Achieved Measurable Residual Disease Negativity Research Articles

Molecular, clinical, and therapeutic determinants of outcome in NPM1 mutated AML

AbstractAlthough NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die. Previous studies identified several molecular and clinical features associated with poor outcomes; however, only FLT3-internal tandem duplication (ITD) mutation and adverse karyotype are currently used for risk stratification because of inconsistent results and uncertainty about how other factors should influence treatment, particularly given the strong prognostic effect of postinduction measurable residual disease (MRD). Here, we analyzed a large group of patients with NPM1 mutations (NPM1mut) AML enrolled in prospective trials (National Cancer Research Institute [NCRI] AML17 and AML19, n = 1357) to delineate the impact of baseline molecular and clinical features, postinduction MRD status, and treatment intensity on the outcome. FLT3-ITD (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.01-1.63), DNMT3A (HR, 1.65; 95% CI, 1.32-2.05), WT1 (HR, 1.74; 95% CI, 1.27-2.38), and non-ABD NPM1mut (HR, 1.64; 95% CI, 1.22-2.21) were independently associated with poorer overall survival (OS). These factors were also strongly associated with MRD positivity. For patients who achieved MRD negativity, these mutations (except FLT3-ITD) were associated with an increased cumulative incidence of relapse (CIR) and poorer OS. However, apart from the few patients with adverse cytogenetics, we could not identify any group of MRD-negative patients with a CIR >40% or with benefit from allograft in first remission. Intensified chemotherapy with the FLAG-Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin) regimen was associated with improved outcomes in all subgroups, with greater benefits observed in the high-risk molecular subgroups.

Dose-Dense Mini-Hyper-CVD, Inotuzumab Ozogamicin and Blinatumomab Achieves Rapid MRD-Negativity in Philadelphia Chromosome-Negative B-cell Acute Lymphoblastic Leukemia

BackgroundThe combination of low-intensity chemotherapy and inotuzumab ozogamicin (INO), with sequential blinatumomab, is highly effective in older adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and in relapsed or refractory B-cell ALL. Earlier, “dose-dense” administration of blinatumomab could lead to earlier and deeper measurable residual disease (MRD) responses and better outcomes. Patients and MethodsWe performed a retrospective analysis of the safety and efficacy of a dose-dense regimen of mini-hyper-CVD (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with mini-methotrexate and cytarabine), INO, and blinatumomab in patients with B-cell ALL. ResultsTwenty-one patients were treated (frontline, n = 9; MRD consolidation, n = 4; relapsed/refractory, n = 8). In the frontline cohort, all patients achieved CR/CRi and MRD negativity by flow cytometry at the end of cycle 1. Across the frontline and MRD consolidation cohorts, 10/11 patients (91%) achieved next-generation sequencing MRD negativity at a sensitivity of 10−6, including 6/10 evaluable patients (60%) who achieved next-generation sequencing MRD negativity after cycle 1. The CR/CRi rate in the relapsed/refractory cohort was 63%, and all responders achieved MRD negativity by flow cytometry at the end of cycle 1. The 1-year overall survival rate for the combined cohort of the frontline and MRD-positive patients was 83%. No new safety signals were observed with the dose-dense mini-hyper-CVD, INO, and blinatumomab regimen. ConclusionDose-dense delivery of mini-hyper-CVD, INO, and blinatumomab was safe and resulted in rapid and deep MRD negativity in patients with B-cell ALL. This regimen is now being prospectively evaluated in both the frontline and relapsed/refractory settings.

Predictors of unsustained measurable residual disease negativity in transplant-eligible patients with multiple myeloma

AbstractThe role of measurable residual disease (MRD) negativity as a biomarker to stop treatment is being investigated in transplant-eligible patients with multiple myeloma (MM). Thus, it is important to identify risk factors of MRD resurgence and/or progressive disease (PD) among patients achieving undetectable MRD to avoid undertreating them. Here, we studied 267 newly diagnosed transplant-eligible patients with MM enrolled in the GEM2012MENOS65 and GEM2014MAIN clinical trials who achieved MRD negativity by next-generation flow cytometry. After a median follow-up of 73 months since the first MRD negative assessment, 111 of the 267 (42%) patients showed MRD resurgence and/or PD. The only prognostic factors at diagnosis that predicted MRD resurgence and/or PD were an International Staging System (ISS) 3 and the presence of ≥0.01% circulating tumor cells (CTCs). Failure to achieve MRD negativity after induction also predicted higher risk of MRD resurgence and/or PD. Patients having 0 vs 1 vs ≥2 risk factors (ISS 3, ≥0.01% CTCs, and late MRD negativity) showed 5-year rates of MRD resurgence and/or PD of 16%, 33%, and 57%, respectively (P < .001). Thus, these easily measurable risk factors could help refine the selection of patients for whom treatment cessation after MRD negativity is being investigated in clinical trials. This trial was registered at www.clinicaltrials.gov as NCT01916252 and NCT02406144.

The Prognostic Impact of Measurable Residual Disease Dynamics in Mantle Cell Lymphoma

Introduction Measurable residual disease (MRD) technologies have greatly enhanced our ability to guide treatment duration and predict outcome in various hematologic malignancies. However, drawing definitive conclusions on the benefits of achieving MRD-negative status in patients with mantle cell lymphoma (MCL) has been challenging due to the limited availability of large-scale MRD detection series. To address this, our study aimed to determine the optimal timing for MRD detection and explore the prognostic value of MRD dynamics in MCL. Methods In present study, we included 102 patients diagnosed with advanced MCL demonstrating clonal B cell involvement in bone marrow (BM) detectable by multiparametric flow cytometry (MFC). 60/102 (58.8%) patients received high dose cytarabine-based intensive immunochemotherapy. BM aspirates were collected and MRD assessment was conducted at specific time points, including the initiation of cycle 3, cycle 5, at the end of induction, and every 6 months during maintenance therapy. Results 77/102 (75.4%) patients reached MRD negativity throughout induction treatment. Of those with MRD − vs MRD + status , 23.4% vs 68.0% were aged &amp;gt;65 years respectively, which was likely a consequence of the greater MRD − rates observed in patients who received intensive immunochemotherapy and auto-transplantation. Besides, elevated lactate dehydrogenase (LDH) level, high-risk MIPI, blastoid/pleomorphic pathology type, and non-cytarabine containing regimen were associated with a lower rate of MRD negativity. Follow-up data revealed that MRD-negative patients had significantly better survival (P&amp;lt;0.001). In subgroup analyses, MRD negativity was prognostic in almost all subgroups. MRD detection serves as a valuable complement to the traditional response evaluation system, particularly benefiting patients who achieve partial remission (PR). This indicated the importance of assessing MRD during induction therapy for PR patients. However, for patients who achieve complete remission (CR), the presence or absence of MRD has minimal impact on prognosis (P=0.921 for progression-free survival (PFS), and P=0.399 for overall survival (OS). Then we evaluated the optimum timing of MRD detection and impact of rapidity of MRD negativity. 31 of the 77 patients (40.3%) had a rapid reduction of tumor burden and achieved MRD negativity after two cycles of treatment. 35 patients (45.5%) were MRD negative after four cycles of treatment. In 14.2% of the patients, MRD turned negative only at the evaluation after six cycles of induction therapy or during maintance duration. Comparing MRD status at different time points, the MRD status after four cycles of therapy was the strongest predictor of survival prognosis (HR=5.37, C-index=0.673). However, the speed of reaching MRD negativity was not significantly correlated with survival prognosis. Patients with high-risk features, such as high-risk MIPI, elevated LDH levels and complex karyotype, tend to achieve MRD negativity at a faster speed, often within two treatment cycles. However, faster rate of achieving MRD negativity did not confer any prognostic benefit to these patients. The overall MRD negativity rate was relatively low, and the prognosis for these patients was worse compared to other patients. In the high dose cytarabine-based intensive immunochemotherapy group, patients who achieved a rapid MRD negativity within two cycles of treatment showed a slightly longer PFS compared to those who achieved MRD negativity after 4-6 cycles (P=0.017). However, there was no significant difference in OS between the two groups. Conclusions In summary,the optimal timing for MRD testing is after four treatment cycles, as this time point demonstrated the best predictive ability for survival prognosis. However, the speed of achieving MRD negativity was not found to be linked with survival prognosis. Although certain high-risk features may lead to faster achievement of MRD negativity, this rapidity did not confer any additional prognostic benefit to these patients. Importantly, our results suggest that the value of MRD negativity as a prognostic marker may be limited in patients who have achieved complete remission and those with blastoid/pleomorphic morphologies. These findings underscore the need for tailored approaches to MRD testing and interpretation in MCL, in alignment with individual patient characteristics and treatment responses.

Prospective Evaluation of Measurable Residual Disease (MRD) and Sustainability of the Response in Patients with Systemic AL Amyloidosis Treated with Daratumumab

Background: Daratumumab can provide deep hematologic responses for patients with light chain (AL) amyloidosis, both through its direct anti-clonal activity and immunomodulatory effects on other cell populations in the bone marrow (BM) microenvironment. Promising efficacy in the frontline setting when combined with CyBorD (per the ANDROMEDA trial), as well as in the relapsed/refractory setting as monotherapy, has led to daratumumab becoming the first FDA-approved therapy for AL amyloidosis. Though it is administered for up to 24 cycles, the optimal duration of treatment is unclear. Dynamic monitoring of measurable residual disease (MRD) may provide insights into changes in the aberrant plasma cell (PC) clone and sustainability of the hematologic response in relation to daratumumab therapy. Aims: We sought to evaluate the rates of MRD clearance and resurgence both during and after daratumumab therapy for AL amyloidosis. Methods: MRD status was assessed for patients followed at the Boston University Amyloidosis Center, who were treated with a daratumumab-based regimen and achieved a hematologic very good partial response (hemVGPR) or complete response (hemCR) according to consensus criteria (Palladini, 2012). MRD assessments were performed by multiparametric 10-color flow cytometry of BM aspirates (sensitivity level of ≤10 -5) and repeated at 12-month intervals during follow-up. Clonal progression was defined as growth in the aberrant PC clone size of &amp;gt;1-log. Results: Between 2019 and 2023, a total of 66 patients achieved ≥hemVGPR and were tested for MRD; 43 (65%) received daratumumab monotherapy in the relapsed/refractory setting and 23 (35%) in combination with CyBorD as frontline therapy. Collectively, 48 (73%) achieved a hemCR and 18 (27%) a hemVGPR. The median age at diagnosis was 60 years (range 35-78); 19 (29%) patients were female; and 11 (17%) identified as non-white race. MRD assessment was performed once, twice or ≥3 times for 33, 18 and 15 patients, respectively. The first MRD evaluation occurred while still receiving daratumumab for 33 patients (at median 12 cycles, range 6-23); the remaining patients had their first MRD evaluation after therapy completion (median one month after, range 0-25). Of the entire cohort, 28 (42%) patients achieved MRD negativity and 38 (58%) MRD positivity (median estimated aberrant PC clone size 1.5 x 10 -4, range 1.4 x 10 -5 to 1.1 x 10 -2, representing 46.9% ± 32.8% of total PCs) at first evaluation. All but one patient with a hemVGPR had detectable MRD. Of the 23 patients who received frontline daratumumab-CyBorD (18 hemCR and 5 hemVGPR), 8 (35%) achieved MRD negativity at first evaluation; whereas 20 (47%) of the 43 patients who received daratumumab as monotherapy (30 hemCR and 13 hemVGPR) achieved MRD negativity. We surveyed MRD profiles based on the number of daratumumab treatment cycles received (Table 1) and found no apparent patterns with increasing cycles. Serial MRD monitoring was performed for 33 patients (Figure 1). Of 10 patients who continued to receive daratumumab between MRD assessments (group 1), 6 had sustained MRD negativity; 2 had persistent MRD positivity (of whom one had clonal progression); and 2 had MRD clearance (conversion from positive to negative). Of 23 patients who underwent serial MRD assessments after completing daratumumab (group 2), 9 (39%) had sustained MRD negativity; 10 (43%) had persistent MRD positivity; 2 (9%) had MRD clearance; and 2 (9%) had MRD resurgence (conversion from negative to positive), which occurred 17 and 26 months after daratumumab cessation. Clonal progression was observed in 5 of the 10 patients with persistent positivity, of whom 3 experienced a hematologic relapse. Conclusions: Our findings show that patients with AL amyloidosis can attain deep responses with daratumumab-based treatments, even to the depth of undetectable MRD. Clearance of MRD was frequent not only during treatment with daratumumab but also after completion of therapy, suggesting continuing effects on the plasma cell clone. Clonal progression after daratumumab completion was often associated with hematologic relapse. Prospective studies are needed to investigate whether daratumumab may be stopped early for those with undetectable MRD, or whether those with persistent detectable disease may benefit from extending daratumumab treatment beyond 24 cycles.

Subgroup Analyses of Progression-Free Survival from the Phase 3 Octans and Alcyone Studies in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Bortezomib, Melphalan, and Prednisone with or without Daratumumab

Introduction:Daratumumab, a human IgGκ monoclonal antibody targeting CD38, has shown clinical efficacy in combination with standard-of-care regimens in patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) significantly improved clinical outcomes vs bortezomib, melphalan, and prednisone (VMP) in phase 3 studies in Asian patients (OCTANS) and a global population (ALCYONE) with transplant-ineligible (TIE) NDMM. Here, we present subgroup analyses of progression-free survival (PFS) by measurable residual disease (MRD) and cytogenetic risk status from OCTANS and ALCYONE. Methods: Eligible patients from OCTANS (NCT03217812) and ALCYONE (NCT02195479) had a diagnosis of NDMM and were TIE due to age or comorbidities. Patients were randomized to receive up to nine 42-day cycles of VMP (bortezomib 1.3 mg/m 2 SC twice weekly in Cycle 1 and weekly in Cycles 2-9, and melphalan 9 mg/m 2 and prednisone 60 mg/m 2 orally on Days 1-4 of each cycle) or D-VMP (VMP + daratumumab 16 mg/kg IV weekly in Cycle 1, every 3 wk in Cycles 2-9, and every 4 wk thereafter until disease progression or unacceptable toxicity). MRD negativity (10 -5) was assessed by multi-parameter flow cytometry in OCTANS and next-generation sequencing in ALCYONE. Cytogenetic risk was assessed by FISH or karyotype testing. Results:A total of 220 Asian patients were randomized (D-VMP, n = 146; VMP, n = 74) in OCTANS, and 706 global patients were randomized (D-VMP, n = 350; VMP, n = 356) in ALCYONE. With a median follow-up of 41.2 mo (range, 0.0-59.9) in OCTANS, the median PFS was 38.7 mo with D-VMP and 19.2 mo with VMP (HR, 0.35; 95% CI, 0.23-0.52; P &amp;lt;0.0001). With a median follow-up of 40.1 mo (range, 0.0-52.1) in ALCYONE, the median PFS was 36.4 mo with D-VMP and 19.3 mo with VMP (HR, 0.42; 95% CI, 0.34-0.51; P &amp;lt;0.0001). The rates of overall and sustained MRD negativity were higher with D-VMP vs VMP. In OCTANS, the MRD-negativity rate was 40.4% with D-VMP vs 10.8% with VMP ( P &amp;lt;0.0001), and more patients in the D-VMP group had sustained MRD negativity lasting ≥12 mo (24.7% vs 1.4%; P &amp;lt;0.0001) and ≥18 mo (15.1% vs 1.4%; P = 0.0008). Similarly, in ALCYONE, the MRD-negativity rate was 28.3% with D-VMP vs 7.0% with VMP ( P &amp;lt;0.0001), with more patients in the D-VMP group having sustained MRD negativity lasting ≥12 mo (14.0% vs 2.8%; P &amp;lt;0.0001) and ≥18 mo (8.9% vs 1.7%: P &amp;lt;0.0001). In both studies, longer PFS was observed for patients who achieved MRD negativity vs those who did not within each treatment group; however, the PFS benefit observed for D-VMP vs VMP was maintained irrespective of MRD status ( Figure). In multivariate analyses, achievement of sustained MRD negativity lasting ≥12 mo was associated with longer PFS vs MRD negativity &amp;lt;12 mo in both OCTANS (HR, 0.23; 95% CI, 0.09-0.62; P = 0.004) and ALCYONE (HR, 0.13; 95% CI, 0.06-0.32; P &amp;lt;0.0001). No other factors showed a significant association with PFS in the multivariate analysis for OCTANS; other factors associated with longer PFS in ALCYONE included age &amp;lt;75 vs ≥75 y (HR, 0.38; 95% CI, 0.20-0.75; P = 0.005) and ISS disease stage I vs II (HR, 0.20; 95% CI, 0.05-0.86; P = 0.03). Data from OCTANS and ALCYONE were pooled for an analysis of PFS by cytogenetic risk subgroup (D-VMP, n = 496; VMP, n = 430). D-VMP prolonged median PFS vs VMP in patients with standard cytogenetic risk (not estimable vs 18.9 mo; HR, 0.33; 95% CI, 0.26-0.42) and high cytogenetic risk (25.6 vs 18.9 mo; HR, 0.54; 95% CI, 0.41-0.71), defined by the presence of t(4;14), t(14;16), del(17p), t(14;20), gain(1q21), and/or amp(1q21). Median PFS was also longer with D-VMP vs VMP for patients with gain and/or amp(1q21) (31.9 vs 18.9 mo; HR, 0.45; 95% CI, 0.32-0.63), 1 high-risk cytogenetic abnormality (HRCA; 24.4 vs 19.3 mo; HR, 0.62; 95% CI, 0.44-0.86), and ≥2 HRCA (28.2 vs 17.5 mo; HR, 0.36; 95% CI, 0.20-0.63). Conclusions:In this subgroup analysis of OCTANS and ALCYONE, the prolonged PFS observed with D-VMP vs VMP in the overall study populations was maintained irrespective of the achievement of MRD negativity or the presence of high cytogenetic risk. In addition, the rates of MRD negativity and sustained MRD negativity were higher with D-VMP vs VMP, and achievement of these deep responses translated into longer PFS, consistent with a prior pooled analysis of the MAIA and ALCYONE studies. These results further support the use of daratumumab in combination with VMP in both Asian and global patients with TIE NDMM.

Pivekimab Sunirine (PVEK, IMGN632), a CD123-Targeting Antibody-Drug Conjugate, in Combination with Azacitidine and Venetoclax in Patients with Newly Diagnosed Acute Myeloid Leukemia

Background In unfit patients (pts) with newly diagnosed (ND) AML, long-term survival remains short (mOS 14.7 months) despite improved responses (CR 37% and CR/CRi 66%) with azacitidine (AZA) and venetoclax (VEN) (VIALE-A, DiNardo NEJM 2020). In a pooled analysis of AZA-VEN in ND AML pts with poor risk cytogenetics the response rates were higher in TP53wt pts (CR/CRi 70%) compared with TP53mut pts (CR/CRi 41%) (Pollyea Clin Cancer Res 2022). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). Pivekimab sunirine (PVEK, IMGN632) is a first-in-class antibody-drug conjugate (ADC) comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The novel IGN payload alkylates DNA and causes single strand breaks without crosslinking (Kovtun Blood Adv 2018). Methods This is an ongoing, open-label, multicenter, Phase 1b/2 study of PVEK in combination with AZA +VEN in adults with ND CD123-positive AML (any CD123+ expression by local flow cytometry or IHC). Pts received the recommended phase 2 dose of PVEK 0.045 mg/kg IV on D7 + AZA 75 mg/m 2 SC or IV daily on D1-7 + VEN up to 400 mg PO daily for 14 to 28 days (based on cohort assignment) in a 28-day cycle. Bone marrow assessment was performed at D14 (cohort 1) or D21 (cohort 2) of cycle 1 to determine VEN duration. The primary endpoints are composite CR rate (CCR [CR+CRh+CRp+CRi]), MRD rate (assessed centrally [Hematologics, Inc.] by flow cytometry; &amp;lt;0.1% defined as negative) and duration of remission. Key secondary endpoints are safety, pharmacokinetics and immunogenicity. Responses were determined using ELN 2017 criteria (with the addition of CRh) and a 14-day post-marrow count recovery window. Results As of July 17, 2023, data is available for 50 ND pts (n=25 per cohort) treated with PVEK+AZA+VEN and are aggregately reported here. The median age was 74 years (range, 46-83), 42% were ≥ 75 years old, 26% had secondary AML, 64% were ELN 2017 adverse risk, and 38% had a TP53mut. The most common non-hematologic treatment-emergent adverse events (TEAE) (all grades [grade 3+]) seen in &amp;gt; 20% of all pts were febrile neutropenia (44% [38%]), constipation (42% [2%]), peripheral edema (36% [4%]), diarrhea (36% [2%]), hypophosphatemia (32% [0%], nausea (28% [4%]), and hypokalemia (24% [2%]). No veno-occlusive disease (VOD) events were reported. In responders, the median time to achieve absolute neutrophil count ≥500/µL and platelet count ≥50,000/µL was 35.5 days (range, 20-55) and 22 days (range, 20-55), respectively. The median post-remission cycle delay (beyond cycle day 28) was 14 days. Two pts discontinued PVEK due to a TEAE (edema; marrow aplasia). The 60-day mortality was 4%. In the ITT population (N=50) the CR rate was 52% (26/50), and the CCR rate was 66% (33/50). In pts ≥ 75 years old, the CCR rate was 76% (16/21). In pts known to be TP53wt, both the CR and CCR rate was 88% (22/25). Additional response subsets in Table 1. Twenty-one pts received 9-14 days of VEN, 9 pts received 15-21 days of VEN and 20 pts received ≥ 22 days of VEN in cycle 1; of those who received ≤ 14 days of VEN the CR rate was 71% (15/21) and the CCR rate was 76% (16/21). Of the 26 pts who achieved CCR and had an MRD-evaluable sample, 73% (19/26) achieved MRD negativity (CCR MRD-, &amp;lt;0.1% residual blasts); notably all had undetectable MRD levels (lower level of detection is 0.02%). MRD-negativity was achieved rapidly with a median of 1.7 months (range, 0.8-4.5). CCR MRD- rates were high across major molecular subsets, including FLT3 (ITD/TKD) at 100% (7/7), IDH1/2 at 89% (8/9), and NPM1 at 89% (8/9), as well as ELN risk groups (intermediate 80% [8/10]; adverse 64% [9/14]). Conclusion With a manageable safety profile in pts with ND AML, the PVEK+AZA+VEN triplet demonstrated anti-leukemia activity with robust CR rates and early MRD negative responses in a cohort enriched for adverse disease characteristics (64% ELN adverse risk; 38% TP53mut). Encouraging CCR MRD- rates were observed across cytogenetic/molecular subsets, and the majority of responding pts achieved early and deep remissions, which may translate to improved clinical outcomes. The regimen was well tolerated with no new safety signals, and the addition of PVEK to the AZA-VEN backbone did not appear to meaningfully prolong count recovery.

FLT3 Inhibitors in Combination with FLAG-IDA in Relapsed or Refractory Acute Myeloid Leukemia

1. Introduction The addition of a FLT3 inhibitor improves overall survival in combination with front-line intensive chemotherapy in acute myeloid leukemia (AML). In the ADMIRAL trial, gilteritinib - a second-generation, type I FLT3 inhibitor - improved survival in relapsed or refractory AML compared to intensive chemotherapy. However, it is unknown whether the combination of a FLT3 inhibitor and intensive chemotherapy improves survival in the relapsed or refractory setting compared with intensive chemotherapy alone or intensive chemotherapy with venetoclax in FLT3 mut AML. 2. Methods We analyzed 27 patients with FLT3 mut AML treated with FLAG-IDA for relapsed or refractory disease from January 1, 2013 to April 18, 2023 at VCU Massey Comprehensive Cancer Center. Baseline disease characteristics were obtained, including molecular profiling either through PCR, NGS, or both, alongside cytogenetic risk, doses of induction regimens, response, and survival. We separated patients that underwent treatment with FLAG-IDA and a FLT3 inhibitor (gilteritinib, midostaurin, or sorafenib), venetoclax, or FLAG-IDA alone. Measurable residual disease (MRD) assays were PCR-based when available; otherwise, MRD was assessed through multiparameter flow cytometry. We used the D'Agostino &amp; Pearson method for normality testing and the Kruskal-Wallis test for between-group comparisons. We applied the Bonferroni correction if multiple comparisons were made. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. 3. Results All 27 patients treated with FLAG-IDA harbored mutations in FLT3-ITD (70.3%) or FLT3-TKD (29.6%). Twelve (44.4%) patients received FLT3 inhibitors with FLAG-IDA: eight (66.7%) with midostaurin, three (25.0%) with gilteritinib, and one (8.3%) with sorafenib. Five (41.6%) patients received a FLT3 inhibitor (FLT3i) for previously untreated disease, then subsequently received a FLT3i at disease progression. Ten (37.0%) patients received FLAG-IDA without a FLT3i, and five (18.5%) received FLAG-IDA and venetoclax. The median FLT3 variant allele frequency was 33.96% (95% CI, 5.1-63.9) in the FLT3i cohort, 18.0% (95% CI, 8.0-27.0) in the FLAG-IDA cohort, and 5.0% (95% CI, 3.0-29.0) in the venetoclax cohort. The median prior lines of therapy were as follows: three for the FLT3i cohort, two for the FLAG-IDA cohort, and three for the venetoclax cohort (p = 0.137). There was no difference in the achievement of CRc between the FLT3i and FLAG-IDA groups (27.3% vs 33.3%, p &amp;gt; 0.999) or between the FLT3i and venetoclax groups (27.3% vs 50.0%, p = 0.560). The proportion of responders that achieved MRD negativity was nonsignificantly higher in the FLT3i cohort (75.0% vs 20.0%, p = 0.206). The median overall survival nonsignificantly favored the FLT3i cohort compared to the FLAG-IDA cohort (7.7 months vs 4.1 months, p = 0.992) and the venetoclax cohort (7.7 months vs 6.3 months, p = 0.902). 4. Discussion The addition of a FLT3 inhibitor resulted in nonsignificantly higher rates of MRD negativity and prolonged overall survival when compared to FLAG-IDA alone or FLAG-IDA and venetoclax. The optimal combination regimen for relapsed or refractory FLT3 mut AML is unknown, but likely should include a FLT3 inhibitor. The limitations of our study include its retrospective nature; subsequent FLT3 inhibitor combinations or maintenance strategies may have provided a survival benefit the FLT3i cohort. Therefore, prospective clinical trial designs are needed to further confirm these findings.

Pediatric Patients with Acute Lymphoblastic Leukemia Treated with Blinatumomab in a Real-World Study

Introduction Pediatric B-cell acute lymphoblastic leukemia (B-ALL) involves chromosomal abnormalities and genetic alterations at an early stage of differentiation of lymphoid precursor cells. Most children (~around 80%) with B-ALL can achieve long-term survival with conventional chemotherapy but a sizable number of patients relapse or do not attain complete remission. Blinatumomab is a bispecific T-cell engager antibody designed to redirect CD3+ T cells to bind to CD19+ target cells. Although blinatumomab has been approved for the treatment of relapsed or refractory B-ALL, it has shown efficacy in newly diagnosed B-ALL also. Here, we studied the effect of blinatumomab in newly diagnosed B-ALL (including infantile B-ALL) and post-induction therapy measurable residual disease (MRD) positive B-ALL in a real-world study. Methods Pediatric patients with B-ALL including newly diagnosed infants (infantile type) or with MRD positivity during the induction remission phase, were enrolled. The patients received a 7-day pre-treatment VCP regimen consisting of intravenous infusions of cyclophosphamide 800 mg/m 2 on day 1, vindesine 3 mg/m 2 on day 1, prednisone 1-2 mg/kg on days 1 to 7 (VCP regimen), followed by 28 days of treatment with blinatumomab at 5µg/m 2/day on the first 1 to 7 days and 15 µg/m 2/day on the next 8 to 28 days. Four patients with economic burden received blinatumomab for 14 days: 5µg/m 2/day for days 1 to 4 and 15 µg/m 2/day from day 5 to 14, after pre-treatment with the VCP regimen. Bone marrow assessment of MRD was done on days 14 and 28. Results Between July 2022 and July 2023, 24 pediatric patients received VCP-blinatumomab. Among them, 11 (45.8%) patients had high-risk disease, and 5 (20.8%) had standard risk. The median age of the cohort was 8.5 years. Among the cohort, there was 1 patient with infantile B-ALL and 1 patient with Philadelphia chromosome-positive (Ph+)-ALL; besides 3 patients were TEL-AML positive, 3 patients were CRLF2 positive, 1 patient was E2A-PBX1 positive, 1 patient was SSBP2-CSF1R positive, and 1 patient was EVI1 positive. Blinatumomab was administered to 5 patients in the induction remission period, and for 2 patients, blinatumomab was administered in consolidation after inotuzumab ozogamicin (INO). While 18 patients were treated with blinatumomab for 28 days, 6 patients were treated with blinatumomab for 14 days. Four patients opted for a 14-day regimen due to financial reasons and 2 patients were transplanted with hematopoietic stem cell transplantation after 14 days of treatment with blinatumomab. All the treated patients achieved MRD negativity (100%). There were no ≥ grade 3 treatment-related toxicity and no deaths reported. Conclusion Our study results showed that a 100% MRD negativity rate was achieved in children with B-ALL after treatment with the blinatumomab consolidation following the chemotherapy and no significant safety concerns were observed. Blinatumomab consolidation therapy was also effective in patients pretreated with INO. Blinatumomab consolidation after induction therapy could be a new and effective strategy for the treatment of patients with newly diagnosed B-ALL.

Adult Acute Lymphocytic Leukemia: Strategies for Selection of Consolidation Therapy

The 2 primary treatment options for adult acute lymphoblastic leukemia (ALL) are pediatric-inspired Berlin-Frankfurt-Münster protocols and the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen—these treatment strategies are now being augmented with novel agents. Current strategies also emphasize measurable residual disease (MRD) quantification as a critical tool for determining the treatment course. For patients with MRD-positive ALL, the standard of care has shifted toward blinatumomab, resulting in improved outcomes and survival rates. Another novel agent, inotuzumab ozogamicin, is also being explored for the treatment of earlier stages of disease in patients with ALL. For Philadelphia chromosome (Ph)–negative ALL, the NCCN Guidelines recommend treatment with blinatumomab followed by allogeneic transplants for patients remaining MRD-positive after initial therapy. For patients achieving MRD negativity at the level of 10-4, blinatumomab is now recommended as consolidation, with or without subsequent allotransplant, depending on patient disease risk features. For Ph-positive ALL, the use of tyrosine kinase inhibitors in combination with blinatumomab has demonstrated excellent efficacy, indicating the growing importance of combination targeted therapies to improve outcomes and decrease the toxicity of therapy in adults with ALL.

Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemia: Topline Efficacy and Safety Results from the Pivotal Augment-101 Phase 2 Study

Background: Most patients (pts) with histone-lysine N-methyltransferase 2A (KMT2A)-rearranged (KMT2Ar) acute leukemia, relapse after conventional chemotherapy and hematopoietic stem cell transplant (HSCT). Remission rates after relapse (complete remission [CR], 5%) and median overall survival (2.4 mo) in ≥2nd salvage therapies in adults remain low (Blood Cancer J. 2021;11[9]:162). In KMT2Ar leukemia, interaction of menin with KMT2A fusion proteins is a key driver of leukemogenesis. However, no therapies targeting the menin-KMT2A interaction have been approved. Revumenib (SNDX-5613; rev), a small-molecule inhibitor of menin-KMT2A interactions, demonstrated preliminary efficacy and safety in a phase 1 study of R/R KMT2Ar and nucleophosmin 1-mutated (NPM1m) acute leukemias. We report topline efficacy and safety for pts with R/R KMT2Ar acute leukemia treated with rev in a pivotal phase 2 study (AUGMENT-101; NCT04065399). Methods: Pts aged ≥30 days with R/R KMT2Ar acute leukemia were enrolled in cohort A (acute lymphoblastic leukemia [ALL]/mixed phenotype acute leukemia [MPAL]) and B (acute myeloid leukemia [AML]); cohort C continues to enroll pts with NPM1m and is not included in this analysis. Pts received rev (163 mg or 95 mg/m2 if body weight &amp;lt;40 kg) q12h with a strong cytochrome P450 3A4 inhibitor orally in 28-day cycles. Treatment continued until unacceptable toxicity or lack of at least morphological leukemia-free state (MLFS) after 4 cycles of treatment. Phase 2 primary objectives were safety and tolerability of rev and CR+CR with partial hematologic recovery (CRh) rate. Key secondary endpoints included composite CR rate (CRc, CR+CRh+CR with incomplete platelet recovery [CRp]+CR with incomplete count recovery [CRi]) and overall response rate (ORR, CRc+MLFS+partial remission). A planned interim analysis (IA) of pooled adult and pediatric pts with KMT2Ar acute leukemia was conducted. Results:As of July 24, 2023, 94 pts with R/R KMT2Ar acute leukemia received ≥1 dose of study drug and were included in the safety analysis (Table 1). Median age was 37.0 y (range, 1.3-75.0). Of the 94 pts, 23 (24.5%) were aged &amp;lt;18 y and 13 (13.8%) were aged ≥65 y. Seventy-eight (83%) had AML and 16 (17.0%) had ALL or MPAL. Over half of pts were female; 17.5% of pts were non-White. Pts were heavily pretreated (median 2 [range, 1-11] prior lines of therapy), with 41 pts (43.6%) having received ≥3 prior lines. Fifty-four pts (57.4%) had refractory relapse disease (unresponsive to most recent salvage treatment), and 47 pts (50%) had prior HSCT. Treatment-related adverse events (TRAEs) were reported in 81.9% of the safety population. Most common TRAEs (≥20%) were nausea (27.7%), differentiation syndrome (26.6%), and QTc prolongation (23.4%). Grade ≥3 TRAEs were observed in 51 pts (54.3%), the most common being differentiation syndrome (16.0%), febrile neutropenia (13.8%), and QTc prolongation (13.8%) (Table 2). Overall, 6.4% of pts discontinued therapy due to TRAEs; none discontinued rev due to differentiation syndrome or QTc prolongation. The pooled efficacy population for the IA (n=57) included all phase 2 pts with centrally confirmed KMT2Ar and ≥5% blasts in bone marrow at baseline who had received ≥1 dose of study drug and started treatment on or before the 38th adult AML efficacy evaluable patient. The IA was specified to occur when the 57 patients have had the opportunity to be followed for 6 months. After median follow-up of 6.1 mo, 13 pts (22.8% [95% confidence interval (CI), 12.7-35.8]) achieved CR+CRh, surpassing the predefined IA efficacy boundary for the pooled KMT2Ar population; CR+CRh rate was similar in adult and pediatric pts. Median duration of CR+CRh was 6.4 mo (95% CI, 3.4-not reached). CRc was 43.9% (95% CI, 30.7-57.6); ORR was 63.2% (95% CI, 49.3-75.6). Most pts with a CR or CRh response, and for whom measurable residual disease (MRD) status was reported, achieved MRD negativity (7/10, 70.0%); most pts with CRc and MRD reported also achieved MRD negativity (15/22, 68.2%). Fourteen of 36 responders (38.9%) proceeded to HSCT, with half resuming rev post HSCT. Conclusions: Rev demonstrated clinically meaningful results in a heavily pretreated KMT2Ar population, including high ORR and rates of MRD negativity and subsequent HSCT. At IA, this pivotal study met its primary endpoint and the KMT2Ar cohorts were stopped early for efficacy.

Survival Outcomes, Efficacy and Tolerability of a Pediatric-Inspired Regimen (MASPORE) for Philadelphia-Negative Acute Lymphoblastic Leukemia in Young Adults at a Tertiary Hospital in Singapore

Introduction: Recent evidence has emerged to support the use of pediatric-inspired regimen as a standard of care in Adolescents and Young Adults (AYA) patients diagnosed with Philadelphia-negative acute lymphoblastic leukemia (Ph- ALL). The backbone of the pediatric regimen is high cumulative doses of steroids, asparaginase, vincristine and more intensive CNS prophylaxis. Most literature, however, has been in the western population, with few data reported in Asia. MASPORE protocol is a locally designed pediatric-inspired regimen for treatment of ALL in AYA. The protocol uses a 3- or 4-drugs induction regimen (L-asparaginase, Vincristine, Dexamethasone +/- Daunorubicin) based on standard or high-risk disease. PCR-based measurable residual disease (MRD) marker was utilized for disease monitoring and dynamic risk stratification, which led to subsequent intensification of regimen as needed. Methods: In this IRB approved retrospective analysis, patients aged 18-39 years old with Ph- ALL who received MASPORE regimen from January 2009 to December 2021 at the National University Hospital Singapore were identified via our institution database. Treatment outcomes, including measurable residual disease (MRD) monitoring, and toxicity profile were analyzed. Survival outcomes were estimated using Kaplan-Meier method. High risk disease at diagnosis was defined as high white blood cell (&amp;gt;30x10 9/L for B-ALL, &amp;gt;100x10 9/L for T-ALL), hypodiploidy, t(4;11) and other MLL gene rearrangement. Results: 32 patients were identified during the study period; 3 patients were excluded due to incomplete data. The median age was 23 years old (range 18-33 years) with majority being male (86.2%). 16 patients (55.2%) had B-ALL and 13 (44.8%) had T-ALL. High risk disease was present in 7 (43.8%) B-ALL patients and 8 (61.5%) in T-ALL patients. 2 patients in B-ALL group had CNS involvement at diagnosis. The majority (96.5%) achieved complete remission after the induction phase. 1 patient died within first 1 month of treatment due to pancreatitis. 5 patients in high risk group received allogenic stem cell transplantation (alloSCT), whereas 2 patients with standard risk required alloSCT due to relapse and persistent MRD positivity. MRD result was available for 26 patients. In the entire cohort, MRD negativity was achieved in 22 patients (75.9%). Subtype was not associated with achievement of MRD negativity (80% in B-ALL vs 90.9% in T-ALL). High risk patients however had a lower odds of achieving MRD negativity after induction (OR 0.114 95% CI 0.017-0.742, p=0.021). The median follow-up for survivors was 41 months (range 27 to 89 months). Relapse and mortality rate was low at 13.8% each. 5-year OS for patients with B-ALL and T-ALL were 92.3% and 75.2%, respectively (Figure 1a). 5-year OS for patients with standard and high-risk disease were 84.4% and 84.0%, respectively (Figure 1b). Delayed achievement of MRD negativity (i.e. after induction) was not associated with inferior survival outcomes, albeit our sample size was small. In terms of adverse events, Asparaginase-related toxicities included 11 patients (37.9%) with thrombotic events (4 cerebral venous thrombosis and 7 deep vein thrombosis), and 5 patients (17.2%) with grade 2 or more pancreatitis. 7 patients (24.1%) had at least 1 episode of grade 3 or 4 transaminitis. 7 patients (24.1%) had grade 3 or 4 sepsis during the course of treatment. 2 patients developed osteonecrosis of the hip requiring operation and cessation of steroids. Conclusion: Our locally designed MASPORE protocol tailored in accordance to risk stratification demonstrated promising survival outcomes. Similar outcomes observed in standard and high-risk disease suggests the benefit of such an approach. Toxicities were mainly related to L-asparaginase use. Individualized dosing based on drug level monitoring will help to further optimize the treatment intensity with reduced toxicities.

Real-World Analysis of Treatment Patterns and the Effectiveness and Safety Profile of Daratumumab-Based Regimens in Chinese Patients with Newly Diagnosed or Relapsed/Refractory Multiple Myeloma

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. Several clinical trials have established DARA-based treatment as a standard of care globally for patients with newly diagnosed or relapsed/refractory multiple myeloma (MM). However, clinical trials do not always reflect routine clinical practice, and real-world (RW) studies thus provide an important complement to conventional clinical trials. Herein, we report results from an observational study that described RW treatment patterns and outcomes in routine clinical practice among patients with MM who were treated with DARA in China. This is possibly the first study to enroll a large population of Chinese patients with MM who were treated with DARA in the RW setting. Methods: This ongoing, multicenter, noninterventional, observational registry study is enrolling Chinese patients who have been diagnosed with symptomatic newly diagnosed or relapsed/refractory MM and either (1) started DARA treatment after August 1, 2019, and were expected to continue ongoing DARA at the time of study initiation (November 3, 2021) or (2) started DARA treatment after study initiation. Patients were excluded from the study if they had received ≥4 prior lines of MM therapy before starting DARA-based treatment or had a diagnosis of other cancers prior to their MM diagnosis. The decision to treat with DARA must have been made prior to and independently of the patient's inclusion in the study, and treatment was administered in accordance with local clinical practice. For patients who started DARA after August 1, 2019, but before study initiation, data were collected both retrospectively through medical chart review and prospectively after enrollment. RW baseline disease characteristics, treatment patterns, response rates, measurable residual disease (MRD), and safety are presented. Outcome and safety analyses were based on the DARA treatment period. Results: As of the cutoff date (April 30, 2023) for this analysis, 210 patients who received ≥1 dose of DARA have been enrolled in the study from 13 participating sites in China. At baseline (last status prior to the first DARA dose), patients had a median age of 64 y (range, 29-89) and a median time since MM diagnosis of 1 y (range, 0-12); the majority of patients had an ECOG performance status of 0 or 1 (82.4%) and a Durie-Salmon MM stage of III (74.4%). Most (83.8%) patients had received ≥1 prior line of therapy before initiating DARA, including 82.4% who had received prior protease inhibitors (PIs) and 58.1% who had received prior immunomodulatory drugs (IMiDs). A summary of prior therapies is provided in Table 1. DARA-based therapy included DARA monotherapy (n = 22) or combination with dexamethasone only (n = 21), PIs ± dexamethasone (n = 57), IMiDs ± dexamethasone (n = 71), PIs and IMiDs ± dexamethasone (n = 29), and other combinations (n = 10). The median DARA exposure time was 5.39 mo (interquartile range [IQR], 2.56-9.69), and the median follow-up time was 10.48 mo (IQR, 7.23-15.31). Of the 179 patients evaluable for response, a best overall response of partial response (PR) or better was achieved by 130 (72.6%) patients and a best response of very good partial response (VGPR) or better was achieved by 93 (52.0%) patients, with responses observed across DARA treatment regimens ( Table 2). MRD results were available for 53/179 (29.6%) patients, with 31/53 (58.5%) patients achieving MRD negativity. Adverse drug reactions were reported for 40 (19.0%) patients overall; events reported in ≥5% of patients included leukopenia (6.2%), thrombocytopenia (5.7%), and neutropenia (5.2%). Serious treatment-emergent adverse events were reported for 29 (13.8%) patients, with pneumonia (n = 10, 4.8%) the only serious event reported in ≥5 patients. Twenty-five patients died as of the cut-off date, regardless of timing (with/without DARA treatment period). Conclusions: This noninterventional, observational study provides RW insights into physician treatment decisions for patients with MM in China and the characteristics of patients who are selected for DARA-based treatment. In addition, the RW effectiveness, duration of therapy, and safety results support the use of DARA-based treatment as a standard of care in Chinese patients with newly diagnosed or relapsed/refractory MM. This study is ongoing, with a total planned enrollment of ~220 patients.

Clinical Significance of Measurable Residual Disease (MRD) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated with Chimeric Antigen Receptor (CAR) T Cells and T-Cell Engagers (TCE)

Clinical Significance of Measurable Residual Disease (MRD) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated with Chimeric Antigen Receptor (CAR) T Cells and T-Cell Engagers (TCE)

Allogeneic Hematopoietic Stem Cell Transplantation in Adolescents and Young Adults with Acute Lymphoblastic Leukemia - Retrospective Dual-Center Study

Background: Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are treated with various chemotherapy regimens. Some patients undergo allogeneic hematopoietic stem cell transplantation (HCT) due to high-risk genetic characteristics, chemo-resistant disease (failure to achieve timely measurable residual disease (MRD) negative remissions, or relapse or refractory disease. There is paucity of data on outcomes of AYA ALL patients receiving HCT. Methods: We performed a dual-center analysis of data from MD Anderson Cancer Center (MDACC) and Dana-Farber Cancer Institute (DFCI) to evaluate outcomes of AYA patients who received HCT for Philadelphia-negative (Ph neg) ALL and examined variables that might have an impact on these outcomes. We included all patients who received their first HCT between the ages of 15-40 years between the years 2010-2022. MRD status was evaluated using flow cytometry with a sensitivity of 0.01%. Acute and chronic graft versus host disease (GvHD) were classified according to consensus criteria. The primary endpoint was overall survival (OS), and secondary endpoints included progression rate and non-relapse mortality (NRM). Cox proportional hazards regression analysis was used to evaluate predictors of OS, and Fine and Gray regression for predictors of relapse and NRM. Competing risks were accounted for in analyses pertaining to progression and NRM. Results: A total of 376 Ph neg ALL AYA patients were included in the analysis, 247 from MDACC and 129 from DFCI. The median age at transplant was 25 (range 15-40) years, 39 patients (10%) were aged ≤18 years at time of HCT and 251 (67%) were males.The majority had B-ALL (n=282, 75%), 42 (11%) had complex karyotype and 28 patients (7%) had translocation (4:11). Most patients received either pediatric-inspired (48%) or hyper- cyclophosphamide, vincristine sulfate, doxorubicin, dexamethasone (CVAD) based (42%) frontline induction regimens, and the median time from diagnosis to HCT was 11 (range 2-283) months. At transplant, most patients were in CR1 or CR2 (44% each); 63% of patients achieved MRD negativity prior to HCT. Most patients received an HCT from a matched unrelated donor (MUD) (33%) or a matched sibling donor (MSD) (32%), and most patients received myeloablative conditioning (MAC) (79%) ( Table 1). The cumulative incidence of grade 2-4 acute GvHD and grade 3-4 acute GvHD at 6 months was 37% (95% CI 33%-42%) and 13% (95% CI 10%-17%), respectively. The cumulative incidence of chronic GvHD at 3 years was 28% (95% CI 23%-33%), with most patients experiencing either mild (39%) or moderate (36%) chronic GvHD, and 25% had severe chronic GvHD. For patients transplanted in CR1, CR2 and CR3/PD the estimated 3-year OS was 69% (95% CI 61%-77%), 53% (95% CI 44%-61%) and 29% (95% CI 16%-43%), respectively; the 3-year NRM rate was 9% (95% CI 5%-15%), 18% (95% CI 13%-25%) and 27% (95% CI 16%-43%), respectively; and the 3-year progression rate was 27% (95% CI 20%-35%), 36% (95% CI 29%-45%) and 48% (95% CI 36%-65%), respectively. In multivariate analysis, HCT in CR3/PD was associated with inferior OS (HR 4.3, p&amp;lt;0.001) and higher NRM (HR 2.3, p=0.04, Table 2), however there was no difference in survival between HCT at CR1 vs. CR2 (p=0.3); &amp;gt;2 lines of therapy prior to HCT was associated with inferior OS (HR 1.8, p=0.004) and higher rate of progression (HR 1.9, p=0.008); HCT-CI&amp;gt;3 was associated with inferior OS (HR 1.6, p=0.01) and higher NRM (2.3, p=0.004); positive MRD status prior to HCT was associated with inferior OS (HR 1.9, p=0.004) and higher rate of progression (HR 3.3, p&amp;lt;0.001); use of bone marrow graft was associated with lower rate of progression (HR 0.6, p=0.02) and use of a matched donor (MSD/MUD) was associated with lower NRM (HR 0.5, p=0.01). Conclusions: In this analysis of a large dual-center cohort of AYA Ph -ALL patients that received HCT, we found that patients transplanted in CR1 had the most favorable outcomes with 69% 3-year OS. Patients not in CR1/CR2, patients who received HCT after &amp;gt;2 lines of therapy and those with positive MRD pre-HCT had inferior OS on MVA. Although patients who received HCT at CR3/PD had inferior OS, an estimated one-third of patients were still alive at 3 years after HCT.

Phase 2 study of inotuzumab ozogamicin for measurable residual disease in acute lymphoblastic leukemia in remission

AbstractThe detection of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). Using inotuzumab ozogamicin in the setting of MRD may improve outcomes. Patients with ALL in first complete remission (CR1) or beyond (CR2+) with MRD ≥ 1 × 10−4 were enrolled in this phase 2 trial. Inotuzumab was administered at 0.6 mg/m2 on day 1 and 0.3 mg/m2 on day 8 of cycle 1, then at 0.3 mg/m2 on days 1 and 8 of cycles 2-6. Twenty-six consecutive patients with a median age of 46 years (range, 19-70 years) were treated. Nineteen (73%) were in CR1 and seven (27%) in CR2+; 16 (62%) had Philadelphia chromosome–positive ALL. Fifteen (58%) had baseline MRD ≥ 1 × 10−3. A median of 3 cycles (range, 1-6) were administered. Eighteen (69%) patients responded and achieved MRD negativity. After a median follow-up of 24 months (range, 9-43), the 2-year relapse-free survival rate was 54% and the 2-year overall survival rate was 60% in the entire cohort. Most adverse events were low grade; sinusoidal obstruction syndrome was noted in 2 patients (8%). In summary, inotuzumab ozogamicin resulted in favorable survival, MRD negativity rates, and safety profiles for patients with ALL and MRD-positive status. This study was registered at www.ClinicalTrials.gov as #NCT03441061.

Humoral immune reconstitution following therapy with daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd), autologous hematopoietic cell transplantation, and measurable residual disease-response-adapted treatment cessation.

Quadruplet induction, autologous hematopoietic cell transplant (AHCT), and measurable residual disease (MRD) response-adapted consolidation yield an unprecedented depth of response in newly diagnosed multiple myeloma. Patients treated on MASTER (NCT03224507) ceased therapy and entered active surveillance (MRD-SURE) after achieving MRD negativity. This study characterizes quantitative changes in the immunoglobulin (Ig) gene repertoire by next-generation sequencing and serum gamma globulin levels. Quadruplet therapy leads to profound hypogammaglobulinemia and reduction in the Ig gene repertoire. Immune reconstitution (IR) is delayed in patients who received post-AHCT consolidation compared to those who do not. Eighteen months after treatment cessation, there was no statistically significant difference between the groups.

Achieving MRD negativity in AML: how important is this and how do we get there?

Multiple studies have demonstrated that patients with acute myeloid leukemia (AML) who have measurable residual disease (MRD) detected during or after treatment have higher relapse rates and worse survival than similar patients testing negative. Updated response criteria for AML reflect the understanding that achievement of complete remission (CR) with no detectable MRD using high-sensitivity tests represents a superior response over conventional cytomorphological CR alone. Potential use cases for AML MRD testing are diverse and include patient selection for clinical trials and therapeutic assignment, early relapse detection and intervention during sequential monitoring, and drug development, including deep quantification for antileukemia efficacy and as a surrogate endpoint for overall survival in regulatory approvals. Testing for AML MRD has not, however, been harmonized, and many technical and clinical questions remain. The implications of MRD test results for specific therapeutic combinations, molecular subsets, test types, treatment time points, sample types, and patient characteristics remain incompletely defined. No perfect AML MRD test or testing strategy currently exists, and the evidence basis for clinical recommendations in this rare disease is sparse but growing. It is unproven whether conversion of an MRD test result from positive to negative by additional therapeutic intervention improves relapse risk and survival. Several national- and international-level consortia have recently been initiated to advance the generation and collection of evidence to support the use of AML MRD testing in clinical practice, drug development, and regulatory approvals.

Improved Outcomes with Low-Dose Inotuzumab and Mini-Hyper-CVD Followed By Blinatumomab Consolidation in Relapsed-Refractory Acute Lymphoblastic Leukemia: Results of a Phase II Study

Background: Patients (pts) with relapsed-refractory (R-R) acute lymphoblastic leukemia (ALL) have a poor prognosis. The combination of low-intensity chemotherapy with mini-hyper-CVD (mini-HCVD) and inotuzumab has shown encouraging results. The aim of this study is to evaluate whether the sequential addition of blinatumomab to mini-HCVD-inotuzumab with lower doses of weekly inotuzumab might further improve outcomes. Methods: Pts with Philadelphia chromosome-negative B-cell ALL were included. Odd cycles of mini-HCVD consisted of cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracyclines. Even cycles consisted of cytarabine (0.5 g/m2 given every 12 h on days 2 and 3) and methotrexate (250 mg/m2 on day 1). During the first 4 courses, pts received rituximab when CD20 expression was ≥20%, and intrathecal chemotherapy. Initially, inotuzumab was administered on day 3 of the first 4 cycles at the dose of 1.3-1.8 mg/m2 in course 1, followed by 1.0-1.3 mg/m2 in subsequent courses. Pts received maintenance therapy with POMP, consisting of 1 year of monthly prednisone 50 mg/d for 5 days and vincristine at 2 mg every month, along with 3 years of 6-mercaptopurine 50 mg twice daily and weekly oral methotrexate 10 mg/m2. An amendment to the protocol was made after the inclusion of 67 pts to add 4 cycles of blinatumomab after 4 cycles of the combination mini-HCVD + inotuzumab. Inotuzumab was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m2 in course 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m2 in subsequent courses; blinatumomab was continuously infused over 28 days every 42-day cycle for 4 cycles. Maintenance therapy was reduced to 12 courses of POMP with 1 course of blinatumomab after each 3 courses of POMP for a total of 4 courses. The decision to undergo allogeneic stem cell transplantation (ASCT) was based on the discretion of the treating physician after discussion with the patient. Results: Between February 2013 and July 2021, 112 pts were treated on study, including 45 pts with mini-HCVD + inotuzumab + blinatumomab. Baseline characteristics and outcomes are summarized in Table 1. The median follow-up is 41 months (range, 3-112). Before the study amendment, 67 pts were treated: 38 (57%) in salvage(S)1, and 29 (43%) in S2+. Nineteen pts (28%) had received prior ASCT. After the amendment, additional 45 pts were treated: 42 (93%) in S1, and 3 (7%) in S2+; 3 (7%) pts had prior ASCT. The overall response rate (ORR) was 83% (CR, 63%) in the entire cohort, 76% (CR, 60%) pre-amendment, and 93% (CR, 67%) post-amendment. Among 91 responders evaluable for measurable residual disease (MRD), 76 pts (82%) achieved MRD negativity by multicolor flow cytometry, with higher rates of MRD negativity in S1 (89%). The rates of MRD negativity before and after the amendment were 82% and 85%, respectively. Overall, 53 (47%) pts underwent ASCT: 29 (43%) pts pre-amendment and 24 (53%) post-amendment. The median overall survival (OS) for the entire cohort was 17 months, with a 3-year OS rate of 41%. After the amendment, the addition of blinatumomab resulted in superior median OS (37 months vs 14 months) and 3-year OS rates (55% versus 34%) (Figure 1). Pts in S1 had better survival compared with those in S2+, with 3-year OS of 51% and 17%, respectively (P=0.001). In a 2-month landmark analysis among pts in S1, the median OS was 57 months in those who received blinatumomab compared with 31 months in those who did not. Overall, pts who achieved MRD negativity had higher 3-year OS rate of 55% compared to 10% in pts who were MRD-positive at best response (P=0.0001). Survival with mini-HCVD + inotuzumab +/- blinatumomab compared favorably to that of inotuzumab monotherapy: 17 months vs 6 months; P<0.0001. A 3-month landmark analysis among responders showed similar 3-year OS rates between pts who underwent subsequent ASCT and those who did not (55% vs 48%, respectively). Veno-occlusive disease (VOD) was observed in 10 of the 112 pts (9%), and its incidence was reduced from 13% with single dose of inotuzumab to 2% with fractionated dose schedule (P=0.056). Conclusion: The addition of blinatumomab to mini-HCVD-inotuzumab, along with a lower weekly dose of inotuzumab, further improves the outcomes of pts with R-R ALL. These adjustments reduced the rate of VOD and improved survival. Long-term survival was similar regardless of subsequent ASCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MRD Status and ELN 2022 Predicts for Outcomes of Venetoclax + Hypomethylating Therapy in AML: Single-Center Real-World Analysis

Background Patients (pts) with Acute Myeloid Leukemia (AML) have a bleak prognosis, particularly those who are elderly and/or have significant comorbidities. The treatment paradigm for such patients has shifted to less-intensive regimens, primarily venetoclax (Ven) plus either azacitidine (Aza) or decitabine (Dec). However, to date, it is unclear which regimen is optimal and which new molecular classifications are relevant. We performed a real-world analysis of our center's experience with Ven-based regimens to address the role of measurable residual disease (MRD) and the new ELN2022 in predicting clinical outcomes. Methods We conducted a retrospective review of consecutive adult pts (aged ≥ 18 yo) at Roswell Park Comprehensive Cancer Center with a confirmed diagnosis of AML who received a Ven-based regimen between July 2017 and December 2021. Newly diagnosed (ND) and relapsed/refractory (R/R) AML pts were included. Demographics, disease-specific variables [including cytogenetics and mutations], and outcomes [responses, MRD status by multiparameter flow cytometry, and transplant status] were collected. Responses were defined according to the 2003 International Working Group criteria. For overall survival (OS), Kaplan-Meier method estimated the survival functions and log-rank test was used for between-group comparisons. Cox proportional hazards model was used for multivariable analysis. Univariate associations between categorical variables were assessed using Fisher's exact tests. Logistic regressions were used to evaluate the multivariable association between independent variables and treatment responses. Results 83 pts (63 ND, 20 R/R) were analyzed. Median age was 73 years (range: 32-89); 62.7% were male. 50 pts (60%) received Aza/Ven, 27 Dec/Ven, and 6 (7%) LDAC/Ven. By ELN 2017 criteria, 42 (51.9%) pts had intermediate-risk cytogenetics while 37 (45.7%) had adverse-risk cytogenetics. Per ELN 2022 criteria, 11 (14.9%) had intermediate-risk disease while 58 (78.4%) had adverse-risk disease. Of note, 18 pts with favorable or intermediate-risk disease based on ELN 2017 criteria were re-classified as adverse-risk by ELN 2022 risk stratification, likely due to the addition of 7 mutations in the ELN 2022 risk stratification. 20 pts (24.1%) underwent allogeneic stem cell transplant (alloSCT) after receiving ven-based regimen. Median OS (mOS) for all pts was 11 months (mos) (95% CI: 8-19.5 mos). No significant differences in mOS were observed with gender, age (<75 vs. ≥ 75 yo), or ELN 2017. ND AML pts had significantly improved mOS, vs R/R disease (13 vs. 5.5 mos; p=0.015). ELN 2022 adverse risk (p=0.01) and TP53 mutation (p=0.006) were associated with significantly poorer OS. Pts who underwent alloSCT after receiving ven-based therapy had improved mOS (19.5 vs. 8 mos; p=0.01). Although there was no statistically significant difference in OS due to regimen, there was a trend towards better mOS with Aza/Ven over Dec/Ven (11.3 vs 8 mos, p=0.17) in ND-AML, likely reflecting higher numbers of TP53 mutant pts in the latter group (11.4% vs 37.5%, p=0.025). There was no difference in OS based on ven-based regimens in secondary AML pts. In the entire cohort, the CR/CRi rate was 43%: Aza/Ven 49% vs Dec/Ven 34.6% (p=0.33). In 67 pts with CR/CRi and MRD results, 36 (53.7%) achieved MRD negativity at any time point following therapy. MRD negativity was associated with improved mOS for all pts in univariate analysis (20.25 vs. 7.25 mos; p=0.0013) (Figure 1). MRD status also predicted for outcomes of either regimen (Figure 2). Pts treated with Aza/Ven demonstrated significantly higher rates of MRD neg CR/CRi than Dec/Ven (72.2% vs 22.2%; p=0.037). Multivariate Cox regression analysis demonstrated MRD status, ND vs R/R AML, alloSCT, and secondary AML (but not regimen) as independent factors for OS. Conclusions In this real-world analysis, MRD-positive CR/CRi, TP53 mutation, and ELN 2022 adverse risk were associated with worse OS following Ven-based therapy. AML pts treated with Aza/Ven had higher rates of MRD-negative CR/CRi and a trend to improved OS vs Dec/Ven, possibly due to higher numbers of TP53 mutant pts receiving the latter therapy. Our results, while limited by small pt numbers, support wider adoption of MRD endpoints and improved molecular classification as predictors of outcomes of ven-based therapy. Further comparison of different hypomethylating agents with ven is also warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal