Leukemia at Pediatric Versus Adult Centers: A Population-Based Study Using the IMPACT Cohort

Blood ◽

10.1182/blood-2019-130145 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4749-4749

Author(s):

Sumit Gupta ◽

Nancy Baxter ◽

Jason Pole ◽

Cindy Lau ◽

Rinku Sutradhar ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Young Adults ◽

Acute Lymphoblastic Leukemia ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Population Based ◽

Adolescents And Young Adults ◽

The Impact ◽

Acute Myeloid

Background: Survival outcomes among adolescents and young adults (AYA) with acute myeloid leukemia (AML) remain poor. In AYA with acute lymphoblastic leukemia, outcomes differ between patients treated in pediatric vs. adult centers. This has not been well evaluated in AML. We therefore compared outcomes between AYA with AML treated at pediatric vs. adult centers using a population-based clinical database. In addition, we determined other predictors of outcome within this population. Methods: The IMPACT Cohort comprises all Ontario, Canada AYA aged 15-21 years diagnosed with one of six common cancers (including AML) between 1992-2012. Detailed demographic, disease, treatment, and outcome data were collected through chart abstraction and validated by content experts. Locus of cancer care (LOC - pediatric vs. adult center) was determined based on where the majority of therapy was delivered in the first three months after diagnosis. Linkage to population-based health administrative data identified additional cancer events (second cancers, relapse, death). Event-free (EFS) and overall survival (OS) were determined using Kaplan-Meier methods. The impact of LOC on EFS and OS was determined using multivariable Cox proportional hazard models, adjusting for demographic, disease, and treatment variables. Events included disease progression, relapse, death, and second malignancies. Results: Among 140 AYA with AML, 89 (63.6%) received therapy at an adult center. AYA treated in pediatric centers were younger than those treated at adult centers (median 16 years vs. 19 years; p<0.001) and were more likely to live in higher-income neighborhoods [37/51 (72.5%) vs. 47/89 (52.8%); p=0.02]. Disease markers such as presenting white blood cell count and AML subtype did not differ by LOC. The 5-year EFS and OS for the whole cohort were 35.0%±4.0% and 53.6%±4.2%. Neither EFS nor OS differed by LOC (Table 1). In multivariable analyses adjusting for disease characteristics, LOC was not predictive of either EFS [adult vs. pediatric center hazard ratio (HR) 1.3, 95thconfidence interval (CI) 0.8-2.2, p=0.27] or OS (HR 1.0, CI 0.6-1.6, p=0.97). AYA with AML living in rural areas however experienced significantly inferior outcomes as compared to their urban counterparts (EFS: HR 2.5, CI 1.3-4.7, p=0.005; OS: HR 2.0, CI 1.1-3.8, p=0.04). Conclusions: In this population-based cohort, outcomes did not differ between AYA with AML treated at pediatric vs. adult centers, unlike what has been previously shown in AYA with acute lymphoblastic leukemia. However, rural AYA experienced substantially inferior outcomes than urban AYA, suggesting that even within a universal single payer system of healthcare, socioeconomic disparities persist in this population. Disclosures No relevant conflicts of interest to declare.

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Ph-Negative Acute Lymphoblastic Leukemia (ALL) in Adolescents and Young Adults (AYA) Treated with Pediatric Argentine BFM-like Protocol: Real-Word Data on Prognostic Factors and Treatment

Blood ◽

10.1182/blood-2021-151448 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4471-4471

Author(s):

Luciana C Ferrari ◽

María M Rivas ◽

Isolda I Fernandez ◽

Federico Sackmann ◽

María J Mela Osorio ◽

...

Keyword(s):

Bone Marrow ◽

Young Adults ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Allogeneic Bone Marrow Transplantation ◽

Adolescents And Young Adults ◽

Prognostic Impact ◽

Allogeneic Bone ◽

Cns Involvement

Abstract Background: ALL in adults is considered a heterogeneous disease with poor prognosis. However, adolescents and young adults (AYA) display intermediate characteristics as compared with children. Risk groups and response predictors are essential to guide the treatment. Aims: The aim of this report was to evaluate the experience of Ph-negative ALL in AYA patients (pts) treated with the pediatric Argentine type-BFM protocol, assessing predictors of response in terms of overall survival (OS) and event-free survival (EFS). Methods: We performed a retrospective multicenter analysis of AYA pts diagnosed between 2013 to 2021, from 16 Argentine institutions who were treated following the pediatric Argentine type-BFM protocol. Response to prednisone (PR) at day(d) 8 (<1.0 and ≥1.0 x10 -9 blasts) in peripheral blood (PB) and complete remission (morphological remission -MCR- together with negative minimal residual disease -MRD- by flow cytometry) were evaluated. Events were defined as relapse, refractoriness or death. Chi2/Fisher's exact test, Kaplan-Meier / log rank test and Cox regression were used for statistical analysis. Results: One hundred and seventy-three patients similarly distributed among private and public institutions were analyzed. The median (Md) age was 22 years (15-40) with a male predominance (66%). At diagnosis, 23% presented central nervous system (CNS) involvement, 79.5% B and 20.5% T immunophenotype, 29% CD20 positive, 16% adverse cytogenetic/molecular findings and 29% no data. Ph-like screening was not routinely performed assessed only in 13% revealing two CRLF2 and one PDGFRB rearrangements. Twenty-one (12%) of pts underwent allogeneic bone marrow transplantation (Allo-HSCT) at 1 st line, 20 with MRD negative and 1 MRD positive at the time of the procedure.Of 171 pts, 155 (91%) achieved MCR, 12 (7%) were refractory, 3 (2%) died prior/during induction and 1 (0.6%) patient dropped out of treatment; 144 (84%) achieved negative MRD, 22 (13%) positive MRD and 5 (3%) were not evaluated. The Md to reach CR and MRD (-) was 33d (IQR 31-42) and 35d (IQR 32-73), respectively. With a Md follow-up of 16 months (1-79), 52 pts (30%) relapsed and 68 pts (39%) died. Early deaths at 3 months occurred in 8 (5%) pts, 5 related to treatment and 3 to disease. The Md OS and EFS were 58 and 34 months, respectively. Prognostic predictors analyzed were sex, white blood counts (WBC) at diagnosis (limit of 30 x10 -9/L), age (limit of 30 years), CNS involvement, cytogenetic/molecular findings, PR at d8, MRD in bone marrow (BM) at d15, 33 and 78. In the univariate analysis, response at d8, MRD at d15, 33 and 78 were useful to predict both OS and EFS, adding age and WBC in terms of OS. Similar results were obtained when patients who underwent Allo-HSCT were censored at the time of the procedure. (Table). In the multivariate analysis, positive MRD at d33 and d78 (and WBC in OS) maintained their independent adverse prognostic impact in relation to OS and EFS. Allo-HSCT showed benefits in pts with MRD >0.1% at d33 and >0.01% at d78 in terms of OS (d33: NR vs. 11 m, p =0.048, HR 0.3, 95%CI [0.1-0.9]; d78: NR vs. 8 m, p =0.009, HR 0.4, 95%CI [0.2-0.8]) and EFS (d33: NR vs. 6 m, p =0.022, HR 0.2, 95%CI [0.1-0.8]; d78: NR vs. 5 m, p =0.003, 0.1 HR, 95%CI [0.02-0.5]). The adverse risk of positive MRD at day 33 and 78 in terms of OS and EFS was overcome when pts were transplanted. Summary/Conclusion: The results show that positive MRD at d33 and 78 independently impacted on OS and EFS in our series and that Allo-HSCT overcame their adverse risk. Our data confirms the relevance of using pediatric protocols in AYA. On the other hand, the importance of prognostic tools in order to improve the outcome of AYA patients, reinforcing their inclusion in current guidelines. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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