Pediatric-inspired Chemotherapy Research Articles

Comparable Outcomes of Relapsed Acute Lymphoblastic Leukemia in Adolescents and Young Adults (AYA) Treated With Pediatric-Inspired Chemotherapy (R3 Protocol) Versus Adult-Based Salvage (FA) Protocol

Comparable Outcomes of Relapsed Acute Lymphoblastic Leukemia in Adolescents and Young Adults (AYA) Treated With Pediatric-Inspired Chemotherapy (R3 Protocol) Versus Adult-Based Salvage (FA) Protocol

ALL-141 Comparable Outcomes of Relapsed Acute Lymphoblastic Leukemia in Adolescents and Young Adults (AYA) Treated With Pediatric-Inspired Chemotherapy (R3 Protocol) Versus Adult-Based Salvage (FA) Protocol

ALL-141 Comparable Outcomes of Relapsed Acute Lymphoblastic Leukemia in Adolescents and Young Adults (AYA) Treated With Pediatric-Inspired Chemotherapy (R3 Protocol) Versus Adult-Based Salvage (FA) Protocol

ALL-151 Impact of Blinatumomab on Survival Outcomes in Adolescents and Young Adults with Philadelphia Chromosome-Negative B-Cell ALL Following the Initial Phase of Pediatric-Inspired Chemotherapy: A Comparative Study

ALL-151 Impact of Blinatumomab on Survival Outcomes in Adolescents and Young Adults with Philadelphia Chromosome-Negative B-Cell ALL Following the Initial Phase of Pediatric-Inspired Chemotherapy: A Comparative Study

Impact of Blinatumomab on Survival Outcomes in Adolescents and Young Adults with Philadelphia Chromosome-Negative B-Cell ALL Following the Initial Phase of Pediatric-Inspired Chemotherapy: A Comparative Study

Impact of Blinatumomab on Survival Outcomes in Adolescents and Young Adults with Philadelphia Chromosome-Negative B-Cell ALL Following the Initial Phase of Pediatric-Inspired Chemotherapy: A Comparative Study

Outcomes and adverse events in older acute lymphoblastic Leukemia patients treated with a pediatric-inspired protocol with Pegylated or native Asparaginase

ABSTRACT This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.6%), febrile neutropenia (38.4%), and transaminitis (34.2%). AEs did not translate into significant differences concerning overall survival, leukemia-free survival, or early mortality. Furthermore, we observed a reduction in early mortality rates (11% vs. 20%) and an increase in median overall survival (54 vs. 48 months) compared to our previous data. These findings suggest that the utilization of a pediatric-inspired chemotherapy protocol, with ASP, is an effective and well-tolerated therapeutic option for older patients with Ph-negative ALL. However, it emphasizes the importance of diligent monitoring and close follow-up throughout treatment.

Comparable Outcomes of Relapsed Acute Lymphoblastic Leukemia in Adolescents and Young Adults (AYA) Patients Treated with Pediatric-Inspired Chemotherapy (R3 protocol) Versus Adult-Based Salvage (FA) Protocol

Background Although the survival rate of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) has improved by using pediatric-based treatment protocols, those who experience a relapse still have poor outcomes when treated with adult chemotherapy salvage-regimens, which have traditionally included high doses of Ara-C. The long-term survival rate for patients treated with these salvage-regimens is less than 10%. Salvage treatment with blinatumomab for adults with relapsed B-cell ALL results in a complete remission (CR) rate of 34%, a median survival of 7.7 months, and an overall survival (OS) of less than 30% at 18 months. In contrast, the ALLR3 protocol for relapsed ALL in patients up to the age of 18 years achieved a CR rate of 97% and an overall survival rate of 72%. Therefore, this study aims to compare the outcomes of AYA patients treated with pediatric-inspired regimen (R3 regimen) to those treated with adult-based regimen (FA (Fludarabine/Cytarabine) protocol). Methods The R3 protocol treated 17 AYA patients with relapsed Philadelphia-negative ALL, aged between 14 to 40 years old, who had received first-line therapy. Patients who achieved CR underwent allogenic transplant. The protocol included vincristine, mitoxantrone, asparaginase, dexamethasone, and intrathecal methotrexate. In comparison, 60 patients were treated with FA protocol, with patients achieved CR proceeded to allogeneic stem cell transplantation. Relapses were classified as very early (< 18 months from diagnosis), early (>18 months from diagnosis and <6 months from the end of therapy), and late (>6 months from the end of therapy). Patients' characteristics, response rate (RR) and overall survival (OS) were analyzed. Results The two arms had comparable characteristics. The median age in the R3 arm was 16 years (range: 14-40 years) compared to 22 years (range: 18-32 years) in the FA protocol arm. In the R3 arm, 88.2% of patients had B-cell ALL, while in the FA protocol arm, 92.2% had B-cell ALL. CNS involvement was seen in 28.8% and 17.6% of cases in the R3 and FA protocol arms, respectively. Relapses were classified as very early, early, or late in 2 (12%), 5 (29%), and 7 (41%) of cases in the R3 arm and were mostly late (25.2%) in the FA protocol arm. Relapses in the R3 arm were isolated bone marrow (BM), isolated extramedullary (EMD), or combined BM and EMD in 14 (82%), 1 (6%), and 2 (12%) cases, respectively, while EMD was around three times higher (16.9%) in the FA arm. The overall CR rate was 60% at the end of R3 induction, with negative MRD (<10 −4 cells) in 47.1% of patients. The overall CR rate was higher in the FA arm (76.3%), but the difference with the R3 arm was not statistically significant (p-value 0.1). The disease was refractory to subsequent salvage therapy in 42% of cases in both arms. About half of the patients who responded to R3 proceeded to allogeneic stem cell transplant (52.3%), while 78% of the patients post-FA underwent transplantation. Eight patients died (47%) in R3 arm, but only one patient died due to treatment-related sepsis, while the other seven patients died due to disease-related causes. At a median follow-up of 4 years, OS was 53% in the R3 arm compared to 30.8% in the FA arm, but the difference was not significant (p-value=0.8). The post-FA mortality was mainly due to infections (15.3% in FA vs. 5.9% in R3). Conclusion Pediatric-inspired protocols that have shown significant benefits in the front-line setting for ALL in the AYA population did not demonstrate a significant difference when compared to traditional adult-based salvage chemotherapy regimens in relapsed disease.

Multicenter Campus ALL Study on Infectious Complications in Ph- Acute Lymphoblastic Leukemia Patients Treated in the Real Life with the Gimema LAL1913 Protocol

Background The Italian national program of pediatric-inspired chemotherapy GIMEMA LAL1913 trial for adult Ph- acute lymphoblastic leukemia (Ph- ALL) has reported favorable results particularly in the younger subgroup of patients (pts) aged 18-40 years (Bassan et al, Blood Adv 2023). After the closure of the trial, this treatment scheme was adopted in the clinical practice by many Italian hematology centers for the treatment of newly diagnosed adult Ph- ALL. The safety of this intensive treatment in terms of infectious complications deserves to be investigated in the real life. Aims To evaluate in the context of the real life the incidence of infectious complications in Ph- ALL pts treated off protocol according to the GIMEMA LAL1913 chemotherapy scheme and to assess the impact of the prophylactic measures adopted. Methods We retrospectively collected data on 178 Ph- ALL pts treated in 13 Italian hematology centers participating to the Campus ALL network in Italy. Pts were homogeneously treated following the GIMEMA LAL1913 scheme, but the use of anti-infective prophylaxis differed among centers and among cycles. We analyzed data with regard to the type and site of the infections, the cycles of treatment during which the infections occurred. Finally, we correlated the incidence of the infections with the presence or absence of anti-infective prophylaxis. Results A total of 301 infectious events were diagnosed during the treatment of 134 of the 178 Ph- ALL pts (75%), including 98 episodes of fever of unknown origin (FUO) reported in 58 pts (33%). The distribution of the different types of documented infections for a total of 195 is reported in Table 1. The severity grading of infections (CTCAE.5) was available in 137 events and was ≥3 in 101. SARS COV2 infection accounted for 22% of the viral infections (8/36 cases). We diagnosed 24 pulmonary infections (in 21 pts): 15 mycotic (13 probable and 2 possible), 6 bacterial and 3 viral infections. The number of pts undergoing an infection/cycle is shown in Table 2: 69 patients had at least one infection during cycle 1 (39% of treated pts); infections were mainly bacterial and occurred in prevalence during cycle 1. Two patients died of sepsis by Pseudomonas aeruginosa during cycle 1 (mortality rate: 1.1%). Pts receiving antibacterial prophylaxis were 94/178 (53%). Bacterial infections were reported in 47 pts receiving prophylaxis and in 41 pts who did not undergo prophylaxis; the difference between the two groups was not significant (p: 0.8). Patients receiving antifungal prophylaxis were 119/178 (67%). Mycotic infections were reported in 14 pts, and in 10 pts who did not receive prophylaxis; again, no significant difference was recorded between the two groups (p: 0.3). Patients receiving antiviral prophylaxis were 151/178 (85%). Viral infections were reported in 30 pts and in 4 pts not receiving prophylaxis; no statistical difference was observed (p: 0.4). Summary/Conclusion The intensive GIMEMA LAL1913 treatment applied in the real life to newly diagnosed adult Ph- ALL pts is associated with a non-negligible rate of infections; >75% of treated pts suffered from at least one infection. Moreover, the large majority of these infections were severe with a CTCAE.5 grading ≥3. However, the infection-related mortality was very low (1.%); the anti-infective treatment together with the achievement of a complete hematologic recovery were able to control and resolve the infectious complications. Bacterial infections were prevalent and bacteremias/sepsis represented 70% of events. Cycle 1 was most affected by infectious complications of all types; mycotic and viral infections were mostly reported during cycle 1, while they decreased markedly during the following cycles. Also incidence of bacterial events decreased during treatment, though they continued to occur also in the late phases of the management suggesting that a high level of attention should be maintained up to the end of treatment. Anti-infective prophylaxis was heterogeneously applied, but it remains unclear if it is necessary. The first analysis of this survey does not show an advantage of prophylaxis in reducing infections; however, particularly for fungal complications, the numbers are too limited to consider these results as conclusive. Data collection is still ongoing, and a larger sample size will allow more robust conclusions.

Age-Adapted Chemotherapy for Adults >40 Years Old with Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia: Single Center Outcomes

Introduction: While pediatric-inspired regimens are preferred in younger adults with Ph-negative ALL, the optimal approach for treating adults age >40 with Ph-negative ALL has not yet been defined. In the U.S., hyperCVAD-based regimens are commonly used in this age group; however, hyperCVAD may be less effective than pediatric-inspired regimens in patients who are appropriate candidates for intensive therapy, and may be excessively toxic in patients who are poor candidates for intensive therapy. We explored giving two different multiagent chemotherapy regimens to adults age >40 with newly diagnosed Ph-negative ALL, depending on the individual patient's age and fitness level. Methods: At our institution starting in September 2020, patients between 40-60yo with good performance status received an intensive pediatric-inspired regimen based on the CALGB 10403 backbone, while patients >60yo (or 50-60 with poor PS) received a moderate-intensity multiagent chemotherapy backbone consisting of 2-part induction (induction-1: infusional doxorubicin/vincristine D1-4 + dexamethasone 40mg D1-4, 9-12, 17-20; induction-2: same as induction-1 plus cyclophosphamide 1000mg/m 2 on day 1) and consolidation with 6 cycles of chemotherapy, alternating between methotrexate (1g/m 2) plus peg-asparaginase (1,000U/m 2), and cytarabine (1g/m 2 x 6 doses). Prior to September 2020, patients in this age group received the hyperCVAD backbone. In both cohorts, patients not proceeding to allogeneic SCT in CR1 received POMP maintenance for up to 2 years. We reviewed charts of patients aged >40 with newly diagnosed Ph-negative ALL at University of Colorado Hospital from 2014-2023 to compare outcomes between patients treated before 09/2020 (“hyperCVAD” cohort) and after 09/2020 (“age-adapted” cohort). Results: Between 09/2020-04/2023, 17 adults with median age of 57 (range 40-81) with newly diagnosed Ph-negative ALL began treatment at our institution. 6 patients (age 40-56) received a modified pediatric-inspired regimen, and 11 patients (age 54-81) received a moderate-intensity regimen. 4 patients underwent allogeneic SCT in CR1 (including 1 for tMDS that developed during maintenance therapy). 3 patients received blinatumomab in CR1, 2 of whom subsequently received allo SCT. With a median follow-up of 16 months (range: 1-32 months), 1 patient relapsed during maintenance and 2 patients died from treatment-related mortality (1 during induction chemotherapy, 1 during salvage therapy for primary refractory disease). All three events occurred in patients who received the moderate-intensity regimen. Grade 3 or 4 asparaginase-related toxicities occurred in 2 patients (1 gr3 hyperbilirubinemia, 1 gr3 pancreatitis) and both resolved with supportive care. Between 2014-2020, 18 adults with median age of 58 (range 42-80) received hyperCVAD for newly diagnosed Ph- ALL. 6 patients received allogeneic SCT in CR1, and no patients received blinatumomab in CR1. With a median follow-up of 31 months (range: 7-94 months), 7 patients relapsed during consolidation or maintenance therapy and 3 relapsed after SCT. Among 10 patients who died during follow-up, 7 deaths were due to relapsed/refractory disease and 3 were due to treatment-related mortality (all 3 TRM were post-transplant). An improvement in relapse-free survival is seen in the cohort treated with age-adapted chemotherapy vs. the hyperCVAD cohort (p=0.045, log-rank test) (Figure 1), while there was no difference in overall survival (p=0.29) (not shown). Conclusions: Age-adapted multiagent chemotherapy is safe and effective in adults age >40 with Ph-negative ALL and may result in better outcomes than hyperCVAD. This is possibly due to better efficacy of pediatric-inspired chemotherapy for younger (40-60yo) patients and better tolerability of moderate-intensity chemotherapy for older (>60yo) patients, compared to hyperCVAD. Broad use of asparaginase in both the pediatric-inspired and moderate-intensity regimens may have also contributed to better outcomes in comparison to hyperCVAD. Incorporation of novel therapies in the frontline setting holds much promise to improve outcomes for older adults with Ph- ALL. Our observations suggest that the specific multi-agent chemotherapy regimen used, and in particular the incorporation of peg-asparaginase, may also affect outcomes significantly.

Socioeconomic Determinants and the Biology and Outcomes of Acute Lymphoblastic Leukemia in Adults

Introduction Implementation of pediatric-inspired chemotherapy regimens improved survival outcomes in adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL). Prior studies demonstrated that Non-Hispanic White (NHW) patients had better survival outcomes in the real-world AYA setting, but this effect was not observed in the pivotal CALGB 10403 clinical trial. To better characterize the socioeconomic versus biologic determinants of ALL outcomes, we conducted a single-institution, retrospective analysis of adult patients with ALL at the University of Chicago. We sought to investigate the impact of socioeconomic factors on ALL outcomes when patients are treated at a multidisciplinary, tertiary-care ALL center. Methods Adult patients with ALL treated at the University of Chicago between 2010 and 2022 were studied. Subtype classification was based on the 2022 WHO criteria. ALL patients were treated according to age-appropriate regimens (AYA with CALGB 10403-based regimens, older adults (>40) with lower intensity approaches). Because of treatment differences, outcomes of AYA and older patients were analyzed separately. Self-reported race was reported with guidelines from the National Cancer Institute (https://www.nih.gov/nih-style-guide/race-national-origin). Body mass index (BMI) was recorded at diagnosis. Annual median income was estimated based on the zip code of residence and categorized as high (>$50,000), middle ($35,000-50,000), and low (<$35,000). Additionally, we extracted data from the public use US population-based cancer registries of the Surveillance, Epidemiology, and End Results (SEER, http://seer.cancer.gov) program to estimate overall survival (OS) of ALL patients diagnosed between 2005 and 2020. Results Demographic and disease characteristics of 221 adult ALL patients treated at the University of Chicago are summarized in Table 1. BCR::ABL1 was more prevalent in Black ALL patients compared to NHW and Hispanic White (HW) patients (59% vs 24% and 20%, respectively, p=0.001). This phenotypic subtype was also associated with higher BMI (OR 7.64; 95% CI=1.17-49.9, p=0.03). Compared to NHW patients, low annual household income was more frequent in HW and Black patients (2% vs 13% and 24%, respectively, p<0.001). Similar OS was seen among NHW, HW, and Black patients when stratified by age (AYA vs older adult), B vs T-lineage phenotype, or median household income. Obesity at B-ALL diagnosis was associated with adverse OS, and median OS for patients with BMI <30, 30-40, and >40 were 113 months, 34 months (HR 2.04; 95% CI=1.27-3.28, p=0.003), and 23 months (HR 2.70; 95% CI=1.34-5.42, p=0.005), respectively. In our multivariable analysis, factors that were independently associated with adverse OS were age and BMI at diagnosis (HR 6.93; 95% CI 2.27-21.1, p=0.0007; HR 10.3; 95% CI 2.56-41.5, p=0.001, respectively), while BCR::ABL1 positivity predicted favorable OS (HR 0.41; 95% CI 0.2-0.87, p=0.02, see Figure 1). Compared to the SEER cohort, OS in older University of Chicago patients was better than the national average (53 months vs 23 months, HR 0.70; 95% CI=0.56-0.88, p=0.003). Among SEER AYA patients from 2015-2020, HW (HR 1.54; 95% CI=1.26-1.91, p=<0.001) and Black (HR 1.64; 95% CI=1.14-2.36, p=0.006) patients had significantly worse OS compared to NHW patients. Finally, SEER data showed that patients with higher median household incomes had better OS than patients with lower incomes. Specifically, older adult patients who reported higher median household income had better OS at 24 months compared to older adults with medium or low income at 15 months (respectively, HR 1.25; 95% CI=1.10-1.47, p=<0.001; HR 1.52; 95% CI=1.07-2.17, p=0.01). Conclusion While SEER data demonstrated significant OS differences based on race and median household income nation-wide, these variables did not predict adverse OS at our institution. The University of Chicago has an ALL center with a dedicated AYA clinic offering resources to support patients throughout their long pediatric-inspired therapies, as well as clinical trial options for both young and older adults. Located in a historically Black and low-income neighborhood, the University of Chicago plays a critical role in addressing socioeconomic disparities in ALL care for our community. Further interventional studies are needed to modify the poor prognostic impact of obesity in patients with ALL.

Venetoclax in Combination with Pediatric-Inspired Chemotherapy in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia: Results of a Phase I Trial

Introduction: Young adults with acute lymphoblastic leukemia (ALL) have favorable outcomes compared with historical standards when treated with an asparaginase-containing pediatric regimen (Stock et al., Blood 2019). We have demonstrated the safety and efficacy of pediatric inspired chemotherapy (PIC) for adults up to age 60 (MSK protocol 12-266, Geyer et al., Haematologica 2021). However, cure rates for adults with ALL remain below 60%, prompting the need for novel agents. Venetoclax (ven) is a BCL2 inhibitor being tested in several clinical trials for ALL. Here, we present the first report of ven used in combination with a multiagent, asparaginase-containing chemotherapy regimen for the upfront treatment of ALL. Methods: We conducted a Phase I, single-center, single-arm clinical trial (NCT05386576) to evaluate the safety and efficacy of ven in combination with PIC in adults with newly diagnosed ALL. Adults aged ≤60 years diagnosed with Philadelphia chromosome negative ALL were eligible for the study. The primary objective was to evaluate the safety of ven in combination with asparaginase-based PIC and identify the maximum tolerated dose and recommended phase II dose. The secondary objectives were to assess the rate of complete remission (CR) and measurable residual disease (MRD) negative CR at day 15 and 28 of Induction I, and end of Induction II. The regimen consisted of 6 treatment phases as previously published (12-266). Ven was administered at a final dose of 400mg (with a rapid dose escalation from 100mg over 3 days) during Induction I (days 5-7 dose escalation, days 7-28 full dose), Induction II (days 1-14 and 29-42), Intensification I & II (days 1-22), and Re-Induction I & II (days 1-14 and 29-42). Measurable residual disease (MRD) was assessed by multiparameter flow cytometry with 10 -4 sensitivity. We used historical data from 22 patients (pts) treated on our previous study, who received the same chemotherapy backbone without ven, as a comparator. Median follow up was calculated using the reverse Kaplan Meier indicator. Duration of treatment was compared using the Wilcoxon rank-sum test. Proportions of pts who achieved MRD-CR were compared with the chi squared test. Results: At the time of analysis, 8 pts had enrolled in the study; all 8 pts completed induction I and 6 (75%) pts had completed induction II (Table 1). Median follow up was 171 days. The median age was 38.5 years (min 25, max 60). 50% of pts had B-cell ALL, and 50% T-cell (including 1 patient with early T-cell progenitor). One patient (12.5%) had CNS disease (CNS 3) at diagnosis. Four (50%) pts had intermediate risk cytogenetics by CALGB 19802 classification (Stock et al., Cancer 2013), 2 (25%) had unfavorable, and 1 (12.5%) favorable. Two (40% of B-ALL) had a Philadelphia-like phenotype. During Induction I & II, 4 (50%) pts experienced febrile neutropenia, 6 (75%) grade 4 thrombocytopenia, and all 8 (100%) grade 4 neutropenia. No dose limiting toxicities, as defined per protocol, were observed. The average duration of Induction I on study was 46.6 days compared to 43.6 on 12-266 (p = 0.11). The average duration of Induction II on study for pts who had completed it at the time of analysis was 102 days compared to 74 days on 12-266 (p = 0.02), primarily due to cytopenias. Three (37.5%) of pts achieved an MRD negative CR by the end of Induction I. Of the 6 pts who had completed Induction II by time of analysis, 5 (83%) had achieved an MRD- CR, compared to 81% on 12-266 (p = 0.90) and 1 patient had refractory extramedullary disease. We assessed kinetics and depth of response by plotting the average blast percentage in the bone marrow by flow cytometry across three different timepoints. Pts on the study had numerically lower blast percentages at day 15, end of Induction I and end of Induction II compared to 12-266 (Figure 1). At the time of this analysis, no patient who entered CR had experienced disease relapse. Conclusions: Ven addition to a PIC backbone was overall safe with high MRD negative remission rates in this preliminary report. Compared to historical controls, pts treated with ven had a longer duration of Induction II primarily due to cytopenias, and we are amending the study to shorten ven duration during induction II. Pts treated with ven had a numerically faster reduction in bone marrow blasts compared to historical controls. Longer follow up in a larger patient population in this ongoing study will be required to assess long term toxicity and efficacy of this regimen.

Impact of MTHFR Polymorphisms C677T and A1298C in Acute Lymphoblastic Leukemia and Burkitt Lymphoma Patients Exposed to Methotrexate and Asparaginase

Background: Asparaginase (Asp) and high-dose methotrexate (HDMTX) are pivotal drugs in the treatment of aggressive hematological malignancies as acute lymphoblastic leukemia (ALL) and Burkitt lymphoma (BL). Asp and MTX present specific drug-related toxicities; for Asp, prothrombotic alteration of the coagulation profile, hepatobiliary and pancreatic toxicities, for MTX, renal, hepatobiliary, hematologic, gastro-intestinal and neuro- toxicity. The 5,10-methylenetetrahydrofolate reductase (MTHFR) is the enzyme involved in conversion of homocysteine into methionine. MTHFR most frequent single nucleotide polymorphisms C677T and A1298C are associated with reduced enzymatic activity up to 60%, that implies hyperhomocysteinemia and increased toxicity of MTX. Numerous studies have explored the relationship between C677T and A1298C polymorphisms of MTHFR and MTX toxicity and/or outcome in children ALL, but results are controversial. Nevertheless, it is common practice to reduce MTX dosage in adult patients in homozygosis. Aims: To explore the relationship between the MTHFR C677T and A1298C polymorphisms in homozygosis and development of MTX toxicity in a cohort of adult patients; furthermore, to evaluate the relationship with thrombotic risk in patients exposed to Asp. Materials and Methods: Data from consecutive adult onco-hematologic patients for whom MTHFR C677T and A1298C polymorphism analysis was available, treated with chemotherapeutic regimens containing HDMTX and/or Asp was retrospectively collected at a single center Italian institution. Adverse events (AEs) were graded according to CTCAE 5.0. Statistical analysis was performed with R language. The impact of MTHFR polymorphisms was evaluated by mean of a multivariate analysis adjusting Odds Ratio (OR) estimates for drug dosage and disease status. Results: Data from 78 patients, 57 affected by ALL, 3 by mixed phenotype leukemia (MPAL) and 18 by BL, was retrospectively collected. Overall, 13 (16.7%) of patients were 677TT and 8 (10.3%) were 1298CC. Patients with ALL/MPAL received mostly pediatric-inspired chemotherapy regimens (containing MTX 2.5 - 5 g/m 2 and Asp 1000-2000 UI/m 2), patients with BL received modified Rituxumab (R)-BFM protocol (MTX 1.5 g/m2); age/comorbidities-adjusted dose reduction was performed according to institutional guidelines. Median age for ALL and BL patients was 37.5 (IQR 27.0-54.2) and 33.5 (26.0-49.7) years, respectively; 54/78 (69.2%) of patients were male. Patients received a median of 3 (IQR 2-6) cycles containing HDMTX and/or Asp, for a total number of 299 cycles (94 containing Asp, 184 HDMTX and 24 both); 142 (48.0%) cycles were administered for active disease (AD), at diagnosis/relapse, and 154 (52.0%) in complete remission (CR). The impact of different dosages of Asp < 1000 UI/m 2 and ≥ 1000 UI/m² and of HDMTX <1.5 g/m 2 and ≥ 1.5 g/m 2 as well as the impact of disease status (AD vs CR) on AEs was explored. Concerning Asp therapy and thrombotic risk, 13 deep vein thrombosis (DVT) were observed, but no association between 677TT nor 1298CC was appreciated. AD status was strongly related to DVT (21.4% vs 1.8%, p 0.003). Coherently with the MTHFR-independent drug's mechanism of action, the polymorphisms had no impact on the development of Asp-related toxicities. Diversely, concerning HDMTX, in multivariate analysis, patients with 677TT were more likely to experience AST increase grade ≥3 (OR 10.55, 95%CI 1.34-83.09) while a protective role versus any grade GGT increase was observed (OR 0.09, 95%CI 0.01-0.71) (Figure 1A). Patients with 1298CC exhibited a superior incidence any grade AST/ALT increase, not confirmed for grade ≥3 (Figure 1B). No significant superior toxicity was observed in terms of renal, gastro-intestinal, hematologic AEs. The impact of a MTX dose reduction >25% of expected dose was then explored in a homogeneous population of 45 front-line pediatric-regimen treated ALL patients (35 received MTX dose ≥75% and 10 < 75%) and no impact in terms of OS and RFS was appreciated. Conclusions: The analysis ofMTHFR polymorphisms in adult patients is useful in identifying patients at higher risk for transaminitis, providing a biological parameter to integrate with hepatosteatosis, liver stiffness evaluation and BMI, for a comprehensive hepatic baseline evaluation. Patients at higher risk for hepatic complications may benefit from MTX dose reduction with no impact on disease outcome.

Pegaspargase-modified risk-oriented program for adult acute lymphoblastic leukemia: results of the GIMEMA LAL1913 trial

AbstractPediatric-inspired chemotherapy is the standard of care for younger adults with Philadelphia chromosome–negative acute lymphoblastic leukemia/lymphoma (Ph– ALL/LL). In LAL1913 trial, the Gruppo Italiano Malattie EMatologiche dell’Adulto added pegaspargase 2000 IU/m2 to courses 1, 2, 5, and 6 of an 8-block protocol for patients aged from 18 to 65 years, with dose reductions in patients aged >55 years. Responders were risk stratified for allogeneic hematopoietic cell transplantation (HCT) or maintenance per clinical characteristics and minimal residual disease (MRD). Of 203 study patients (median age, 39.8 years), 91% achieved a complete remission. The 3-year overall survival, event-free, and disease-free survival (DFS) rates were 66.7%, 57.7%, and 63.3%, respectively, fulfilling the primary study end point of a 2-year DFS >55%. Although based on the intention-to-treat, the DFS being 74% and 50% in the chemotherapy (n = 94) and HCT (n = 91) assignment cohorts, respectively, a time-dependent analysis proved the value of HCT in patients who were eligible (DFS HCT 70% vs no HCT 26%; P <.0001). In multivariate analysis, age and MRD were independent factors predicting DFS rates of 86% (age ≤ 40 and MRD-negative), 64%-65% (MRD-positive or age > 40) and 25% (age > 40 and MRD-positive); P < .0001. Grade ≥2 pegaspargase toxicity was mainly observed at course 1, contributing to induction death in 2 patients but was rare thereafter. This program improved outcomes of patients with Ph– ALL/LL aged up to 65 years in a multicenter national setting. This trial was registered at www.clinicaltrials.gov as #NCT02067143.

Abstract 5517: Pegaspargase is a viable option in elderly adults with acute lymphoblastic leukemia

Abstract Pegaspargase (peg-asp) is a pegylated form of asparaginase with a longer half-life used in pediatric-inspired chemotherapy for treatment of adult acute lymphocytic leukemia (ALL). Peg-asp appears to confer a survival advantage, but use in older adults is limited by concern for toxicity, though incidence and associated factors are poorly characterized. Our primary objective was to compare peg-asp tolerability in different age groups; secondary objectives were assessment of patient- (pt) and disease-dependent factors associated with toxicity. We retrospectively reviewed 58 ALL pts treated with at least 1 dose of peg-asp (500-2500IU/m2) at our institution between 2016-2021. We used χ-squared- and Fisher’s test, and multivariable regression analysis to assess relationships between pt-factors and toxicities. Median doses received was 2 (range 1-7). 38 pts were 40 years or older, 20 were &amp;gt;60 years. 18 received PEG during induction only, 8 in consolidation only, 27 in both, and 5 during salvage therapy post-relapse. 17 had Philadelphia (Ph) positive B-ALL; 32 Ph negative B-ALL; 7 T-ALL; and 2 had mixed phenotype acute leukemia. Pts were 19-78 years old (median 48.5). Grade 3 or 4 toxicities observed in &amp;gt;10% of cases included hepatotoxicity (81%, 47/58); antithrombin 3 depletion (72.4%, 42/58); hypofibrinogenemia &amp;lt;100 (58.6%, 34/58); hypertriglyceridemia (20.8%, 10/48); venous thromboembolism (12.1%, 7/58) and hemorrhage (12.1%, 7/58). Acute pancreatitis (8.6%, 5/58) and hypersensitivity (2/58, 3.4%) were less common. On univariate analysis, grade 3 liver injury was significantly associated with younger age groups (18-40 and 40-60 vs &amp;gt;60 years; p=0.025), likely due to older age strongly correlating (p &amp;lt;0.01) with receipt of &amp;lt;2000IU/m2 pegaspargase. No other toxicity was significantly associated with age. Hypofibrinogenemia and hepatotoxicity were significantly associated with initial receipt of pegaspargase during induction vs consolidation (p=0.042, p=0.013, respectively) but age was not. Pts receiving a max dose PEG of &amp;lt;2000IU/m2 had significantly lower odds of developing hepatotoxicity and hypertriglyceridemia than those receiving 2000 IU/m2 or more (p=0.008, p=0.003, respectively). On multivariate analysis, higher max dose of PEG received (2000 IU/m2 or over) correlated with greater odds of hepatotoxicity, hypertriglyceridemia and acute pancreatitis (OR 1.72, CI 1.23-2.38; OR 1.31, CI 2.18, CI 1.59-3.03; and OR 1.46, CI 1.13-1.88, respectively). Hypertriglyceridemia was also associated with older age and BMI &amp;gt;30 (OR 1.31, CI 1.05-1.62, and OR 1.31, CI 1.09-1.59, respectively). In summary, low dose pegaspargase is a viable option in ALL in adults over 60, with only hypertriglyceridemia associated with older age. Future work might correlate serum pegaspargase activity to intolerance and outcomes, and examine whether prophylactic treatment e.g. with levocarnitine might prevent toxicity. Citation Format: Yosef Joseph Rene Amel Riazat-Kesh, Hannah Levavi, Sangeetha Venugopal, Carli Beall, Ronald Hoffman, Marina Kremyanskaya, John Mascarenhas, Sara Kim, Michal Bar-Natan. Pegaspargase is a viable option in elderly adults with acute lymphoblastic leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5517.

Pediatric chemotherapy versus allo-HSCT for adolescent and adult Philadelphia chromosome-negative ALL in first complete remission: a meta-analysis.

Pediatric-inspired chemotherapy significantly improves survival for adolescent and adult patients with acute lymphoblastic leukemia (ALL). However, the benefits over allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unclear. To compare clinical outcomes between pediatric-inspired chemotherapy and allo-HSCT in consolidation therapy of adolescent and adult Philadelphia chromosome-negative (Ph-neg) ALL in first complete remission (CR1), related studies from MEDLINE, Embase, and Cochrane Controlled Register of Trials updated to July 2022 were searched. A total of 13 relevant trials including 3161 patients were included in the meta-analysis. Compared with allo-HSCT, pediatric-inspired chemotherapy achieved better OS (hazard risk (HR), 0.53; 95% confidence interval (CI), 0.41 to 0.68) and DFS (HR, 0.64; 95% CI, 0.48 to 0.86), with a significant reduction in NRM (risk ratio (RR), 0.30; 95% CI, 0.18 to 0.51), but no difference in the relapse rate (RR, 1.13; 95% CI, 0.93 to 1.39). When only studies based on intention-to-treat analysis were included, pediatric-inspired chemotherapy consistently conferred a survival advantage. In subgroup analyses, patients with baseline high-risk features demonstrated similar OS and DFS between pediatric-style chemotherapy and allo-HSCT, while pediatric-style chemotherapy had an OS and DFS advantage in standard-risk subgroup. Particularly, patients with positive minimal residual disease (MRD) achieved better OS and DFS if proceeded to allo-HSCT.

Outcomes of Philadelphia Positive Acute Lymphoblastic Leukemia in Adolescent and Young Adults.

Background Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) accounts for 25% of acute lymphoblastic leukemia cases in the adolescent and young adult (AYA) age subgroup. It is associated with poor outcomes and is considered a standard indication for allogeneic stem cell transplant (Allo-SCT). Improved outcomes have been reported with addition of tyrosine kinase inhibitors (TKIs) to chemotherapy in children and the role of Allo-SCT is now being debated in the first remission. Complete response (CR) at three months is associated with improved survival even without Allo-SCT in first CR. In this study, we have analyzed disease-free survival (DFS), overall survival (OS), and factors affecting survival outcomes of Ph+ALL in the AYA subgroup, in resource-limited settings treated with chemotherapy and TKIs. Materials and methods This is a retrospective, multicenter cohort study of Ph+ ALL AYA patients, aged 18-40 years, and registered between January 2015 and December 2020. Primary objectives are to calculate disease-free survival (DFS) and overall survival (OS). Secondary objectives are to identify prognostic factors affecting response rates and outcomes. List of cases was obtained from hospital information system (HIS) and data were collected from patient case notes and electronic medical records. Data analysis was done utilizing the SPSS statistical program (Armonk, NY: IBM Corp.). Results Forty-nine patients were identified with Ph+ ALL with a median age of 23 years (range: 18-40 years) and a male-to-female ratio of 2.5:1. None of the patients had central nervous system (CNS) disease. White cell count was >30,000 per mm3 in 26% of patients, while 13% had additional cytogenetic abnormalities. Thirty-three percent patients received adult (hyper-cyclophosphamide, vincristine, Adriamycin, and dexamethasone {CVAD}) protocols while 67% received pediatric-inspired (Berlin-Frankfurt-Munster {BFM} 2000 or UK-ALL 2003/2011) protocols. TKI therapy was received by 66% of patients during treatment (early: 37%; late: 29%) and 34% did not receive TKIs due to financial constraints. CR after induction was achieved in 69% cases. Induction mortality was 16%. The median DFS for the entire cohort was 27 months (0.93-53.06) and the median OS was 29 months (8.89-49.10). The median OS in Allo-SCT group was not reached vs 8.0±8.8 months (p=0.05) with chemotherapy only. The OS was significantly better in patients with no additional cytogenetic abnormalities, pediatric-inspired chemotherapy protocols, early use of TKIs in induction phase, Allo-SCT, and post-Allo-SCT use of TKIs. Conclusion Addition of TKIs to pediatric-inspired chemotherapy protocols in Ph+ALL AYA patients and Allo-SCT results in better overall survival. TKI availability remains a significant issue in low-income countries due to significant financial burden on the patients. Allo-SCT continues to be an attractive option, particularly in low-income countries providing an option for cure in Ph+ ALL.

Prognostic Significance of Epigenetic Modifiers Gene Mutations in Adult Acute Lymphoblastic Leukemia at Diagnosis

Background: Epigenetic modifiers (EMs) play an important role in the occurrence and development of acute lymphoblastic leukemia(ALL). However, the prognostic significance EMs gene mutation have been poorly investigated in adult ALL. Thus, we aimed to investigate the prognostic significance of EMs gene mutation in patients with ALL. Patients and Methods: The clinical data of 205 patients with ALL diagnosed in Nanfang Hospital between July 2017 and July 2020 who received Pediatric-inspired chemotherapy were retrospectively analyzed. The patients were divided into EMs mutation(EMs-mut) group (75 case) and EMs wild type(EMs-wt) group (130 cases) base on the next generation sequencing result. Kaplan-Meier was used to analyze overall survival(OS) and event free survival(EFS) and Cox regression model was use to the univariate and multivariate analysis of OS and EFS. Results: Among 205 ALL patients,75 cases(36.6％) were positive for EMs-mut, and a total of 91 EMs mutations were detected, including 70 missense mutations(76.9％),15 frameshift mutations(16.5％) and 6 nonsense mutations(6.6％).Compared to patients with EMs-wt, the proportion of abnormal karyotype and positive for fusion gene were lower in patients with EMs-mut(χ2＝8.245,5.985;P=0.004,0.014).These patients also experienced worse early effects of induction therapy including the minimal residual disease(MRD) at the 14th day, MRD at the 28th day and MRD before consolidation therapy(P<0.001,P=0.009,P=0.007,respectively).In 205 patients with ALL,OS and EFS were significant shorter in patients with EMs-mut compared with patients with EMs-wt(median 26.6 months vs not reached, median 16.8 months vs 37.2 months; P＝0.008,0.021,respectively). Furthermore, in subgroups of 46 patients with Ph positive B-ALL,OS and EFS were also significant shorter in patients with EMs-wt compared with patients with EMs-mut(median 16.5 months vs not reached, median 12.5 months vs not reached; P=0.011,0.044,respectively).Multivariable analysis showed that harboring EMs-mut was an independent adverse factor of OS and EFS (HR＝1.853,1.647;P＝0.020,0.031,respectively) for ALL. In contrast, receiving allogeneic hematopoietic stem cell transplantation(allo-HSCT) was an independent favorable factor of OS and EFS(HR＝0.364,0.483; P<0.001,P=0.002, respectively) for ALL. Next, the 205 ALL patients were divided into 4 subgroups: EMs-mut/ chemotherapy group, EMs-mut/ HSCT group, EMs-wt/ chemotherapy group and EMs-wt/ HSCT group. We found that EMs-mut/ chemotherapy group had significantly lower OS, EFS than other subgroups. In the EMs-mut cohort, allo-HSCT significantly improved OS and EFS compared to non-allo-HSCT(not reached vs median 14.1 months, not reached vs median 7.1 months; P＝0.001,0.021,respectively). Conclusion: Mutation of EMs in adult ALL correlate with poor early effect to induction therapy. Pediatric-inspired chemotherapy was unable to completely reverse the negative effect of mutation of EMs on prognosis. Pediatric-inspired regimen therapy combined with allo-HSCT, in contrast, significantly improved the overall prognosis of EMs mutation ALL. Key words: Gene, epigenetic modifiers; Leukemia, lymphoblastic, acute; Minimal residual disease; Allogeneic hematopoietic stem cell transplantation

Improved Survival of Adolescents and Young Adults (AYA) Patients Aged 14-40 Years with First Relapse of Acute Lymphoblastic Leukemia Using Pediatric-Inspired Chemotherapy Salvage Protocol (R3 induction protocol)

Background: Although survival of adolescent and young adults (AYA) with acute lymphoblastic leukemia (ALL) has improved using pediatric-inspired protocols, the outcomes of those who relapse remain poor using adult chemotherapy salvage-regimens that have historically incorporated high dose Ara-C based regimen, with long term-survival of less than 10%. The CR rate with blinatumomab for salvage in adult ALL is 34% with a median survival of 7.7 months, with an OS of less than 30% at 18 months. In contrast, pediatric salvage regimens have historically been based on multi-agent therapy and have reported superior outcomes. The ALLR3 protocol for relapsed ALL in patients up to the age of 18 years reported a CR rate of 97% and an overall survival of 72%. We therefore aimed to analyze the outcomes of young adolescents and adults treated on the R3 regimen +/- blinatumomab. Methods: Seventeen AYA patients with Philadelphia-negative ALL aged between 14 and 40 years who relapsed after first-line therapy and treated with ALLR3-protocol were identified. Relapses were classed as very early (<18 months from diagnosis) early (>18m from diagnosis and <6 months from end of therapy) and late (>6 months from end of therapy). The protocol consisted of vincristine (1.5mg/m2 IV D3,10,17,24); mitoxantrone ( 10mg/m2 IV d1 &2); PEG-asparaginase (1000 u/m2 IV d3 & 17); dexamethasone (10mg/m2 BID day d1-5 and d15-20); and intrathecal methotrexate (12mg d1 & d8) were identified. Patient aged 30-40 years received L-Asparaginase instead of PEG-Asparaginase, and 8mg/m2 of dexamethasone instead of 10mg/m2. Patients' characteristics, response rate (RR) and overall survival (OS) were analyzed. Patients who achieved minimal residual disease (MRD) negative CR proceeded with an allogeneic transplant. MRD-positive patients received blinatumomab followed by a transplant. Results: The median age at relapse was 16 years (14-40 years), 88.2% of patients were B-cell ALL and 11.8% were T-cell ALL. Most patient had standard cytogenetics on presentation (76.5%) and were CNS negative (82.4%). Relapses were very early, early or late in 2 (12%) , 5 (29%) , and 7 (41%) of cases, respectively. Relapses were isolated bone marrow (BM), isolated extramedullary (EMD) or combined BM and EMD in 14 (82%),1 (6%) and 2(12%) cases, respectively. Overall complete remission (CR) rate was 60% at the end of R3 induction; CR with negative minimal residual disease (MRD negative, <10−4 cells) at the end of R3-induction was achieved in 47.1% of patients, while 11.8% of patients had CR with positive MRD (≥10−4 cells) who received Blinatumumab thereafter with eradication of MRD. Refractory disease was seen in 41.2% of patients. Almost all patients who responded to R3 proceeded to allogeneic stem cell transplant (88.8%). Eight patients died (47%), but only one patient died because of treatment-related sepsis, while the other 7 patients died because of disease-related causes. At a median follow up of 4 years, OS was 47.3%. Conclusion: Compared to traditional adult-based chemotherapy regimens and antibody therapies used in relapsed ALL, the use of pediatric-inspired protocol (R3) in relapsed AYA-ALL patients showed favorable response rates and overall survival. Further trials are required of pediatric inspired salvage regimens, preferably incorporating antibody therapies in adult patients, especially in 1st relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Acute Lymphoblastic Leukemia in Patients 60 Years and Older Treated with Pediatric-Inspired Protocols, 20 Years of Follow-up

Background Chemotherapy-based approaches remain an essential component of current adult acute lymphoblastic leukemia (ALL) treatment. Poor outcomes in older patients with ALL result from the disease's adverse biology and poor tolerance to chemotherapy. Pediatric-inspired protocols have been used over the past 20 years in our center for patients > 60-year-old, both Philadelphia negative (Ph-), and Philadelphia positive (Ph+). Historically, Ph+ patients have been believed to have inferior outcomes. Our goal was to estimate the outcomes of this subgroup of patients and to compare outcomes between Ph- and Ph+ patients. Methods All newly diagnosed patients with ALL aged > 60 years, and receiving induction chemotherapy with a modified pediatric-inspired regimen between January 2002 and January 2022 were included. The treatment regimen consisted of induction, central nervous system prophylaxis, seven 3-week cycles of intensification, and 24 3-week cycles of maintenance (PM DFCI-based protocols). Only Ph- patients received asparginase. All Ph+ patients received a Tyrosine Kinase Inhibitor (TKI) during all phases of treatment and continued indefinitely after maintenance. There were adjustments in the type of drugs and dosages over the years. Standard descriptive statistics were used. Ninety-five percent confidence intervals were provided for estimates of interest where possible. Fisher's exact test was used to assess the impact of categorical covariates. P < 0.05 were considered to indicate a significantly different result. Kaplan-Meier survival estimate was used to evaluate Leukemia free survival (LFS) and overall survival (OS). Results A total of 122 patients were included: Ph- B-ALL, 50% (N=61); Ph+ B-ALL, 38% (N=46); Mixed Phenotype Acute Leukemia (MPAL), 4% (N=5); and T-ALL, 8% (N=10). Out of the Ph+ patients, only one had an MPAL diagnosis, the rest of them had B-ALL diagnoses. Patient and disease characteristics by Ph status are presented in table 1. For the whole cohort, the complete remission rate after induction (CR) was 83% (N=101), and allogeneic stem cell transplantation (alloSCT) in CR1 was carried out for 10% (N=12). Ten patients (8.2%) died during induction and the cumulative incidence of relapse (CIR) at 1-year was 11.7 % (95% CI 6.7 - 18.2). CR, mortality at induction, alloSCT, and CIR rates were similar in the Ph- and Ph+ groups. With a median follow-up of 52 months (range 4-209 months) among survivors, the median OS was 54 months (95%CI: 28-82). The 1-year and 4-year OS rates were 76% (95%CI: 68-83%) and 51.2% (95%CI: 41.4-60.2%), respectively. Leukemia-free survival (LFS) at years 4 years was 41.9% (95%CI: 32.7-50.9). There were no statistical differences in median OS and LFS between Ph- and Ph+ patients. OS at 4 years for patients with Ph- ALL was 49.7% (95%CI: 37.1-61) vs 53.9% (95%CI:37.9-67.5) in Ph+ ALL patients (p=0.72) (Figure 1). At 4 years LFS was 40.8% (95%CI: 29 - 52) for Ph- patients and, 43.6% (95%CI: 28 - 57) for the Ph+ population (p=0.68). Conclusion Pediatric-inspired chemotherapy protocols with appropriate dose adjustments for age are associated with good outcomes in older ALL patients. Clinical and disease characteristics and outcomes were similar between Ph- and Ph+ ALL patients. We aim to further define the optimal therapy for this group of patients with this challenging disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Outcomes and Adverse Events of Elderly Patients with Ph-Negative Acute Lymphoblastic Leukemia Treated with a Pediatric-Inspired Protocol

Poor outcomes in elderly patients with Acute Lymphoblastic Leukemia (ALL) result from the disease's adverse biology and poor tolerance to chemotherapy, leading to dose reductions, treatment delays, and high rates of early death and treatment-related mortality. Some reports indicate that pediatric-inspired chemotherapy protocols can be safely and efficiently used in older adults, resulting in improved median overall survival (mOS) ranging from 17 to 40 months. Despite such reports, front-line implementation of pediatric-inspired approaches to elderly patients with ALL remains a topic of discussion. Our goal is to estimate OS and define adverse events (AEs) in patients with ALL, aged > 60 years, and treated with a pediatric-inspired protocol. Methods All newly diagnosed patients aged > 60 years with Ph-negative ALL who received induction chemotherapy with a modified, asparaginase-intense, pediatric-inspired regimen between January 2002 and January 2022 were included. The treatment regimen consisted of induction, central nervous system prophylaxis, 7 cycles of intensification, and 24 cycles of maintenance. During these 20 years, we switched from native to pegylated E.coli asparaginase. Standard descriptive statistics were used to summarize patients’ demographics and outcomes of interest. 95% confidence intervals were provided where possible. Fisher's exact test was used to assess the impact of categorical covariates of interest on induction mortality. Using Fine-Gray methods, the Multivariable Cox proportional hazards regression model was used to determine the joint effect of potential factors for outcomes. P<0.05 was considered significant. Results A total of 76 patients were included. Patient and disease characteristics are presented in table 1. The median dose of Peg-asparaginase and L- asparaginase were 935 iu/m2 (477-1,111 iu/m2) and 5,944 iu/m2 (4,388-15,000 iu/m2) respectively. AEs rates found were severe pancreatitis 3.9%, thrombosis at any time during treatment 43.2%, hypofibrinogenemia <1g/L 30.6%, CTCAE grade IV transaminases, and total bilirubin 35.2%, and 17.3% respectively. The induction mortality rate was 12% (N=9) and the complete remission rate after induction (CR1) was achieved at 79% (n=60). Allogeneic hematopoietic stem cell transplantation in CR1 was carried out for 9.2% (N=7). The median follow-up among survivors was 49.7 months (range: 9-155) and the mOS was 35.1 months (95%CI: >19.3) (figure 1). OS rate at 1 and 4 years was 73.6% (95%CI: 62 - 82) and 42.2% (95%CI: 29.3 - 54.6) respectively, with a cumulative incidence of relapse from the date of diagnosis at 12 months of 12% (95% CI: 5.8 - 20). Leukemia-free survival rate at 4 years was 42.4% (95% IC 30 - 53). For the patients with early mortality, 5 patients had L-asparaginase, 3 patients had no asparaginase, and one Peg-asparaginase (11.11%). In contrast, in the no early mortality group, 46 (68.6%) patients received L-asparaginase, 2 (2.9%) patients had no asparaginase, and 19 (28.3%) patients received Peg-asparaginase (p=0.011). In univariate analysis, variables significantly associated with worse OS were: older age [<70 years old (n=46) median OS 70.8 months (95%CI >31.1) vs >70 years old (n=30)14.4 months (95%CI 9.2-54.2) (p=0.016)], higher WBC count [<11x10e9/L (n=54) median OS was 70 months (95%CI 27-NA), while in those with WBC >11x10e9/L (n=22) was 17.2 months (95%IC 6-31) (p= 0.004)], and no asparaginase given [OS at 12 months was: 85% (95%CI 60.4 -94.9) in patients treated with Peg-asparaginase; 72.4% (95%CI 57.9-82.6) in patients treated with L-asparaginase, and 40% (95%CI 5.2-75.3) in patients that did not receive asparaginase (p=0.0021). In multivariable analysis, younger age and lower WBC remained independent significant prognostic factors for increased OS [Patients <70 years old HR 2.67 (95% CI[1.38 - 5.17], p=0.0034) and patients with WBC <11x10e9/L HR 2.5 (95% CI [1.30- 4.82], p= 0.007)]. Conclusions The use of a pediatric-inspired chemotherapy protocol is shown to be effective and well tolerated in patients with Ph-negative ALL aged >60 years. Although AE rates were not negligible, outcomes were excellent and, early mortality improved over prior reports (Marc Poch Martell et al, BJH 2013, early mortality 20%). Further research will be needed to understand how the outcomes could be improved further using newer targeted treatments. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

In Adults with Ph-Negative Acute Lymphoblastic Leukemia (ALL), Age-Adapted Chemotherapy Intensity and MRD-Driven Transplant Indication Significantly Reduces Treatment-Related Mortality (TRM) and Improves Overall Survival - Results from the Graall-2014 Trial

Background During the 2005-2014 period, the GRAALL conducted the GRAALL-2005 trial in patients (pts) with Philadelphia chromosome (Ph)-negative ALL aged 18-59y. In this trial, all pts received a pediatric-inspired chemotherapy, whatever their age. Post-hoc analysis revealed an unacceptable TRM in pts aged 45-59y (Huguet et al. J Clin Oncol 2018; 36:2514-23). Allogeneic hematopoietic stem cell transplantation (HSCT) was offered in first complete remission (CR) to most CR pts, defined at high-risk (HR) by at least one baseline clinical or biological HR factor (CNS involvement, complex karyotype [≥5 abns.], low hypodiploidy/near triploidy, poor early blast clearance, late CR, as well as WBC ≥ 30x109/L, lack of CD10 expression, KMT2A rearrangement or TCF3::PBX1 fusion for B-cell precursor [BCP] ALL). Minimal residual disease (MRD) response was not considered for HSCT indication at that time. In the next GRAALL-2014 trial conducted in a similar population, we introduced two major changes in the treatment strategy. First, chemotherapy intensity (steroids, anthracycline and L-asparaginase) was reduced in pts aged 45-59y to decrease excessive TRM. Secondly, the indication for HSCT was modified, relying on IG/TR MRD response only (post-induction MRD ≥10-3 and/or post-consolidation MRD ≥10-4) while not on any former baseline HR criterion. Here, we compare the outcomes of the two trials, focusing on the impact of these two major evolutions. Patients & Methods A total of 743 pts treated in the GRAALL-2014 trial between 2015 and 2020 were compared to the 787 pts from the historical GRAALL-2005 trial, in terms of CR and induction death rates, rate of HSCT in CR1, cumulative incidence of TRM (CITRM) and relapse (CIR), relapse-free (RFS) and overall (OS) survival. It should be noted that two nested Phase 2 trials were introduced by amendment during the GRAALL-2014 course (in 2017 and 2018, respectively), aiming to evaluate post-remission addition of nelarabine and blinatumomab in 87 T-ALL and 94 BCP-ALL selected pts, respectively. Results Main patient characteristics, including age, gender, BCP/T-ALL, WBC, and historical baseline HR features, did not significantly differ between the two trial cohorts, even if CNS disease at diagnosis was more frequent in the 2014 cohort (12 vs 7%, p= 0.001). Outcome comparisons are shown in Table 1. Overall, the induction death rate was significantly reduced in the GRAALL-2014 (3 vs 6%, p= 0.005). As expected, this was only observed in pts aged 44-59y (3 vs 11%, p= 0.001), in whom dose-intensity reduction also translated into a higher need for second induction course (9 vs 5%, p= 0.05) eventually resulting in a higher CR rate (92 vs 86%, p= 0.05). Due to the newly introduced MRD-based stratification, the rate of pts with HSCT indication was markedly reduced (30 vs 65%, p<0.001), especially in pts aged 18-44y (21 vs 40%, p<0001). Consequently, the rate of pts transplanted in CR1 dropped down from 38 to 23% (p<0.001). The GRAALL-2014 strategy also yielded a significant reduction in CITRM (5 vs 11% at 3 years; p<0.001; Figure 1B) after CR achievement. This reduction was more pronounced in pts aged 45-59y (7 vs 17%, p<0.001 compared to 4 vs 8%, p= 0.02 in 18-44y pts). This was associated with an increased CIR (35% vs 28% at 3 years; p= 0.01), with more late relapses as depicted in Figure 1A. Even if the resulting RFS was similar in both cohorts (59 vs 62% at 3 years; p= 0.77), OS was significantly longer in the GRAALL-2014 (71 vs 64%; p= 0.002) (Figure 1C) likely due to better post-relapse outcomes. When censoring those GRAALL-2014 pts who received nelarabine or blinatumomab in CR1, observations were basically unchanged, even if the difference in CIR was even more marked. Finally, using a 3-month RFS landmark in the 211 GRAALL-2014 pts eligible for HSCT in CR1 based on their poor early MRD response, HSCT significantly prolonged RFS (HR= 0.46 [95% CI, 0.27-0.78]; p= 0.004). Conclusions In adults with Ph-negative ALL enrolled in the GRAALL-2014, age-adapted chemotherapy intensity and MRD-driven indication for HSCT significantly reduced induction and post-remission TRM. This translated into a prolonged OS, indicating that this strategy was safe, despite a higher incidence of late relapses. Newly available salvage options along with HSCT in CR2 might also have played a role. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal