Adult Adult Acute Lymphoblastic Leukemia Research Articles

Secondary Histiocytic Sarcoma in a Pre-B-Acute Lymphoblastic Leukemia

AbstractHistiocytic sarcoma (HS) is a rare malignancy with grave prognosis. Adult acute lymphoblastic leukemia (ALL) patients developing HS as a secondary malignancy reported in the literature is even rarer. Through our case report, we aim to describe an adult pre-B-ALL patient who subsequently developed extensive HS while on maintenance therapy. We present the course of the disease, the management, and the resultant outcome. Active reporting of the course and management of secondary HS in adult ALL patients need to be emphasized to gain better insight into the presentation and the course of the disease, incidence as well as molecular pathology, especially given the relative silence of the literature in this regard.

Management of adult acute lymphoblastic leukemia in the Gulf Cooperation Council (GCC) countries: A consensus report from the GCC Adult ALL Working Group.

Leukemia burden is growing in the Gulf Council Cooperation (GCC) countries. Nonetheless, there is no unified protocol for managing adult acute lymphoblastic leukemia (ALL) patients in the GCC-countries. Therefore, the GCC Adult-ALL Treaters working group developed this consensus to address the adult-ALL treatment protocols in the GCC-countries and related toxicities' management. Besides, the consensus aimed to highlight the current unmet needs and treatment gaps and provide recommendations to optimize adult-ALL care and patient-centered communication. A three-step modified Delphi method to develop evidence-based recommendations through two-voting rounds and in-between virtual meetings are used in the manuscript development. A 12 experts' panel from five GCC-countries and two international experts were invited to participate in this consensus. This consensus consisted of 35-statements that highlighted the experts' recommendations to optimize ALL adults' care in the first line setting and manage pediatric or pediatric-inspired regimens-related toxicities. Besides, guidance was provided for future research direction and improve patient-centered communication. In conclusion, the adult-ALL management landscape is evolving, and the current evidence highlights better response and survival outcomes with pediatric or pediatric-inspired regiments. Therefore, protocols are needed to optimize the adult-ALL management in the GCC and tailored clinical-trials findings according to the GCC patients' characteristics and local-healthcare infrastructure.

Prognostic Impact of TP53 Mutation in Adult Acute Lymphoblastic Leukemia Treated with Pediatric-Inspired Regimen

Abstract Background: TP53 is one of the most extensively studied genes in human cancer. However, the prognostic impact of TP53 mutations (TP53mut) in adult acute lymphoblastic leukemia (ALL) remained debatable, especially in those treated with pediatric-inspired regimen. Herein, we determined the characteristic of TP53mut in adult acute ALL patients and investigated the clinical significance of these TP53mut in newly diagnosed ALL. Patients and Methods: We performed TP53 mutation analysis in 283 adult ALL patients (B-ALL n=227; T-ALL n=56) including 57 diagnose-relapse pairs using targeted next-generation sequencing (NGS). TP53 mutations were analyzed for their association with adult ALL enrolled in pediatric-inspired regimen evaluating clinical characteristics and treatment outcomes. Results: A total of 35 TP53mut sites were detected in 31 diagnosed samples among 283 diagnosed patients and 17 among 57 paired diagnose-relapse samples, with a significant difference (11.0% vs 29.8%; c2=13.9, P<0.001). The major variant was missense mutation (n=32), followed by frameshift (n=11), nonsense mutation (n=4), in-frame (n=3), and splicing mutation (n=2). In paired diagnose-relapse samples, we identified acquired and/or loss of TP53mut in the samples at the time of relapse. In 283 newly diagnosed patients, patients with TP53mut had a higher proportion of the older population, complex karyotype, and MRD positivity before consolidation therapy (P=0.023, 0.002, 0.024). Survival analysis revealed that TP53mut was associated with inferior outcomes in the whole cohort of newly diagnosed ALL (4-year OS rates, 43.6% vs 63.6%, P=0.0086; 4-year EFS rates, 30.4% vs 52.2%, P=0.0056). Additional survival analysis showed that TP53mut did not confer poor outcomes in the AYA population (4-year OS rates, 60.6% vs 68.1%, P=0.55; 4-year EFS rates, 52.5% vs 55.5%, P=0.57). For the older patients, however, TP53mut predicted inferior OS and EFS in older patients (4-year OS rates, 18.2% vs 46.2%, P=0.0033; 4-year EFS rates, 0 vs 39.6%, P=0.00028). Conclusion: Our data revealed that TP53mut was present at a low incidence at diagnosis and increase at relapse. TP53mut were potential biomarkers associated with poor prognosis in older patients with newly diagnosed ALL treated with pediatric-inspired regimen. This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012). 【 Key words 】TP53; Acute lymphoblastic leukemia; Pediatric-inspired regimen; Next-generation sequencing; Prognosis

Selecting the Right Alternative Donor: Comparison of Outcomes of HLA-Mismatched Alternative Donor Hematopoietic Cell Transplantations in Adult Patients with Acute Lymphoblastic Leukemia Regarding KIR-Ligand Mismatch

Background: Allogeneic hematopoietic cell transplantation from cord blood (CBT) or haploidentical donor (HIDT) has proved to be a viable option for patients unable to find a human leukocyte antigen (HLA)-matched conventional donor. However, few single-centered studies have compared outcomes of the two alternative donor transplantations in adult acute lymphoblastic leukemia (ALL). Aim: Our aim is to compare outcomes of adult ALL patients treated with CBT with those treated with HIDT. Secondly, we tried to find out factor that could be considered in selecting donor for alternative donor transplantation to improve clinical outcomes. Methods: We compare outcomes of adult ALL patients treated with CBT (n=134) between 2008 and 2022 with those treated with HIDT (n=47) between 2018 and 2022.Conditioning regimen for CBT consisted of total body irradiation (12Gy) plus cytarabine (9g/m 2) plus fludarabine (150mg/m 2). Graft-versus-host disease (GVHD) prophylaxis was attempted using tacrolimus and mycophenolate mofetil. For HIDT, we used reduced toxicity conditioning (RTC) regimen including fludarabine (150mg/m 2) plus busulfan (6.4mg/kg). GVHD prophylaxis was done with ATG 1.5mg for 4 days plus short course methotrexate (MTX) (15mg/m 2) plus tacrolimus. Killer cell immunoglobulin-like receptor (KIR) ligand mismatch was calculated in both GVH and HVG direction using HLA-KIR ligand database, and its effect on clinical outcomes of alternative donor transplantation was investigated. Results: In HIDT, CD34+ cell count (´10 6/kg) was significantly higher (7.4 vs. 0.1, P<0.001), and the patients were older (49 vs. 33.5, P<0.001) compared to CBT. Other characteristics, such as cytogenetic risk and leukocyte count at diagnosis, did not show significant difference between the two groups. Incidence of acute GVHD II-IV (51.1% vs. 50.0%), III-IV (25.5% vs. 17.9%), and moderate to severe chronic GVHD (10.8% vs. 11.0%) between HIDT vs. CBT were similar. After median follow-up of 39.4 months (range: 5.5-167.4), HIDT showed higher cumulative incidence of relapse (CIR) compared to CBT (47.9% vs. 18.9%, P<0.001), which remained true even after stratifying by age subgroup (Age<40: P=0.033, Age≥40: P=0.002). Conversely, CBT showed higher non-relapse mortality (NRM) than HIDT (22.8% vs. 9.0%, P=0.038), but the same was true only in the older age subgroup (Age<40: P=0.484, Age≥40: P=0.002). These effects summed up to produce comparable results in estimated 3-year disease-free survival (DFS) of CBT and HIDT (58.4% vs. 43.5%, P=0.103), especially in the older subgroup (38.7% vs. 40.7%, P=0.897). Multivariate analysis also revealed that HIDT was related with higher relapse (HR 3.47; 95%CI 1.92-6.27, P<0.001), and CBT with higher NRM (HR 4.18; 95%CI 1.42-12.3, P=0.009). GVH direction KIR ligand mismatching worked for lower 3-year DFS in CBT (40.3% vs. 74.4%, P=0.007), although CIR and NRM did not show significant difference (27.8% vs. 15.6%, P=0.178; 35.0% vs 18.4%, P=0.057, respectively). On the other hand, the mismatch resulted in lower incidence of acute GVHD II-IV (32.0% vs. 54.2%, P=0.011). The trend remained when such effect was investigated separately in CBT and HIDT, but it was not statistically significant (33.3% vs. 53.1%, P=0.082; 28.6% vs. 57.6%, P=0.053, respectively). Conclusions: Our data shows higher NRM in CBT, and unexpected higher relapse rate in HIDT. Age of the patient should be considered when choosing CBT, because in older patients CBT showed notably worse NRM compared to HIDT. Higher incidence of relapse in HIDT may be attributable to ALL disease characteristics itself or insufficient elimination of leukemic cells by RTC regimen with stronger GVHD prophylaxis. Similar to what is known in acute myeloid leukemia, GVH direction KIR incompatibility showed protective effect against acute GVHD in ALL. However, the mismatch resulted in worse DFS in ALL patients treated with CBT, but not in those treated with HIDT. Possible explanation to this phenomenon is that the number of NK cells in cord blood was insufficient for mismatch-induced graft-versus-leukemia effect, while its immune response against infected cells was suppressed by the same mechanism that resulted in lower acute GVHD. Keywords: Acute lymphoblastic leukemia, Cord blood transplantation, Haploidentical donor transplantation, HLA-mismatched transplantation, Killer-cell immunoglobulin like receptor

Mitoxantrone Hydrochloride Liposome Containing Regimen in Patients with Adult Acute Lymphoblastic Leukemia: A Multicenter, Retrospective, Real-World Study

Background Although the initial overall response rate is high (70%-90%) in adult acute lymphoblastic leukemia (ALL) patients (pts), a large percentage of them frequently relapse. Prognosis of relapsed/refractory (R/R) ALL remains poor and there are no clear guidelines on the best treatment approach. Currently, an anthracycline-based multidrug chemotherapy regimen remains the treatment cornerstone in ALL. Mitoxantrone is a synthetic anthracenedione anti-cancer drug that is effective in lymphoma, leukemia, and other solid tumors. Mitoxantrone hydrochloride liposome (PLM60) is the first approved mitoxantrone nano-drug, which has shown favorable pharmacokinetic characteristics and significantly prolong the survival time of animals compared with the same dose of mitoxantrone. However, there is still a lack of systematic reports about the real-world application of PLM60 in ALL. Methods A multicenter retrospective analysis was performed for 38 pts with newly diagnosed and R/R ALL, who received at least one cycle of PLM60-containing regimen between February 2022 and June 2023 (ChiCTR2200067172). Pts aged 18 years or older with ECOG PS 0-2 and diagnosed with ALL were eligible. Efficacy was assessed by complete remission (CR) rate, overall response rate (ORR), relapse-free survival (RFS), overall survival (OS), and correlative analyses. Adverse events were assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results At the data cut-off of 15 July 2023, 38 eligible pts who received induction, consolidation or pre-transplant therapy were enrolled. The median age was 40.5 years (range 24.0-71.0), 50.0% were male, median white blood cell (WBC) count was 7.9 x 10 9 /L (range 1.4-160.9) and 68.4% had B-lineage ALL. In addition, two pts had received hematopoietic stem cell transplantation. The median dose of PLM60 in the regimen was 16.2 (range 5.4-43.2) mg/m 2. Among the 23 newly diagnosed pts, the CR rate was 91.3% (21/23, 95%CI 72.0%-98.9%) and ORR was 91.3% (21/23, 95%CI 72.0%-98.9%), the ORR after induction therapy was 75.0% (6/8). The ORR was 95% and 66.7% in the WBC＜30×10 9 /L and ≥30×10 9 /L groups, respectively. Among the 15 R/R pts, the CR rate was 33.3% (5/15, 95%CI 11.8%-61.6%) and ORR was 46.7% (7/15, 95%CI 21.3%-73.4%), the ORR after induction therapy was 42.9% (6/14). The ORR was 57.1% and 37.5% in the WBC＜30×10 9 /L and ≥30×10 9 /L groups, respectively. The ORR of pts with 1 and ≥ 2 previous induction regimens was 71.4% and 25.0%, respectively. Other efficacy indicators were RFS and OS, but data are still too early and will be reported after a long-term follow-up. Treatment-related adverse events (TRAEs) of any grade occurred in 79.0% pts. Common grade 3/4 AEs included decreased neutrophil count (50.0%), thrombocytopenia (36.8%), anemia (34.2%), febrile neutropenia (5.3%). The overall safety was acceptable and controllable. Conclusion The PLM60-containing regimen had an encouraging efficacy and showed a manageable safety profile in adult ALL with the most adverse events being hematologic toxicities.

Prognostic impact of TP53 mutations in adult acute lymphoblastic leukemia treated with a pediatric-type regimen

The prognostic impact of TP53 mutations (TP53mut) in adult acute lymphoblastic leukemia (ALL) remains debatable. Herein, we determined the clinical significance of TP53mut in 283 adult ALL patients treated with a pediatric-type regimen. TP53mut were found in 11.0% (31) of patients, including 19 cases in adolescent and young adult (AYA) patients and 12 cases in non-AYA patients. Patients with TP53mut had poorer overall survival (OS) and event-free survival (EFS) in the non-AYA subgroup (n = 64) (3-year OS, 18.2% vs 50.9%, p = .0033; 3-year EFS, 0 vs 45.3%, p = .00028). however, this had to be taken cautiously due to a limited number of patients. In the AYA subgroup (n = 219), TP53mut did not impact OS or EFS (3-year OS, 60.6%vs71.0%, p = .55; 3-year EFS, 52.5%vs59.6%, p = .57). Collectively, our data reveal that the pediatric-type regimen eliminated the poor prognostic impact of TP53mut in AYA ALL. However, in non-AYA ALL patients, TP53mut remain a potential biomarker associated with poor outcomes.

MAPK/ERK and PI3K/AKT signaling pathways are activated in adolescent and adult acute lymphoblastic leukemia.

The mitogen-activated protein kinase (MAPK)/ERK signaling cascade and the phosphoinosytol-3 phosphate/Akt (PI3K/Akt) pathways are involved in proliferation and differentiation of hematopoietic cells. The frequency of PI3K/Akt and MAPK pathway activation in adult acute lymphoblastic leukemia (ALL) still need to be elucidated. To assess the activity and prognostic implications of MAPK/ERK and PI3K/Akt pathways in adult (ALL). We examined 28 precursor-B-cell ALL and 6 T-cell primary ALL samples. Flow cytometry was employed to analyze the expression levels of phosphorylated ERK and phosphorylated Akt. Ten out of 15 (67%) ALL fresh samples (7 B-cell, 3 T-cell) showed constitutive p-ERK expression. The p-ERK mean fluorescent index ratio (MFI (R)) showed a tendency to be higher in ALL than in normal T lymphocytes (1.26 [0.74-3.10] vs. 1.08 [1.02-1.21], respectively [p = .069]) and was significantly lower than in leukemic cell lines (median MFI (R) 3.83 [3.71-5.97] [p < .001]). Expression of p-Akt was found in 35% (12/34) (10 B-cell, 2 T-cell). The median MFI (R) expression for p-Akt in primary blast cell was 1.13 (0.48-9.90) compared to 1.01 (1.00-1.20) in normal T lymphocytes (p = ns) and lower than in leukemic cell lines (median MFI (R) 2.10 [1.77-3.40] [p = .037]). Moreover, expression of p-ERK was negatively associated with the expression of CD34 (1.22 [0.74-1.33] vs. 1.52 [1.15-3.10] for CD34(+) and CD34(-) group, respectively, p = .009). Our findings suggest that both MAPK/ERK and PI3K/Akt are constitutively activated in adult ALL, indicating a targeted therapy potential for ALL by using inhibitors of these pathways.

Correlation between methylation level of the SLC19A1 promoter region and methotrexate metabolism in adult acute lymphoblastic leukemia.

Aims: To analyze the methylation level in the promoter region of SLC19A1 in adult acute lymphoblastic leukemia (ALL) patients, and explore the relationship between methotrexate (MTX) drug metabolism and SLC19A1 methylation. Methods: The methylation levels of the SLC19A1 promoter region in 52 adult ALL patients who received high-dose MTX chemotherapy were retrospectively analyzed in combination with clinical indicators and plasma MTX concentration. Results: Methylation levels of 17 CpG units were differently correlated with clinical parameters of ALL patients including gender, age, immunophenotype and Philadelphia chromosome status. Patients with delayed MTX drug excretion had higher methylation levels in the SLC19A1 promoter region. Conclusion: The methylation may affect the MTX plasma level and adverse reactions, which may predict patients at risk of adverse reactions after high-dose MTX therapy.

General condition and comorbidity of long-term survivors of adult acute lymphoblastic leukemia.

Cure rates in adult acute lymphoblastic leukemia (ALL) improved using pediatric-based chemotherapy and stem cell transplantation (SCT). However, limited data on the health condition of cured adults are available whereas pediatric data cannot be transferred. The GMALL analyzed the health status in survivors of adult ALL retrospectively. Physicians answered a questionnaire on general condition (Eastern Cooperative Oncology Group [ECOG] status) and comorbidity or syndrome occurrence observed after treatment. Five hundred and thirty-eight patients with a median age of 29 (range, 15-64) years at diagnosis were analyzed, median follow-up was 7 (range, 3-24) years. Thirty-one percent had received SCT. ECOG status was 0-1 in 94%, 34% had not developed significant comorbidities. Most frequent comorbidities involved the neurologic system (27%), endocrine system (20%), skin (18%), graft-versus-host-disease (15%), cardiac system (13%), fatigue (13%). SCT impacted ECOG status and comorbidity occurrence significantly. ECOG 0-1 was observed in 86% of SCT and 98% of non-SCT patients (P<0.0001); comorbidity was observed in 87% and 57% respectively (P<0.0001). Our analysis elucidates the spectrum of comorbidities in cured adult ALL patients, with higher risk for transplanted patients, providing stimulations for the design of adequate aftercare programs. Overall, a large proportion of non-SCT patients achieved unrestricted general condition. The data provide a reference for new patient-centered endpoints in future trials.

Higher Survival Advantage with Hyper-CVAD Chemotherapy Regimen Before Allogeneic Stem Cell Transplantation in Patients with High Risk Adult Acute Lymphoblastic Leukemia: Two-Center Experience

While promising results have been achieved in the treatment of childhood, the optimal initial treatment for adult acute lymphoblastic leukemia (ALL) has not yet been defined. Hyper-CVAD has become a widely used treatment for approximately 2 decades in the treatment of adult ALL. We conducted a retrospective analysis of 30 patients treated with Hyper-CVAD at two centers between 2014 and 2020. In all (n=30) patients treated with Hyper-CVAD, complete response (CR) rate was 86.7%, induction mortality was 10%, refractory disease was 3.3%, the median overall survival (OS) was 38 months (95% CI 7.78–68.2 months), the median disease-free survival (DFS) was 29 months (95% CI 9–49 months), the 2-year OS rate was 56.5%, and the 2-year DFS was rate 56.7%. For standard risk (n=12) ALL patients, the median OS was 20 months (95% CI 0–43 months), and median DFS was 7 months (95% CI 0–25 months). For high risk (n=18) ALL patients, the median OS was 38 months (95% CI 0–76 months), and median DFS was not reached. These results indicate that Hyper-CVAD regimen should be considered as an option for induction treatment of adult ALL patients who are newly diagnosed and eligible for allo-HSCT.

Overall Survival of Adult Acute Lymphoblastic Leukemia (ALL) Patients By Facility Volume and Type: A National Cancer Database Report

Introduction: The majority of acute lymphoblastic leukemia (ALL) deaths occur in adults, with only 40% of adult ALL patients achieving 5-year leukemic-free survival, and decreasing cure rates with increasing age (Abuasab 2021). ALL treatment is variable across facilities, based on patient and disease features, along with institutional factors (Khullar, 2022). Currently, there are limited studies that investigate adult ALL overall survival (OS) outcomes by facility characteristics. The primary objective of our study was to determine adult ALL OS by facility volume and type for adult patients. Methods: This retrospective study analyzed de-identified National Cancer Database (NCDB) files from 2004-2016. ALL patients >18 years of age met inclusion criteria. Facility type was not available for patients <40 years of age, and was excluded from analysis. Baseline patient characteristics were extracted and sub-grouped by age >18 to <40 and >40. Summary statistics included frequency (%) for categorical variables and median [IQR] for non-normal continuous variables. Group differences were compared with Chi-square or Kruskal-Wallis rank sum tests. Facility volume was determined by a maximally selected log-rank statistics, with high volume (HV) versus low volume (LV) cut point at >91%. Academic programs (APs) included academic/research and integrated network cancer programs. Community programs (CPs) included community and comprehensive community programs. OS Kaplan Meier (KM) curves censored by death or last follow-upwere created for facility volume and type. Analysis was conducted with R software 4.0.3. The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, these institutions have not verified and are not responsible for the methodology or findings of this research. Results: 22,453 ALL patients were included in the study (>18 to <40 years N=7860; >40 years N=14,593). 12,453 (55.5%) patients were treated at HV and 10,000 (44.5%) at LV centers. 9708 (66.5%) of patients >40 years were treated at APs and 4885 (33.5%) patients were treated at CPs. For both age cohorts, patients were more likely to be male, White, Non-Hispanic, have a Charlson Comorbidity Index of 0, private insurance, a median income >$63,000, and reside in a metro area 10-100 miles from the treatment center (P < 0.001)(Table 1). Analysis of patients >18 to <40 years found no significant OS difference between patients treated at LV and HV centers (mOS 64.4 mo., 95% CI 62.2-67.6 vs. 60.9 mo., 58.2-63.4; p = 0.1). Analysis of patients >40 years found longer OS in patients treated at LV CP (red line) compared to HV AP (purple line) (mOS 71.1 mo., 95% CI 66.6-75.8% vs. mOS 56.9 mo., 95% CI 56.6-62.7; P <0.0001) (Figure 1). OS was greater at LV compared to HV centers (mOS 68.7 mo., 95% CI 65.2-71.5 vs. 59.5 mo., 95% CI 56.6-62.3; P < 0.0001) and OS was greater at CPs compared to APs (mOS 69.2 mo., 95% CI 65.0-72.6 vs. 61.2 mo., 95% CI 58.5-63.4; p = 0.00049). Discussion: This large, national study provides insight into OS in adult ALL patients by treatment facility. Despite a paucity of differences in patient characteristic trends between age cohorts, we found OS differed by facility volume in older ALL patients but not younger adult patients. Interestingly, OS of young adult ALL patients was not uniformly superior to older patients. OS in patients >40 years was longest in those treated at LV and CPs, and shortest amongst patients treated at HV and APs. Potentially, patients with more advanced/high-risk disease, and therefore worse prognosis, were selectively treated at HV and APs, accounting for inferior OS. Additionally, perhaps more aggressive treatments were attempted at HV and APs, increasing risk of death in the older adult population. Finally, differences in sociodemographics may have driven OS differences. Our study was limited by its retrospective nature, the delay in reported NCDB data and current clinical practice, and missing facility type for patients <40 years. Conclusion: OS in adult ALL patients >40 years was significantly different by facility volume and type, with the greatest OS in patients treated at LV and CPs, and the least OS at HV and APs. Amongst patients >18 to 40 years of age, there was no difference in OS by facility volume. Future research is needed to understand and improve adult ALL OS trends observed between treatment facilities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ultra-Sensitive Next-Generation Sequencing Establishes the Prognostic Value of Very Low MRD in Adults with Acute Lymphoblastic Leukemia Undergoing Hematopoietic Cell Transplantation

BACKGROUND The prognostic utility of measurable residual disease (MRD) in adult acute lymphoblastic leukemia (ALL) has been defined at a sensitivity of 10-4. Measurement of MRD by ultra-sensitive next-generation sequencing (NGS) of Ig and/or TCR rearrangements has a sensitivity of 10-6 and is increasingly used across the United States to evaluate treatment response. However, the clinical utility of very low level NGS-based MRD (<10-4) is unknown. In this large multicenter cohort of adult ALL patients who underwent allogeneic hematopoietic cell transplant (HCT), we evaluated the prognostic value of ultra-sensitive NGS-based MRD. METHODS Adults (18+) with ALL who underwent HCT at Stanford University or Oregon Health and Science University (OHSU) between January 2014 and April 2021 with planned MRD monitoring using the NGS-based clonoSEQ assay (Adaptive Biotechnologies, Seattle, WA) were included. Pre-HCT MRD (MRDpre) and post-HCT MRD (MRDpost) were followed for up to one-year post-HCT. MRD was evaluated as residual clonal cells per million nucleated cells and was defined as undetectable (0), low (<10-4), high (≥10-4 to ≤10-3) and very high (>10-3). Patients were followed for leukemia relapse for up to two years. Competing-risks analyses were used to model the hazard of relapse according to MRDpre and MRDpost levels. A univariate analysis using a Fine-Gray subdistribution hazard competing risk regression model was used to estimate the effect of MRDpre level on the cumulative incidence of relapse. A Cox regression model with time-varying covariates was fit to evaluate the association between MRDpre and MRDpost levels with relapse. RESULTS 158 ALL patients who underwent HCT (Stanford n = 116, OHSU n = 42) had a trackable clonoSEQ clone. The median age was 43 years (range 18-77); 136 patients (86%) had B-ALL, 22 (14%) had T-ALL, and 131 (83%) underwent myeloablative HCT. Of the 122 patients with MRDpre assessment, MRDpre was undetectable, low, high, and very high in 82 (67%), 24 (20%), 11 (9%), and 5 (4%), respectively. Of the 111 patients with both MRDpre and at least one MRDpost assessments, 38 had at least one positive MRDpost result. The cumulative incidence of relapse differed significantly according to level of MRDpre (Figure 1), including among patients with low MRDpre of <10-4 where post-HCT relapse risk was strikingly higher than in patients with undetectable MRDpre (HR 3.56, 95% CI 1.39-9.15, p = 0.01). A very strong association with post-HCT relapse was also seen in patients with detectable MRDpost at any level (including <10-4), even after controlling for MRDpre (HR 4.41, 95% CI 2.90-6.70, p < 0.0001). Finally, we found that patients entering HCT with undetectable MRDpre who remained undetectable through the first year of MRDpost monitoring had <10% likelihood of relapse in the second post-HCT year (Figure 2). In contrast, patients entering HCT with detectable MRDpre had an ongoing risk of continued detectable of MRDpost without a clear plateau of relapse risk post-HCT. CONCLUSION In this analysis across two large transplant centers, we found that detection of MRD by ultra-sensitive NGS at a level of 10-6 offers significant prognostic value in adults with ALL undergoing HCT. Detectable MRDpre even at a low level of <10-4 increases the risk of post-HCT relapse. The presence of MRDpost at any level following HCT also substantially increases the risk of relapse. Finally, we found that patients with undetectable MRDpre who continue to have undetectable MRDpost through the first year of monitoring have excellent post-HCT outcomes. *ECL, SD, and JS contributed to this work equally Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dual Targeting of MDM2 and BCL2/Bclxl Demonstrates Potent Synergistic Activity in High-Risk Adult Acute Lymphoblastic Leukemia

Despite the use of both intensive multi-modal cytotoxic therapeutic regimens and novel immune-based therapies in adult acute lymphoblastic leukemia (ALL) outcomes remain dismal, with five-year survival rates less than 45%. As such, there is an urgent need to identify novel therapies to improve patient outcomes. While TP53 mutations are infrequent in ALL, alternative mechanisms such as MDM2 overexpression or CDKN2A/B deletion may otherwise phenotypically disrupt and circumvent normal p53 function. We previously demonstrated encouraging pre-clinical activity of p53-MDM2 antagonist idasanutlin (RG7388) in diverse high-risk primary and patient-derived xenograft (PDX) ALL samples at concentrations well-below clinically attainable plasma levels [Bell et al., ASH 2020]. However, clinical studies reveal only modest responses to idasanutlin monotherapy in various hematological malignancies, emphasizing the need to identify effective drug combinations. To systematically identify combination treatments which enhance cytotoxic idasanutlin activity, we performed comprehensive high-throughput phenotypic combination screening against 1971 FDA-approved and clinically advanced drugs. Extensive use of an ex vivo coculture system of ALL blasts and hTERT-immortalized mesenchymal stem cells (MSCs) was employed to support growth and survival of the ALL blasts, complemented by high-content image analysis to discriminate and enumerate the respective cell populations. Using the relapsed NALM6 B-ALL cell line and a panel of 6 PDX ALL samples - including relapsed and high-risk cytogenetic subtypes - we iteratively identified drugs (n=10) exhibiting significant synergistic and potent interaction with idasanutlin at concentrations well-below respective drug peak plasma concentrations reported in patients (Bliss synergy δ > 10). These included clinical ALL drugs dexamethasone and daunorubicin, proteasome inhibitor carfilzomib, BCL2/BCLxL inhibitor navitoclax, and histone deacetylase inhibitors romidepsin and pracinostat. Counter-screening of each drug candidate in a NALM6 TP53-isogenic cell model confirmed on-target p53-dependent combination activity (p<0.05). Further interrogation of each drug candidate was performed across a broad landscape of drug combination ratios with idasanutlin in primary (n=5) and PDX samples (n=6), including high-risk KMT2A-rearranged, ABL class T-ALL, and ETP-ALL. Combination of idasanutlin with navitoclax exhibited both the greatest and most consistent synergistic interaction (δ = 24.7±8.7, n=11) of the candidate combinations (n=10) across an extensive landscape of dose combinations; additionally alluding to synergy indiscriminate of ALL subtype. Further characterizing the cytotoxic antileukemic activity of navitoclax, single-agent exposure achieved low nanomolar range, dose-dependent ex vivo sensitivity in a panel of B- (n=10) and T-ALL (n=4) primary and PDX samples, with half maximal inhibitory concentrations (IC50) in the range of 3 to 11 nM (mean IC50 = 6.4 nM) - almost 1000-fold lower than clinically attainable concentrations [Roberts et al., BJH2015]. While both idasanutlin and navitoclax effectively induced apoptosis in their own right, combination exposure markedly enhanced cell death. In an exceptionally high-risk TCF3-HLF PDX sample, 24 hours exposure to the drug combination increased annexin-V positive cells by 37.3±5.0% and 33.3±3.5% as compared to either drug (IC50s, p<0.0001). In the NALM6 and RS4;11 relapsed ALL cell lines, combination exposure significantly increased annexin-V positive cells by at least two-fold (p<0.001) and enhanced apoptotic hallmark products cleaved poly(ADP-ribose) polymerase (PARP) (p<0.01) and cleaved caspase-3 as compared to either drug alone (IC50s). Mechanistically, we found protein levels of MCL-1-binding pro-apoptotic sensitizer NOXA to be up to 3-fold increased in combination-treated blasts (p<0.05), potentially inhibiting compensatory anti-apoptotic MCL-1 activity - a known clinical resistance factor to BH3 mimetics. Together, we provide strong evidence that concurrent targeting of MDM2-p53 binding and BCL2/BCLxL leads to potent and synergistic enhancement of apoptotic cell death in a range of high-risk ALL subtypes. The proposed combination of two clinical-stage compounds could have considerable positive clinical impact for the treatment of adult ALL.

ALL-097 Elevated CD83 in Adult Acute Lymphoblastic Leukemia Associated With Poor Clinical Outcome

CD83 is expressed by mature dendritic cells and activated lymphocytes but not by other peripheral blood cells. Some tumor cells have high expression of CD83 on the cell surface, such as Hodgkin lymphomas (HLs), diffuse large B-cell lymphoma, adult acute lymphoblastic leukemia (ALL), gastric extra-nodal marginal zone lymphomas, and lung cancer cells. To determine the prognostic role of CD83 in adult ALL and correlated it with clinical outcome. Prospective study. The patients were followed up for 12 months. Clinical Hematology and Oncology Unit, Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt. 60 subjects (40 newly diagnosed adult ALL patients and 20 age- and sex-matched healthy controls. We analyzed CD83 expression by flow cytometry. Cases have been followed up for one year after enrollment into the study. To measure CD83 in newly diagnosed ALL patients and correlate its level with clinical outcome and treatment response. ALL patients exhibited a statistically significant increase in CD83 expression on their lymphoblast compared to the control group median 19.5% (IQR 5.4-48.15%) vs 7% (IQR 6.1-8.5%), respectively. Based on CD83 expression on BM lymphoblast, patients were divided into two groups: a group with high CD83 (≥9.8%) and the other with normal CD83 expression (<9.8%) compared to the control group. The median (IQR) of the overall survival and disease-free survival was longer than those normally expressed CD83 versus those with higher expression [180days (IQR 60-240) and 105 days (IQR 30-160) vs 80 days (IQR 60-240) and 51 days (IQR 22-150), respectively]. We concluded that elevated serum CD83 at diagnosis can be used as a prognostic marker and predictor of disease response to chemotherapy in patients with ALL and is associated with inferior overall and disease-free survival.

An easy-to-use nomogram predicting overall survival of adult acute lymphoblastic leukemia.

Adult acute lymphoblastic leukemia (ALL) is heterogeneous both biologically and clinically. The outcomes of ALL have been improved with the application of children-like regimens and novel agents including immune therapy in young adults. The refractory to therapy and relapse of ALL have occurred in most adult cases. Factors affecting the prognosis of ALL include age and white blood cell (WBC) count at diagnosis. The clinical implications of genetic biomarkers, including chromosome translocation and gene mutation, have been explored in ALL. The interactions of these factors on the prediction of prognosis have not been evaluated in adult ALL. A prognostic model based on clinical and genetic abnormalities is necessary for clinical practice in the management of adult ALL. The newly diagnosed adult ALL patients were divided into the training and the validation cohort at 7:3 ratio. Factors associated with overall survival (OS) were assessed by univariate/multivariate Cox regression analyses and a signature score was assigned to each independent factor. A nomogram based on the signature score was developed and validated. The receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to assess the performance of the nomogram model. This study included a total of 229 newly diagnosed ALL patients. Five independent variables including age, WBC, bone marrow (BM) blasts, MLL rearrangement, and ICT gene mutations (carried any positive mutation of IKZF1, CREBBP and TP53) were identified as independent adverse factors for OS evaluated by the univariate, Kaplan-Meier survival and multivariate Cox regression analyses. A prognostic nomogram was built based on these factors. The areas under the ROC curve and calibration curve showed good accuracy between the predicted and observed values. The DCA curve showed that the performance of our model was superior to current risk factors. A nomogram was developed and validated based on the clinical and laboratory factors in newly diagnosed ALL patients. This model is effective to predict the overall survival of adult ALL. It is a simple and easy-to-use model that could efficiently predict the prognosis of adult ALL and is useful for decision making of treatment.

RUNX1 and RUNX3 Genes Expression Level in Adult Acute Lymphoblastic Leukemia-A Case Control Study.

The genetic factors of adult acute lymphoblastic leukemia (ALL) development are only partially understood. The Runt-Related Transcription Factor (RUNX) gene family play a crucial role in hematological malignancies, serving both a tumor suppressor and promoter function. The aim of this study was the assessment of relative RUNX1 and RUNX3 genes expression level among adult ALL cases and a geographically and ethnically matched control group. The relative RUNX1 and RUNX3 genes expression level was assessed by qPCR. The investigated group comprised 60 adult patients newly diagnosed with ALL. The obtained results were compared with a group of 40 healthy individuals, as well as clinical and hematological parameters of patients, and submitted for statistical analysis. ALL patients tend to have significantly higher RUNX1 gene expression level compared with controls. This observation is also true for risk group stratification where high-risk (HR) patients presented higher levels of RUNX1. A higher RUNX1 transcript level correlates with greater leukocytosis while RUNX3 expression is reduced in Philadelphia chromosome bearers. The conducted study sustains the hypothesis that both a reduction and increase in the transcript level of RUNX family genes may be involved in leukemia pathogenesis, although their interaction is complex. In this context, overexpression of the RUNX1 gene in adult ALL cases in particular seems interesting. Obtained results should be interpreted with caution. Further analysis in this research field is needed.

Improvements in allogeneic hematopoietic cell transplantation outcomes for adults with ALL over the past 3 decades

AbstractAllogeneic hematopoietic cell transplantation (allo-HCT) is a promising treatment for adult acute lymphoblastic leukemia (ALL), an intractable hematological malignancy. The trends in allo-HCT outcomes over the past 30 years were examined to verify the efficacy of evolving treatment methods and to identify further challenges. We analyzed data from a registry database that included 8467 adult ALL patients who underwent their first allo-HCT between 1990 and 2019. The period was divided into three 10-year intervals for analysis. Five-year overall survival improved from 48.2% to 70.2% in the first complete remission (CR1), from 25.6% to 44.1% in subsequent CR, and from 10.0% to 22.7% in non-CR. Nonrelapse mortality improved over the 3 decades in each disease stage. However, the relapse rate only improved in CR1 every decade (26.3% to 15.9% in CR1, 33.4% to 32.8% in subsequent CR, and 53.6% to 54.8% in non-CR). Although there were continual improvements in adjusted survival for Philadelphia chromosome (Ph)-positive patients, the improvement was inadequate for Ph− patients with t(4;11), t(8;14), t(14;18), or hypodiploidy. Allo-HCT outcomes for adults with ALL have improved over the past 30 years. Improved outcomes in the future will require more effective prevention of relapse in patients with ALL not in CR1 and in those with high-risk chromosomal abnormalities.

Evaluating the Role of Cytokine Receptor-like Factor 2 and Janus Kinase 2 in Adult Acute Lymphoblastic Leukemia

AIM: The aim of the present study was to assess the diagnostic, prognostic, and predictive roles of the cytokine receptor-like factor 2 (CRLF2) and the Janus Kinase 2 (JAK2) genes expression in adult acute lymphoblastic leukemia (ALL) patients. METHODS: The expression levels of CRLF2 and JAK2 genes were evaluated in the bone marrow (BM) samples of 105 adult ALL patients, compared to 12 healthy controls. The data were correlated to the patients’ relevant clinic-pathological features, response to treatment and survival rates. RESULTS: There was a significant overexpression of JAK2 in ALL patients compared to the control group [0.04 (0–160.8) and 0.006 (0–0.009), respectively, p &lt; 0.001]. Similarly, CRLF2 was overexpressed in ALL patients in comparison to control subjects [0.008 (0–78.2) and 0.0005 (0–0.006), respectively, p &lt; 0.001]. The sensitivity, specificity, and the area under curve (AUC) for JAK2 were 78.1%, 81.8%, and 0.796, respectively (p &lt; 0.001), and that of CRLF2 were 92.4%, 90.9%, 0.958, respectively (p &lt; 0.001). When combining both JAK2 and CRLF2 for the diagnosis of ALL patients, it revealed 90.9% sensitivity, 91.4% specificity, and AUC of 0.957 (p &lt; 0.001). The JAK2, CRLF2, or their combined expression associated significantly with the increased expression of MHC-II (p = 0.015, 0.001, and 0.004, respectively). However, they had no significant impact on patients’ response to treatment, overall (OS), and disease-free survival (DFS) rates (p &gt; 0.05 for all). CONCLUSION: JAK2 and CRLF2 could be a potential useful diagnostic molecular marker for ALL patients, which allow them to be successful targets for ALL therapy.

Evaluating outcomes of adult patients with acute lymphoblastic leukemia and lymphoblastic lymphoma treated on the GMALL 07/2003 protocol.

Chemotherapy-based approaches still constitute an essential feature in the treatment paradigm of adult acute lymphoblastic leukemia (ALL). The German Multicenter Study Group (GMALL) is a well-established protocol for ALL. In this study, we assessed our recent experience with the GMALL 07/2003 protocol reviewing all adult ALL patients who were treated with GMALL in three major centers in Israel during 2007-2020. The analysis comprised 127 patients with a median age of 41 years (range 17-83). Sixty-two were B-ALL (49%), 20 (16%) patients were Philadelphia chromosome positive ALL, and 45 (35%) were T-ALL. The 2-year and 5-year overall survival rates were 71% and 57%, respectively. The 2-year relapse rate was 30% with 2-year and 5-year leukemia-free survival rates of 59% and 50%, respectively. Adolescents and young adults experienced significantly longer overall survival (84 months versus 51 months; p=0.047) as well as leukemia-free survival compared with older patients (66 months versus 54 months, p=0.003; hazard ratio=0.39, 95% confidence interval, 0.19-0.79; p=0.009). T-ALL patients had longer survival compared to B-ALL patients while survival was comparable among Philadelphia chromosome positive patients and Philadelphia chromosome negative patients. An increased number of cytogenetic clones at diagnosis were tightly associated with adverse prognosis (15-month survival for ≥2 clones versus 81 months for normal karyotype; p=0.003). Positive measurable residual disease studies following consolidation were predictive for increased risk of relapse (64% versus 22%; p=0.003) and shorter leukemia-free survival (11 months versus 42 months; p=0.0003). While GMALL is an effective adult regimen, a substantial patient segment still experiences relapse.

Outcome of adult acute lymphoblastic leukemia, a single-center experience

BACKGROUND: Adult acute lymphoblastic leukemia (ALL) has a dismal outcome within the optimal situations as the 5-year overall survival (OS) is not reaching 40%. OBJECTIVE: The objective of this study was to evaluate the outcome of adult ALL in Erbil, Iraq, and to see the factors predicting better survival among them. PATIENTS AND METHODS: We analyzed data from 71 adult ALL patients aged 14–81 years (mean age: 28.6 years). Diagnosis is based on the peripheral blood film, bone marrow examination, and flow cytometry. RESULTS: The median OS was 21 months and the median relapse-free survival (RFS) was 13 months. The 3-year OS and the 3-year RFS were 49.3% and 40.8%, respectively, while the 5-year OS and the 5-year RFS were 37.5% and 32.5%, respectively. CONCLUSION: Factors predicting better survival included in the study; age at diagnosis, remission achievement at first induction, risk assessment, and allogeneic stem cell transplantation optimal response.