Adult Lymphoblastic Leukemia Research Articles

Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults

BackgroundMany older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)–negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission.MethodsIn a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point.ResultsThe data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P=0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group.ConclusionsThe addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.)

Molecular subgroups of T-cell acute lymphoblastic leukemia in adults treated according to pediatric-based GMALL protocols

In contrast to B-cell precursor acute lymphoblastic leukemia (ALL), molecular subgroups are less well defined in T-lineage ALL. Comprehensive studies on molecular T-ALL subgroups have been predominantly performed in pediatric ALL patients. Currently, molecular characteristics are rarely considered for risk stratification. Herein, we present a homogenously treated cohort of 230 adult T-ALL patients characterized on transcriptome, and partly on DNA methylation and gene mutation level in correlation with clinical outcome. We identified nine molecular subgroups based on aberrant oncogene expression correlating to four distinct DNA methylation patterns. The subgroup distribution differed from reported pediatric T-ALL cohorts with higher frequencies of prognostic unfavorable subgroups like HOXA or LYL1/LMO2. A small subset (3%) of HOXA adult T-ALL patients revealed restricted expression of posterior HOX genes with aberrant activation of lncRNA HOTTIP. With respect to outcome, TLX1 (n = 44) and NKX2-1 (n = 4) had an exceptionally favorable 3-year overall survival (3y-OS) of 94%. Within thymic T-ALL, the non TLX1 patients had an inferior but still good prognosis. To our knowledge this is the largest cohort of adult T-ALL patients characterized by transcriptome sequencing with meaningful clinical follow-up. Risk classification based on molecular subgroups might emerge and contribute to improvements in outcome.

Effect of sustained measurable residue disease negativity and post-remission treatment selection on the prognosis of acute lymphoblastic leukemia in adults.

To explore the effects of monitoring measurable residual disease and post-remission treatment selection on the clinical outcomes of B-cell acute lymphoblastic leukemia (B-ALL) in adults. Between September 2010 and January 2022, adult patients with B-ALL who received combination chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (allo-HSCT), were included in the retrospective study, which was approved by the Ethics Committee and the observation of Declaration of Helsinki conditions. One hundred and forty-three B-ALL patients achieved complete remission (CR) were included in the study, of whom 94 patients (65.7%) received allo-HSCT in first complete remission (CR1). Multivariate analysis showed that the most powerful factors affecting OS were transplantation (hazard ratio [HR] = 0.540, p = 0.037) and sustained measurable residue disease (MRD) negativity (HR = 0.508, p = 0.037). The subgroup analysis showed that the prognosis of the allo-HSCT group was better than that of the chemotherapy group, regardless of whether MRD was negative or positive after two courses of consolidation therapy. After consolidation therapy, the prognosis of patients with positive MRD remained significantly better in the allo-HSCT group than in the chemotherapy group. However, no significant difference was observed in the prognosis between the allo-HSCT and chemotherapy groups with negative MRD after consolidation therapy. B-ALL patients who achieve sustained MRD negativity during consolidation therapy have excellent long-term outcomes even without allo-HSCT. Allo-HSCT is associated with a significant benefit in terms of OS and DFS for patients who were with positive MRD during consolidation therapy.

Socioeconomic determinants of the biology and outcomes of acute lymphoblastic leukemia in adults

AbstractVarious socioeconomic and biologic factors affect cancer health disparities and differences in health outcomes. To better characterize the socioeconomic vs biologic determinants of acute lymphoblastic leukemia (ALL) outcomes, we conducted a single-institution, retrospective analysis of adult patients with ALL treated at the University of Chicago (UChicago) from 2010 to 2022 and compared our outcomes with the US national data (the Surveillance, Epidemiology, and End Results [SEER] database). Among 221 adult patients with ALL treated at UChicago, BCR::ABL1 was more frequent in patients with higher body mass index (BMI; odds ratio [OR], 7.64; 95% confidence interval [CI], 1.17-49.9) and non-Hispanic Black (NHB) ancestry (59% vs 24% in non-Hispanic White (NHW) and 20% in Hispanic patients; P = .001). In a multivariable analysis, age (hazard ratio [HR], 6.93; 95% CI, 2.27-21.1) and higher BMI at diagnosis (HR, 10.3; 95% CI, 2.56-41.5) were independent predictors of poor overall survival (OS). In contrast, race or income were not predictors of OS in the UChicago cohort. Analysis of the national SEER database (2010-2020) demonstrated worse survival outcomes in Hispanic and NHB patients than in NHW patients among adolescent and young adults (AYAs) but not in older adults (aged >40 years). Both AYA and older adult patients with higher median household income had better OS than those with lower income. Therefore, multidisciplinary medical care coupled with essential supportive care services offered at centers experienced in ALL care may alleviate the socioeconomic disparities in ALL outcomes in the United States.

Efficacy and Safety of Chimeric Antigen Receptor T Cells Therapy Strategy That Dual Targeting CD19 and CD22 to Treat Relapsed/Refractory Acute Lymphoblastic Leukemia in Adults

Background: Chimeric antigen receptor T-cells (CAR-T) targeting CD19 therapy is reported to induce 83-93% response in relapsed/refractory acute lymphoblastic leukemia (r/r-ALL) in adults. However, 30-60% of patients relapse after CAR-T treatment, of which 14-25% CD19-negative relapse. In spite of CAR-T cells persistence, CD19 absent causing tumors that evade CAR-T cells mediated recognition and clearance. For CD19-negative relapse, it is necessary to explore more effective targets. There are some research proved that compared with single-targeted CARs, CD19/CD22 dual-targeted CARs induce more IFN-γ and IL-2 in vitro and eradicate patient-derived xenografts (PDX) produced with CD19-negative relapse of CD19-directing CAR-T treatment. Therefore, our study explored the efficacy and safety of clinical studies on mixture of CD19 CAR-T and CD22 CAR-T cells in the treatment of r/r ALL in adults. Patients and Methods: CD3 + cells were selected from the apheresis PBMC and activated before lentiviral CAR T cells infection. The cells were transduced with a caspase9-inducible, safety-engineered lentivector CAR containing anti-CD19 or -CD22 scFv fused with multiple intracellular signaling domains: CD28/CD27/CD3z-iCasp9. The quality of apheresis cells, gene transfer and T cell proliferation efficiencies, and effective CAR-T infusion dose were quantitatively scored and documented. All enrolled patients expressed CD19 and CD22 positively. All patients received fludarabine (FLU) and cyclophosphamide (CTX) conditioning chemotherapy (FLU 30mg/m 2, d1-3; CTX 500mg/m 2, d1-3) before CAR-T infusions. Results: The study included 16 r/r ALL patients, median age is 26 years, and median of previous theraples is 6, all of patient details can be found in the table (Fig.1). In the first month after CD19/CD22 CAR-T cells infusion, total of 93.8% (15/16) of patients achieved complete response (CR), 1 case (6.25%) was evaluated as non-remission (NR). In the evaluation of safety, 68.75% (11/16) of patients did not experience cytokine release syndrome (CRS), 25% of patients (4/16) occurred grade 1 CRS and 6.25% (1/16) of patients occurred grade 2 CRS, no case of severe CRS defined as≥grade 3 and no any immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. After a median follow-up of 9.9 months, 4 patients maintained CR, while other 11 patients were relapsed, with a duration of response (DOR) of 25% (4/16), median LFS was 6.1 months and median OS were not reached (Fig.2). Conclusions: In summary, CD19/CD22 exhibited a manageable safety but limited antileukemia activity. Our study showed that mixture of CD19 CAR-T and CD22 CAR-T cells infusion is fail to expected to compensate for the treatment of relapsed in r/r ALL and prolonging the leukemia-free survival of patients. The low-efficacy of dual-targeted CAR-T cells may be caused by the CAR19 and CAR22 cells interfere with each other and weaken the CAR-T amplification in vivo. From our data, it seems that the timing of treatment and tumor burden status may play a more important role rather than new targets CAR-T cells infusion for r/r ALL in adults.

A Phase II Study of Flumatinib with Chemotherapy for Newly Diagnosed BCR::ABL1-Positive Acute Lymphoblastic Leukemia in Adults: Updated Results from RJ-ALL2020.2A Trial

Background The introduction of the second-generation TKIs further improved outcomes in BCR::ABL1-positive acute lymphoblastic leukemia (BCR::ABL1+ ALL). Flumatinib is a novel second-generation TKI approved in China in 2019. It has shown better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL. Herein, we report the updated results of the RJ-ALL2020.2A trial, which is the first reported registered clinical trial of flumatinib in adult BCR::ABL1+ ALL last year. The enrollment will be completed at the end of Aug. 2023. Methods In this prospective phase II study, patient (pt) eligibility mainly includes: 18≤age＜65 years; newly diagnosed BCR::ABL+ ALL; with adequate organ function. Once the diagnosis is confirmed, the combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is given promptly. Allo-HSCT is recommended for all eligible pts. Blinatumomab is allowed to administer for MRD clearance before allo-HSCT. All pts receive central nervous system (CNS) prophylaxis once achieving remission. The choice of subsequent salvage treatments is based on the discretion of physicians. Multiparameter flow cytometry (minimal residual disease[MRD]&amp;lt;10 -4) and RT-qPCR (BCR-ABL1 transcript&amp;lt;10 -5) are used to monitor MRD. The primary endpoints are MRD clearance, PFS, and OS. (Clinical Trial Registration Number: ChiCTR2100042248) Results From Dec. 2020 to Jun. 2023, 81 adult pts with de novo BCR::ABL1+ ALL were enrolled. Seventy-eight pts were included in the efficacy and safety assessment (3 were excluded due to the short duration of treatment), and 76 were available for survival analysis (2 withdrew). Median age was 42 years (range, 18-63). Median WBC count at diagnosis was 38.7×10 9/L (0.6-675.3). Four pts had primary CNS leukemia (Table 1). Among 78 pts, 75 (96.2%) achieved CR/CRi at the end of induction, and 78 (100%) achieved CR/CRi at any time. No early death occurred during the induction course. MRD flow negative rates were 67.1% (51/76) and 79.7% (55/69), while the CMR rates were 31.1% (23/74) and 52.2% (36/69) at the end of induction and 3 months, respectively. With a median follow-up time of 16.2 months (range, 1.8-29.2), the estimated 2-year PFS and OS rates were 64.8% and 81.3% (Figure 1). Among the 69 survived pts, 61 were in continuous remission, and 8 were relapsed (4 had CNS involvement). Among 7 deaths, 6 died of disease progression (4 had CNS involvement), and 1 of pulmonary infection post-HSCT. There was a survival superiority in pts who achieved MRD flow negativity (PFS: p=0.091, OS: p=0.005) or CMR (PFS: p=0.055; OS: p=0.033) at 3 months. With a median time of 6.4 months (range, 1.6-10.3) from diagnosis, 46 pts (median age of 39 years [range, 20-60]) received allo-HSCT with 45 pts in CR1. The MRD flow negativity and CMR rates were 82.2% (37/45) and 70.5% (31/44) before HSCT, respectively. PFS and OS significantly improved in patients who underwent HSCT (PFS: p&amp;lt;0.001, OS: p=0.012). In multivariate analysis for PFS and OS, MRD flow negativity at 3 months (PFS: HR: 0.129, p=0.016; OS: HR: 0.151, p=0.029) and allo-HSCT (PFS: HR: 0.247, p=0.036; OS: HR: 0.176, p=0.042) still had a significant effect on PFS and OS as protective factors. When including CMR as a variable, CMR at 3 months (PFS: HR: 0.221, p=0.02; OS: HR: 0.115, p=0.054) and allo-HSCT (PFS: HR: 0.169, p=0.01; OS: HR: 0.139, p=0.021) had the similar impact on survival. Among 75 pts evaluable for ABL1 mutations, 24 (32%) pts were mutated, and T315I was the most frequently identified (75%). Pts with T315I mutation showed a poorer outcome than non-T315I mutation (PFS: p&amp;lt;0.001, OS: p=0.01). Meanwhile, the safety profiles of the flumatinib-based therapy were acceptable. Non-hematological AEs were mostly G1-2, which were reversible rapidly after symptomatic management. Most of the G3-4 AEs were hematological, possibly related to chemotherapy. No permanent discontinuation or death related to flumatinib was observed. Conclusion This prospective study further confirmed the efficacy and safety of the promising second-generation TKI flumatinib combined with chemotherapy in newly-diagnosed Chinese adult pts with BCR::ABL1+ ALL. Achieving MRD flow negativity or CMR at 3 months and bridging allo-HSCT could further improve survival. The long-term follow-up data will be disclosed soon.

Safety and Efficacy of Single Cycle Blinatumomab Plus VP Chemotherapy for High Tumor Burden Acute Lymphoblastic Leukemia in Adults

Background: Blinatumomab, a CD3×CD19 T cell-engaging antibody was developed for immunotherapy in patients with relapsed/refractory B-lineage acute lymphoblastic leukemia (R/R B-ALL) and positive minimal residual disease complete remission. However, high tumor burden is thought able to predict a lower object response rate (ORR) after treatment with blinatumomab monotherapy, so combination treatment regimens are needed to improve the therapeutic effect of blinatumomab. Previous studies have reported the clinical trial results of adding blinatumomab to chemotherapy such as Mini-hyper-CVD and CAM for the treatment of adult or infant R/R B-ALL patients. In this retrospective study, we set out to test the safety and efficacy of single-cycle blinatumomab plus VP scheme in adult R/R B-ALL patients with high tumor burden. Method: Adult patients (≥18 years of age) diagnosed as R/R B-ALL with a high tumor burden (blast count in the bone marrow &amp;gt;50%), previously received 1 to 3 lines of chemotherapy, and received single-cycle blinatumomab plus VP were enrolled. These patients were given blinatumomab (9μg/d in d1-d7, 28μg/d in d8-d28), vincristine 2mg/week and dexamethasone (10mg/d in d1-d14, 5mg/d in d15-d28), for a total of 28 days. For patients with Philadelphia chromosome-positive, a BTK kinase inhibitor (TKI), including imatinib/dasatinib/olverembatinib, etc., was administered simultaneously. Eligible patients were treated with allo-HSCT or CAR-T therapy after they achieved remission with single-cycle blinatumomab plus VP. All patients underwent bone marrow examination before and after treatment to determine tumor burden and therapeutic effect. Flow cytometry was used to monitor patients' MRD status, with abnormal cells ≤0.01% defined as MRD-negative. OS is defined as the time from the initiation of the treatment to death for any cause. RFS is defined as the time from achievement of CR to disease recurrence or death after the treatment. Results: Sixteen patients started this treatment between August 2021 and February 2023. The median age of the 16 patients were 29.5 years (range, 20-72), and their baseline characteristics were shown in the table. Seven of the patients were Philadelphia chromosome-positive. Prior to receiving blinatumomab, all patients had received at least first-line chemotherapy and had refractory or recurrent events. At the end of single-cycle blinatumomab plus VP treatment, 12 patients (75%) achieved objective response (CR+CRi), 1 patient (6.25%) achieved PR, 3 patients (18.75%) did not achieve response, and no patients died during treatment. Of the 12 patients in objective response, 3 patients (18.75%) achieved CR with MRD-negative, 2 patients achieved CRi with MRD-negative, and 7 patients achieved CRi with MRD-positive. Six patients were bridged with allo-HSCT after the treatment, and four patients were subsequently treated with CD19 CAR T cells. With a median follow-up of 11.07 months, the median overall survival was 23.13 months and the median RFS was 17.23 months. The majority of adverse events during treatment were mild and acceptable. Twelve patients (75%) developed fever, of which nine patients (56.25%) were diagnosed with febrile neutropenia, and eight patients (50.00%) had an infection requiring antibiotic treatment, but none required high-flow oxygen (≥6L/min) or vasoactive agents to maintain blood pressure. Almost all patients (93.75%) had myelosuppression during treatment (neutrophil in peripheral blood &amp;lt;1.0×10 9/L), the median time was 17.5 days (range, 0d~28d). Elevated ALT/AST was observed in only one patient. No above grade 3 cytokine release syndrome (CRS) and any grade of immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Conclusion: Blinatumomab combined with VP resulted in a higher response rate in adult R/R B-ALL patients with high tumor burden and increased tolerability and safety of the treatment.

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 (&amp;gt;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 (&amp;gt;$50,000), middle ($35,000-50,000), and low (&amp;lt;$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&amp;lt;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 &amp;lt;30, 30-40, and &amp;gt;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=&amp;lt;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=&amp;lt;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.

Dose Reduced Chemotherapy in Sequence with Blinatumomab for Newly Diagnosed Older Patients with Ph/BCR::ABL Negative B-Precursor Adult Lymphoblastic Leukemia (ALL): Preliminary Results of the GMALL Bold Trial

Older patients (pts) with newly diagnosed ALL are ineligible for unmodified pediatric-based therapies. Although results are improved with age-adapted, dose-reduced regimens including MRD-based treatment modification, there is much space for further improvement.Therefore, the GMALL study group developed a trial to evaluate Blinatumomab, a CD19 directed bi-specific T-cell engager, in sequence with chemotherapy in this patient population with high medical need (NCT 03480438). Importantly, Blinatumomab replaced three cycles of standard consolidation chemotherapy.Pts aged 56 - 76 years (yrs) with CD19-positive, Ph-neg B-precursor ALL wereeligible. The primary endpoint was complete hematologic remission (CR) afterinduction (1 cycle chemo, 1 cycle Blinatumomab) and the key secondary endpoint was molecular response (table 1). The efficacy population included pts treated with dose reduced and shortened induction I (IP1) and Blinatumomab 1 or early death (ED). Induction was followed by 3 further Blinatumomab cycles alternating with age adapted consolidation cycles (HDMTX/ASP, HDAC, reinduction and maintenance) according to GMALL protocols for older pts (Gökbuget et al, ASH 2021). The median age was 66 (56-76) yrs. 21% had pro-B-ALL and 79% c/preB subtype. 40% had comorbidities according to the Charlson Score; most frequent were diabetes (13%) myocardial infarction (10%) or vascular diseases (10%). 50 pts were evaluable for IP1: 76% achieved CR/CRu and 2 pts (4%) died due to infections. 33% (N=11) had a molecular response and 18% MolCR (table 1). 47 pts were evaluable for the primary endpoint after Blinatumomab 1: CR/CRu was observed in 85%; 2 experienced ED (4%; those mentioned above; no additional ED). 88% of the CR pts had a molecular response (82% MolCR). The median follow-up is 757 (61-1584) days. Overall Survival (OS) after 1 and 3 yrs was 80% and 67% for the efficacy population (figure 1). The resp results for the total population were 82% and 65%. The 3y OS was 69% for c/pre-B-ALL and 58% for pro-B-ALL (p&amp;gt;.05). 3y OS was 81% for pts aged 55-65 yrs and 53% for those older than 65 yrs (p=.025). Only three pts received an allogeneic stem cell transplantation in CR1. 6 pts relapsed, 2 pt developed a secondary malignancy (Colon Ca, MDS) and 3 pts died in CR (1 HLH, 1 arterial disease, 1 Covid19). EFS was 60% at 3 yrs. We compared the results with those of the current GMALL standard therapy for older pts with B-precursor ALL (N=186) (Gökbuget et al, ASH 2022). Patient characteristics were similar. CR rates after induction were 85% vs 78% for BOLD vs standard (p&amp;gt;.05). Molecular CR rates in pts with hematologic CR were 82% vs 55% (p=.006). OS at 3 yrs was 67% and 49% (p=0.08) and Remission Duration (RD) was 83% vs 58% (p=0.055). Overall tolerability and efficacy of the regimen was very promising with a high hematologic and molecular response rate; mortality in induction and consolidation was low. In comparison with the current standard therapy the MRD response rates were significantly better. OS and RD was superior despite the omission of several chemotherapy cycles in contrast to other trials with unmodified chemotherapy but additional cycles of Blinatumomab. An ongoing randomized trial (NCT04994717) compares an even more dose reduced combination of Blina and chemotherapy with standard of care. This is an independent academic trial initiated by the GMALL Study Group which received free supply of Blinatumomab and financial support by Amgen.

Dasatinib and CAR-T Cell Therapy for Newly Diagnosed Ph-Positive Acute Lymphoblastic Leukemia in Adults

Introduction The use of tyrosine kinase inhibitors has improved outcomes of Ph-positive Acute lymphoblastic leukemia (ALL), but combinations with other agents are needed to achieve molecular response. CAR-T cell therapy has made a breakthrough in refractory or relapsed ALL, but has not yet been applied in newly diagnosed patients. Methods We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL. Dasatinib in combination with a two-week vincristine and glucocorticoids regimen were administered, followed by sequential infusions of CD19 and CD22 CAR-T cells. All patients received single-agent dasatinib maintenance after CAR-T cell therapy. The primary endpoint was complete molecular response (defined as undetectable BCR/ABL1 transcript with a sensitivity of 0.001%) in the bone marrow after this treatment. Here we report initial results from this study. Results At the cut-off date of 31 May 2023, 18 patients have received CD19 CAR-T cell infusions, and 14 of these patients have received subsequent CD22 CAR-T cell infusions. At the end of induction therapy, the complete hematologic remission rate was 100%, and 27.8% (5/18) of the patients had a complete molecular response. The percentage of complete molecular response increased to 72.2% (13/18) after CD19 CAR-T cell therapy, and increased further to 76.9% (10/13) after CD22 CAR-T cell therapy (1 patient has not been evaluated). Notably, of the 5 patients who did not achieve complete molecular response after CD19 CAR-T cell therapy, 4 have received CD22 CAR-T cell therapy, of which 1 eventually achieved complete molecular response and 2 experienced relapses. One patient had a CD19+ CD22+ relapse accompanied by mutations in BCR/ABL1 (F317L and Y253H) and the other patient had a CD19dim CD22+ relapse. After a median follow-up of 13.5 months, 16 patients remained in complete hematologic remission, and 14 patients remained in sustained complete molecular response. No patient received allogeneic stem cell transplantation. No grade 3 or higher cytokine release syndrome or Immune effector cell-associated neurotoxicity syndrome was observed during CAR-T cell therapies. Conclusions Dasatinib in combination with CAR-T cell therapy has enabled chemotherapy-free treatment in newly diagnosed Ph-positive ALL. This treatment is characterized by high complete molecular response, high long-term survival, low toxicity and short treatment cycles.

Matching-Adjusted Indirect Comparisons of Brexucabtagene Autoleucel with Alternative Standard Therapies for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients.

Brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, is approved for relapsed/refractory B-cell precursor acute lymphoblastic leukemia in adults aged 18+/26+ years in the US/European Union (EU), based on efficacy results from the single-arm ZUMA-3 trial. This study aimed to estimate the relative treatment effects of brexu-cel versus inotuzumab ozogamicin (InO), blinatumomab (blina), and chemotherapies using unanchored matching-adjusted indirect comparison (MAIC) methods. Individual patient data from ZUMA-3 and published aggregate level data from two randomized controlled trials, INO-VATE (InO versus chemotherapy) and TOWER (blina versus chemotherapy), were used. Patient-level data from ZUMA-3 were weighted to match the mean of the following prognostic variables at baseline, which were pre-specified based on clinical input, for each comparator population: primary refractory disease, duration of first remission < 12months, prior stem-cell transplantation, age, performance status, salvage status, bone marrow blast, complex karyotype, and Philadelphia chromosome status. The base case analysis was conducted using the modified intention-to-treat population (i.e., received brexu-cel) from ZUMA-3. Relative treatment effects for overall survival (OS) and event-free survival (EFS) were expressed as hazard ratios (HR) and differences in restricted mean survival time (RMST) with 95% confidence intervals (CI). The base case MAIC results suggested brexu-cel improved OS and EFS compared to blina (OS HR 0.46 [95% CI 0.28, 0.75]; EFS HR 0.37 [95% CI 0.25, 0.56]) and pooled INO-VATE/TOWER chemotherapy (OS HR 0.32 [95% CI 0.18, 0.56]; EFS HR 0.27 [0.18, 0.40]). Brexu-cel also improved OS compared to InO (HR 0.45 [95% CI 0.24, 0.85]). The point estimate for EFS favored brexu-cel over Ino but the difference was not statistically significant (HR 0.67 [95% CI 0.41, 1.10]). Findings were consistent between the HR and RMST analyses. Despite limitations, these MAIC results suggest that brexu-cel may improve OS and EFS versus currently used therapies in this population.

AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival

BackgroundAUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm/Tcm...

Place of Allogeneic Hematopoietic Stem Cell Transplantation in the First Complete Remission in Ph-positive Acute Lymphoblastic Leukemia in Adults

Introduction. Ph-positive acute lymphoblastic leukemia (ALL) is a high risk group of B-lineage acute lymphoblastic leukemia (B-ALL). Since tyrosine kinase inhibitors (TKIs) were introduced, controversial data have been obtained on the efficacy of allogeneic hematopoietic stem cell (allo-HSCT) in the first complete remission.The objective was to evaluate the efficacy of allo-HSCT in the first complete remission of Ph-positive ALL in adult patients after remission induction with continuous chemotherapeutic exposure in combination with TKIs.Methods and materials. The retrospective analysis included 74 patients with a median age of 32 years (range 18–59) after allo-HSCT in the first complete remission and 58 patients with a median age of 39 years (range 18–65) in the first complete remission after conservative therapy. Ninety-one per cent and 83 % of patients received imatinib as TKIs in remission induction in the allo-HSCT and conservative therapy groups, respectively. The median time from the first complete remission to allo-HSCT was 7 months (range 2–33). Thirty-six patients (49 %) had positive minimal residual disease (MRD) status prior to allo-HSCT. Eighteen patients (14 %) over 40 years underwent allo-HSCT in the first complete remission.Results. Allo-HSCT improves overall survival (OS) and relapse-free survival (RFS) and by 9 months since the achievement of the first complete remission, they were 70.1 (95 % CI 56.4–88.6) in the allo-HSCT group versus 45.1 (95 % CI 33.4–61.0) in the conservative group, p=0.025 and 63.3 % (95 % CI 47.6–84.1) in the allo-HSCT group versus 44.8 % (95 % CI 33.2–60.4) in the conservative therapy group, p=0.04, respectively. Allo-HSCT in patients over 40 years does not improve 5-year OS and RFS and were 57.2 % (95 % CI 30.0–84.4) versus 59.8 % (95 % CI 36.9– 82.7), p=0.69, and 42.6 % (95 % CI 14.0–71.2) vs. 50.9 % (95 % CI 29.5–72.3), p=0, 88, respectively.Conclusion. Allo-HSCT performed before 9 months from achievement of the first complete remission after induction with imatinib is the preferred method of remission consolidation in patients from 18 to 40 years old. The optimal therapy for patients older than 40 years in the first complete remission is a conservative approach in combination with TKIs.

Osteoarticular manifestation of acute lymphoblastic leukemia in adults: a literature review.

Osteoarticular manifestations such as arthritis and bone pain are scarce among adults with acute lymphoblastic leukemia (ALL). We present a systematic review of osteoarticular first clinical manifestation related to ALL in adults, and we report a case of an adult patient with a B-cell ALL revealed by refractory pygalgia and arthritis. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline using the MEDLINE database, including case reports and case series describing osteoarticular manifestations revealing ALL in adults. There were 29 patients with osteoarticular manifestations, revealing ALL (including our case). The mean age was 34.00 ± 13.29years. Osteoarticular manifestations were peripheral articular signs (7 cases), axial manifestations (17 cases), and osteolytic lesions (21 cases). Vertebral fractures were reported in 4 cases. MRI was performed in 15 cases, showing heterogeneous signal changes in the vertebra, skull, and sacroiliac bones. It showed avascular necrosis of the femoral head in one case. PET scan, performed in 7 cases, showed diffuse or localized FDG uptakes in the bone marrow. Hypercalcemia was noted in 9 cases. The treatment was based on chemotherapy (23 patients) and radiotherapy (4 cases). During the follow-up, remission was noted in 14 cases, death in 9 cases, and was not available in 6 patients. Our review showed that axial manifestations, joint swelling, bone pain, and hypercalcemia could be the first and only symptoms of ALL in adults, making the diagnosis of ALL difficult to recognize, leading to a diagnosis delay. Key Points • Acute lymphoblastic leukemia in adults revealed by osteoarticular manifestations can be misdiagnosed as rheumatic diseases. •Axial manifestations, joint swelling, bone pain, and hypercalcemia could be the first and only symptoms of acute lymphoblastic leukemia in adults. • Complete blood count and calcium blood test should be performed as first-line investigations in adults with axial or peripheral articular symptoms. •Physicians should be aware of this clinical presentation to avoid diagnosis delay and improve prognosis.

Single Cycle of Blinatumomab Followed By High-Dose Chemotherapy in the Induction Therapy for Ph-Negative Acute Lymphoblastic Leukemia in Adults. Primary Endpoint Analysis of the Blina-Cell Trial

Background: Blinatumomab induces a high proportion of complete molecular responses in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and ALL with persistent or recurrent measurable residual disease (MRD) after initial therapy. However, responses are generally short if they are not followed by allogeneic stem cell transplantation (HSCT). We infer that blinatumomab needs to be incorporated sequentially into the early phase of treatment to enhance rates of MRD negativity, lower the need of HSCT and improve survival. Methods: Induction therapy in the Blina-CELL Phase 2 trial (NCT04554485) consisted of run-in phase (dexamethasone 10 mg/m2 days 1-7, cyclophosphamide 200 mg/m2 days 3-5, vincristine 2 mg day 6, and daunorubicin 45 mg/m2 days 6-7), first induction phase (blinatumomab 9 µg/day days 12-19 and 28 µg/day days 20-40), and second induction phase (dexamethasone 10 mg/m2 days 50-54, vindesine 3 mg/m2 day 50, methotrexate 1.5 g/m2 day 50, etoposide 250 mg/m2 days 53-54, and cytarabine 2x 2 g/m2 day 54). Consolidation chemotherapy was identical to the GMALL 07/2003 protocol. Intensive intrathecal prophylaxis was given in both induction and consolidation phases. The primary endpoint was MRD evaluated by quantification of IG/TR rearrangements at week 11 (at the end of induction II). The minimum sensitivity and quantitative range of all assays was 10e-4. Results: Twenty-nine patients started this treatment between May 2019 and March 2022. One patient terminated the study after 3 days of blinatumomab infusion due to elevated liver function tests, one was considered a screening failure due to the missing MRD target. Twenty-seven patients were evaluable. Median age was 41 years (range, 19-65). Median white blood cell count (WBC) at diagnosis was 6.2 x 109/L (range, 0.6-67.7). Twenty-five patients (93%) achieved complete remission (CR) at the end of induction I, 2 (7%) were refractory (both had BCR::ABL1-like phenotype). No patient died during the induction phase. Of the 25 patients in CR, 13 (52%) had complete molecular response (CMR) at day 40 (upon termination of blinatumomab infusion), 11 (44%) had positive non-quantifiable MRD and one (4%) patient had quantifiable MRD >10e-4. Primary endpoint assessment at week 11 showed 20 (80%) patients in CMR, 3 (12%) with positive non-quantifiable MRD and 2 (8%) with MRD ≥10e-4. Four (16%) patients underwent HSCT due to MRD failure or reappearance, all were pre-treated with a further 1-2 cycles of blinatumomab. Three of them (75%) entered HSCT in CMR. One patient was transplanted in CMR for high-risk features (proB, KMT2A rearrangement). The follow-up period is still ongoing. With 18 months of median follow, the overall and relapse-free survival in the study is 18.2 and 15.9 months, respectively. The most frequent grade 3-4 adverse events of blinatumomab therapy were: febrile neutropenia (15%), elevated ALT/AST (11%), soft tissue infection (7%) and low fibrinogen (7%). Only one case of grade 3 cytokine release syndrome was documented. No neurotoxicity events were observed during the induction phase of treatment. Conclusion: Remission induction strategy combining one cycle of blinatumomab with one cycle of high-dose chemotherapy provides a high molecular response rate (CMR or non-quantifiable MRD) of 92%. This approach translates into a low transplant rate due to a high MRD response and has a favourable safety profile. Longer follow-up is needed to evaluate survival benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase II Study of Flumatinib with Chemotherapy for Newly Diagnosed Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia in Adults：Preliminary Results from RJ-ALL2020.2A Trial

A Phase II Study of Flumatinib with Chemotherapy for Newly Diagnosed Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia in Adults：Preliminary Results from RJ-ALL2020.2A Trial

Osteolytic Bone Lesions As an Initial Presenting Manifestation of Acute Lymphoblastic Leukemia in Adults

Introduction Hematological malignancies can lead to bone lesions, most commonly the osteolytic lesions found in multiple myeloma (MM). Cases of osteolytic lesions have been rarely reported in acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma, Waldenström macroglobulinemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and myeloproliferative neoplasms (MPN). This review sheds light on the association between ALL and osteolytic bone lesions. Methods A literature search was performed for English language articles using PubMed, Scopus, and Google Scholar, for any date up to May 2022. The following keywords were used "ALL," "acute lymphoblastic leukemia," osteolytic bone lesions," and "osteolysis." Search results were initially reviewed by title and abstract, and articles were selected for more in-depth analysis if deemed relevant. Pertinent articles were examined in-depth for this report. Results To our knowledge, we found 15 cases of patients with ALL who developed osteolytic lesions. They were reported in 14 articles published between April 1998 and May 2022. Most patients were males (12 out of 15). The median age was 29 years (ranging from 22 to 78 years), with most patients being young (in the third and fourth decades). B-ALL was the most common type of ALL associated with osteolytic lesions (14 cases). All patients presented with bone pain, and hypercalcemia was found in 80% of the reported cases. Osteolytic lesions were detected by plain radiography(x-ray) in approximately half of the patients. The osteolytic lesions were confirmed in the remaining patients by CT, MRI, or PET scans. The most affected bones were the vertebrae, skull, and pelvis. The clinical outcomes among these patients were variable; two of the reported cases died after the diagnosis of osteolytic lesions. Discussion Bone metastases are classified as osteolytic, osteoblastic, or mixed based on the primary interference mechanism with bone remodeling. The destruction of normal bone characterizes osteolytic bone metastasis, occurring in multiple myeloma (MM), renal cell carcinoma, melanoma, non-small cell lung cancer, non-Hodgkin lymphoma, thyroid cancer, or Langerhans-cell histiocytosis. Osteolytic metastasis in adults with ALL is an extremely rare condition. The exact pathophysiology of osteolysis in ALL patients is unknown.PTHrP secretion by lymphoblasts has been shown to be the primary cause of osteolysis in ALL patients. Additionally, serum from ALL patients with osteolysis can induce in vitro proliferation of osteoclasts, indicating the mechanism of lymphoblasts induces osteoclasts activation in vivo. Based on our review, there was no association between osteolytic bone lesions and the Philadelphia chromosome detected in only one patient. Osteolytic bone lesions in ALL patients mainly present with bone pain. Pathological fracture of the vertebral body leading to spinal cord compression is a complication of osteolytic lesions in patients with MM. However, there is no case of spinal cord compression in ALL patients attributed to osteolytic lesions of the vertebra. Given that our review is based on case reports, we could not conclude if the presence of osteolytic bone lesions is a prognostic factor for adverse outcomes or indicates an "aggressive" form of leukemia in adult patients with ALL. Conclusion Osteolytic bone lesions in adult patients with ALL is an infrequent finding and mainly occurs in young adults. Plain radiography is often sufficient in diagnosing osteolytic bone lesions; however, other imaging modalities are sometimes required. Based on our review, the osteolytic lesions do not indicate a poor prognosis in adult patients with ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chromothripsis is a frequent event and underlies typical genetic changes in early T-cell precursor lymphoblastic leukemia in adults

Chromothripsis is a mitotic catastrophe that arises from multiple double strand breaks and incorrect re-joining of one or a few chromosomes. We report on incidence, distribution, and features of chromothriptic events in T-cell acute lymphoblastic leukemias (T-ALL). SNP array was performed in 103 T-ALL (39 ETP/near ETP, 59 non-ETP, and 5 with unknown stage of differentiation), including 38 children and 65 adults. Chromothripsis was detected in 11.6% of all T-ALL and occurred only in adult cases with an immature phenotype (12/39 cases; 30%). It affected 1 to 4 chromosomes, and recurrently involved chromosomes 1, 6, 7, and 17. Abnormalities of genes typically associated with T-ALL were found at breakpoints of chromothripsis. In addition, it gave rise to new/rare alterations, such as, the SFPQ::ZFP36L2 fusion, reported in pediatric T-ALL, deletions of putative suppressors, such as IKZF2 and CSMD1, and amplification of the BCL2 gene. Compared to negative cases, chromothripsis positive T-ALL had a significantly higher level of MYCN expression, and a significant downregulation of RGCC, which is typically induced by TP53 in response to DNA damage. Furthermore we identified mutations and/or deletions of DNA repair/genome stability genes in all cases, and an association with NUP214 rearrangements in 33% of cases.

Overcoming minimal residual disease using intensified conditioning with medium-dose etoposide, cyclophosphamide and total body irradiation in allogeneic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia in adults

Background aimsAn intensified conditioning regimen incorporating medium-dose etoposide (VP16) is an option for patients with acute lymphoblastic leukemia (ALL). However, the prognostic impacts of the addition of VP16 to cyclophosphamide (CY) and total body irradiation (TBI) in patients with Philadelphia chromosome-positive (Ph+) ALL with regard to minimal residual disease (MRD) status have not been elucidated. MethodsThe authors retrospectively compared the outcomes of patients with Ph+ ALL who underwent allogeneic transplantation following VP16/CY/TBI (n = 101) and CY/TBI (n = 563). ResultsAt 4 years, the VP16/CY/TBI group exhibited significantly better disease-free survival (DFS) (72.6% versus 61.7%, P = 0.027) and relapse rate (11.5% versus 21.1%, P = 0.020) and similar non-relapse mortality (16.0% versus 17.2%, P = 0.70). In subgroup analyses, the beneficial effects of the addition of VP16 on DFS were more evident in patients with positive MRD status (71.2% versus 48.4% at 4 years, P = 0.022) than those with negative MRD status (72.8% versus 66.7% at 4 years, P = 0.24). Although MRD positivity was significantly associated with worse DFS in patients who received CY/TBI (48.4% versus 66.7%, P < 0.001), this was not the case in those who received VP16/CY/TBI (71.2% versus 72.8%, P = 0.86). ConclusionsThis study demonstrated the benefits of the addition of VP16 in Ph+ ALL patients, especially those with positive MRD status. VP16/CY/TBI could be a potential strategy to overcome the survival risk of MRD positivity.

Asparaginase in the Treatment of Acute Lymphoblastic Leukemia in Adults: Current Evidence and Place in Therapy.

Acute lymphoblastic leukemia (ALL) is a rare hematologic malignancy resulting in the production of abnormal lymphoid precursor cells. Occurring in B-cell and T-cell subtypes, ALL is more common in children, comprising nearly 30% of pediatric malignancies, but also constitutes 1% of adult cancer diagnoses. Outcomes are age-dependent, with five-year overall survival of greater than 90% in children and less than 20% in older adults. L-asparaginase, an enzyme not found in humans, depletes serum levels of L-asparagine. As leukemic cells are unable to synthesize this amino acid, its deprivation results in cell death. The success of asparaginase-containing regimens in the treatment of pediatric ALL, and poor outcomes with conventional cytotoxic regimens in adults, have led to trials of pediatric or pediatric-inspired regimens incorporating asparaginase in the adolescent and young adult (AYA) and adult populations. Initially purified from Escherichia coli, newer formulations of asparaginase have been developed to address short half-life, high immunogenic potential, and manufacturing difficulties. Unfamiliarity with asparaginase use and management of its unique toxicities may result in treatment-decisions that negatively impact outcomes. In this review, we address the current use of asparaginase in the treatment of ALL, with an emphasis on its role in the treatment of adults, key clinical trials, recognition and management of toxicities, and ongoing directions of study.