Post-induction Minimal Residual Disease Research Articles

Abstract PR008: Cell state transitions drive the evolution of disease progression in B-cell acute lymphoblastic leukemia

Abstract A mathematical framework is constructed to predict the risk of B-lymphoblastic leukemia (B-ALL) relapse post-induction chemotherapy. The framework is a Markov chain model that quantifies spontaneous cell state transitions between distinct immunophenotypic subpopulations defined by CD34 and CD38 expression relative to neutrophils. Cell states are analyzed via flow cytometry pre- and post-treatment, providing insight into the evolution of cell state transition rates during disease progression. Cancer stem cells (CSCs) are hypothesized to promote tumor progression through innate chemoresistance and self-renewal. Ostensible CSCs were first identified in acute myeloid leukemia and were found to have a CD34+/CD38- immunophenotype similar to hematopoietic stem cells. However, the isolation of CSCs from B-ALL has proved more difficult. B-ALL cells with stem cell-like properties have been reported with variable immunophenotype, perhaps due to temporal variation of CD34 and CD38 expression in this setting. We hypothesized that transitions between stem cell-like, hematogone-like, and naive B-cell-like leukemia subpopulations play a significant role in B-ALL disease progression. To test this hypothesis, we trained a Markov chain mathematical model using flow cytometry characterization of four B-ALL cell states with their normal counterpart appearing in parentheses: CD34+/CD38- (hematopoietic stem cells), CD34+/CD38+ (stage 1 hematogones), CD34-/CD38+ (stage 2 and 3 hematogones), and CD34-/CD38- (naïve B-cells). An iterative numerical search procedure was used to derive patient-specific Markov matrices, describing the stochastic cell state transitions. This flow cytometry evaluation was performed on a cohort of patient samples of peripheral blood (N=46) and bone marrow (N=63) with matched clinical features such as BCR::ABL1 status, comprehensive genomic profiling, minimal residual disease (MRD) post-induction chemotherapy, and 3-year relapse. Critical to our goal of quantifying the evolution of state transition rates, we also obtained bone marrow measurements for a cohort of normal/healthy individuals. Patients were divided into post-induction flow MRD positive (N=16), MRD negative (N=30), healthy (N=6) cohorts, as well as relapsed and non-relapsed cohorts to compare features of the transition matrices. Importantly, pre-treatment flow cytometry derived cell state distribution alone is not predictive of relapse or MRD. In contrast, pre-treatment Markov chain transition parameters are found to be clinically predictive of relapse and MRD. MRD correlates to high reciprocity (the product of incoming and outgoing transitions) of the stem cell state. This approach provides supporting evidence that cell state transitions drive B-ALL disease progression. There is an additional strong correlation between Markov transition parameters and both BCR::ABL1 and BCR::ABL1-like B-ALL classification. Finally, comparison of Markov parameters pre- and post-treatment quantifies the evolutionary selection pressures acting on transition rates induced by chemotherapy treatment. Citation Format: Curtis Gravenmier, Ling Zhang, Lynn Moscinski, Jeffrey West. Cell state transitions drive the evolution of disease progression in B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR008.

TBI, etoposide, and cyclophosphamide conditioning for intermediate-risk relapsed childhood acute lymphoblastic leukemia.

In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care. We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025). Twenty patients with post-induction MRD ≥ 10-3 and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively. Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL.

Outcomes of Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia: An Indian Multi-Institution, Prospective Study from the Haematology Cancer Consortium (HCC)

Introduction One of the commonest genetic abnormalities seen in adult Acute Lymphoblastic Leukemia (ALL) is the reciprocal translocation between chromosomes (Chr.) 9 and 22, leading to the formation of the BCR-ABL fusion gene. This manifests as a shortened Chr 22 (Philadelphia chromosome, Ph+ALL). Despite the widespread use of tyrosine kinase inhibitors (TKI) which target the BCR-ABL fusion protein, Ph+ALL is considered high risk with more relapses and lesser long-term cures. The Haematology Cancer Consortium (HCC) maintains a multi-center database of several hematological malignancies. The ALL database was established in 2018, and the data of the Ph+ALL patients entered into the registry are presented here. The baseline presenting features and induction outcomes were available for all patients, while the survival data is yet to mature. Methods Prospective data of patients (≥ 18 years) with Ph+ ALL (Diagnosed between January 2018 to December 2022) from 10 centers were entered into an independent centralized online data capture system and analyzed for presenting characteristics, treatment, and survival outcomes. Ph+ ALL was defined by the demonstration of t(9,22) [conventional karyotype/ Fluorescent in situ hybridization (FISH)] or the demonstration of BCR-ABL (by polymerase chain reaction) at diagnosis. Treatment (protocol for ALL, TKI used) was per individual-center preference. Intensive protocols (MCP-841, BFM-95, COG), predominantly meant for children, were labeled as “pediatric-type,” and less intense protocols (GMALL, Hyper CVAD, UKALL) were considered “adult-type”. Results In the four years, 1684 patients with ALL registered and 1409 had been tested for Phor BCR-ABL gene, and 292 were labeled as Ph+ALL [Males: 183(63%), Median age: 35 years (18-77); Subtype: B -ALL: 271(93%), T-ALL: 6 (2%), Mixed phenotype: 13 (4%) ; CNS 2 or 3: 60 (18%)]. Of these, 289 underwent treatment. “Pediatric-type” protocols (BFM, MCP841, ICICLE) were used in 241 (84%) patients, followed by the GMALL protocol in 44 patients (15%) and others in 5 patients. TKIs were used in 234 patients (81%) [Imatinib (29%) and Dasatinib (49%)]. Figure 1 shows the baseline characteristics. Induction complications (all grades) were as follows: tumor lysis (18%), pneumonia (11%), neuropathy (15%), pancreatitis (4%), venous thrombosis (5%), and hyperglycemia (44%). After induction, 72% achieved complete remission (CR), 8% were refractory, and 8% died during induction. The rest (12%) were lost from follow-up during induction and were not evaluable. Post-induction minimal residual disease (MRD) status was assessed in 177 patients and was positive in 75 (42%). To date, 21 patients have undergone allogenic transplants. Survival analysis: After a median follow-up of 12 months (0.06-59), 61 patients have relapsed and 57 have died, and 52 (18%) have been lost from follow-up. The estimated 1-year event-free (EFS), relapse-free (RFS), and overall survival (OS) were 85% (S.E:+/-0.027), 87% (+/- 0.033), and 89%(+/- 0.024) respectively ( Figure 2). No factors affecting prognosis were identified in the current analysis. Conclusions In a large prospective database of 12 centers, we found that most adult Ph+ALLs in India are treated with a pediatric-type intensive protocol. Dasatinib is the preferred TKI, followed by imatinib. There was a high degree of treatment abandonment, with an 18% loss from follow-up within six months (including 12% during the induction phase).

A modified CALGB 10403 in adolescents and young adults with acute lymphoblastic leukemia in Central America.

Mexico and Central America have a high incidence of acute lymphoblastic leukemia (ALL) in adolescents and young adults. Historically, this patient group has been treated using adult-based regimens, which entails a high rate of treatment-related mortality and a poor overall survival (OS). The use of the CALGB 10403, a pediatric-inspired regimen, has been proven effective in this patient subgroup. Nonetheless, low- and middle-income countries (LMICs) may present limited access to standard care treatments implemented elsewhere, warranting the need for further research to improve outcomes among vulnerable populations. In this study, we present the outcomes in terms of safety and effectiveness of using a modified CALGB 10403 regimen to reflect drug and resource availability in LMICs. Modifications included the use of Escherichia coli asparaginase,6-mercaptopurine instead of thioguanine and the use of rituximab among patients with CD20+. A total of 95 patients with a median age of 23 (range, 14-49) years treated with this modified scheme were prospectively assessed at 5 centers in Mexico and 1 in Guatemala. Among these, 87.8% achieved a complete response after induction. During follow-up, 28.3% of patients relapsed. Two-year OS rate was 72.1%. Factors associated with worse OS included hyperleukocytosis (hazard ratio [HR], 4.28; 95% confidence interval [CI], 1.81-10.10) and postinduction minimal residual disease (HR, 4.67; 95%CI, 1.75-12.44). Most patients presented hepatotoxicity (51.6% and 53.7% during induction and consolidation, respectively), and the treatment-related mortality was 9.5%. Overall, results highlight that implementing a modified CALGB 10403 regimen in Central America is feasible, and it is associated with improvements in clinical outcomes and a manageable safety profile.

Carfilzomib, lenalidomide, and dexamethasone (KRd) versus elotuzumab and KRd in transplant-eligible patients with newly diagnosed multiple myeloma: Post-induction response and MRD results from an open-label randomized phase 3 study.

8000 Background: In medically fit patients with newly diagnosed (ND) multiple myeloma (MM), triplet or quadruplet induction regimens, high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) remain a standard of care. Carfilzomib (K), lenalidomide (R) and dexamethasone (d, KRd) induction/consolidation has proven exceptionally effective. Elotuzumab (E), an anti-SLAMF-7 monoclonal antibody bears favorable tolerability in relapsed/refractory MM while its role in NDMM remains unclear. Methods: Transplant-eligible (TE) NDMM patients (pts) up to 70 years (yrs) were randomized 1:1 to receive six cycles (C) of KRd or E-KRd, (chemomobilisation for ASCT after C3), single (tandem, if <CR/high risk NDMM) HDT/ASCT, followed by four consolidation C (KRd/E-KRd) and R or ER maintenance. Induction (IND, 28-day C) consisted of K on D1/2, 8/9 and 15/16 (20 mg/m² IV on D 1/2 in C1 and 36 mg/m² thereafter), R (25 mg PO, D1-21) and d (36/40 mg D 1, 8, 15, 22). E was given on D 1, 8, 15, and 22 (C1/C2) and on D 1 and 15 (C3-6; 10 mg/kg IV). After IND, pts underwent restaging when bone marrow was analyzed for minimal residual disease (MRD) by next-generation flow cytometry. The first co-primary endpoint of the study was the rate of pts who were in ≥ VGPR and were MRD negative. The study is registered as NCT03948035. Results: 579 pts (574 of whom received treatment) were randomized between 08/2018 and 10/2021 at 52 sites and included in the intent-to-treat analysis. Median age was 60 (range, 31-71) yrs.15.4% had ISS stage III disease. 108/459 evaluable pts (23.5%) had high-risk cytogenetics (del[17p]; t[4;14]; t[14;16]; ≥ 3 1q21 copies). 525/574 pts (91.5%) completed 6 IND cycles. MRD negativity and ≥ VGPR was achieved in 145 of E-KRd (49.8%) and 102 (35.4%) of KRd patients, respectively (p=.0005). 212 (72.9%) of E-KRd versus 177 (62.5%) of KRd patients experienced treatment-emergent AEs (TEAEs) of ≥ grade 3. Febrile neutropenia occurred in 26 (6.4%) E-KRd versus 14 (4.9%) KRd pts. Grade 3/4 thrombocytopenia was seen in 36 (12.4%) E-KRd and 30 (10.6%) KRd pts. Pneumonia occurred in 24 E-KRd (8.2%) and 18 KRd (6.4%) pts. Grade 3/4 cardiac events occurred in 16 E-KRd (5.5%) and of grades 3 to 5 in 16 (5.7%) of KRd pts. 12 E-KRd (4%) and 9 KRd (3.2%) pts had COVID-19 infections with one grade 5 event each (0.3% and 0.4%, respectively). Three pts on E-KRd (1.0%) versus 7 on KRd (2.5%) died on induction due to infections (N=3), MM progression (2), AML (1), a cardiac event (N=1), other (N=3). Conclusions: In this study, the addition of elotuzumab to KRd significantly improved the rate of early, deep (≥ VGPR) MRD-negative remission in TE NDMM. E-KRd pts had slightly more TEAEs. Events were mainly hematotoxicity. To the best of our knowledge, this is the first study to show a benefit for the addition of elotuzumab to a front-line regimen. Clinical trial information: NCT03948035 .

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

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

ALL-312 Ig/T-Cell Receptor Clonality Testing as a Method for Minimal Residual Disease Monitoring in T-Cell Acute Lymphoblastic Leukemia Patients

Assessment of early response to therapy by minimal residual disease (MRD) monitoring in T-cell acute lymphoblastic leukemia (T-ALL) has been proven to be a fundamental tool for guiding further therapy. Polymerase chain reaction (PCR)-based immunoglobulin (Ig)-T-cell receptor (TCR) clonality testing is a standardized technique for routine diagnosis of lymphoproliferation. It is also widely applied for MRD detection in T-ALL and is most suitable for patients without additional rearrangements detected. To present the clinical significance and utility of a molecular-based approach for post-induction MRD detection in patients with T-ALL. Single-center, descriptive, retrospective study including 11 adult patients with T-ALL treated at the University Clinic for Hematology - Skopje from January 2018 to January 2022. TCR gene analyses were performed in 11 adults with T-ALL. TCR rearrangements in bone marrow samples were analyzed by multiplex fluorescent PCR amplifications of the TCRB-Vβ-Jβ, Dβ-Jβ, TCRG-Vγ-Jy, TCRD-Vδ-Dδ-Jδ, Dδ-Dδ, Vδ-Dδ, and Dδ-Jδ regions and subsequent capillary electrophoresis of PCR products by automatic DNA analyzer, following EuroClonality/BIOMED-2 guidelines. MRD status was assessed at the end of the induction cycle. Patients received a BFM-based protocol or Hyper-CVAD/high-dose methotrexate (HDM) and cytarabine (ARA-C) regimen. TCR rearrangements were detected in all 11 patients. All patients were negative for additional molecular prognostic markers. TCRB and TCRG gene rearrangements were slightly dominant over TCRD (64.3% vs. 50%). A total of 6 adolescents and young adults (mean age: 24 years) were treated with BFM. At the end of the induction regimen, MRD negativity was obtained in 5 patients (83.3%) and was sustained up to 3 months from stem cell transplantation (SCT) in 3 patients. The other 2 patients died from CNS infiltration. Hyper-CVAD/HDM-ARA-C was administered in 5 patients (mean age: 49 years). One patient died during the induction protocol due to intracerebral hemorrhage. Among the others, CR at the end of the first cycle was achieved in 3 patients, and a total of 4 cycles were applied. Two patients proceeded to SCT. The molecular technique for testing Ig/TCR clonality is a useful tool for post-induction MRD monitoring in patients with ALL, directing the further approach and clinical decisions.

Evaluation of MRD-status in post-induction period in pediatric patients with acute lymphoblastic leukemia.

The need to study the significance of minimal residual disease (MRD) at the induction therapy in patients with acute lymphoblastic leukemia (ALL) is beyond doubt. This has been confirmed by many years of work by many research groups. The role of MRD in the late stages of treatment and the impact of these values on patients survival requires research and discussion. To evaluate the influence of MRD-status in post-induction period on survival in patients with acute lymphoblastic leukemia. From 2010 to 2022, 135 patients with primary B-ALL enrolled in ALL-IC BFM 2009 protocol. Median age was 5.4 year (range 1-17). Male was 62 (49,5%) and female 73 (54,1%). The diagnosis was based on WHO 2016 criteria. Stratification on prognostic risk groups was carried out according to protocol criteria. Prednisone response evaluated at day 8 of treatment. The 15th, 33th, and 78th (as post-induction) day response was assessed by bone marrow cytology and level of MRD by flow cytometry. 5y-overall survival (OS) for patients with MRD-negative status on day 15 was 94,4±5,4% and 87,0±3,4% for MRD-positive (p=0,5). On day 33 patients with MRD-negative status achieved 5y-OS in 86,7±5,8% and 89,6±3,5% for MRD-positive (p=0,6).5y-OS for patients with MRD-negative status on day 78 was 90.8±4.0%, MRD-positive - 90,4+6.5%. DFS for MRD-negative status was 88.5±4.5%, for MRD-positive - 66.3±11.8% (p=0,1). EFS for MRD-negative patients was 87.2±4,6% and for MRD-positive 66.3±11.8% (p=0,09). We have found a tendency between MRD status on day 78 and the frequency of relapses in patients. At the moment, there are no reliable data on the effect of post-induction MRD status on survival. The assessment of MRD in the post-induction period has prognostic prospects and requires further study.

Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL

AbstractOncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph− B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10−4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.

Post-Induction Undetectable Minimal Residual Disease at 10 -5 Sensitivity Level within Marrow and/or Stem Cell Graft Overrides Cytogenetic High Risk

Introduction: Post-induction minimal residual disease (MRD) within but not outside (peripheral blood/stem cell graft) of marrow among transplant eligible patients with multiple myeloma (MM) is currently recognized as poor-prognostic. Emerging number of studies are evaluating MRD within the context of cytogenetic risk. In this study we aimed to quantify circulating plasma cells (PCs) by flow in apheresis products (graft=gMRD) and compare with marrow MRD(mMRD) and outcome according to cytogenetics.Patients & Methods: Four hundred eleven subsequent newly diagnosed multiple myeloma (NDMM) patients transplanted (AHCT) between September 2006 - June 2021 were included prospectively. Standard-risk cytogenetics(SR) is defined as t(11;14), t(6;14), or a normal karyotype , whereas del(17p13), t(4;14), t(14;16), t(14;20), + 1q21 and complex findings are high-risk cytogenetics (HR). In the sample drawn for HPSC quantification of the graft and bone marrow, the number of clonal PCs were quantified by Flow. CD27 PC7 orCD27 A750, CD56 A700, CD19 ECD, CD38 FITC orCD38 A750, CD138 APC, CD45 KO, CD81 PE, CD117 PC7, polyclonal Rabbit Anti-Human Kappa or Lambda Chains /FITC antibodies and acquisition of at least 10 5 cells per tube Analysis was performed using the Navios Flow Cytometer (3L10C, Beckman Coulter) using the Kaluza software (Beckman Coulter, USA) according to the criteria defined by Montero et al and also abnormal distribution of kappa vs. Lambda expression. Undetectable MRD was defined as absence of clonal PCs at a sensitivity of 10 -4 prior to 2017(n=217) and 10 -5 after 2017(n=131). MRD assessment is similar in the graft and marrow. Impact of postinduction MRD analysis was performed in 131 patients with MRD data of 10 -5 sensitivity level. Results were reported in the intention-to-treat (ITT) population for mMRD.Results: Median follow-up after AHCT was 61.5 months (range:3.2-168) (prior to 2017) and 17.7 months (range: 3-47.4) (after 2017). Induction regimen consisted of bortezomib without or with immunomodulatory drug (IMID) 78.8%, 2.8% (prior to 2017) and 74.1%, 22.9% (after 2017). Consolidation 18% (n=39/217), 22.1% (n=29/131) (prior and after 2017) and maintenance 21.2% (n=46/217), 35.1% (n=46/131) (prior and after 2017) were administered based on the response to AHCT. Cytogenetically HR was observed 14.1% (n=47) (among total cohort) and 15.8% (n=19) (after 2017 cohort). Post-induction biochemical response distribution among patients with undetectable MRD are shown in Table-1. MRD assessments were performed at a sensitivity of 10 -4 and 10 -5 in graft (n=147 and 76), marrow (n=18 and 4) or both (n=52 and 51). A statistically significant correlation was detected between marrow and graft MRD only at sensitivity level 10 -5 (SE: 0.638, p<0.001). Additionally, correlations between CR and gMRD (Kappa coefficient (SE): -0.284, p=0.03); CR and mMRD (SE: -0.452, p:0.001) were found. Since marrow and graft MRD results are correlated, all graft and marrow results were merged for the multivariate analysis (MVA) (Table-2). Having undetectable vs detectable MRD in either graft or marrow estimates a 2 years-PFS of 83.6% vs 46.5% (p=0.007). Among 42 MRD(-) patients, only four (two with HR)have relapsed. There is a tendency for better two year probability of PFS with undetectable mMRD vs gMRD at 10-5 ( not reached vs 84.7% ; ns)(Figure 1). The patients (after 2017) are divided into four groups according to MRD status and cytogenetic risk stratification: MRD(-)SR (n=35; 29.2%), MRD(-)HR (n=7; 5.8%), MRD(+)SR (n=66; 55%), MRD(+)HR (n=12; 10%). Kaplan-Meier curves revealed significant differences in PFS among these groups (p=0.03) (Figure-2).Conclusion: Our real-world triplet drug induction-based experience shows for the first-time post-induction mMRD and MRD to be correlated with each other and with PFS. PFS with MRD(-) at 10 -5 results have displayed a better outcome compared to 10 -4. MVA showed MRD and age to determine PFS, independent from post-induction CR, ISS and cytogenetic risk. Although observed less frequently, achieving post-induction MRD(-) either in graft or marrow may ameliorate the poor prognosis of HR. With improvement in induction it may be possible to achieve more frequent MRD(-) and thus analyze the impact of each cytogenetics risk group ie 1q amplification separately. Furthermore, MRD in graft may be a non-invasive therapeutic efficacy tool which is subject to less sampling variation. [Display omitted] DisclosuresBeksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau.

Effectiveness and Security of a Modified CALGB10403 in Adolescents and Young Adults with Acute Lymphoblastic Leukemia in Low-and-Middle-Income Countries: A Multicentric Experience in Central America

▪Background:Mexico and Central America have a high incidence of acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA). Chemotherapy with Hyper-CVAD has been widely used with poor outcomes, with a 3-year overall survival (OS) of 25.7% in this group of age.In low-and middle-income countries (LMIC), limitations in supportive care such as low access to neutrophil stimulant agents, antifungal prophylaxis and limited intensive care access, may increase treatment-related mortality. On the other hand, reports suggest that specific high-risk subgroups may be more frequent in Hispanic patients from Mexico and Central America.We hypothesize that the use of a less-myeloablative regimen, based on L-asparaginase could overcome the bad outcomes previously reported.MethodsWe modified the original CALGB 10403 based on local drug-access. We include patients with newly diagnosed Philadelphia-negative B- or T-cell ALL between 14-49 years from 4 centers in Mexico and one in Guatemala.We modified the regimen as following: replaced pegaspargase by E. Coli asparaginase, thioguanine by 6-mercapatopurine and incorporate rituximab 375mg/m2 for 6 doses in CD20 positive patients. After the first interim analysis (October 2019), we replaced the prednisone by dexamethasone during induction. Minimal residual disease (MRD) was assessed by flow cytometry after induction and after first consolidation. We considered high-risk karyotype if MLL-rearrangements, complex or hypodiploid and high-white blood cell count (WBC) if >30 x10 3/mcL for B-ALL or >100 x10 3/mcL for T-ALL.The main objective was to evaluate OS and as secondary objectives to evaluate complete response (CR) rate, relapse-free survival (RFS) and to assess the safety of this regimen.ResultsFrom January 2017 to December 2020, 95 patients have been enrolled with a median age of 23 years (range 14-49). One third (34.6%) had overweight and 11.7% were obese.The majority (92.6%) had a B-cell ALL and a normal karyotype (81.2%). The median WBC was 18.4 x10 3/mcL (0.2-427.7) and 40.9% had a high-WBC.During induction, adverse events (AE) included grade 3/4 elevated bilirubin (21.1%), transaminases (14.7%), hyperglycemia (14.7%), hypofibrinogenemia (44.2%), thrombosis (10.5%), hypersensitivity (2.2%) and pancreatitis (2.1%). During consolidation, AE included grade 3/4 hepatic toxicity (18.9%), hypertriglyceridemia (14.8%), thrombosis (5.3%) and pancreatitis (2.1%).Neutropenic fever occurred in 55.8% during induction (grade 4: 31.5%), and in 32.9% during consolidation (grade 4/5: 5.3%).A dose adjustment due to AE was required in 22.1% during induction and in 23.2% during consolidation. The induction related-mortality (IRM) rate was 7.4%The CR rate was 87.8%. After-induction, MRD was <0.01% in 39.1%, 0.01-0.1% in 39.1% and > 0.1% in 24.6%. Post-consolidation MRD was only measured in 43 patients and was <0.01% in 37.2%. During follow-up, 26.7% relapsed: 62.5% bone marrow (BM) relapses, 25.0% central nervous system (CNS) relapses and 12.5% CNS + BM relapses. Eight patients (8.4%) received an allogeneic-stem cell transplant (HSCT) as consolidation.The 2-year OS was 72.1%. The post-induction MRD <0.1% was associated with a better OS (figure 1A) (HR: 0.17 (95%CI: 0.06-0.55), p=0.003) and a high-WBC with an inferior OS (figure 1B) (HR: 4.13 (95%CI: 1.68-10.14), p=0.002).The 2-year RFS was 65.2%. The post-induction MRD <0.1% was associate with a better RFS (figure 1C) (HR: 0.19 (95%CI: 0.07-0.50), p=0.001) and a high-WBC and overweight / obesity with an inferior RFS (HR: 4.08 (95%CI: 1.71-9.73), p=0.001 and 2.50 (95%CI: 1.06-5.86), p=0.036 respectively) (figure 1D).Conclusions:The adoption of modified CALGB10403 regimen in Central America based on local resources is feasible. It is associated with a significant improvement in the OS and decrease in IRM when compared with previous reports. Despite a very high-rate of hepatic and metabolic toxicities, these were manageable. As reported by other groups, MRD, high-WBC and overweight/obesity are associated with poor outcomes.Despite being encouraging results, a significant number of patients persist with positive MRD and the main cause of dead is disease progression. Access to cellular therapies, and BiTes is cost restricted in LMIC. Hence, we should generate strategies to intensify treatment in MRD positive patients and expand transplant access to overcome outcomes. [Display omitted] DisclosuresRangel-Patiño: Bristol: Consultancy; Abbvie: Speakers Bureau. Ceniceros: Amgen: Speakers Bureau. Espinosa: Amgen: Speakers Bureau; Janssen: Consultancy; Pfizer: Consultancy. Amador: Abbvie: Consultancy, Speakers Bureau; Bristol: Consultancy. Cabrero Garcia: Takeda: Speakers Bureau; Abbvie: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Astellas: Consultancy; BD: Speakers Bureau. Inclan-Alarcon: Janssen: Speakers Bureau; Boehringer: Speakers Bureau. Neme Yunes: Janssen: Consultancy, Speakers Bureau; Bristol: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bristol: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Meillon-García: Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Astellas: Consultancy. Apodaca: Sanofi: Consultancy; Asofarma: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Demichelis: Bristol/Celgene: Consultancy, Speakers Bureau; Astellas: Consultancy; Gilead: Consultancy; ASH: Research Funding; Abbvie: Consultancy, Speakers Bureau; AMGEN: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Jazz: Consultancy.

Clinical Features and Survival According to Minimal Residual Disease in a Colombian Population Diagnosed with B-Cell Acute Lymphoblastic Leukemia

IntroductionAcute lymphoblastic leukemia (ALL) is a clonal hematopoietic disorder that originates from B or T lymphoid progenitors and has well validated prognostic and predictive factors that influence outcomes. One of the strongest prognostic factors is the detection of minimal residual disease (MRD) which measures residual cell population after treatment when a morphologic complete response has been achieved. MRD positivity is associated with a higher risk of relapse and poor response to chemo or radiotherapyObjectivesThe aim of the study was to assess the prognostic impact of post-induction MRD status in a cohort of ALL Colombian patients in terms of relapse-free survival (RFS) and overall survival (OS).MethodsThis is a retrospective observational study conducted at a Colombian university hospital and included a cohort of ALL patients diagnosed between 2013 and 2020 treatment according to protocol PETHEMA (Spanish Program for Hematology Treatments). MRD was measured with 8-color flow cytometry evaluate on bone marrow. MRD status was classified as negative MRD (NMRD) or positive MRD (PMRD) based on a sensitivity threshold of <0,01% or ≥0,01% leukemic cells, respectively, following to international guides. Demographic and clinical characteristics were analyzed using descriptive statistics. Kaplan-Meier method was used to assess overall RFS and OS.ResultsA total 128 patients were included. The median age at diagnosis was 34 years (range 0-89 years), 54% were men, 26% were overweight, 22% obese, 6.2% had type 2 DM (T2DM), and most had a ECOG PS of £2 (94%). Most patients (80.5%) had high risk according PETHEMA, B-ALL and were classified as ALL-2 (58%) according to FAB classification with Pre-B cell ALL being the most common phenotype (54.7%). Ph+ ALL was diagnosed in 12% of patients. Most used treatments protocols were PETHEMA-AR and PETHEMA-RI in 43.8% and 11.6% of patients, respectively. Post-induction MRD measurement was available in 98 patients, 36 (36.7%) had NMRD and 62 (63.3%) PMRD. From the 36 patients with NMRD, eight patients (22.2%) received Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT): two of them, were transplanted in first complete remission, one because of high risk and the other one for BCR-ABL positivity. The other six patients received alloHSCT in second remission and all of them relapsed after late consolidations. Finally, alloHSCT was done in 28 patients with PMRD (45.2%).The 12-month OS for patients with NMRD was 68.7% (95%CI 50.5-81.2) compared to 63.7% (95%CI 50.3-74.4) in the ones with PMRD, p=0.375. 12-month RFS was 83.3% (95%CI 61.5-93.4) in patients with NMRD and 90.0% (95%CI 72.1-96.7) in patients with PMRD, p=0.436. (Figure 1). OS was significantly higher for the PMRD patients who underwent AlloHSCT 96.4% (95%CI 77.2-99.4) versus not underwent 36.8% (95%CI 20.6-53.2), HR: 0.39 (95%CI 0.005-0.29) p=0.002 (Figure 2).ConclusionMRD assessment is a strong prognostic in ALL, however it was not associated with significant differences in RFS or OS in this single institution cohort of Colombian patients. Patients with PMRD taken to AlloHSCT had superior OS compared to NMRD that underwent transplant. A small sample size and short follow-up could explain our results. Larger cohorts with extended follow up and with different MRD methods are needed to better understand the role of MRD assessment in minority ALL populations, such as Colombian patients. [Display omitted] DisclosuresPeña: Amgen: Research Funding. Salazar: Amgen: Research Funding. Sandoval-Sus: BMS: Other: Advisory Board, Speakers Bureau; SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board. Sossa: Amgen: Research Funding.

P-038: Postinduction minimal residual disease (MRD) within stem cell graft (gMRD) correlates with marrow MRD (mMRD) and progression free survival (PFS) following autologous stem cell transplantation

<h3>Background</h3> Earlier studies have reported the impact of clonal plasma cell contamination within stem cell grafts as a negative prognostic factor. In this study we aimed to quantify circulating plasma cells (cPCs) by flow in apheresis products (gMRD) and compare with marrow (mMRD) and outcome. <h3>Methods</h3> All consecutive (September 2006 - July 2020) newly diagnosed transplant eligible multiple myeloma (MM) patients were included prospectively. In the sample drawn for HPSC quantification of the graft and bone marrow (only if response is ≥VGPR), the number of cPCs were quantified by Flow. As described earlier (Montero et al.) undetectable MRD is defined as absence of cPCs at a sensitivity of 10-4 (n=54) between 2006-2016 and 10-5 (n=37) after 2017. MRD assessment is similar in the graft and marrow. Statistical analysis was performed on merged data regardless of sensitivity of MRD assessment. Results were reported in the intention-to-treat (ITT) population for mMRD. <h3>Results</h3> Patients were given either Bortezomib based triplet without immunomodulatory drug (IMID) ((85.7%)) or with an IMID (17.6%) as induction. The median age was 62 years (range:37-75 years). 86 (94.5%) patients had cytogenetics by FISH at diagnosis, of which 14% had high risk. Extramedullary disease was detectable among 14.3%. Post-induction complete response (CR) was achieved in 28.6% (n=26). Following mobilization, gMRD was detectable in 57.1% of patients. CR rate among gMRD (+) vs. (-) patients were: 14/26 (26.9%) vs 12/39 (30.8%). Kappa coefficient (SE): -0.036, p:0.8) pointing to lack of correlation between gMRD and biochemical response. Undetectable mMRD was reached among 26.4%. Among the patients with CR mMRD detectable vs. undetectable: 15/67 (22.4%) vs 11/24 (45.8%) (SE: -0.151, p:0.03) points to a correlation between mMRD levels and biochemical response. Among 39/91 gMRD(-) patients, undetectable mMRD(-) was also observed in 46.2%. A statistically significant correlation between gMRD and mMRD (SE: 0.364, p<0.001) was calculated. Patients with undetectable gMRD displayed a better PFS compared to patients with detectable gMRD (NR vs 37.5 months). There were insignificant differences in median PFS according to the undetectable mMRD (n=24) at level 10-5 vs 10 -4 (NR vs 37.5 months; p=0.9). In addition, achievement of post-induction undetectable mMRD plus gMRD was also associated with improved PFS (HR: 0.04 p=0.01) with no relapse. Having detectable MRD in either graft or marrow estimates a 2 years-PFS of 61.1 % (p=0.07). <h3>Conclusions</h3> Our real-world triplet drug induction-based experience shows for the first time postinduction marrow and graft MRD to be correlated with each other and with PFS. A non-invasive cellular residual disease measurement within graft at either 10-4 or 10-5 level may be an additional end point for therapeutic efficacy.

Early Detection of WT1 minimal Residual Disease Predicts Outcome in Acute Myeloid Leukemia and Identify Patients with High Risk of Relapse Independently of Allogeneic Stem Cell Transplantation

Background:WT1 overexpression is frequently identified in acute myeloid leukemia (AML) andhas been reported as a potential marker for minimal residual disease (MRD) monitoring. However, the role of WT1 MRD response as prognostic and/or treatment stratifying factor is still under debate.Aims: In this work, we evaluated the prognostic value of post-induction WT1 MRD level, as well as the interaction between post-induction WT1 MRD response and the effect of allogeneic stem cell transplantation (SCT) in first complete remission (CR), in a cohort of AML patients aged 18 to 59 years old treated in the Acute Leukemia French Association (ALFA)-0702 trial.Methods: Among the 713 patients enrolled in ALFA-0702 study (X. Thomas et al, JCO 2017), 539 had an overexpression of WT1 at diagnosis (75.6%) defined as a ratio WT1 transcript/100 ABL transcript above 25% in bone marrow (BM) or 5% in peripheral blood (PB) samples (WT1+). After induction, MRD levels were assessed using cDNA-based real-time quantitative PCR. Occurrence of a WT1 MRD ratio >2.5% in BM or >0.5% in PB was defined here as positive MRD (MRDpos), while ratio under these threshold was defined as negative MRD (MRDneg). The prognostic value of MRD was assessed by comparing cumulative incidence of relapse (CIR) with death in remission as competing event, relapse-free survival (RFS) and overall survival (OS) among patients who achieved first CR. As patients with favorable-risk AML according to European LeukemiaNet (ELN)-2010 classification were not eligible for SCT in first CR, interaction between MRD response and SCT effect was evaluated in patients with intermediate/unfavorable-risk AML by comparing the influence of SCT, considered as a time-dependent covariate, on the outcomes of MRDneg and MRDpos patients.Results: Among the 539 WT1+ patients at diagnosis, 473 achieved CR (87.7%). Post-induction WT1 MRD evaluation was available in 339/473 patients (71.7%), 279 patients were MRDneg and 60 were MRDpos. At this early time point, MRD was predictive of relapse: 4-year CIR was 36.5% in MRDneg patients versus 69.2% in MRDpos patients (Cause-Specific Hazard Ratio, 2.88 [1.93-4.29]; p<0.001). When adjusted on age, cytogenetics, NPM1 mutation status and FLT3-ITD status, MRD remained independently associated with relapse incidence (CSHR, 2.15 [1.41-3.29]; p<0.001). This translated into longer survival in MRDneg patients. At 4 years, RFS was 60.9% versus 24.9% (HR, 2.69 [1.89-3.83]; p<0.001) and OS was 71.6% versus 43.3% (HR, 2.34 [1.56-3.51]; p<0.001) in MRDneg and MRDpos patients, respectively. When adjusted on age, cytogenetics, NPM1 mutation status and FLT3-ITD status, MRDneg remained independently associated with longer RFS (HR, 2.12 [1.47-3.07]; p=0.001) and OS (HR, 1.79 [1.18-2.73]; p<0.001).We then analyzed the role of SCT in 254 patients with intermediate/unfavorable-risk AML and available post-induction WT1 MRD evaluation (199 MRDneg, 55 MRDpos). SCT was performed in 155 patients. Overall, both MRD and SCT were independent prognostic factors. Post-induction MRD response remained of strong prognostic value, since MRDpos patients had a higher CIR (CSHR, 2.33 [1.54-3.53]; p<0.001) and a shorter RFS (HR, 2.25 [1.55-3.26]; p<0.001). In this population, SCT was beneficial and significantly improved CIR (CSHR, 0.33 [0.22-0.51]; p<0.001) and RFS (HR, 0.53 [0.37-0.76]; p=0.001). Despite a higher effect of SCT in MRDneg patients (Figure 1), the interaction between MRD status and SCT effect was not statistically significant (p= 0.3).Conclusions: Our study confirms the prognostic value of post-induction WT1 MRD in younger adults with AML treated in the prospective ALFA-0702 study. The observation that early WT1 MRD response retains its prognostic value among patients independently of allogeneic SCT in first CR might help selecting these patients more accurately in the next future. [Display omitted] DisclosuresRenneville:CELGENE: Research Funding. Recher:Novartis, Celgene, Jazz, Sunesis, Amgen: Consultancy; Celgene, Sunesis, Amgen, Novartis: Research Funding. Rousselot:BMS: Research Funding; Pfizer: Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Presence of Post Induction Minimal Residual Disease (MRD) Is an Independent Predictor for Relapse and Is Associated with Inferior Survival in Acute Myeloid Leukemia (AML)

Background:Acute myeloid leukemia (AML) is a highly heterogenous condition. Current risk stratification based on cytogenetics and molecular genetic markers at point of diagnosis is used to predict treatment response and relapse risk. The conventional way of defining complete remission (CR) is based on morphological identification of ≤5% blasts seen in bone marrow. However, this does not provide adequate insight to the quality of response as there is still a high proportion of patients that relapse despite being in CR.A significant proportion of AML patients have detectable MRD post induction. There is increasing evidence to support MRD as a significant prognostic factor for clinical outcome. Despite this, MRD status has yet to become an important factor in deciding on subsequent allogeneic stem cell transplant (allo-SCT). This study assessed the role MRD in predicting risk of relapse and survival rates and also looked into the role of allo-SCT in abrogating the adverse risk of MRD.Methods:All AML cases excluding acute promyelocytic leukemia who underwent curative chemotherapy from year 2001 until 2015 were retrospectively identified. Clinical data was gathered from computerized patient data system. Baseline patients and disease characteristic were correlated with post induction MRD status. MRD was assessed by flow cytometry analysis of bone marrow samples taken on day 26-30 days of post-induction. Samples from year 2001 to 2011 were analyzed using 4 color flow, and from 2011 onward, all samples were analyzed using 8 color flow. Leukemia-associated antigens were identified at baseline and followed up for MRD. Data collected were analyzed using SPSS Statistic Desktop V22.0.Results:235 patients underwent intensive chemotherapy. 61.7% achieved complete remission (CR) after induction chemotherapy. Among those who achieved CR after induction, 41.3% have detectable MRD. 42.8% eventually relapsed, after a median follow-up of 36.6 months. Median duration of CR was 49.5 months. The presenting WBC, LDH, time taken for neutrophil count or platelet count recovery after induction, cytogenetic risk group and FLT3-ITD and NPM1 molecular status did not correlate with MRD status.Post induction MRD positive status was associated with higher relapse rate, 42.6% vs 22.4% for MRD positive and negative respectively, p=0.015, (OR = 1.9) (95% CI: 1.14-3.19).In the multivariate analysis that include presenting WBC, LDH, BM blasts, risk group and post induction MRD status, risk group and MRD status remained an independent predictor for relapse. HR 1.95 (95% CI: 1.00-3.79), p=0.049 for positive MRD status, while adverse risk group gave a HR of 7.15 (95%CI: 2.01-25.49), p=0.002.The 3-year Leukemia free survival (LFS) was 38.3% and 59.6% for MRD+ and MRD- group respectively (p=0.043) (figure 1), while the overall survival (OS) was 55.5% and 69.5% for MRD+ and MRD- group respectively (p=0.388).55 patients underwent allo-SCT, 26 in MRD+ group and 29 in MRD- group. There was no statistical significance in terms of LFS among those who underwent allo-SCT according to MRD status (Median LFS were 13.1 months for MRD+, 29.2 months for MRD-, p=0.328). In the intermediate or adverse risk group who did not undergone allo-SCT, the median LFS in MRD+ group was only 2.5 months (95%CI: 0.0-21.2) compared to MRD- group, 39.9 months (p=0.041), (figure 2).Conclusions:Post induction MRD+ was associated with higher relapse rate and reduced LFS. Post induction MRD- status was associated with excellent LFS among AML with intermediate and adverse risk even without allo-SCT. Allo-SCT may be able to abrogate the adverse outcome of MRD+ AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic Significance of Minimal Residual Disease in Patients with Secondary Acute Myeloid Leukemia

BACKGROUNDSecondary acute myeloid leukemia (AML) is defined as AML that develops from a prior myelodysplastic or myeloproliferative disorder, or from exposure to chemotherapy, radiation, or environmental toxins. Patients with secondary AML have inferior prognosis compared to those with de novo AML,1 and are more likely to be elderly with increased comorbidities and worse performance status.2 The detection of minimal residual disease (MRD) also has independent prognostic value in patients with AML.3-6 In elderly AML patients, MRD predicts worse outcomes independent of the poor treatment risk factors associated with increased age.7Due to the similar disease pathogenesis between elderly AML and secondary AML patients, it is likely that MRD testing will have similar implications. However, there is limited data on the prognostic role of MRD testing in secondary AML. METHODSWe retrospectively analyzed de novo and secondary AML patients at Washington University Medical Center who received post-induction, post-consolidation, pre-transplant, or post-transplant MRD testing during their treatment. MRD testing was performed with multiparameter flow cytometry testing using the “different from normal” method at one reference laboratory,8,9 with positive MRD defined as detection of an abnormal myeloblast population above 0.1%. A total of 180 patients were included. Any patient with at least one positive MRD was considered “MRD positive.” Baseline pretreatment characteristics were compared between groups with Mann-Whitney, Chi-square, or Fisher's exact test, when appropriate. We evaluated overall survival (OS) and relapse rates in de novo and secondary AML patients stratified by MRD status using Kaplan-Meier curves and the log rank test, or cumulative incidence function, as appropriate. Multivariate Cox proportional hazards model was also fitted to determine if MRD testing has similar prognostic value across de novo and secondary AML patients. RESULTSOur analysis included 133 patients with de novo and 47 patients with secondary AML. Secondary AML patients were significantly older at age of diagnosis (mean age 59.85 versus 51.17, p<0.001), however had similar rates of MRD positivity (28% versus 29%, p=0.830). There was a trend toward poorer cytogenetic risk profiles and worse Karnofsky Performance Status in secondary AML (Table 1). In all patients, we confirmed that MRD positivity confers significantly worse OS (45.5% versus 70.8%, p=0.020) and relapse rates at 2 years (53% versus 25.5%, p=0.029) (Figure 1). In de novo AML patients, MRD positivity continued to demonstrate significantly worse 2-year OS (44.1% versus 76.3%, p=0.006) and relapse rates (57.6% versus 20.7%, p=0.008). However, in secondary AML patients, there were no differences in OS (p=0.69) or relapse rates (p=0.98) between MRD positive and negative patients. Multivariate analysis demonstrated significant interaction (p=0.042) between MRD status and AML subtypes. MRD positivity emerged as an independent prognostic indicator of worse OS in de novo patients (HR 2.8, 95% CI 1.524-5.405) but not in secondary patients (HR 1.5, 95% CI 0.188-2.336). DISCUSSIONWe confirm that MRD status is a poor prognostic indicator in all AML patients, and this also holds true in patients with de novo AML. However, we found that MRD status has less prognostic value in secondary AML patients. This may be due to the overall poor prognosis seen in secondary AML patients, suggesting that MRD monitoring in this group of patients may be less useful for risk stratification. However, our study is limited by the small sample size, particularly in the number of secondary AML patients who displayed MRD positivity (N=13). In addition, we defined MRD positivity across all time points of testing, which may decrease patient homogeneity. A larger study with increased follow-up is necessary to confirm our findings, as these results have important implications in risk-stratification and treatment of patients with secondary AML. [Display omitted] DisclosuresDiPersio:BMS, Asterias, Amphivena, Bluebird: Other: Travel, Accomodations, Expenses; Hemedicus, DAVA Oncology: Speakers Bureau; Celgene, Bioline, Vasculox, Cellworks, Rivervest: Consultancy; Magenta Therapeutics: Equity Ownership.

Prognostic Implications of Minimal Residual Disease Detection in Acute Myeloid Leukemia (AML) with Cytarabine Based Therapy of Differing Dose Intensities

Prognostic Implications of Minimal Residual Disease Detection in Acute Myeloid Leukemia (AML) with Cytarabine Based Therapy of Differing Dose Intensities

MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL.

Simple SummaryIn acute lymphoblastic leukemia (ALL), once a complete remission is achieved following induction chemotherapy, the study of submicroscopic minimal residual disease (MRD) represents a highly sensitive tool to assess the efficacy of early chemotherapy courses and predict outcome. Because of the significant therapeutic progress occurred in adolescent and young adult (AYA) ALL, the importance of MRD in this peculiar age setting has grown considerably, to refine individual prognostic scores within different genetic subsets and support specific risk and MRD-oriented programs. The evidence coming from the most recent MRD-based studies and the new therapeutic directions for AYA ALL are critically reviewed according to ALL subset and risk category.In many clinical studies published over the past 20 years, adolescents and young adults (AYA) with Philadelphia chromosome negative acute lymphoblastic leukemia (Ph− ALL) were considered as a rather homogeneous clinico-prognostic group of patients suitable to receive intensive pediatric-like regimens with an improved outcome compared with the use of traditional adult ALL protocols. The AYA group was defined in most studies by an age range of 18–40 years, with some exceptions (up to 45 years). The experience collected in pediatric ALL with the study of post-induction minimal residual disease (MRD) was rapidly duplicated in AYA ALL, making MRD a widely accepted key factor for risk stratification and risk-oriented therapy with or without allogeneic stem cell transplantation and experimental new drugs for patients with MRD detectable after highly intensive chemotherapy. This combined strategy has resulted in long-term survival rates of AYA patients of 60–80%. The present review examines the evidence for MRD-guided therapies in AYA’s Ph− ALL, provides a critical appraisal of current treatment pitfalls and illustrates the ways of achieving further therapeutic improvement according to the massive knowledge recently generated in the field of ALL biology and MRD/risk/subset-specific therapy

Caloric and nutrient restriction to augment chemotherapy efficacy for acute lymphoblastic leukemia: the IDEAL trial

Being overweight or obese (OW/OB) during B-cell acute lymphoblastic leukemia (B-ALL) induction is associated with chemoresistance as quantified by minimal residual disease (MRD). We hypothesized that caloric and nutrient restriction from diet/exercise could lessen gains in fat mass (FM) and reduce postinduction MRD. The Improving Diet and Exercise in ALL (IDEAL) trial enrolled patients 10 to 21 years old, newly diagnosed with B-ALL (n = 40), in comparison with a recent historical control (n = 80). Designed to achieve caloric deficits ≥20% during induction, reduce fat intake/glycemic load, and increase activity, IDEAL's end points were FM gain (primary), MRD ≥0.01%, and adherence/feasibility. Integrated biology explored biomarkers of OW/OB physiology. IDEAL intervention did not significantly reduce median FM change from baseline overall (+5.1% [interquartile range [IQR], 15.8] vs +10.7% [IQR, 16.0]; P = .13), but stratified analysis showed benefit in those OW/OB (+1.5% [IQR, 6.6] vs +9.7% [IQR, 11.1]; P = .02). After accounting for prognostic factors, IDEAL intervention significantly reduced MRD risk (odds ratio, 0.30; 95% confidence interval, 0.09-0.92; P = .02). The trial exceeded its adherence (≥75% of overall diet) and feasibility (≥80% completed visits) thresholds. Integrated biology found the IDEAL intervention increased circulating adiponectin and reduced insulin resistance. The IDEAL intervention was feasible, decreased fat gain in those OW/OB, and reduced MRD. This is the first study in any hematologic malignancy to demonstrate potential benefit from caloric restriction via diet/exercise to augment chemotherapy efficacy and improve disease response. A prospective, randomized trial is warranted for validation. These trials were registered at www.clinicaltrials.gov as #NCT02708108 (IDEAL trial) and #NCT01317940 (historical control).

Low incidence of ABL-class and JAK-STAT signaling pathway alterations in uniformly treated pediatric and adult B-cell acute lymphoblastic leukemia patients using MRD risk-directed approach \u2013 a population-based study

BackgroundABL-class and JAK-STAT signaling pathway activating alterations have been associated with both a poor post-induction minimal residual disease (MRD) response and an inferior outcome in B-cell acute lymphoblastic leukemia (B-ALL). However, in most of the studies patients received non-uniform treatment.MethodsWe performed a population-based analysis of 160 (122 pediatric and 38 adult) Lithuanian BCR-ABL1-negative B-ALL patients who had been uniformly treated according to MRD-directed NOPHO ALL-2008 protocol. Targeted RNA sequencing and FISH analysis were performed in cases without canonical B-ALL genomic alterations (high hyperdiploids and low hypodiploids included).ResultsWe identified ABL-class fusions in 3/160 (1.9%) B-ALL patients, and exclusively in adults (p = 0.003). JAK-STAT pathway fusions were present in 4/160 (2.5%) cases. Of note, P2RY8-CRLF2 fusion was absent in both pediatric and adult B-ALL cases. Patients with ABL-class or JAK-STAT pathway fusions had a poor MRD response and were assigned to the higher risk groups, and had an inferior event-free survival (EFS) / overall survival (OS) compared to patients without these fusions. In a multivariate analysis, positivity for ABL-class and JAK-STAT fusions was a risk factor for worse EFS (p = 0.046) but not for OS (p = 0.278) in adults.ConclusionsWe report a low overall frequency of ABL-class and JAK-STAT fusions and the absence of P2RY8-CRLF2 gene fusion in the Lithuanian BCR-ABL1 negative B-ALL cohort. Future (larger) studies are warranted to confirm an inferior event-free survival of ABL-class/JAK-STAT fusion-positive adult patients in MRD-directed protocols.