Unfavorable Cytogenetics Research Articles

Expression Pattern and Prognostic Significance of the Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 in Chronic Lymphocytic Leukemia.

Dysregulated expression of the long non-coding RNA MALAT1 has been implicated in the pathogenesis and progression of a variety of cancers, including hematological malignancies, but it has been poorly investigated in chronic lymphocytic leukemia (CLL). In this study, the expression of MALAT1 was measured using a quantitative reverse-transcriptase polymerase chain reaction in the peripheral blood mononuclear cells of 114 unselected, newly diagnosed CLL patients in order to analyze its association with clinical, laboratory, and molecular patients' characteristics at diagnosis, as well as its prognostic relevance. MALAT1 was found to be upregulated in CLL patients in comparison to healthy controls, and expression levels were not related to age, leukocyte, lymphocyte and platelet count, serum β2-microglobulin, and IGHV somatic hypermutational status. On the other hand, high MALAT1 expression was associated with several favorable prognostic markers (high hemoglobin, low serum lactate dehydrogenase, earlier clinical stages, CD38-negative status), but also with unfavorable cytogenetics. Furthermore, an association between high MALAT1 levels and longer time to first treatment and overall survival in IGHV-unmutated CLL subtype was observed. In summary, our results imply that high MALAT1 expression at diagnosis may be a predictor of better prognosis and point to MALAT1 expression profiling as a candidate biomarker potentially useful in clinical practice.

The roles of phosphorylation of signaling proteins in the prognosis of acute myeloid leukemia.

Signaling pathways of Retinoblastoma (Rb) protein, Akt-kinase, and Erk-kinase (extracellular signal-regulated kinase) have an important role in the pathogenesis of acute myeloid leukemia. Constitutive activation of these proteins by phosphorylation contributes to cell survival by regulation of cell cycle, proliferation and proapoptotic signaling processes. According to previous data phosphorylated forms of these proteins represent a worse outcome for cancer patients. We investigated the presence of phosphorylated Rb (P-Rb), Akt (P-Akt) and Erk (P-Erk) proteins by Western blot technique using phospho-specific antibodies in bone marrow or peripheral blood samples of 69 AML patients, 36 patients with myelodysplastic syndrome (MDS) and 10 healthy volunteers. Expression level of PTEN (Phosphatase and tensin homolog) and PHLPP (PH domain and leucine-rich repeat Protein Phosphatase) phosphatases, the negative regulators of Akt kinase pathway were also examined. We tested the effect of these proteins on survival and on the correlation with known prognostic features in AML. We found 46.3% of AML patients had detectable P-Rb, 34.7% had P-Akt and 28.9% had P-Erk protein. 66.1% of patients expressing PTEN, 38.9% PHLPP, 37.2% both PTEN and PHLPP and 32.2% neither PTEN nor PHLPP phosphatases. Compared to nucleophosmin mutation (NPMc) negative samples P-Erk was significantly less in nucleophosmin mutated patients, P-Rb was significantly less in patients' group with more than 30G/L peripheral leukocyte count by diagnosis. PHLPP was significantly present in FAB type M5. The expression of P-Rb represented significant better overall survival (OS), while P-Akt represented significantly worse event-free survival (EFS) in unfavorable cytogenetics patients. The presence of both PHLPP and PTEN phosphatases contributes to better OS and EFS, although the differences were not statistically significant. We confirmed significant positive correlation between P-Akt and PHLPP. Assessing the phosphorylation of Rb, Akt and Erk may define a subgroup of AML patients who would benefit especially from new targeted treatment options complemented the standard chemotherapy, and it may contribute to monitoring remission, relapse or progression of AML.

MRD Assessment in Patients with Newly Diagnosed Multiple Myeloma Using Tokenized Real World Data Sources

Introduction The depth of response in multiple myeloma (MM) after therapy is closely related to the prognosis of the disease. Robust data supports minimal residual disease (MRD) as prognostic after induction, auto-SCT, consolidation; during maintenance therapy; and in the R/R treatment setting. MRD is also prognostic despite unfavorable cytogenetics or transplant eligibility. Accordingly, clinical practice guidelines recommend the assessment of MRD after each phase of treatment, and MRD negativity is increasingly considered an important treatment goal. However, understanding how MRD is currently utilized in routine clinical practice across institutional and community settings is challenging. We have adopted an existing claims-based algorithm and linked MRD test results to explore assessment patterns and attainment of MRD negativity across lines of treatment and patient transplant status in the real-world setting. Methods The study uses Adaptive's internal MRD data linked with HealthVerity closed payer claims data through privacy-preserving record linkage (PPRL) tokenization. PPRL allows for private patient records across different data sources to be linked and shared without transmitting protected health information (PHI). The data source used is Source 20 from the Healthverity Marketplace, representing the largest available source of closed medical and pharmacy claims from health insurers. The data covers 120 million total individuals from over 120 unique payers including commercial, Medicare, and Medicaid, providing a comprehensive treatment journey of the patients. Newly diagnosed MM patients (NDMM) were identified as adults with a diagnosis of MM between January 2015 and December 2022 (the first observed MM diagnosis as Index Diagnosis), with continuous Medical and Pharmacy coverage at least 6 months during pre-index and 12 months during post-index periods. Patients were further required to have initiated MM treatment within 60 days of Index Diagnosis, had at least one MRD assessment using NGS MRD (clonoSEQ® Assay - Adaptive Biotechnologies), and no enrollment in clinical trials nor prior MM treatment pre-index. Lines of therapy were identified following an established algorithm (Fonseca, 2020). We describe patient characteristics, treatment journey, and assessment of MRD test results at a sensitivity of 10 -5 in accordance with IMWG guidance. Results The study identified 244 NDMM patients meeting the above criteria, of which 79 received transplant. Median age was 63 for transplant patients and 65 for non-transplant patients, 60% of all patients were male, and 80% were diagnosed before 2021. The percentage moving to next treatment was greater for transplant patients compared to non-transplant patients (2L: 46%, 3+ line: 19% vs. 2L: 35%, 3+ line: 12%). In both cohorts, front-line therapy usually consisted of an IMiD + dex doublet. For transplant patients, 62% and 46% achieved MRD- at some point during treatment at 10 -5 and 10 -6 thresholds, respectively. Similar MRD- attainment was seen in the non-transplant group (70% and 50%). A total of 562 MRD assessments were performed for these cohorts with a mean of ~2 per patient. The number of patients with >=2 MRD was 50 (63.3%) for transplant, and 91 (55.2%) for non-transplant. Among transplant patients, 88.8% of the MRD tests were performed post-transplant. Among non-transplant patients, 92.9% of the MRD tests were performed on 2L or later. Conclusion This analysis allows us to understand attainment of MRD negativity by transplant status and line of treatment in the real-world setting. Additional data sources are required to confirm outcomes. This study represents the first effort to enrich MRD test results with external claims data sources though tokenized linkage and provides additional patient treatment journey information as identified by the claims data.

Patients with Down Syndrome and High-Risk B-Acute Lymphoblastic Leukemia Demonstrate Improved Outcomes on a Modified Chemotherapy Regimen: A Report from Children's Oncology Group Study AALL1131

Introduction: Children with Down syndrome (DS) have a 20-fold increased risk of developing B-acute lymphoblastic leukemia (B-ALL), and demonstrate an increased risk of both relapse and treatment-related mortality (TRM). The Children's Oncology Group (COG) High-Risk (HR) B-ALL trial AALL0232 was permanently closed to DS HR patients due to excessive TRM, primarily due to overwhelming sepsis during times of severe neutropenia. On the successor HR B-ALL trial AALL1131, a primary objective for DS patients was therefore to reduce TRM by enhancing supportive care and modifying some elements of therapy. Methods: DS HR patients were treated on a single non-randomized stratum, with several modifications compared to non-DS HR patients. The majority of DS HR patients received a three-drug Induction, with only slow early responders (M2/M3 marrow at Induction day 15) receiving a single dose of anthracycline (daunorubicin 50 mg/m 2). Interim Maintenance 1 (IM-1) consisted of four IV courses of intermediate dose (ID; 2,000 mg/m 2) rather than high-dose methotrexate (HD MTX; 5,000 mg/m 2), with leucovorin rescue beginning earlier, at hour 30 and advancing if tolerated to hour 36, rather than at hour 42. Maintenance modifications included administration of vincristine/steroid pulses every 12 instead of every 4 weeks, and equal duration of therapy for boys and girls. Results: Patient characteristics (Table 1) were similar among the 280 DS HR patients and 5,612 non-DS HR patients except for more frequent bone marrow minimal residual disease (BM MRD) >0.01% in DS vs non-DS patients both at end of Induction (EOI; 54.1% vs 34.9%, p <0.0001) and at end of consolidation (EOC; 23.9% vs 12.0%, p=0.001). DS HR patients were also less likely to have favorable or unfavorable cytogenetics (p <0.0001). In terms of tolerability of the modified IM-1 phase, the duration was significantly longer in DS vs non-DS patients (mean 80.0 ± 16.6 days vs 74.0 ± 14 days, p <0.0001), and delays over 14 days were significantly more frequent (9.7% vs 4.7%, p=0.001). Nevertheless severe toxicities during IM-1 were low, with only 2 DS HR cases of grade 4 mucositis, 2 grade 4 infections, and 1 grade 5 event (sudden death, not otherwise specified). AALL1131 successfully achieved an induction death rate <10% in DS HR patients, although the rate remained significantly higher than in non-DS patients (3.6% vs 1.7%, p=0.035). Event-free survival (EFS) and overall survival (OS) in DS HR patients were improved compared to outcomes on older trials but remained significantly lower than non-DS patients (Figure 1), with 5-year EFS 69.1 ± 3.1% vs 79.5 ± 0.6% (p <0.0001), and 5-year OS 83.3 ± 2.5% vs 88.4 ± 0.5% (p=0.0005). Among DS HR patients, outcomes were particularly poor among those with EOC MRD >0.01% compared to those with EOC MRD <0.01% (5-year EFS 25.8 + 9.9% vs 62.2 + 6.6%, p <0.0021; 5-year OS 54.0 + 12.2% vs 88.1 + 4.5%, p <0.0003). Conclusion: AALL1131 achieved the goal of decreasing induction mortality for DS HR patients, and the modified IM-1 phase utilizing ID MTX with early leucovorin rescue was well-tolerated, with minimal grade 4-5 toxicities, despite a longer mean duration and more frequent treatment delays compared to non-DS patients receiving HD MTX. DS HR patients continued to demonstrate disparities in EOI and EOC MRD levels, as well as in 5-year EFS and OS. Innovative strategies utilizing targeted therapies and immunotherapy are needed to further improve outcomes for patients with DS HR ALL.

Real-World Utilization of Daratumumab in Front-Line Treatment of Newly Diagnosed Multiple Myeloma: A Retrospective Observational Study

Introduction: Daratumumab (DARA), a CD38 monoclonal antibody, has demonstrated remarkable efficacy among newly diagnosed (ND) and relapsed/refractory multiple myeloma (MM) patients. The introduction of a quadruplet therapy with an addition of DARA per the GRIFFIN trial has improved the treatment paradigm. However, the real-world data on treatment patterns and utilization of DARA in front-line treatment are limited. This study aimed to evaluate the real-world utilization of DARA in front-line treatment and examine factors that may impact the utilization of DARA-based regimen in NDMM. Methods: We conducted a retrospective observational study of all patients, age ≥ 18, with clinical MM who were newly diagnosed and treated within the Yale New Haven Health (YNHH) system between August 1, 2020 and August 31, 2022. We manually reviewed clinical presentation, age at diagnosis, gender, race, ethnicity, Revised International Staging System (R-ISS) stage, Eastern Cooperative Oncology Group (ECOG) performance status (PS), insurance type, practice setting, immunoglobulin (Ig) isotype, hemoglobin (Hb), creatinine (Cr), and calcium (Ca) at diagnosis, presence of bone lesion, bone marrow plasma cell (BMPC) %, cytogenetic abnormalities, transplant eligibility, and treatment response based on the International Myeloma Working Group (IMWG) criteria at 3 months after front-line therapy. Descriptive statistics were performed with Pearson's χ²-test using GraphPad PRISM version 9.0.0. Results: We identified 241 patients with NDMM during the study period within the YNHH system. Overall median age at diagnosis was 69 years (interquartile range: 61-78). 60.2% (n=145) were male, 68% (n=164) identified themselves as white and 90% (n=217) as non-Hispanic. 51.9% (n=125) had R-ISS stage II and 65.6% (n=158) had ECOG PS of 0-1. 63.1% (n=152) were treated at a community practice setting and 53.9% (n=130) had commercial insurance. 55.6% (n=134) had IgG isotype and 41.1% (n=99) had unfavorable risk cytogenetics which was defined as a 17p deletion, t(4;14), t(14;16), t(14;20), gain or amplification of 1q, 1p deletion, and chromosome 1 translocations. 28.2% (n=68) received front-line quadruplet therapy: DARA+lenalidomide (LEN)+bortezomib (BORTE)+dexamethasone (DEX) (n=54), DARA+cyclophosphamide+BORTE+DEX (n=10), or DARA+LEN+carfilzomib (CARFIL)+DEX (n=4). 58.5% (n=141) received triplet therapy, 8.3% (n=20) received doublet therapy, 0.83% (n=2) received monotherapy, and 4.1% (n=10) opted for hospice care. 41.5% (n=100) received DARA in front-line treatment: quadruplet as above (n=68), triplet of DARA+LEN+DEX, DARA+BORTE+DEX, or DARA+CARFIL+DEX (n=31), and doublet of DARA+DEX (n=1). Factors including gender (male vs. female, p=0.018), practice setting (academic vs community, p=0.014), R-ISS stage (I vs II vs III vs unknown, p=0.003), Ig isotype (IgG vs IgA vs light chain vs other, p=0.006), cytogenetic abnormalities (standard risk vs unfavorable risk, p=0.02), and transplant eligibility (transplant eligible vs transplant ineligible, p=0.001) were associated with the adoption of DARA in front-line treatment. While 51.7% (n=46) of the patients treated at an academic practice setting received DARA in front-line treatment, only 35.5% (n=54) of the patients treated at a community practice setting received such treatment. 69% (n=69) of those who received DARA-based regimen in front-line treatment achieved at least a very good partial response (VGPR) at 3 months compared to 54.6% (n=77) of those who received non-DARA-based regimen. There were no significant differences in age, race, ethnicity, ECOG PS, insurance type, laboratory data (Hb, Cr, and Ca) at diagnosis, presence of bone lesion, and BMPC % between the group treated with DARA-based regimen and the group treated with non-DARA-based regimen. Conclusion: This analysis of real-world data from patients with NDMM highlighted underutilization of DARA in front-line treatment, especially at a community practice setting. Gender, practice setting, R-ISS stage, Ig isotype, cytogenetic abnormalities, and transplant eligibility were significantly associated with the adoption of DARA in front-line treatment. Additionally, utilization of DARA in front-line treatment was associated with a better treatment response at 3 months, suggesting that interventions to promote the utilization of DARA will help improve outcomes of NDMM patients.

Uproleselan Added to Cladribine Plus Low Dose Cytarabine (LDAC) in Patients with Treated Secondary Acute Myeloid Leukemia (TS-AML)

AML arising from HMA-treated myeloid disorders, also known as “treated-secondary AML” (ts-AML) is associated with an adverse prognosis (Complete Remission [CR] rates 15-30% and median Overall Survival [OS] 6-10 months). E-selectin, a marker of cell survival and resistance to chemotherapy, is highly expressed in the leukemic microenvironment. Exposure of leukemic blasts to HMAs has been shown to increase its expression. Uproleselan is an e-selectin antagonist that has demonstrated antileukemic activity in AML. We sought to study the combination of low-intensity chemotherapy with Cladribine + LDAC (CLAD/LDAC) with uproleselan to overcome local and microenvironmental resistance. This Phase Ib/II clinical trial (NCT04848974) evaluate the safety, tolerability, and efficacy of Uproleselan added to Cladribine and LDAC. A 3+3 dose-escalation approach was implemented to evaluate 2 different dose levels for Cladribine (CLAD)+ LDAC; each 4-week cycle consists of Uproleselan (at fixed dose of 800mg intravenously [IV]). Induction and reinduction if required, included IV uproleselan twice a day from day 1-12; consolidation was given same days but once a day if patients(pts) achieved response (complete response[CR] with incomplete hematological recovery [CRi] or morphologic leukemia-free state [MLFS]). CLAD was IV for 5 days (3.75mg/m2 and 5mg/m2; level -1 and 1 respectively) and subcutaneous LDAC twice daily 10 days (15mg, and 20mg; level -1 and 1 respectively) during induction; consolidation was similar except it was with 3-days of CLAD, for up to 6 cycles, pts aged ≥18 years with a diagnosis of ts-AML with adequate organ function, who have not received therapy for their AML were enrolled. ts-AML is defined as AML arising from previously treated myeloid neoplasm. Presence of the e-selectin was assessed as exploratory analysis. 20 pts have been treated, 18 pts evaluable: 14 (70%) male, median age was 72 yrs (range, 58-86); at the start of therapy, the median bone marrow blasts were 26.5% (20-82%), median WBC was 2.1x10 9/L (0.6-26.4), and median platelets were 26x10 9/L (4-667). Pts had received a median of 1 (1-6) treatments prior to AML transformation. Prior diagnoses were: Chronic Myelomonocytic Leukemia (CMML), MDS, and MDS/MPN in 3 (25%), 14 (70%), and 1 (5%) respectively; all had received HMA, 11 (55%) additionally had received Ven, and 5 (25%) had stem cell transplantation (SCT) prior to enrolling. All pts had unfavorable cytogenetics by ELN 2022. The most frequent mutations were: TET2, TP53, RUNX1 and SRSF2 in 9 (45%), 7 (35%), 6 (30%) and 6 (30%) pts respectively. 18 pts were evaluable for e-selectin; median plasmatic concentration was 26.2ng/mL (15.3-131 ng/mL). Most common AEs were grade(gr) ≥3 neutropenic fever (13 pts, 65%; including 2 gr 5 events), gr 3 bleeding (10%) and gr 2 thrombosis (5%). There were no dose-limiting toxicities observed on dose levels -1 or 1. The chosen dose level was 1 as described above. 2/3 pts who received dose level -1 died during the study follow-up due to sepsis in the first 4-week after induction. Median time to 0.5x10 9/L neutrophil and 50x10 9/L platelets recovery was 30 (17-52) and 38 (20-69) days, respectively. The response rates were 2 (11%) CRi, 1 (6%) CRp, and 4 (22%) MLFS. There was a reduction in BM blasts in 13 pts (72%) (Figure 1). The ORR was 50%(5/10) ( p=0.60) and 20% (1/5) ( p=0.06) among pts who had prior Ven exposure or prior SCT, respectively. The median cycles received was 1.5 (1-4), median cycles at which the best response was achieved was 1 (1-2). 12 pts were taken off protocol due to progression, 3 for death, 3 for allogeneic SCT and 1 continued in remission. The pt who achieved negative MRD-negative by flow cytometry underwent SCT and is still alive. The median follow-up is 8.1 months. Median OS and EFS were 5.3 and 1.4 months respectively; 4-month RFS (CRi, CRp and MLFS) was 30% (Fig 2). In the univariate analysis by Cox regression for plasmatic E-selectin concentration the HR for OS was 1.016 (95% CI 1.002-1.031). Ts-AML, progressing from previously treated antecedent myeloid disorders, is associated with low rates of remission and poor OS. Uproleselan combined with Cladribine + LDAC was well-tolerated with minimal therapy-related AEs - allowing a safe approach to marrow blast reduction and disease control in preparation for a potential allogeneic SCT. We are currently determining the relationship of plasmatic e-selectin concentration and response to treatment.

Prognostic impact of complex and/or monosomal karyotypes in post-transplant poor cytogenetic acute myeloid leukaemia: Aquantitative approach.

To evaluate the prognostic impact of complex karyotype (CK) and/or monosomal karyotype (MK) in combination with various clinical factors on allogeneic stem cell transplantation (HSCT) outcomes of patients with acute myeloid leukaemia (AML), we analysed the registry database of adult AML patients who underwent allogeneic HSCT between 2000 and 2019 in Japan. Among 16 094 patients, those with poor cytogenetic risk (N = 3345) showed poor overall survival (OS) after HSCT (25.3% at 5 years). Multivariate analyses revealed that CK and/or MK (hazard ratio [HR], 1.31 for CK without MK; 1.27 for MK without CK; and 1.73 for both), age at HSCT ≥50 years (HR, 1.58), male sex (HR, 1.40), performance status ≥2 (HR, 1.89), HCT-CI score ≥3 (HR, 1.23), non-remission status at HSCT (HR, 2.49), and time from diagnosis to HSCT ≥3 months (HR, 1.24) independently reduced post-HSCT OS among patients with poor cytogenetic risk AML. A risk scoring system based on the multivariate analysis successfully stratified patients into five distinct groups for OS. This study confirms the negative effects of CK and MK on post-HSCT outcomes, and offers a powerful risk scoring system for predicting prognoses after HSCT among AML patients with unfavourable cytogenetics.

Efficacy and safety of allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients aged > 65 years with unfavorable cytogenetics

Unrelated donor bone marrow transplantation (UR-BMT), unrelated donor cord blood stem cell transplantation (UR-CBT), and haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) are the main alternative stem cell sources for allogeneic hematopoietic cell transplantation (HCT) in Japan. The present study aimed to identify factors associated with the outcomes of UR-BMT, UR-CBT, and Haplo-PBSCT in older patients with acute myeloid leukemia (AML) and intermediate- or poor-risk cytogenetics to improve the clinical efficacy and safety of allogeneic HCT. We retrospectively analyzed data for 448 AML patients aged > 65 years who received UR-BMT (n = 102), UR-CBT (n = 250), or Haplo-PBSCT (n = 96) between 2014 and 2020. Overall survival (OS) in the UR-BMT group was superior (P = 0.033) to that in the other groups. However, all patients without complete remission (non-CR) who had Karnofsky performance status (KPS) < 80 at HCT and poor-risk cytogenetics died within 1 year after HCT. Multivariate Cox regression analysis identified KPS <80 at HCT and poor-risk cytogenetics as independent predictors of worse OS in non-CR patients. KPS < 80 may be an alternative indicator for non-CR AML patients with poor-risk cytogenetics during the selection of HCT, alternative treatments, or best supportive therapy, and the optimal KPS is important for the success of HCT.

Therapy-related core binding factor acute myeloid leukemia.

Therapy-related acute myeloid leukemia (t-AML) usually stems from exposure of the bone marrow to cytotoxic chemotherapy and/or radiation therapy. t-AML is usually associated with poor overall survival, but occasionally t-AML can involve favorable-risk cytogenetics, including core binding factor AML (CBF-AML), which shows a recurrent chromosomal rearrangement with t(8;21) (q22;22) and 'inv(16) (p13.1;q22)/t(16;16)(p13.1;q22)', leading to 'RUNX1::RUNX1T1 and CBFB::MYH11' fusion genes, respectively. Therapy-related CBF-AML (t-CBF-AML) accounts for 5-15% of CBF-AML cases and tends to have better outcomes than t-AML with unfavorable cytogenetics. Although CBF-AML is sensitive to high-dose cytarabine, t-CBF-AML has worse overall survival than de novo CBF- AML. The objective of this review is to discuss the available data on the pathogenesis, mutations, and therapeutic options in patients with t-CBF-AML.

SMYD2 Expression: Its Relationship to Cytogenetic and Prognosis in a Newly Diagnosed Childhood B-Acute Lymphoblastic Leukemia.

The SMYD2 gene adjusts lysine residues on histones and non-histone proteins such as transcription factors, signaling kinases, and cell cycle regulators affecting the cell fate and other genes' expression. As it acts as an oncogene, SMYD2's expression levels may affect tumor progression. In this prospective study, our main aim was to determine the association of SMYD2 gene expression with the prognostic parameters of childhood B-acute lymphoblastic leukemia (B-ALL) and evaluate its influence on disease prognosis. SMYD2 gene expression was measured in the peripheral blood (PB) samples of 116 newly diagnosed B-ALL patients and 23 controls using real-time polymerase chain reaction (RT-PCR). SMYD2 expression was significantly higher in the childhood B-ALL patients compared with the control group, p-value < 0.001. The patients with unfavorable rather than favorable structural chromosomal abnormalities had significantly higher SMYD2 mRNA levels, p < 0.001. SMYD2 expression levels were positively correlated with total leucocytes count (r = 0.206, p-value = 0.027) and peripheral blood blasts (r = 0.225, p-value = 0.015). There was a statistical difference between the B-ALL cases with high versus low SMYD2 levels regarding translocation (t12; 21), p-value = 0.015. Cox regression analysis identified the increased levels of SMYD2 as an independent prognostic factor affecting both OS and DFS. The SMYD2 gene plays a vital oncogenic role in childhood B-ALL. The association of high SMYD2 levels with unfavorable cytogenetics in childhood B-ALL may be helpful in understanding the relationship between structural chromosomal abnormalities and epigenetic dysregulation. High SMYD2 levels may be useful in the prediction of prognosis in childhood B-ALL.

Proteomics-Based Strategy for the Recommendation of Conventional Chemotherapy Vs Venetoclax Plus Hypomethylating Agents in Adult Acute Myeloid Leukemia (AML)

INTRODUCTION: Newer AML therapies with Hypomethylating Agents & Venetoclax (HV) provide an alternative to Conventional Chemotherapy (CC), with anthracycline and cytosine arabinoside, but criteria to select which to use are lacking. We investigated whether proteomic classification could provide guidance. METHODS: Using Reverse Phase Protein Array (RPPA) methodology, the level of 405 proteins (327 total; 78 post-translational modified) were measured in 818 samples from newly diagnosed adult AML patients and normalized to normal CD34+ cells. Patients treated with HV (N=85) or CC (N=335) were analyzed. Overall Survival (OS) and Complete Remission Duration (RD) analysis was performed with pairwise LogRank tests (p < 0.05), adjusted for False Discovery Rate (FDR), to identify individual proteins predictive of outcome. Patients were clustered based on protein expression. Categorical clinical variables were compared with Fisher's Exact test with simulated p-values (10000 replicates), and continuous ones with Kruskal-Wallis test. Univariate (UV) and Multivariate (MV) models were built with Cox proportional hazards model (CoxPH). Deep neural network analysis using random forest was performed to create a Protein Classifier for treatment recommendation. RESULTS: Individual protein analysis found 55 prognostic proteins (Protein Selector 1 - PS1), which clustered patients into 3 groups. A preferred therapy for cluster 2 was not identified with PS1, so a second Protein Selector 2 (PS2) was generated, identifying 45 predictive proteins in this subset. From the PS1/2 analysis, the 95 proteins formed 4 distinct expression profiles (C1=red, C2=gold, C3=magenta, C4=green) which were stratified by treatment (HV or CC), as shown in Fig. 1. Patients in C2 were enriched for secondary AML (57% vs C1=41%, C3=33%, C4=32%; p<0.001) and unfavorable cytogenetics (41% vs C1=32%, C3=39%, C4=35%; p<0.001), and were older (60yo vs C1=61yo, C3=54yo, C4=56yo; p<0.001). Mutations in CEBPA, GATA2, FLT3 and NPM1 were more common in C4 (22%, 13%, 35%, 35% vs C1=12%, 1.7%, 5.7%, 6%; C2=7.8%, 6.2%, 18%, 15%; C3=9.3%; 1.4%, 29%, 21%; p=0.037, p=0.013, p<0.001, p<0.001, respectively), highlighting the heterogeneity between groups. We evaluated OS and RD (Fig. 2) in each cluster (C1=red, C2=gold, C3=magenta, C4=green), considering each treatment (HV= solid line, CC=dashed line). Patients in C1 and C2 treated with HV had a diametrically different and superior response compared to those treated with CC (C1-HV: Median OS (MS)>65mo, Median RD (MRD)>60mo; C2-HV: MS=15mo, MRD=24mo vs C1-CC: MS=20mo, MRD=39mo; C2-CC: MS=10mo, MRD=17mo). C3 showed the opposite, with CC outperforming HV (MS=19mo, MRD>102mo vs MS=7mo, MRD=9mo). Similarly, in C4, CC patients did dramatically better, (MS=40mo, MRD>96mo vs MS=9mo, MRD=7mo). In the UV CoxPH model, we included variables for PS cluster and treatment and all groups predicted OS, except for C3-CC and C4-CC, as did age, secondary AML, complex karyotype, and CEBPA, FLT3, KIT, MLL, NPM1, PTPN11 and TP53 mutations. In the MV model, all clusters were predictive for OS, together with age, secondary AML, complex karyotype and NPM1 mutation. Regarding RD, in the UV model, only C2-HV, C2-CC, and C4-HV predicted RD, as did age, secondary AML, complex karyotype, unfavorable cytogenetics, and FLT3, RUNX1 and TP53 mutations. In the MV model of RD, all clusters, except for C3-HV were predictors, together with age. Importantly, optimized treatment triaging based on PS1/2 would have reassigned 52% (218/420) of cases, and is estimated to increase the 3yrs OS of the whole cohort from 35.6% to 48.8%, a 37.2% increase. Moreover, the 2yrs Relapse Free Survival would increase from 57,9% to 63,9%, a 10.39% increment. Furthermore, our Protein Classifier identified a set of 3 proteins (SPI1, NOTCH1.cle, and TGM2) whose expression can be used to rapidly classify patients and recommend either HV or CC. This classifier has a very high c-index (a measure of individual patient discriminatory power) of 0.93 (>0.7 is considered predictive, 1 would indicate perfection) demonstrating that it robustly predicts optimal therapy choice. CONCLUSION: Protein profiling identified protein expression patterns which had diametrically different responses according to treatment (HV or CC). Given the US annual incidence of 20000 newly diagnosed AML cases, proteomic triaging could result in ~2600 more cures using existing therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Response to Intensive Induction Chemotherapy after Failure of Frontline Azacitidine+Venetoclax in Acute Myeloid Leukemia

Introduction: Venetoclax (Ven) in combination with hypomethylating agent (HMA) is approved for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients 75 years or older or who are not candidates for standard intensive induction chemotherapy (IC) due to comorbidities. Due to the high efficacy of HMA/Ven, an increasing number of newly diagnosed AML patients who may have historically been considered to be candidates for IC are instead receiving HMA/Ven due to patient and/or provider preference, especially patients who are >= 60 years or those with adverse risk disease biology. Several ongoing studies are also evaluating the efficacy of Ven/HMA in newly diagnosed younger AML patients (NCT03573024, NCT04801797, NCT04752527). Although response rates with HMA/Ven are high, approximately 1/3 of patients are refractory and many patients relapse. It is unknown whether salvage IC after Ven/HMA failure is feasible or whether initial therapy with HMA/Ven may impact response to subsequent IC. Methods: To investigate outcomes of patients treated with IC after failure of frontline HMA/Ven, charts of patients with newly diagnosed AML treated with azacitidine (Aza) + Ven (Aza/Ven) between January 2015 and December 2021 at a single institution were reviewed. Patients that were either refractory to or relapsed on Aza/Ven and received IC (7+3 or other cytarabine-based regimen) as immediate next-line therapy were identified. Baseline patient demographic and clinical information was recorded. The primary endpoint was overall response rate (ORR) with IC after Aza/Ven failure. Secondary endpoints included rate of CR/CRi, the rate of bridging to allogeneic transplant, and overall survival (OS). Responses were assessed according to ELN criteria. An exemption for this retrospective study was obtained from the Institutional Review Board. Results: Of 208 patients treated with frontline Aza/Ven, 19 received IC as immediate next-line therapy after Aza/Ven failure, including 13 patients who were treated with IC after their AML was refractory to Aza/Ven up front and 6 patients who received IC after relapsing following a prior response to first-line Aza/Ven. The median age of this cohort was 62 years (range 22 to 68 years) (Table 1). Most patients had unfavorable cytogenetics (16/19, 84.2%) and ELN adverse risk disease (15/19, 78.9%). The median number of cycles of Aza/Ven received prior to IC was 2 (range 1 to 5 cycles). Regarding IC regimen selected, 17 patients received 7+3, including 3 where midostaurin was added due to the presence of a FLT3 mutation, 1 patient received GCLAC, and 1 received FLAG-Ida+venetoclax. Among all patients, the ORR with IC was 57.9% (11/19) (Table 2). The rate of CR/CRi was 52.6% (10/19). Seven patients (36.8%) had AML that was refractory to IC, and 1 subject died within 30 days of IC. Of the 13 patients who had AML that was refractory to Aza/Ven up front, the CR/CRi rate was 61.5% (8/13), including 6 patients who achieved a CR and 2 who achieved a CRi. Of the 11 patients who responded to IC, 9 (81.8%) proceeded to allogeneic stem cell transplant. One patient declined transplant, and 1 transitioned to hospice due to a progressing fungal infection. Conclusions: For a select patient population, salvage IC after Aza/Ven failure is feasible. In our cohort of patients with predominantly adverse risk disease biology who received IC after failure of Aza/Ven, the ORR with IC was 57.9%, which compares favorably to response rates observed with frontline IC. Whether Aza/Ven and IC targeted different subclones and represent complementary sequential therapies in this high-risk group of AML patients is an ongoing correlative investigation. Overall, this data suggests that initial therapy with HMA/Ven in older and/or adverse risk AML patients with a plan to proceed with IC as second line therapy in the event of Aza/Ven failure is a reasonable strategy in select patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Hematopoietic Stem Cell Transplantation for Myelofibrosis: Role of Disease Status and Chimerism on Long-Term Outcomes

Introduction. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only curative option for Myelofibrosis (MF), a myeloproliferative neoplasm characterized by severely reduced survival. Despite a recognized superiority of transplant compared to medical options in higher risk MF, short-term complications substantially limit its use. Also, relapse can occur in a significant proportion of patients after allo-HCT. In this regard, controversial results have been reported on the predictive role of mixed chimerism. While CD33+ mixed chimerism was reported to correlate with worse OS due to higher risk of both relapse and non-relapse mortality (NRM), incomplete CD3+ chimerism was associated to an improved relapse-free survival. However, CD33 and CD3 antigens may not represent optimal markers for MF, since their expression, in contrast to CD34 antigen, has never been extensively described in MF. Herein we present a single Center experience on MF allo-HCT patients periodically monitored with CD34+, CD34- and mononuclear cells (MNC) donor chimerism with the aim to evaluate predictive factors for transplant outcome. Patients and methods. Overall, 31 MF patients were transplanted at the Unit of Bone Marrow Transplant of ASST Spedali Civili of Brescia from May 2014 to June 2022. Patients’ characteristics at time of transplant are detailed in table 1. Regarding transplant features, 15 patients received a myeloablative conditioning and 20 double-alkylators regimen (TBF in 19 and BuCy in 1 case). Donor was sibling, unrelated or haploidentical in 22.6%, 51.6% and 25.8% of cases. HCT-CI was high in 45.2%, FIL score unfit in 9.7% and KPS was 80 or less in 6.5% of cases, respectively. After transplant, the large majority of surviving patients underwent 1, 3, 6, 9, 12, 18 and 24-month donor chimerism, by using single tandem repeats (STR) PCR on patients’ bone marrow samples. Kaplan Meier was employed for computing OS. The Fine and Gray method was used for NRM and incidence of relapse (CIR). Three- and 6-month landmark analysis was utilized in order to evaluate the effect of mixed chimerism on outcomes. Univariate and multivariate analyses for OS were carried out using the Cox regression model. Logistic regression was employed for identifying factors associated with full donor chimerism. Results. After a median follow-up of 2.33 years (95%CI 1.02-3.20), 15 patients had died (6 relapse, 3 acute GVHD, 3 infections, 3 other causes) for a 5y CIR, NRM and OS of 21.7% and 30.5% and 48.6%. In Univariate analysis, high risk DIPSS (HR 3.91, 95%CI 1.40-10.95, p=0.009), FIL unfitness (HR 7.00, 95%CI 1.71-28.73, p=0.007), unfavorable cytogenetics (HR 4.88, 95%CI 4.88-1.36-17.49, p=0.015), accelerated phase disease (HR 3.84, 95%CI 1.32-11.17, p=0.013) and spleen palpable >15 cm below LCM (HR 4.50, 95%CI 1.49-13.53, p=0.008) were associated to reduced survival. In Multivariable analysis, accelerated phase disease (HR 8.03, 95%CI 1.68-38.52, p=0.009), splenomegaly (HR 15.64, 95%CI 3.12-78.47, p<0.001) and FIL unfitness (HR 33.43, 95%CI 3.97-281.40, p=0.001) maintained prognostic information. Importantly, high risk mutations did not prove any ability to predict survival after transplant (HR 1.60, 95%CI 0.51-4.98, p=0.420). Figure 1 illustrates the evolution of chimerism over time. Interestingly, 3 and 6-month MNC, CD34+ and CD34- mixed donor chimerism (<97.5%) was associated with significantly reduced survival (3-month landmark OS: 92.9% vs 20.0% [p=0.001], 100% vs 33.3% [p=0.003] and 100% vs 0% [p<0.001] at 1y; and 6-month landmark OS: 100% vs 0% [p<0.001], NA [only one patient with <97.5% donor chimerism], and 100% vs 0% [p=0.002] at 1 year, respectively), caused by increased CIR (data not shown). Double alkylator (HR 14.70, 95%CI 1.16-185.00, p=0.038) was the only parameter predicting an higher probability of reaching full donor chimerism after allo-HCT. Conclusions. Our study confirms the efficacy and safety of early transplant in MF. Patients submitted for transplant with massive splenomegaly or advanced stage disease appear to have a poor outcome. In addition, multidimensional geriatric assessment may represent an effective method to select MF allo-HCT candidates. The early achievement of full donor chimerism, as evaluated on MNC and CD34 lineages can predict a reduced risk for relapse and long-term survival. In this regard, use of double alkylating conditioning regimen could be relevant. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

How Often Do Cytogenetics and NGS Information Impact Upfront Treatment in AML?

Introduction: Over the past ten years, the treatment of Acute Myeloid Leukemia (AML) has substantially changed. New therapies emerged, and with the advance in understanding the genetic and molecular basis of AML, we incorporated new biomarkers into the standard evaluation of patients. The 2022 ELN recommends immunophenotyping, cytogenetics, and molecular studies as the basic initial testing of any new patient. Those are necessary to establish risk stratification and diagnosis. In our retrospective study, we looked into whether we would have decided to change therapies or had more options presented to a patient in case we had molecular and cytogenetics studies upfront and before starting treatment. Methods: We collected data from patients with AML treated at our university hospital from June 2020 to June 2022. The specific information we captured was: blood counts on admission, ELN risk stratification, Charleston score, type of treatment, time to cytogenetics results, time to Next Generation Sequence results, the best response to therapy, MRD status, and consolidation with allogeneic stem cell transplant. After we collected all information, each patient had a reevaluation. If a patient had any of the following molecular/cytogenetics changes (FLT3, cytogenetics changes associated with myelodysplasia, p53 mutation, complex karyotype, BCR-ABL1, RUNX1-RUNX1T1, CBFB-MYH11, Variant-type PML/RARA), he was carefully reevaluated and included in the "other options of therapy" subgroup. We included 17 patients in the "other options of therapy" subgroup and twenty-two in the "standard" group.Results: We included 39 individuals. The mean age of diagnosis was 62.18 (27-83). Three patients were stratified as good ELN risk, 17 as adverse risk, and 19 as intermediate risk. The mean Charlson Comorbidity Index (CCI) was 5.51 (2-10); 17 patients received high intense chemotherapy and 22 low intense chemotherapy. The mean wait to start therapy was of 7 days. The mean waiting time for NGS results was 12.71 and 7.30 days for cytogenetics. Seventeen patients were classified in the "other options of therapy" group. And twenty-two on the "standard" group. In the standard group, the mean overall survival was 496.5 days, and on "other options of therapy" it was 447.7. There was no statistically significant difference in survival between the two groups (p=0.602). (figure 1)The main reason for other therapy options was the presence of myelodysplastic genes (3), tp53 (3), RUNX1-RUNX1T1(2), CBFB-MYH11(1), cytogenetics suggesting myelodysplastic changes (6), Variant-type PML/RARA (1) and FLT3 (3). Conclusions: In this study, we retroactively evaluated if having more initial therapy options would have impacted the overall survival of newly diagnosed AML patients. Our survival analysis showed no significant statistical difference between the two groups. The median time to results of NGS was 12.71, and for cytogenetics, 7.3 days. In our cohort, the median time for therapy from diagnosis was 7.00 days. The reasons to change therapies were: midostaurin on FLT3 patients, Gemtuzumab ozogamicin on good risk patients, CPX-351, or alternative induction strategies in patients with p53 or unfavorable cytogenetics, and alternative induction on patients with Variant-type PML/RARA. This study has limitations due to its retrospective nature, small population, and short follow-up period. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Preliminary Results from a Phase 2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of Cfi-400945 As a Single Agent or in Combination with Azacitidine or Decitabine in Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (TWT-202)

Background: CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase, Polo-like kinase 4 (PLK4). PLK4 is a highly conserved master upstream regulator of centriole duplication and is critical for maintenance of genomic integrity. Aberrant expression of PLK4 results in centrosome amplification, often seen in aneuploid cancers, pointing to a potentially causative role for PLK4 in genome instability and cancer progression. An investigator-initiated study using a 28-day continuous CFI-400945 dosing schedule at the Princess Margaret Cancer Center (PMCC) demonstrated clinical activity in AML [Murphy et al., 2020] and responses were seen in high-risk pts with adverse cytogenetics, including those with TP53 mutations. CFI-400945 was tolerated with clinically manageable toxicities and the dose limiting toxicity (DLT) was colitis. The recommended phase 2 dose was 96mg. A newer crystal form of CFI-400945 was introduced after the PMCC study. Consequently, the optimal dosing of CFI-400945, including as a combination agent, are not yet clinically defined and are the rationale for this study. Study Design and Methods: This study is a multi-part phase 1/2 study of CFI-400945 as a single agent and in combination with hypomethylating agents (HMA) (NCT04730258). For Part 1, pts with relapsed and/or refractory AML, MDS, or CMML after >1 prior therapy will be included. Pts with MDS or CMML must have progressed or had a lack of response after at least 4 cycles of hypomethylating agents. For Part 2, pts should have relapsed and/or refractory AML or untreated MDS or CMML. Untreated pts who decline or are ineligible for intensive therapy may be included. The study uses a standard 3 + 3 design, and the dosing schedule is 21 days on and 7 days off (28-day cycle) - this is to potentially avoid the colitis seen in the study at PMCC. The maximum tolerated dose (MTD) will be defined as the dose level where the number of dose-limiting toxicities (DLTs) is <1 out of 6 at highest dose level at or below the maximally administered dose. Pharmacokinetics (PK) and pharmacodynamic (PD) markers will be assessed. Results: As of the 30Jun22 data cut off, 9 pts had been enrolled into the study. Four (44%) pts had AML, 2 (22%) had MDS, 3 (33%) had CMML. The median number of prior therapies was 2 (range 1-4), and 2 (22%) pts had received a stem cell transplant. Six (66%) were male and the median age was 69 (range 22-75). Three of 4 AML pts had unfavorable risk cytogenetics by ELN 2017 criteria, and 2 pts (1 each with MDS, CMML) with TP53 mutations. Five pts received 32mg and 4 pts 48mg. There have been no DLTs. There have been 8 (89%) SAEs with the following occurring in >2 pts (febrile neutropenia (6 pts), pneumonia (2 pts)). Common treatment emergent adverse events (TEAE) in > 2 pts were febrile neutropenia 6 pts (67%), hypokalemia 5pts (56%), anemia and hypomagnesemia 4 pts each (44%), hypophosphatemia, diarrhea, abdominal pain, nausea, vomiting, dyspnea, peripheral edema 3 pts each (33%). Thirty-three percent (20 events, 3 pts) of the grade 3 or greater TEAE's were considered related to CFI-400945. There have been no CR or PR per ELN response criteria observed to date, however, there were 2 (50%) SD per IWG criteria at the 48 mg dose level (1-MDS, 1-CMML). Pharmacokinetic (PK) evaluations indicated that the mean terminal-life ranged from 7 - 10 hours. Low accumulation was observed after 21 days of daily dosing (AR <2-fold). In general, exposure in this study is overlapped with that observed in the PMCC study. PD studies evaluating the effect of CFI-400945 on markers of mitosis, ploidy, and centriole function are ongoing. Conclusion: CFI-400945 has been generally well tolerated and TWT-202 continues to enroll in Part 1. There have been no responses per ELN to date but there was SD in 2 pts (48 mg dose). Lack of DLTs suggest dose level is still suboptimal at time of submission. PK characteristics support daily dosing of CFI-400945 and PD studies are ongoing. Dose escalation continues in this study and updated data will be presented.

AML-434 Retrospective Review of Outcomes in Newly Diagnosed Leukemia Patients Aged 65 and Older When Admitted to the Hospital: A Single Center Experience

Acute leukemia patients have a diminished survival inversely proportional to their age. 5-year overall survival in younger AML patients is 50%, however reduced to <10% if age >70. Factors contributing include poor performance status, decreased response to induction therapy, increased treatment related mortality, unfavorable cytogenetics and secondary leukemia. Report observed characteristics and outcomes of elderly leukemia patients. Retrospective chart review of newly diagnosed acute myeloid leukemia (AML) patients >65 admitted from 7/1/2015 through 6/30/2021. Demographic information, classification, duration of hospital stay, blood products administered, treatment, discharge condition, 3 and 6 month remission, and survival data collected. Academic medical center. 149 patients identified. AML[n=130], acute promyelocytic leukemia (APL)[n=9], and acute leukemia not otherwise specified (AML-NOS)[n=10]. 97 patients treated. AML treatment: Induction therapy, daunorubicin and cytarabine (liposomal), or hypomethylating agent +/-venetoclax. APL treatment: all-trans retinoic acid (ATRA) +/- arsenic trioxide (ATO). One patient with AML-NOS received hypomethylator. Patients separated into three groups: <70[n=55], 70 to 74[n=52], and >75[n=60]. Percent of patients who did not receive any therapy increased as age group increased (21.8%, 32.7%, and 41.7%). Length of hospital stay, reflective of treatment, was greatest in the younger population (28 days, 17.6 days, and 15.3 days). 6-month survival 51% younger, 42.3% middle and 23.4% for eldest cohort. Treatment related mortality (TRM) including transitioning to hospice care increased as age increased (29%, 34% and 50%). 25/130 patients received induction chemotherapy. Nineteen patients were <70. The expected TRM for the younger cohort was 10.68% (1 - 41%) and 10.1% (1-20%) for elder cohort. The observed TRM was 10.5% in the younger cohort and 50% in the older cohort. Most of the eldest AML patients received a hypomethylating mono- or combination therapy. Nearly 50% of all AML were discharged home. The 6-month survival was 50% for younger, 26.8% for middle and 13.3% for eldest cohort. Nine APL patients were identified with 5 being in the eldest cohort. Only 3(33.3%) survived 6 months. None of the patients with AML-NOS were alive at 6 months. Acute leukemia in the elderly population remains a challenge with poor outcomes despite considering patient's age and performance status.

Molecular Aspects in Chronic Lymphocytic Leukemia patients with Autoimmune Cytopenias: single center experience

Autoimmune cytopenia's, particularly autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), complicate up to 25% of chronic lymphocytic leukemia (CLL) patients. Their occurrence correlates with a more aggressive disease. AIHA and ITP are more frequently found in patients with unfavorable biological risk factors for CLL. B lymphocytes at CLL are responsible of pathogenic mechanisms, involving aberrant antigen presentation and cytokine production. The aim of this study was evaluation of autoimmune cytopenia's in chronic lymphocytic leukemia patients from Republic of North Macedonia in correlation with genetic structure of pathologic B lymphocyte. This is a retrospective study of patients with CLL, diagnosed and followed in the period between January 2011 and January 2021. Individual data from 100 treatment naïve CLL patients were analyzed, and mutational status and configuration of IGHV-IGHD-IGHJ rearrangements and genetics were analyzed using reverse transcriptase– polymerase chain reaction (RT-PCR) and sequencing methodology at the center for bimolecular pharmaceutical analyses, faculty of pharmacy, Skopje, Republic of North Macedonia. Our evaluation have shown that 10% of CLL patients had AIHA and 4% had ITP. Most of the patients with autoimmune cytopenias had unmuteted IGHV genes. The most frequently expressed IGHV subgroup was IGHV1-69 (71%), followed by IGHV3-13 and IGHV4-4 (14%). The genetic results presented unfavorable cytogenetics with 11q deletions and NOTHCH mutation. The results of our study are consistent with published studies with specific molecular signature.

PB2011: CHIDAMIDE COMBINED WITH THALIDOMIDE, CYCLOPHOSPHAMIDE AND DEXAMETHASONE (TC2D) AS AN ORAL QUADRUPLET REGIMEN FOR RELAPSED/REFRACTORY MYELOMA PATIENTS: INITIAL RESULTS OF A PHASE IIA, MULTICENTER TRIAL

Background: Research has showed histone deacetylase (HDAC) is overexpressed in plasma cells. Panobinostat was the first HDAC inhibitor (HDACi) approved by FDA for patients with relapse and refractory multiple myeloma (RRMM) in 2015. Chidamide is an oral subtype-selective HDACi, independently developed in China and approved for peripheral T-cell lymphoma. Preclinical findings have demonstrated the anti-myeloma activities of chidamide in vitro and in vivo. Aims: Here we report the initial efficacy and safety of this prospective, phase IIa, multicenter clinical trial with the chidamide based oral quadruplet regimen in patients with RRMM (ChiCTR2000035100). Methods: The TC2D regimen (thalidomide 100mg on days 1-28, chidamide 5mg on days 1-24, cyclophosphamide 50mg on days 1-24, dexamethasone 20mg on days 1,8,15,22) was administered to patients with RRMM of a 28-day cycle. Overall response rate (ORR) was based on patients whose response ≥MR and clinical beneficial rate (CBR) was calculated in patients completed at least 3 cycles and reached ≥SD. Results: A total of 32 patients were enrolled as of June 30, 2021, with a median age of 63.5 years (range 49–74). 82% (19/23) of which had unfavorable cytogenetics (defined by the presence of del (17p) or p53 mutation, t (4:14), t (14:16), t (14:20), amp (1q)). 75% were double refractory to bortezomib and lenalidomide. 43% (14/32) were heavily pre-treated (>3 lines). 59% (19/32) of patients completed ≥ 3cycles at the cut-off date (Table 1). With the median follow-up of 6 months (range 0.7–19.5), the median progression free survival (PFS) was 3.3 months and the 6-mon PFS rate was 27.5% (Fig 1a). Median overall survival (OS) has not reached yet, 6-mon survival rate was 82%, and the estimated 12-month survival rate was 65% (Fig 1b). Study end points were death (8 cases, 25%) and disease progression (24 cases, 75%). Patients who received ≥3 cycles of treatment had a superior median PFS (3.8 vs 1.4 months, P=0.01) than < 3 cycles. Of the 28 patients whose follow-up time more than 3 months, ORR was 25% and CBR was 46.4%, respectively. Better CBR (56.3% vs. 33.3%) and ORR (31.3% vs. 16.7%) were observed in patients received less than 3 prior lines, although with no significant statistical difference. Stratified analysis of PFS and OS showed no significant differences in sex, age, clinical classification, cytogenetic risk, prognosis score (DS and ISS staging system), and the status of ASCT. Grade 3/4 adverse events were mainly hematological toxicity (neutropenia 28%, anemia 34%, thrombocytopenia 15.6%), which could be tolerated. Fatigue was reported in 68.8% (22/32) of the patients. The incidence of all-cause infection was 37.5% (12/32). There were no treatment related deaths observed. Image:Summary/Conclusion: To our knowledge, this is the first report of chidamide-based oral quadruplet regimen for patients with RRMM. Preliminary results suggested efficacy and relatively high safety, and different groups of patients could benefit from this regimen. A longer treatment period may strengthen this effect. The most common adverse events were hematological toxicity which could be controlled. Choices of treatment are also influenced by physical and emotional impact of hospitalization or frequent hospital visits, which reflects the patient’s ability to continue their treatment and quality of life. Hospitalization and intravenous fluids are not involved in this regimen, which bring far more convenience and could be a cost-effective alternative for patients. Updated results will be presented at the following trial.

PB1784: CYTOGENETIC LANDSCAPE OF 87 MOROCCAN ACUTE MYELOID LEUKEMIA PATIENTS

Background: Cytogenetics and molecular biology are the most important diagnostic tools for determining prognosis in acute myeloid leukemia (AML). In our country, access to molecular biology tests is limited compared to conventionnal cytogenetics. Still data about cytogenetics in AML moroccan patients are scarce. Aims: Describe cytogenetic landscape of patients diagnosed with acute myeloid leukemia treated in our center. Methods: We conducted a descriptive retrospective analysis of 87 adult patients diagnosed with acute myeloid leukaemia treated in our unit. Results: 87 patients diagnosed with acute myeloid leukmemia were included. Median age was 45 years and 25% of patients were older than 60 years. The cytogenetic analysis failed in 13 patients (15%). Prognostic group distribution according to the ELN 2017 was found to be favorable in 17 patients (19,5%) with 6 cases of t (8; 21) and 7 cases of inv (16), 4 patients had t(15;17). Intermediate group was predominant (48,5%), 28 patients (32%) had normal karyotype.15 patients (17%) had unfavourable cytogenetics including 9 patients with complex karytype and 3 patients with del7q. Intermediate risk cytogenetics were predominant in patients under 60 years old whereas Unfavourable karyotypes were more frequent in older patients. Summary/Conclusion: The landscape of karyotype abnormalities in our population found a predominance of intermediate risk group enhancing the need of molecular biology to refine prognosis and guide the treatment of AML patients in Morocco.

Adjunction of a fish oil emulsion to cytarabine and daunorubicin induction chemotherapy in high-risk AML

The treatment of acute myeloid leukemia (AML) with unfavorable cytogenetics treatment remains a challenge. We previously established that ex vivo exposure of AML blasts to eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or fish oil emulsion (FO) induces Nrf2 pathway activation, metabolic switch, and cell death. The FILO group launched a pilot clinical study to evaluate the feasibility, safety, and efficacy of the adjunction of a commercial FO emulsion to 3 + 7 in untreated AML with unfavorable cytogenetics. The primary objective was complete response (CR). Thirty patients were included. FO administration raised the plasma levels of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids (p < 0.001). The pharmacokinetics of cytarabine and daunorubicin were unaffected. A historical comparison to the LAM2001 trial (Lioure et al. Blood 2012) found a higher frequency of grade 3 serious adverse events, with no drug-related unexpected toxicity. The CR rate was 77%, and the partial response (PR) 10%, not significantly superior to that of the previous study (CR 72%, PR 1%). RT-qPCR analysis of Nrf2 target genes and antioxidant enzymes did not show a significant in vivo response. Overall, FO emulsion adjunction to 3 + 7 is feasible. An improvement in CR was not shown in this cohort of high-risk patients. The present data does not support the use of FO in adjunction with 3 + 7 in high-risk AML patients.ClinicalTrials.gov identifier: NCT01999413.