Saygin, Caner

Abstract Background: Older adults with newly diagnosed ALL treated with conventional chemotherapy have poor survival due to high rates of toxic death and disease relapse. The Alliance A041703 trial (NCT0373981) tested chemotherapy-free treatment with the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin (InO) followed by the anti-CD19-CD3 bifunctional T-cell engager blinatumomab (blina) without maintenance in older adults to reduce toxicity and increase efficacy of therapy for this patient (pt) population. We previously reported with 22-month (mo) median follow-up that the study met its primary endpoint with a 1-year (yr) event-free survival (EFS) of 75% (90% confidence interval [CI] 63-89% lower bound exceeding null rate of 10%; JCO 2023 41, 7006). Here we report secondary outcomes with 45-mo median follow-up: 3-yr EFS, 3-yr overall survival (OS), response, and relapse characteristics. Methods: Eligible pts were ≥60 yrs old with newly diagnosed, Ph-negative, CD22-positive (≥20% of blasts) B-cell ALL without planned allogeneic HCT (alloHCT), liver disease, or CNS involvement at enrollment. Induction IA was InO 0.8 mg/m2 day (d) 1, 0.5 mg/m2 d8, d15 IV on a 21d cycle. Pts with adequate cytoreduction (marrow blasts reduced ≥50% or marrow cellularity ≤20%) after IA went to IB if in CR/CRi (InO 0.5 mg/m2 d1, d8, d15 IV; 28d cycle) or IC if no CR/CRi (InO 0.8 mg/m2 on d1 and 0.5 mg/m2 on d8 and d15 IV; 28d cycle). Those without cytoreduction to IA started course II blina. Pts without events in IA/B/C received course II blina continuous IV (9 mcg/d x 7d then 28 mcg/d x 21d; 14d break; 28 mcg/d x28d). Pts with CR/CRi to InO received 2 more 28d cycles of blina; others received 3 more. CNS prophylaxis was methotrexate 15 mg intrathecal x 8 doses. EFS was time from therapy start to failure to achieve CR/CRh/CRi by the end of course II, progression, relapse, or death, whichever occurred first, censored at last follow up. OS was time from registration to death from any cause censored at the last known alive date. Results: The median age of the 33 treated pts was 71 yrs (range 60-84). Eight pts had prior therapy for alternate malignancy in CR for >2 yrs prior to enrollment (6 multiple myeloma, 1 non-Hodgkin lymphoma, 1 breast cancer). Median CD22 expression was 92% (range 21-100%) and 49% had NCCN poor-risk genetics. Five pts underwent alloHCT in first CR/CRi and 2 pts received POMP maintenance after early discontinuation of blina (1 toxicity, 1 physician choice). The CR/CRi rate after InO was 85% (1 early death/refractory, 2 refractory, 2 undetermined due to low marrow cellularity on remission assessment marrow) with CR/CRi rate of 97% by completion of course II blina. With 45 mo median follow-up, the estimated 3-yr EFS was 48% (95% CI 33-70%) with a median EFS of 31 mo (95% CI 17.4-not reached [NR]) and no events after 31 mo. Sixteen events occurred: 12 relapses, 1early death, and 3 deaths in remission (1 encephalopathy, 1 relapse of multiple myeloma, 1 pulmonary complications after alloHCT). No isolated CNS relapse has been reported. Among relapses, 10 had immunophenotyping. Four (40%) were CD19-negative, one of which was also CD22-negative. Among CD19-negative relapses, genetics were hypodiploid (2), Pax5alt (1), and ZNF384-like (1, also CD22-negative). TP53 mutation or loss was observed in 5/12 (42%) relapses. Thirteen pts died. The estimated 3-yr OS was 59% (95% CI 44-79%) with median OS NR (95% CI 32-NR) with no deaths after 36 mo. In univariate analysis, EFS and OS were not impacted by age, gender, genetic risk (NCCN), prior therapy for alternate malignancy, or alloHCT in first remission. EFS was better with higher CD22 expression at diagnosis (≥90% vs <90%, 3-yr EFS 60% vs 25%, P=0.044). EFS and OS were worse for detectable minimal residual disease (MRD) at any timepoint by ASO-PCR. Undetectable MRD after course IA (1 cycle InO induction) was associated with EFS with a 3-yr EFS of 52% vs 0% for detectable MRD (median NR vs 8 mo, hazard ratio [HR] 0.07, P=0.004) and a 3-yr OS of 100% vs 0% for detectable MRD (median NR vs 20 mo, HR 0.00, P=0.0014). Conclusions: Longer follow-up of chemotherapy-free treatment with InO and blina for older pts with newly diagnosed, Ph-negative, CD22-positive, B-cell ALL reveals durable remissions and survival. The A041703 regimen is a compelling option for first-line treatment of this pt population. Support: U10CA180821, U10CA18088; https://acknowledgments.alliancefound.org.

PURPOSE Older patients with ALL receiving conventional chemotherapy have poor survival due to toxic death and relapse. We hypothesized that a chemotherapy-free, targeted regimen using the anti-CD22 antibody-calicheamicin conjugate inotuzumab ozogamicin followed by the bispecific anti-CD19/CD3 T-cell engager blinatumomab would reduce toxic death and yield high rates of prolonged remission and survival. METHODS Eligible patients were age 60 years and older with untreated, Philadelphia chromosome (Ph)–negative, CD22-positive, B-cell ALL. Patients received up to two cycles of inotuzumab ozogamicin followed by four or five cycles of blinatumomab with intrathecal methotrexate CNS prophylaxis. The primary end point was 1-year event-free survival (EFS). RESULTS The 33 eligible patients had a median age of 71 years (range, 60-84) and a median CD22 expression of 92% (range, 21%-100%). Eight (24%) had previous chemotherapy or radiation for other cancers, six for multiple myeloma. The composite complete remission rate was 85% after two cycles of inotuzumab ozogamicin and 97% by the end of two cycles of blinatumomab. At a median follow-up of 30 months, the 1-year EFS and overall survival were 75% (95% CI, 61 to 92) and 85% (95% CI, 73 to 98), respectively. EFS was shorter with lower CD22 expression or detectable measurable residual disease at any time point. CONCLUSION Inotuzumab ozogamicin then blinatumomab without maintenance chemotherapy in older patients with untreated, Ph-negative, CD22-positive, B-cell ALL yields a high remission rate and excellent EFS. Given the lack of standard, safe, and effective therapies in this population, the regimen should be considered a standard treatment option.

Introduction: The development of increasingly sensitive tests for the detection of measurable residual disease (MRD), such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) assays, has changed clinical practice in acute lymphoblastic leukemia (ALL). IGH V(D)J-based NGS MRD is the most sensitive assay to predict relapse in patients (pts) with B-ALL (Short, Blood Adv 2022). However, data regarding the use of T-cell receptor (TR) NGS MRD in T-ALL are limited and recent reports from pediatric cohorts suggest that persistent TR MRD may not predict relapse in T-ALL (Roy, ASH 2023, abstract 2976). With limited options for the treatment of relapsed/refractory T-ALL, accurate prediction of high relapse risk may provide an opportunity for early intervention. In this study, we evaluated the prognostic utility of TRB/TRG NGS MRD and its correlation with MFC MRD in adult patients with T-ALL. Methods: We retrospectively evaluated the MRD data and clinical outcomes of precursor T (pre-T) and early T precursor (ETP) ALL patients treated at four academic centers in the US. MRD was evaluated using MFC in CLIA-certified labs at individual sites with a sensitivity of 10-4, and the clonoSEQ (Adaptive Technologies, lnc) NGS assay, with a sensitivity of 10-6. Pts were included if they had a trackable TR clone and NGS MRD remission assessment in at least one time point. The correlation between the percentage of MRD by MFC vs NGS was calculated with the Pearson correlation coefficient, using every available MRD assessment for T-ALL pts in complete remission. Relapse-free survival was stratified based on NGS MRD level at the time of post-induction and post-consolidation assays, and comparisons were made with the log-rank test. The positive predictive value (PPV) for relapse of NGS MRD was calculated for pts with MRD > 10-6 at the post-induction and post-consolidation period. Results: A total of 19 pts who met our inclusion criteria, with a median age of 30 years (range, 18-65). 9 pts (47%) had ETP-ALL, 10 pts had pre-T ALL. Pts had a trackable TRB/TRG clone in 76% of cases, with 66% having a trackable TRG clone and 38% having a trackable TRB clone. 10 pts (53%) were treated with a modified AALL0434 regimen as first line therapy, 6 pts (32%) were treated with CALGB10403, 1 pt (5%) was treated with hyperCVAD, 1 pt (5%) was treated with a BFM regimen, and 1 pt (5%) was treated with CALGB9511. Out of 11 T-ALL pts with MRD data available post-induction, 6 pts (55%) had detectable MRD by NGS and no detectable MRD by MFC. Out of 13 pts with available post-consolidation MRD data, 2 pts (15%) had undetectable MRD by both NGS and MFC and 9 pts (69%) had detectable MRD by NGS only. There were no pts with detectable MRD by MFC and undetectable MRD by NGS at either timepoint. A total of 64 MRD data points from 19 pts were available to evaluate MRD correlation by MFC vs NGS, for which the Pearson correlation coefficient showed a statistically significant linear correlation (p < 0.01). At post-induction, 9 pts had NGS MRD > 10-4 and 2 pts had NGS MRD < 10-4. With a median follow-up time of 19.8 months, pts with NGS MRD > 10-4 had a median RFS of 19.8 months and pts with NGS MRD < 10-4 had a median RFS of 14.8 months. The log-rank test comparing RFS between these two groups was not statistically significant (p= 0.18). Persistent NGS MRD at post-induction had a PPV for relapse of only 18%. At post-consolidation, 7 pts had NGS MRD > 10-4, 4 pts had NGS MRD < 10-4, and 2 pts had undetectable MRD by NGS. With a median follow-up time of 17.3 months, pts with NGS MRD > 10-4 had a median RFS of 15.3 months and pts with NGS MRD < 10-4 or undetectable had a median RFS of 20.6 months. The log-rank test comparing RFS between these two groups was not statistically significant (p= 0.6). Persistent NGS MRD at post-consolidation had a PPV for relapse of only 27%. Conclusion: Despite statistically significant linear correlation between MFC and NGS MRD testing, there were no RFS differences between pts with NGS MRD > 10-4 vs NGS MRD < 10-4. All patients had persistent NGS MRD post-induction, which is markedly lower than the reported 20-25% NGS undetectable MRD rate in B-ALL post-induction. Persistent NGS MRD has low PPV for relapse in T-ALL, which limits its utility in clinical decision making for this population.

Introduction: Inotuzumab ozogamicin (INO) is an antibody targeting CD22 conjugated with a cytotoxic antitumor antibiotic (calicheamicin) approved for treatment of relapsed/refractory CD22 positive B-cell acute lymphoblastic leukemia (ALL) (Kantarjian et al. NEJM 2017). CD22 is expressed on the surface of lymphoblasts in ALL (~95%). Young adult patients (pts) 18-39 years (yrs) treated on the pediatric regimen CALGB 10403 resulted in a 3-yr event-free survival (EFS) of 59% (95% CI: 52-67%) and an estimated 3-yr overall survival (OS) of 73% (95% CI: 68-78%) (Stock et al. Blood 2019). Alliance A041501(NCT03150693), a phase 3 NCTN sponsored cooperative group trial was conducted to determine if the addition of INO to the CALGB 10403 pediatric regimen would significantly improve EFS. Methods: Eligibility included pts 18-39 years with newly diagnosed CD22 positive ALL, defined as baseline expression in > 20% of lymphoblasts by local institution. Pts with Burkitt-type ALL, BCR::ABL1 positive ALL, or Down syndrome were excluded. Eligible pts received the CALGB 10403 regimen modified to omit extended induction, include dexamethasone as opposed to prednisone as steroid backbone, cap the pegaspargase dose to 3750 units, and adding rituximab for pts with CD20 expression (> 20%). An amendment added blinatumomab for minimal residual disease (MRD) positivity. Pts achieving a complete remission (CR/CRi) or partial remission (PR) were eligible for randomization. Following a 6 pt safety run-in with INO, pts were randomized 1:1 to receive INO or continue CALGB 10403 backbone. Two cycles of INO (1.5 mg/m2/cycle) were administered following induction in the experimental arm. Pts were stratified by age, disease status post induction (M0/M1 vs M2), CD20 status, and LDA Card, which tests for the Ph-like status. The primary endpoint was to determine if the addition of INO would improve the EFS of the pediatric regimen CALGB 10403 without censoring for stem cell transplant (SCT). Key secondary endpoints included the impact of INO on disease-free survival (DFS), OS, and MRD. The Alliance Data and Safety Monitoring Board halted enrollment after 273 out of a planned 341 pts were registered because of increased grade (gr) 5 events in the INO arm compared with the control arm. Results: 273 pts were enrolled between 6/15/2018, and 5/24/2022. Median age was 27.0 yrs, 65.2% were White, 30.4% were Hispanic, and 63.4% were male. Baseline CSF analysis revealed 14% with CNS-2/3 disease. The overall CR rate was 86.8% (82.8-90.8%). 46 pts were not randomized due to death (5), withdrawal (6), ineligibility (3), toxicity (5), receipt of non-protocol therapy (8), progression (5), and other (14). 227 eligible pts were randomized 1:1 to receive INO (N=111) or not (N=116)). For randomized pts, 92.5% achieved M0/M1 marrow status, 48.9% had a positive LDA Card defining Ph-like ALL, 50.7% were CD20 positive. Only 36 pts (13%) received a SCT. With a median follow up of 28.3 months for randomized pts, 3-yr EFS was 69.0% (59.1-80.5%) for the INO arm and 66.7% (57.1-78.1%) for the control (HR=0.97; 0.58-1.63). Similarly, the 3-yr OS was 79.4% (71.0-88.7%) for the INO arm and 80.3% (71.9-89.6%) for the control (HR=1.05; 0.55-2.01). The MRD undetectable rate at Course II Day 56 was 80.6% in the INO arm and 74.2% in the control arm. Univariate analysis suggests improved EFS with INO in pts with a positive LDA card (Ph-like ALL) and of Hispanic ethnicity. There were 22 gr 5 events, 7 occurred prior to randomization. Of the 15 gr 5 events on the randomized cohort, 12 were reported in the INO arm and 3 in the control arm. Of the 12 gr 5 events in the INO arm, all occurred during intensive consolidation courses complicated by prolonged pancytopenia infection/sepsis (8), hepato-biliary in setting of infection (2), multi-organ failure (1), or post-surgical complication (1). These events occurred after INO during Course II (3), Course III (5), or Course IV (4). Conclusions: Although this trial did not meet the primary EFS endpoint for the addition of INO to the pediatric regimen CALGB 10403, these data provide compelling evidence for continued use of pediatric regimens in young adults with ALL as the EFS and OS compares favorably with prior published results. INO may still be efficacious if late toxicity can be mitigated. A pilot study is planned that will decrease INO dose, add 2 cycles of blinatumomab and strict infectious prophylaxis guidelines. Support: U10CA180821, U10CA180882

PURPOSE Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2 -, DUX4 -, and KMT2A -rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.