Ph-negative Acute Lymphoblastic Leukemia Research Articles

Treatment completion, asparaginase completion, and oncologic outcomes among children, adolescents and young adults with acute lymphoblastic leukemia treated with DFCI Consortium Protocols.

Adolescents and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) face worse outcomes than children. While pediatric-inspired protocols have improved outcomes, the ability of patients to complete these intensive regimens and the reasons for discontinuation are unknown. We analyzed a cohort of 332 AYA patients (aged 15-49 years) and 1159 children (aged 1-14 years) with Ph-negative ALL treated on DFCI consortium protocols. We found that AYA patients completed treatment at lower rates than children (60.8% vs. 89.7%, p < 0.001), primarily due to higher rates of early treatment failure (14.5% vs. 2.4%, p < 0.001). Withdrawal from treatment for toxicity, social/personal, or unknown reasons was uncommon, but higher among AYA patients (9.3% vs 4.7%, p = 0.001). Patients who remained on assigned therapy for one year had favorable overall survival (AYA 5-year OS 88.9%; children 5-year OS 96.4%; p < 0.001). Among patients who continued treatment for 1 year, AYA patients completed asparaginase (defined as receiving 26+ weeks) at lower rates than children (79.1% vs. 89.6%, p < 0.001). Patients who received more weeks of consolidation asparaginase had higher overall and event-free survival. Efforts should focus on identifying patients at risk for early treatment failure and optimizing asparaginase delivery.

Percutaneous Perirenal Mass Biopsy in a Sitting Position Revealed Extramedullary Relapse of Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is a blood malignancy characterized by a rapid proliferation of lymphoid progenitor cells. Extramedullary relapse (EMR) is the recurrence of leukemia that occurs outside the bone marrow. The central nervous system is the most prevalent site of EMR in ALL, whereas other organs, particularly the renal organs, are less commonly involved. A 49-year-old man diagnosed with Philadelphia chromosome-negative ALL (Ph-negative ALL) received a second umbilical cord blood transplant (uCBT) and was confirmed to be in his third hematological complete remission. However, the perirenal mass lesion emerged after two weeks, and was difficult to detect on echography in the prone position. We successfully performed a percutaneous biopsy of the mass in a sitting position and pathologically identified it as EMR. After the diagnosis, chemotherapy was restarted, and the patient was scheduled to receive a third uCBT. This is the first report of EMR in a perirenal lesion of ALL and shows that this novel biopsy can be performed as a renal biopsy, even in a sitting position. This case is the first to describe a biopsy technique in detail and demonstrates the value of collaboration between hematologists and nephrologists in diagnosing EMR of the kidneys.

Should patients with Ph-negative acute lymphoblastic leukaemia who reach minimal residual disease negativity have HSCT?

Should patients with Ph-negative acute lymphoblastic leukaemia who reach minimal residual disease negativity have HSCT?

Should patients with Ph-negative acute lymphoblastic leukaemia who reach minimal residual disease negativity have HSCT?

Should patients with Ph-negative acute lymphoblastic leukaemia who reach minimal residual disease negativity have HSCT?

Adverse Prognostic Role of Copy Number Alterations and Mutations in Adults with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Background: The impact of copy number alterations (CNAs) or mutations on outcomes has been broadly analyzed in pediatric acute lymphoblastic leukemia (ALL). However, the magnitude of the effect was often marginal, frequently restricted to specific genetic subtypes and rarely replicated across independent cohorts in adult ALL. Aim: We tried to analyze the prognostic relevance of genetic copy number alterations and gene mutations in patients with Ph-negative ALL who were treated with modified hyper-CVAD based chemotherapy followed by allogeneic hematopoietic cell transplantation (alllo-HCT). Methods: We investigated the role of CNAs or mutations to refine risk stratification in 128 adults with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell precursor ALL treated with intensive chemotherapy followed by allo-HCT for post-remission therapy. We performed multiplex ligation-dependent probe amplification (MLPA) to detect deletions of 11 genes ( IKZF1, CDKN2A/B, EBF1, ETV6, PAX5, BTG1, JAK2, RB1, PAR1, ZFY) and high throughput sequencing (HTS) of 70 gene mutations. Results: MLPA analysis showed that IKZF1 and CDKN2A/B deletions were observed in 54 (42.2%) and 52 (40.6%) patients, respectively. The remaining gene deletions were: PAX5 in 29 (22.6%), ETV6 in 22 (17.2%), BTG1 in 15 (11.7%), EBF1 in 14 (10.9%), RB1 in 13 (10.1%), JAK2 in 8 (6.2%), and PAR1 in 4 (3.1%). By HTS, NRAS (n=21, 16.4%), KRAS (n=11, 8.6%), TP53 (n=14, 10.9%), and PTPN11 (n=12, 9.4%) mutations were frequently detected. Overall, multivariate analysis for disease-free survival (DFS) and cumulative incidence of relapse (Table 1) showed that TP53 mutations (HR 5.04, 95%CI 2.29-11.30, P&amp;lt;0.001) and CDKN2A/B deletions (HR 1.88, 95%CI 1.10-3.31, P=0.026) were significantly associated with a poorer DFS. Patients with TP53 mutations (HR 5.64, 95%CI 1.95-16.20, P&amp;lt;0.001) and IKZF1 deletions (HR 1.91, 95%CI 1.09-3.31, P=0.022) had a higher relapse risk. To better define the prognostic role of CNAs, further analyses were restricted to patients excluding 14 TP53 mutations (n=114). Here, we classified patients into 4 subgroups; (1) No deletions (n=45, 39.5%), (2) IKZF1 deletion-alone (n=11, 9.6%), (3) IKZF1plus (n=40, 35.1%), and (4) CDKN2A/B±other deletions without IKZF1 deletions (n=18, 15.8%). Patients with IKZF1plus or CDKN2A/B±other deletions had an inferior DFS ( P=0.023) and higher relapse incidence ( P=0.002) than patients having no deletions. The results were similarly reproduced in patients receiving allo-HCT in first complete remission. Conclusions: Our data showed that IKZF1 or CDKN2A/B deletions and TP53 mutations may confer a poor prognosis for adult Ph-negative B-cell precursor ALL in the setting of intensive chemotherapy and allo-HCT. The combination of genomic abnormalities and minimal residual disease response may further refine risk stratification and better select patients who could benefit from novel therapeutic approaches.

Development of a Modified Prognostic Index for Adult Patients with Acute Lymphoblastic Leukemia

Background:Acute lymphoblastic leukemia (ALL) is associated with inferior overall survival (OS) and progression-free survival (PFS) in adults due to biologic factors and lower tolerance to chemotherapy 1,2. Prognostic stratification is essential to guide therapy intensification and indication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, a prognostic index 2 integrating measurable residual disease (MRD), white blood count (WBC) and cytogenetic/molecular subtypes has been validated in children and young adults with ALL. However, in adult patients, age, allo-HSCT, other genetic subtypes 3 and center reality, may also play role in prognosis. To incorporate new variables to the pre-established prognostic index 2, a multicenter PFS analysis was performed to develop a modified/adpated risk score. Material and Methods: a multicenter (three Brazilian centers and the Spanish PETHEMA AR-03 trial cohort), retrospective study, reviewed medical charts and database of 398 adult patients with Ph-negative ALL (treated between 2003 and 2022), including risk variables: age, WBC count, cytogenetic/molecular classification, MRD, allo-HSCT, clinical outcomes and follow-up. The prognostic index 2 was calculated individually, then through multivariate analysis the coefficients (HR/OR) to incorporate age and allo-HSCT to the model have been determined. The methods of logistic regression, Cox model, Kaplan-Meier, log rank, ROC analysis and competitive risk regression were used in the statistical analysis. Subsequently, patients were stratified into 3 prognostic risk categories. Results: A total of 398 patients, 77% from the PETHEMA protocol and 23% Brazilian centers; 55.2% males; mean age 38.1 years (range 18-60; 67.4% (268) B-ALL; 31.4% (125) T-ALL; 1.2% (5) biphenotypic ALL. median WBC 22.4x10 9/L; 8.9% with central nervous system involvement; 22.9% high risk cytogenetics. Regarding treatment, 93.9% (373) received pediatric-inspired protocols (AR-03, GRAALL, CALGB, St. Jude TOTALXVI), 6.1% (26) (Hypercvad and others). Regarding the response, 83.3% (309/371) achieved complete remission (CR); CR rate was higher in pediatric inspired versus other protocols: 84.6% vs 57.9% (p 0.006). 45.6% (127/278) reached MRD-neg status after induction and 71.4% (125/175) after consolidation; 21.7% (67/309) underwent allo-HSCT in first remission. After a median follow-up of 3.9 years, 4-year-OS was 42.1% (95%CI 47.2-36.8%) and PFS was 33.4% (95%CI 38.5-28.4%). Cumulative incidences of relapse and non-relapse mortality were: 38.0% and 27.6%, respectively. In multivariate analysis, both allo-HSCT (OR:0.36 95%CI 0.19-0.66 p&amp;lt;0.001) and original 2 prognostic index (OR:2.47 95%CI:1.71-3.55 p &amp;lt;0.001) predicted significantly PFS, so allo-HSCT coefficient has been determined and incorporated to the model. According to this modified prognostic index, patients were stratified into 3 risk groups: low (100/285, 35.1%), intermediate (93/285, 32.6%) and high (92/285, 32.3%) high. At 4-years, PFS was significantly superior in low-risk group (55.9% - 95% CI 65.8-44.5%) compared to the intermediate-risk group (37.3% - 95%CI 47.5-27.1%) and high-risk group (182% - 95%CI 27.0-10.8%), p &amp;lt;0.001. Conclusion: The incorporation of the main risk factors in ALL and the role of allo-HSCT into prognostic index for adults can adequately stratify the PFS of patients into 3 risk categories and could assist in clinical decision-making. Reference 1. Fernandes da Silva Junior W, Medina AB, Yamakawa PE, Buccheri V, Velloso EDRP, Rocha V. Treating Adult Acute Lymphoblastic Leukemia in Brazil-Increased Early Mortality Using a German Multicenter Acute Lymphoblastic Leukemia-based regimen. Clin Lymphoma Myeloma Leuk. 2018 Jun;18(6):e255-e259. doi: 10.1016/j.clml.2018.03.001. Epub 2018 Mar 14. PMID: 29605423. 2. Amir Enshaei , David O'Connor , Jack Bartram , Jeremy Hancock , Christine J. Harrison , Rachael Hough , Sujith Samarasinghe , Monique L. den Boer , Judith M. Boer , Hester A. de Groot-Kruseman , Hanne V. Marquart , Ulrika Noren-Nystrom , Kjeld Schmiegelow , Claire Schwab , Martin A. Horstmann , Gabriele Escherich , Mats Heyman , Rob Pieters , Ajay Vora , John Moppett, Anthony V. Moorman; A validated novel continuous prognostic index to deliver stratified medicine in pediatric acute lymphoblastic leukemia. Blood 2020; 135 (17): 1438-1446. doi: https://doi.org/10.1182/blood.2019003191

A Phase I Study of Venetoclax in Combination with Inotuzumab Ozogamicin for Relapsed or Refractory ALL in Adults

Introduction Adults with acute lymphoblastic leukemia (ALL), especially those who are older and/or have unfavorable disease biology frequently relapse. Inotuzumab ozogamicin (INO), an anti-CD22 monoclonal antibody covalently linked to calicheamicin, is approved for treatment of relapsed or refractory (R/R) CD22+ ALL. Although INO induces measurable residual disease negative (MRD-neg) complete remission (CR) in &amp;gt;75% of patients (pts), the duration of response (DOR) is limited (&amp;lt;6 months). Pre-clinical work demonstrates that malignant lymphoblasts are BCL2-dependent (Del Gaizo Moore Blood 2008). Initial results of the BCL2 inhibitor venetoclax (VEN) combination therapies for ALL are promising (Jain ASH 2019, Pullarkat Cancer Discov 2021). Due to distinct mechanisms of activity, non-overlapping toxicity, and possible synergy (Kirchhoff Blood 2021), we hypothesized that INO and VEN can be safely and effectively combined. Study Design and Eligibility This is an investigator-sponsored phase I study (NCT05016947) with a 3+3 dose escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of VEN plus INO at the FDA-approved doses in adults with R/R CD22+ ALL. Secondary objectives assess efficacy (hematologic response, MRD by multi-parametric flow cytometry [MFC] threshold &amp;lt;0.01%, and DOR). A 14 pt expansion cohort is planned. Dose-limiting toxicity (DLT) is defined as treatment-related CTCAE v5 non-heme toxicity grade 3+, sinusoidal obstructive syndrome (SOS) any grade, or liver toxicity during Induction (Ind) Cycle (C) 1 and/or failure of hematologic recovery (ANC ≥500, Plts ≥25 K/mL) by day 42 of Ind C1 in responding pts. Eligibility: ≥18 years (yrs); ALL (≥5% blasts) or LBL (marrow involvement not required); CD22 expression on ≥20% of blasts; R/R to one or more cycles of CC or in the case of Philadelphia-chromosome (Ph)-positive ALL, failed by two or more TKIs, or refractory to/ineligible for ponatinib; ≥60 days from bone marrow transplant (BMT), and off immune suppression ≥2 weeks; adequate liver and kidney function; no history of liver disease including SOS; blast count ≤25 K/mL prior to treatment; no symptomatic central nervous system (CNS) disease. Pts with prior INO or VEN treatment for R/R ALL are excluded. Regimen Pts are treated with a VEN Ramp-Up over 3 days (DL1: 100/200/200; DL2: 100/200/400) followed by Induction C1: IV INO days 1, 8, 15 (0.8/0.5/0.5 mg/m2) and VEN daily per DL days 1-21. DEX 10 mg/m2 IV/PO is administered during Ramp-Up and Ind C1 days 1-4 (7 days total). Pts with &amp;gt;5% blasts after C1 receive Ind C2 without DEX. Pts with &amp;lt;5% blasts after Ind (1 or 2 cycles) continue with up to four 28-day consolidation cycles (INO 0.5 mg/m2 days 1, 8, 15 plus VEN per DL days 1-21). Pts receive CNS prophylaxis with intrathecal chemotherapy. Results The 2-level dose-escalation phase has been completed; we enrolled 9 pts (5 female/4 male) with Ph-negative (n=7) or Ph-positive (n=2) ALL. The median age was 45 yrs (range 25 -74). Pts had received 1 (n=5) or 2 (n=4) prior lines of therapy. DL1 enrolled 3 pts without DLT. All DL1 pts achieved an MRD-neg CR and bridged to consolidation: 1 pt XRT to involved disease site (ankle) after 3 cycles and 2 pts to BMT after 2 cycles (Table). Three pts enrolled at DL2; no DLTs were observed. All achieved an MRD-neg CR. Two pts bridged to consolidation (donor lymphocyte infusion after 3 cycles, blinatumomab after 5 cycles) while 1 pt with KMT2A-r ALL experienced early relapse with lineage switch during second cycle. A confirmatory cohort of 3 pts enrolled at DL2 without DLT. All achieved a CR (n=2, MRD-neg; n=1, MRD-pos). The pt with MRD-pos CR as best response proceeded to blinatumomab as bridge to BMT after 2 cycles with 2 pts continuing treatment (currently cycle 2). Overall, CR was achieved in 100% (9/9) of pts with 7/8 (87%) achieving MRD-negativity. With median follow-up of 195 days (95% CI 80 - NR), 2 pts have relapsed 48 (on treatment) and 177 (after BMT) days from registration while other pts remain alive in CR. Non-heme grade 3-4 AEs include febrile neutropenia (2), DIC (1), tumor lysis syndrome (1), anxiety (1), hypertension (1), and hypotension (1). There have been no SOS. There were no delays in count recovery during C1, with median time from C1 to C2 being 30 days (range 27-42). Conclusion VEN 400mg x 21 days in combination with INO at standard doses was well tolerated and declared the recommended phase 2 dose (RP2D) with a CR rate of 100%.

Philadelphia-like B-Cell Acute Lymphoblastic Leukemia in a Largely Hispanic Population: Disease Features and Outcomes in the Era of Immunotherapy a Single Institutional Study

Introduction: Philadelphia (Ph)-like B-cell acute lymphoblastic leukemia (ALL) is a high-risk subgroup of B- cell ALL with distinct genotypes, unified by a gene expression profile similar to Ph-positive ALL but lacking the BCR: ABL1 fusion. Previous studies have noted the increased prevalence of Ph-like B-cell ALL in Hispanic patients. Our study evaluates Ph-like B- cell ALL clinical/genomic features and outcomes in a predominantly Hispanic population. Methods: This is a retrospective chart review of ALL patients that underwent treatment for B-cell ALL at Norris Comprehensive Cancer Center (NCCC) between 2011 and 2023. Identification of fusions associated with Ph-like B-cell ALL was performed using cumulative results from RNA-seq, conventional cytogenetics, and fluorescence in situ hybridization (FISH) with reflex gene fusion transcript analysis. Additionally, we used the Anchored Multiplex PCR™-based multi-gene NGS assay designed to detect known and novel fusions and elevated gene expression levels using a proprietary algorithm in ALL. Cumulative incidence of relapse (CIR) was evaluated using competing risk regression (Fine-Gray method), with death as a competing outcome. Overall survival (OS) and event-free survival (EFS) were analyzed using Cox proportional hazards model. Events of interest for EFS were relapse, treatment failure, and death. Ph-negative B-cell ALL patients were set as the reference for survival analysis. Results: 253 patients were included with a median age at diagnosis of 42 years (range: 18-80). ALL subtypes included 64(25.3%) Ph-like, 77(30.4%) Ph-positive, and 112(44.3%) Ph-negative. Most were Hispanic (N = 186, 73.5%), and the median follow-up time was 27 months. The 3-year OS, EFS, and CIR were 81.3% (95% CI 75.7-87.4%), 49.1% (95% CI 42.7-56.5%), and 39.9% (95% CI 33.0-46.7%). CRLF2 related mutations constituted 44(68.8%) of Ph-like patients, with 9(14.0%) CRLF2-P2RY8, 24(37.5%) CRLF2-IGH, and 11(17.2%) CRLF2-other gene rearrangements. 19 Ph-like patients had non-CRLF2 mutations consisting of 13(20.3%) IGH, 3(4.7%) ABL1/2, 3(4.7%) JAK2, and 1(1.6%) EPOR rearrangements. Compared to Ph-negative, Ph-like patients were more likely to have a refractory disease (20.6% vs. 6.2% P=0.006) and require Blinatumomab (67.2% vs. 39.3% P&amp;lt;0.001), with a non-significant trend towards lower rates of CR (84.1% vs 90.9% P=0.21). Ph-like patients had significantly worse EFS (HR = 1.63; 95% CI 1.09-2.45; P=0.018), but similar OS (HR = 0.88; 95% CI 0.39-1.99; P=0.75) and CIR (HR = 1.06; 95% CI 0.65-1.70; P = 0.83). Ph-positive patients displayed improved EFS relative to Ph-negative (HR = 0.56; 95% CI 0.35-0.91; P = 0.018), similar OS (HR = 0.73; 95% CI 0.35-1.50; P = 0.39), and a trend towards improved CIR (HR = 0.67; 95% CI 0.40-1.10; P=0.11). When controlling for age, sex, and treatment type, EFS was worse in Ph-like (HR = 1.57; 95% CI 1.03-2.41; P = 0.037) and improved in Ph-positive (HR = 0.56; 95% CI 0.33-0.93; P = 0.026). Our incidences of CRLF2 mutations in Ph-like patients aged&amp;gt;40 compared to age ≤40 was (73.3% vs 64.7%, P=0.591). On subgroup analysis of Ph-like patients, univariate regression revealed CRLF2-related Ph-like patients had a worse CIR (HR = 5.68; 95% CI 1.91-16.9; P = 0.002) but similar OS(P=0.99) and EFS(P=0.18). PAX5 expression was also a predictor of poor OS (HR = 8.89; 95% CI 1.06-74.7; P = 0.044) and EFS (HR = 2.51; 95% CI 1.09-5.77; P = 0.031), with a trend towards increased CIR (HR = 2.30; 95% CI 0.92 -5.78; P = 0.075). Compared to non-CRLF2 mutations, CRLF2-Ph-like had worse CIR (HR = 5.68; 95% CI 1.91 -16.9; P = 0.002). Relative to Ph-like patients who achieved MRD negativity during induction, patients who remained MRD positive had worse CIR(HR = 2.92; 95% CI 1.23 -6.94; P = 0.015) and EFS (HR = 4.32; 95% CI 1.890-9.84; P &amp;lt; 0.001). However, after controlling for Blinatumomab administration, the effect diminished (CIR: P=0.73, EFS P=0.28). There were no differences in EFS(P=0.34), CIR(P=0.69), and OS(P=0.36) between Ph-like patients who were transplanted vs not. Conclusions: Ph-like B- Cell ALL represents a high-risk disease subtype of adult B-ALL, with poor EFS and frequent treatment failure. CRLF2 translocation confers worse CIR and EFS within Ph-like patients and requires novel treatment approaches.

Updated Results from a Phase II Study of Hyper-CVAD, with or without Inotuzumab Ozogamicin, and Sequential Blinatumomab in Patients with Newly Diagnosed B-Cell Acute Lymphoblastic Leukemia

Background Blinatumomab improves overall survival (OS) compared with chemotherapy in patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and is also FDA-approved for eradication of persistent or recurrent measurable residual disease (MRD). Blinatumomab also improves OS when added to standard chemotherapy, irrespective of MRD status, in newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL. Inotuzumab ozogamicin (INO) improves OS in the relapsed/refractory setting, and we hypothesized that the addition of INO to hyper-CVAD plus blinatumomab would lead to deeper and more durable responses, reduce relapses, and improve survival. Methods In this phase II study, pts age 14-59 with newly diagnosed Ph-negative B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts had to have a performance status of ≤3, total bilirubin ≤2 mg/dl, creatinine ≤2 mg/dl, and no significant CNS pathology (except for CNS leukemia). Pts received hyper-CVAD alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C) for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2). Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). Those with high-risk disease features started blinatumomab after 2 cycles of hyper-CVAD. Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C (which was also dose reduced to 500 mg/m2 of MTX and 1 g/m2 of Ara-C with this amendment) and to 2 cycles of blinatumomab consolidation (4 total cycles with INO). Results As of June 2023, 75 pts have been treated (38 without INO and 37 with INO). Pt characteristics are shown in Table 1. The median age across both cohorts was 33 (range, 18-59). 36 pts (48%) had ≥1 high-risk pretreatment characteristic at enrollment (e.g. poor-risk cytogenetics, CRLF2 overexpression by flow and/or TP53 mutation). Sixteen pts were in complete remission (CR) at enrollment after 1-2 cycles of off-protocol therapy, 10 of whom were MRD-negative by 6-color flow cytometry. All 59 pts (100%) with active disease upon study entry achieved CR, with 50 pts (84%) achieving CR after the first cycle. MRD negativity by flow (sensitivity 10 -4) was achieved in 60 of 65 evaluable pts (92%), with 43 pts (66%) achieving flow MRD negativity after the first cycle. Two of the 5 patients who did not achieve flow MRD negativity had NUP214::ABL1 fusion, 1 had KMT2A rearrangement, and 2 are still early in treatment and have not yet received blinatumomab. Overall, 25 of 36 tested pts (69%) achieved next-generation sequencing-based MRD negativity at a sensitivity of 10 -6. The median duration of follow-up is 26 months (range, 1-77 months). Overall, 8 pts (11%) relapsed in the absence of SCT, 23 pts (31%) underwent stem cell transplantation (SCT) in first remission (2 of whom relapsed post-SCT), 3 pts (4%) died in CR, and 41 pts (55%) remain in continuous remission without SCT. Among the 10 relapses, 3 were in the CNS, 2 of which were CNS-only. All but one relapse occurred in pts with ≥1 poor-risk feature(s). Across both cohorts, the estimated 3-year OS was 88% and the 3-year relapse-free survival (RFS) was 79% . The 3-year OS rate for pts without a high-risk baseline feature was 93% vs 83% in pts with ≥1 high-risk feature. In a landmark analysis, there was no difference in outcomes between pts who underwent SCT in first remission versus those who did not (3-year OS: 90% versus 87%). With a median follow-up of 18 months in the INO group, 3 pts (8%) have relapsed, 2 with CNS-only relapses, and none have died. The 18-month RFS in the cohorts with and without INO were 92% vs 76% (p=0.18), and the OS was 100% vs 84% (p=0.04) ( Figure 1). One pt discontinued blinatumomab due to a related adverse event (grade 2 encephalopathy and dysphasia). No pts discontinued INO due to toxicity, and no cases of veno-occlusive disease have been observed.

SIOG2023-4-P-260 - Impact of treatment intensity on outcome in older Ph-negative acute lymphoblastic leukemia patients

SIOG2023-4-P-260 - Impact of treatment intensity on outcome in older Ph-negative acute lymphoblastic leukemia patients

Higher incidence of delayed methotrexate clearance in pediatric acute lymphoblastic leukemia patients treated with imatinib

BackgroundPediatric patients with Philadelphia chromosome positive (Ph+) or ABL-class fusion positive acute lymphoblastic leukemia (ALL) are currently treated with the tyrosine kinase inhibitor (TKI) imatinib added to a chemotherapy backbone that also contains several courses of high-dose methotrexate (HDMTX). A limited number of case studies suggested delayed MTX clearance in patients concomitantly using HDMTX and imatinib. MethodsMTX clearance and serum creatinine in 24 newly diagnosed Ph+/ABL-class fusion positive pediatric ALL patients treated with imatinib (imatinib group) were compared with 281 randomly selected age-matched Ph-negative pediatric ALL patients treated without TKI (control group), receiving in total 61 and 897 HDMTX courses, respectively. ResultsMild to severe delayed MTX clearance (MTX level at T48 hours>0.4 µM) was more frequently found in the imatinib group than in the control group in all courses (55.7% vs 41.1% p = 0.036). After the first HDMTX course, 12.5% (n = 3) of the imatinib group presented with a severe delayed MTX clearance (T48 > 5 µM) versus 2.3% in the control group (p = 0.039). In two (8.3%) of these patients in the imatinib group, this was accompanied by increased creatinine, therefore meeting the criteria for Delayed MTX Elimination (DME). In the control group 12/281 (4.3%) patients presented with DME. Glucarpidase was administered in 2 (8.3%) vs 4 (1.4%) patients in the imatinib group and control group, respectively. ConclusionImatinib increased the risk of delayed MTX clearance in newly diagnosed pediatric Ph+ chromosome or ABL-class fusion positive ALL patients. We therefore recommend stringent supportive care measures and for patients with severe delayed MTX clearance resulting in severe toxicities temporary discontinuation of imatinib or a lower dose of MTX during the next HDMTX courses.

POSTER: ALL-329 Ph-Negative Acute Lymphoblastic Leukemia (ALL) in Adolescent and Young Adults: Long-Term Outcomes After Treatment According to the Adult Strategy RALL Protocol

POSTER: ALL-329 Ph-Negative Acute Lymphoblastic Leukemia (ALL) in Adolescent and Young Adults: Long-Term Outcomes After Treatment According to the Adult Strategy RALL Protocol

ALL-329 Ph-Negative Acute Lymphoblastic Leukemia (ALL) in Adolescent and Young Adults: Long-Term Outcomes After Treatment According to the Adult Strategy RALL Protocol

ALL-329 Ph-Negative Acute Lymphoblastic Leukemia (ALL) in Adolescent and Young Adults: Long-Term Outcomes After Treatment According to the Adult Strategy RALL Protocol

Positioning blinatumomab in the frontline of adult B-cell acute lymphoblastic leukemia treatment.

Blinatumomab is a bispecific T cell engager that has shown efficacy in relapsed/refractory Philadelphia chromosome (Ph)-positive and Ph-negative acute lymphoblastic leukemia (ALL). Considering its favorable safety and activity in advanced ALL, blinatumomab as a targeted immunotherapy is fast gaining a frontline position in the ALL treatment paradigm. There have been multiple completed and ongoing studies showing significant promise with improved response rates and survival outcomes and decreased treatment toxicity and need for multi-agent chemotherapy regimens. The early use of blinatumomab has established success in Ph-negative and Ph-positive B-ALL, and this has extended to older adults with ALL who have historically had substantially inferior outcomes compared to their pediatric and young adult counterparts. Herein we will review the current data describing the early use of blinatumomab in newly diagnosed adults with B-cell ALL and future directions.

The use of pegaspargase in adult Ph-negative acute lymphoblastic leukemia patients in the treatment according to the all-2016 protocol

The use of pegaspargase in adult Ph-negative acute lymphoblastic leukemia patients in the treatment according to the all-2016 protocol

Rituximab plus multiagent chemotherapy for newly diagnosed CD20-positive acute lymphoblastic leukemia: a prospective phase II study.

We performed a prospective study to determine the efficacy and safety of rituximab including chemotherapy in CD20-positive acute lymphoblastic leukemia (ALL). Patients with newly diagnosed ALL, aged ≥ 15 years, were eligible for the study if their leukemic blast cells in bone marrow expressed CD20 ≥ 20% at the time of diagnosis. Patients received multiagent chemotherapy with rituximab. After achieving complete remission (CR), patients received five cycles of consolidation with concomitant rituximab. Rituximab was administered monthly from day 90 of transplantation for patients who received allogeneic hematopoietic cell transplantation. In patients with Philadelphia (Ph)-negative ALL, 39 of 41 achieved CR (95.1%), the 2- and 4-year relapse-free survival (RFS) rates were 50.4% and 35.7%, and the 2- and 4-year overall survival (OS) rates were 51.5% and 43.2%, respectively. In the group with Ph-positive ALL, all 32 patients achieved CR, the 2- and 4-year RFS rates were 60.7% and 52.1%, and the 2- and 4-year OS rates were 73.3% and 52.3%, respectively. In the Ph-negative ALL group, patients with higher CD20 positivity experienced more favorable RFS (p < 0.001) and OS (p = 0.06) than those with lower CD20 positivity. Patients who received ≥ 2 cycles of rituximab after transplantation had significantly improved RFS (hazard ratio [HR], 0.31; p = 0.049) and OS (HR, 0.29; p = 0.021) compared with those who received < 2 cycles. The addition of rituximab to conventional chemotherapy for CD20-positive ALL is effective and tolerable (Clinicaltrials. gov NCT01429610).

Mini-hyper-CVD plus inotuzumab ozogamicin (InO), with or without blinatumomab (Blina), in older patients with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (ALL): Updates from a phase II trial.

e19025 Background: The overall survival (OS) of patients (pts) with relapsed/refractory B-ALL has improved with the introduction of InO and Blina. Compared to conventional chemotherapy, the incorporation of these agents into the frontline setting of older pts with ALL may allow the use of less chemotherapy and potentially improve outcomes. Methods: Adults ≥60 yrs with newly diagnosed Ph-negative B-ALL received mini-Hyper-CVD (mini-HCVD) for up to 8 cycles. Initially, InO was given at 1.3-1.8mg/m2 on Day (D) 3 of Cycle (C) 1 and 0.8-1.3mg/m2 on D3 of C2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responders received POMP maintenance for up to 3 yrs. Beginning with pt #50, InO was given in fractionated doses each cycle (0.6 mg/m2 on D2 and 0.3 mg/m2 on D8 of C1; 0.3 mg/m2 on D2 and 8 of C2-4) and 4 cycles of Blina were given following 4 cycles of mini-HCVD plus InO. Maintenance was with 12 cycles of POMP and 4 cycles of Blina (1 cycle of Blina after 3 cycles of POMP). Results: 83 pts were treated, of whom 6 were in complete remission (CR) at enrollment(Table 1). Among 77 evaluable pts, 76 (99%) responded (CR, 90%). Among responders, the rates of MRD negativity by flow cytometry were 79% and 94% after C1 and overall, respectively. No early death was observed. Among 82 pts in remission, 11 (13%) relapsed, 4 (5%) underwent ASCT, 34 (41%) remain in ongoing continuous remission, 33 (41%) died in remission, of whom 9 died after developing MDS/AML. Three pts (4%) developed veno-occlusive disease, 2 after subsequent ASCT. After a median follow-up of 65 months (range, 6-126), the 5-yr continuous remission duration and OS rates were 78% and 48%, respectively. Age ≥70 and adverse cytogenetics were associated with worse outcomes. The inferior outcome in pts ≥70 yrs was primarily attributed to higher rates of death in CR. The 5-yr OS for pts age 60-69 yrs without adverse cytogenetics (n=40), age 60-69 with adverse cytogenetics (n=15), age ≥70 without adverse cytogenetics (n=24) and age ≥70 with adverse cytogenetics (n=4) were 72%, 27%, 38% and 0%, respectively. Conclusions: Favorable outcomes were observed in older pts with newly diagnosed Ph-negative ALL treated with mini-HCVD plus InO, with or without Blina. The 5-yr OS was 48%. Clinical trial information: NCT01371630 . [Table: see text]

Mini-hyper-CVD with venetoclax (Ven) for patients with relapsed/refractory (R/R) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL): A phase II study.

e19039 Background: In preclinical studies, Ven has shown promising clinical activity in patients (pts) with R/R ALL. The combination of Ven with low intensity mini-HCVD chemotherapy could improve outcomes in ALL pts. Methods: Pts ≥18 years with R/R Ph-negative B- or T-cell ALL received mini-HCVD alternating with methotrexate and cytarabine for up to 8 cycles. Ven was given at a dose of 400 mg/d on Days (D) 1-14 of Cycle (C) 1 and on D1-7 of C2-8. Rituximab (if CD20+ B-ALL) and prophylactic IT chemotherapy x8 doses were given for the first 4 cycles. Pts with T-ALL received additional 2 cycles of nelarabine and peg-asparaginase during consolidation without Ven, and 2 cycles during maintenance. Maintenance with vincristine, prednisone and Ven was given for up to 2 years. Results: Between 6/2019 and 2/2021, 23 pts were treated, with a median age of 45 years (range, 20-70). 18 (78%) pts had B-ALL and 5 (22%) T-ALL, including 1 pt with ETP ALL. Among the 23 pts, the median number of prior therapies was 2 (range, 1-6) and 13 (57%) had undergone prior allogeneic stem cell transplant (ASCT). Among the 18 B-ALL pts, 16 (89%) had received prior blinatumomab and 7 (39%) prior inotuzumab. Among 23 pts, 1 was in CR at enrollment. Overall, 12 of 22 (55%) pts responded to therapy (complete response, n=9), of whom 9 achieved best response after C1 and 3 after C2. An additional pt achieved partial response. The overall response rate among the 18 pts who had at least a bone marrow assessment after C1 was 67%. The median duration of follow-up was 26 months (range, 2-35). Among the 13 responders (including the pt in CR at start), 6 (46%) relapsed, 5 (39%) underwent ASCT (4 subsequently relapsed), and 2 (15%) died in remission. The median RFS and OS were 6.4 and 8.1 months, respectively, and the 1-year RFS and OS rates were 15% and 37%, respectively. Survival was worse in pts with adverse cytogenetics versus others (median OS, 6 vs 12 months; 1-yr OS rate, 17% vs 44%; P=0.15). In C1, the median time to platelet recovery was 27 days (range, 0-81) and neutrophil recovery was 21 days (range, 0-36); in C2+, median times to recovery were 25 days (range, 0-76) and 15 days (range, 0-26), respectively. The 30-day and 60-day mortality rates were 0% and 13%, respectively. Conclusions: The combination of low-intensity chemotherapy mini-HCVD with Ven in pts with R/R Ph-negative ALL was well-tolerated and resulted in a response rate of 67%. Further studies examining the role of Ven-based therapies in ALL are needed for newly diagnosed and R/R pts. Clinical trial information: NCT03808610 . [Table: see text]

A phase II study of hyper-CVAD with blinatumomab (blina) and inotuzumab ozogamicin (INO) for newly diagnosed Philadelphia chromosome (Ph)–negative B-cell acute lymphoblastic leukemia (ALL).

e19017 Background: Consolidation with blina, regardless of measurable residual disease (MRD) status, improves overall survival (OS) in adults with newly diagnosed B-cell ALL. The addition of INO may deepen responses and further improve outcomes. Methods: Patients (pts) 14-59 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts received hyper-CVAD alternating with high-dose MTX/Ara-C for up to 4 cycles, followed by 4 cycles of Blina at standard doses. Pts with CD20+ disease received 8 doses of an anti-CD20 antibody. Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (maintenance cycles 1-3, 5-7, 9-11, and 13-15) and Blina (maintenance cycles 4, 8, and 12). Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C and to 2 cycles of Blina consolidation (4 total cycles with INO). Results: To date, 69 pts have been treated (38 without INO and 31 with INO). Baseline characteristics are summarized in the table. Among 53 pts with active disease at study entry, 100% achieved CR. MRD negativity by flow was achieved in 56/59 evaluable pts (95%). Of the 3 pts who did not achieve MRD negativity, 2 were later found to have a NUP214: ABL1 fusion, and 1 had KMT2A rearrangement. The median follow-up of the entire cohort is 26 months. Overall, 8 pts (12%) relapsed while on study, 22 (32%) underwent stem cell transplant (SCT) in first remission (2 of whom relapsed post-SCT), 2 (3%) died in CR, and 37 (54%) remain in continuous remission without SCT. For the entire cohort, the estimated 3-year OS was 87% and the 3-year continuous remission duration was 83%. With a median follow-up in the INO cohort of 15 months, 3 pts (10%) have relapsed, all with CNS-only relapses, and none has died. The 15-month OS in the cohorts with and without INO were 100% and 87%, respectively (P=0.06). One pt discontinued Blina due to recurrent grade 2 neurotoxicity. No pts have discontinued INO due to toxicity and no cases of SOS/VOD have been observed. Conclusions: In pts with newly diagnosed Ph-negative B-cell ALL receiving hyper-CVAD with sequential Blina, OS may be improved with the addition of INO. Clinical trial information: NCT02877303 . [Table: see text]

PH negative acute lymphoblastic leukemia in adolescents and young adults treated according a MRD adapted BFM ALL IC 2009 protocol: Argentine real-world data on 171 patients.

Intensified pediatric chemotherapy regimens to treat adolescents and young adults (AYA) patients with Philadelphia negative acute lymphoblastic leukemia (ALL) have been associated with better outcomes. The local BFM 2009-based scheme complements the risk stratification assessing the measurable residual disease (MRD) along the induction phase with increasing levels of sensitivity. The present retrospective multicenter analysis included 171 AYA (15-40 years) patients treated accordingly between 2013 and 2019. Ninety-one percent obtained morphological complete remission, 67% a negative (<0.1%) MRD at day 33 (TP1), and 78% a negative (<0.01%) MRD at day 78 (TP2). The overall survival (OS) and the event-free survival (EFS) at 2 years were 62%±4.1 and 55%±4.1, respectively. The OS and EFS were significant better for prednisone responders, who achieved <10% BM blast at day 15, a negative MRD at TP1 or at TP2, and for low-risk patients. Age ≤30 years and WBC <30×109/L, particularly among B-phenotype, were also associated with longer OS. In the multivariable analyses, TP1 MRD positive (OS HR 2.8, 95% CI 1.4-5.7, p=0.004; EFS HR 3.0, 95% CI 1.6-5.7, p=0.001) and at TP2 (OS HR 2.6, 95% CI 1.3-5.3, p=0.012; EFS HR 2.6, 95% CI 1.3-5.1, p=0.006) were independently associated with earlier events. Age >30 years was also associated with a shorter survival (HR 3.1, 95% CI 1.3-7.5, p=0.014). Therefore, those 68 patients ≤30 years with TP1/TP2 negative MRD depicted a longer OS (2 years 85%±4.8). Based on our real-world data, the pediatric-based scheme is feasible in Argentina associated with better outcomes for younger AYA patients who achieved negative MRD at day 33 and 78.