Acute Lymphoblastic Leukemia Lymphoma Research Articles

Beyond the Marrow: Unveiling Uncommon Sites of ALL Relapse with 18F-FDG PET/CT

AbstractExtramedullary infiltration of acute lymphoblastic leukemia/lymphoma (ALL) to genital organs is extremely rare. Here, we present a case report of an asymptomatic 49-year-old female, known case of precursor B-cell ALL, who was incidentally detected with thickened and heterogeneously hyperechoic endometrium on sonography. Contrast magnetic resonance imaging detected large polypoidal enhancing lesions showing intense diffusion restriction occupying the endometrial cavity and similar lesions in the left adnexa, left ovary, and fallopian tube which were suspicious for leukemic infiltration because of the clinical history and atypical appearance of the lesions. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was done which revealed intensely metabolically active lesion in the endometrial cavity, left adnexa, omental nodules, retroperitoneal lymph node, pancreatic lesion, and few irregular nodules in the right lower lobe. Biopsy findings confirmed extramedullary relapse of ALL. Hence, 18F-FDG PET/CT can act as a good whole body survey to look for extramedullary sites of relapse.

Retrospective review of the toxicities and change in dosing patterns for pegaspargase in patients with acute lymphoblastic leukemia/lymphoma and T-cell lymphoma.

Pegaspargase (PEG) is a key component of standard regimens for acute lymphoblastic leukemia/lymphoma (ALL) and extranodal natural killer/T-cell lymphoma (NKTCL). Emerging evidence suggests an opportunity to decrease incidence of PEG-associated toxicities with dose capping, but evidence is limited. This study aims to evaluate whether a significant difference in PEG-associated toxicities related to dosing strategy exists and to identify patient-specific or regimen-specific factors for PEG-related toxicity. A retrospective analysis of PEG-associated toxicities was completed in adult patients with ALL or NKTCL who received PEG within Cancer and Leukemia Group B (CALGB) 10403 or modified dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) regimens at the UW Medical Center/Fred Hutchinson Cancer Center. PEG-associated toxicities that occurred through 8 weeks after PEG doses were noted. Twenty-eight patients received dose-capped PEG, and 29 received noncapped PEG. Fewer all-grade and grade 3/4 toxicities were observed in the dose-capped cohort. Grade 3/4 toxicities observed were hepatotoxicity, hyperglycemia, hypersensitivity, and hypertriglyceridemia. In addition, fewer grade 3/4 pancreatitis and thrombosis events occurred in the dose-capped cohort. Hypertriglyceridemia and hepatotoxicity were associated with the highest cumulative incidence proportions among all toxicities. Dose capping of PEG was associated with a similar or later median onset for most toxicities, a less heterogeneic toxicity profile, and a lower recurrence of most toxicities upon PEG rechallenge compared to the non-dose-capped cohort. Standardizing PEG dose capping in the CALGB 10403 and mSMILE regimens may translate to improved tolerance compared to a historical standard of no dose capping PEG.

Similar Survival But Less Chronic GVHD in Antithymocyte Globulin-Based Myeloablative Haploidentical Transplant Compared With Matched Sibling Transplant for Adult T-cell Acute Lymphoblastic Leukemia/Lymphoma.

The annual number of human leukocyte antigen (HLA)-haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HCT) is increasing steadily. Comparative studies about haplo-HCT versus HCT with HLA-matched sibling donors (MSD-HCT) have been tried in acute myeloid leukemia and B-cell acute lymphoblastic leukemia/lymphoma (ALL). Few studies were reported in adult T-cell ALL (T-ALL). In this retrospective study, a total of 88 consecutive patients with T-ALL were enrolled who underwent MSD-HCT (n = 24) and haplo-HCT (n = 64) with antithymocyte globulin (ATG)-based graft versus host disease (GVHD) prophylaxis between 2010 and 2022. Median follow-up for survivors was similar (43.5 [range: 7-88] months for MSD-HCT versus 43.5 (range: 6-144) months in the Haplo-HCT group). The 100-day cumulative incidence of grade II to IV acute GVHD (aGVHD) was similar, 33% (95% confidence interval [CI], 16%-52%) after MSD-HCT versus 44% (95% CI, 31%-55%) after haplo-HCT, P = 0.52. The cumulative incidences of grade III-IV aGVHD were 8% (95% CI, 1%-23%) in the MSD-HCT group and 5% (95% CI, 1%-12%) in the haplo-HCT group (P = 0.50). The 2-year cumulative incidence of chronic GVHD (limited and extensive) in the haplo-HCT, 11% (95% CI, 5%-20%) was significantly lower than that in the MSD-HCT group (42% [95% CI, 21%-62%], P = 0.002). The cumulative incidence of 4-year relapse rates (44% versus 37%, P = 0.56) and non-relapse mortality (7% versus 21%, P = 0.08) did not differ between these two groups. There were also no differences in 4-year overall survival (46% versus 47%, P = 0.44) and progression-free survival (49% versus 42%, P = 0.45) between these two groups. On multivariate analysis, using busulfan/fludarabine (BU/Flu) conditioning regimen was found to be associated with worse clinical outcome. Our results suggested that ATG-based haplo-HCT platform could work as an alternative to MSD-HCT for adult patients with T-ALL. Compared with MSD-HCT, haplo-HCT might carry a low risk for cGVHD.

Constitutively active CaMKII Drives B lineage acute lymphoblastic leukemia/lymphoma in tp53 mutant zebrafish.

Acute lymphoblastic leukemia/lymphoma (ALL) is the most common pediatric cancer and is a malignancy of T or B lineage lymphoblasts. Dysregulation of intracellular Ca2+ levels has been observed in patients with ALL, leading to improper activation of downstream signaling. Here we describe a new zebrafish model of B ALL, generated by expressing human constitutively active CaMKII (CA-CaMKII) in tp53 mutant lymphocytes. In this model, B cell hyperplasia in the kidney marrow and spleen progresses to overt leukemia/lymphoma, with only 29% of zebrafish surviving the first year of life. Leukemic fish have reduced productive genomic VDJ recombination in addition to reduced expression and improper splicing of ikaros1, a gene often deleted or mutated in patients with B ALL. Inhibiting CaMKII in human pre-B ALL cells induced cell death, further supporting a role for CaMKII in leukemogenesis. This research provides novel insight into the role of Ca2+-directed signaling in lymphoid malignancy and will be useful in understanding disease development and progression.

Retrospective Analysis of Adolescent Young Adult Patients with Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma Treated with the CALGB 10403 Regimen Since Completion of Trial Enrollment

INTRODUCTION The outcomes of adolescent and young adult (AYA) patients (ages 15-39 years) with acute lymphoblastic leukemia/lymphoma (ALL) have improved in part with the adoption of pediatric ALL regimens in the adult treatment setting. The Cancer and Leukemia Group B (CALGB) 10403 trial (C10403) was the largest prospective trial conducted in the United States (U.S.), demonstrating the safety and efficacy of delivering an intensive pediatric regimen utilizing asparaginase in the adult oncology treatment setting to AYAs with ALL, with 3-year event-free survival (EFS) and overall survival (OS) of 59% (95% CI, 54%-65%) and 73% (95% CI, 68%-78%), respectively (Stock et al., Blood 2019). Although this regimen is widely used in the U.S., outcomes for patients treated with C10403 outside of a clinical trial setting remain unknown. We thus conducted a multi-center retrospective study to examine the real-world, off-trial efficacy of the C10403 regimen delivered across U.S. cancer centers. METHODS AYAs ages 17-40 years with newly diagnosed Ph-neg B-ALL or T-ALL between October 1, 2012 and July 1, 2020 who received initial treatment with the C10403 regimen (off trial) across 5 U.S. centers were included. Patients were excluded if they had Ph+ or Burkitt-type ALL. Previously treated patients, except with hydroxyurea, steroids, or one dose of single-agent therapy were excluded; patients given rituximab for CD20+ B-ALL were included. Primary endpoints were induction response rate (IRR), 3-year EFS, and 3-year OS. Induction response was defined as achieving <5% blasts on bone marrow by end of induction or extended induction. Patients were censored for EFS at the time of change in regimen, the addition of another agent (eg blinatumomab) or if they proceeded to hematopoietic cell transplant (HCT). Patients with deviation from the C10403 regimen were included in the 3-year OS analysis. Events were defined as: 1) failure to achieve bone marrow response by the end of induction or extended induction, 2) failure to achieve metabolic response of lymphoma on PET-CT as determined by the clinician 3) death, 4) relapse at any site, or 5) development of second malignancy. RESULTS Among 101 included in the cohort, 54% were 20-29 years old, 69% were male, 55% were Caucasian and 31% identified as Hispanic. Of those with B-cell immunophenotype (70%), 49% had CD20 expression. The majority had normal karyotype (40%), while 3% were hypodiploid, 7% were KMT2a-rearranged, and 30% of the 27 patients assessed had Ph-like ALL. CNS involvement at diagnosis was documented in 20% (9% CNS2/11% CNS3) and 14% had a mediastinal mass. Of the B-ALL cohort (N=71), 16 (23%) received at least one dose of rituximab. Among the entire cohort, the IRR was 91% (54% MRD negative; threshold of at least 10 -4). Of the 101 patients who began induction with C10403, 72 (71%) completed induction and continued to consolidation; 51 (50%) continued beyond consolidation, and 31 (31%) completed the entire C10403 regimen through end of maintenance. Two patients (2%) died while in remission and still receiving treatment. Forty-four patients (44%) were taken off C10403 while in CR; 20 (20%) for allogeneic HCT, 23 (23%) for non-HCT alternative treatments including Hyper-CVAD or blinatumomab, and 1 (1%) for patient preference. The 3-year EFS and OS were 65% (95% CI, 53.8%-78.5%) and 82.7% (95% CI, 75.5%-90.5%), respectively (Figures 1 and 2). Conclusion In this multi-center, real world study of the C10403 regimen administered to newly diagnosed AYA ALL patients across adult U.S. centers, we demonstrate survival outcomes as favorable as the reported clinical trial results. While only 31% of patients completed the regimen through end of maintenance, a majority of patients who came off regimen either underwent consolidative HCT or alternative therapy while in CR. These data confirm the pediatric regimen as an excellent front-line option in AYA ALL.

Array CGH + SNP in ALL Enhances Detection of Complex Cytogenetic Profiles and Suggests That PRSS1 Loss May Play a Role in Leukemogenesis

Introduction Cytogenetic alterations are essential prognostic biomarkers in patients (pts) with acute lymphoblastic leukemia/lymphoma (ALL), but are limited by the propensity of leukemic blasts to undergo apoptosis in culture, poor-quality chromosomes, and overgrowth by normal cells. Array CGH + SNP has 10,000-fold higher resolution than conventional cytogenetics and can identify submicroscopic gains, losses and copy number neutral loss of heterozygosity (cnLOH) irrespective of mitotic rate. Few studies outside of clinical trials have investigated microarray findings in adults with ALL or correlated microarray findings with clinical outcomes. Methods We retrospectively reviewed pts with ALL and mixed phenotype acute leukemia (MPAL) aged ≥18 years at diagnosis at our institution between 2017 and 2022. Array analysis was performed on diagnostic bone marrow or peripheral blood samples using high resolution CGH + SNP Genetisure cancer array platform (Agilent). Statistical analysis was done using R software (R core team, 2022). Results Baseline characteristics of included pts (n = 60) are shown in Table 1. CGH + SNP analysis identified 93.3% (56/60) of pts with genomic changes with a mean of 7 (range 0 - 28) aberrations per pt. Among pts with a normal karyotype, 81.8% (9/11) had new genomic abnormalities revealed by CGH + SNP, but significantly fewer aberrations were detected per pt compared to those with abnormal karyotypes (mean 3.09 v. 7.67, p = .008). Pts with Ph-like B-ALL/MPAL had significantly more aberrations on array than pts without Ph-like phenotype (mean 12.0 v. 5.85, p.= .002). Among the 78.3% of pts without complex cytogenetics on chromosome analysis, 44.7% (21/47) were found to have a complex genomic profile (≥5 aberrations) with the addition of CGH + SNP. However, there was no difference in CR rates or OS in pts with <5 or ≥5 microarray aberrations (p = .515 and p = .970, respectively). Quantity of copy number alterations (CNAs) as detected on array was not predictive of achieving end of induction CR/CRi/CRh (mean 6.08 in pts who achieved CR/CRi/CRh v. 7.02 in pts with primary refractory disease, p = .310). Hispanic pts had the same number of CNAs as non-Hispanic pts (mean 6.69 v. 6.94, p = .435). On linear regression analysis, there was no correlation between number of CNAs and age (r 2 = -.01, F = 0.1941, p = .661) or BMI (r 2 = 5.21 x10 -5, F = 0.0029, p = .957). The most frequent focal aberrations were detected in CDKN2A/B (n = 19), IKZF1 (n = 17), PRSS1 (n = 11), PAX5 (n = 8), BTG1 (n = 8) and RB1 (n = 8) (Figure 1). RB1 loss was enriched in pts with T-ALL (45.5% v. 6%, p = .003),and occurred at significantly higher rates than previously reported in T-ALL (Schraders, 2009). Loss of PRSS1 was detected in 18.3% (11/60) of the cohort. Homozygous PRSS1 deletions were identified in 3/11 (27.3%) pts. We identified the minimal overlapping deleted region on 7q34 in all 11 pts, which included the PRSS1 gene within the 124 kb region. Five of 6 pts who had repeat arrays performed at the end of induction had resolution of this aberration. The one pt who retained PRSS1 loss after induction had primary refractory disease, but after further treatment and attainment of CR1, this pt cleared the PRSS1 loss. Asparaginase associated pancreatitis, which has been linked to PRSS1 variations, occurred in only 1 pt with PRSS1 loss. Pts harboring PRSS1 loss were significantly less likely to achieve MRD negativity after induction (50% vs. 82%, P = .041) and had numerically more relapses (37.5% vs. 19%, p = .300), but no OS difference was observed (p = .290). Conclusions In our institutional cohort, the addition of CGH + SNP array reclassified almost half (44.7%) of pts without complex cytogenetics to harbor complex genomic changes (≥5 aberrations). Pts with Ph-like ALL had significantly more aberrations on array than those with Ph-positive or -negative B-ALL. Focal PRSS1 loss was associated with reduced rates of MRD clearance at the end of induction. This aberration resolved upon disease remission, raising the possibility that both homozygous and/or heterozygous deletions of 124 kb from the 7q34 chromosomal region of the PRSS1 gene may potentially have a role in ALL pathogenesis. Further studies with larger cohorts utilizing CGH + SNP analyses at additional time points during treatment are needed to explore the potential integration of microarray data for refined ALL risk stratification as well as to elucidate the functional role of PRSS1 in leukemogenesis.

A Phase I Clinical Trial of Fully Human Anti-CD19 Chimeric Antigen Receptor T Cells for Relapsed or Refractory Lymphoid Malignancies

Background: Chimeric antigen receptor (CAR) T-cells have revolutionized the standard of care for numerous lymphoid malignancies but continue to present challenges related to toxicity, long-term efficacy, cost, and accessibility. Novel CAR-T cell constructs hold promise for improving desired outcomes. CD19 CAR-T cells with fully humanized chimeric antigen receptors have demonstrated excellent preclinical activity and the potential for lower rates of cytokine release syndrome (CRS) and severe immune effector associated neurotoxicity syndrome (ICANS). To evaluate safety, we conducted a phase 1 clinical trial evaluating fully human Hu19-CD841BBZ CAR-T cells with a 4-1BB costimulatory domain against relapsed or refractory (R/R) CD19-positive lymphoid malignancies, utilizing a single lymphodepletion regimen and local CAR-T cell manufacturing using the Prodigy® Device. Methods: We designed a parallel-group phase I trial with two clinical groups. Group A enrolled subjects with relapsed and refractory CD19+ lymphomas and chronic lymphocytic leukemia (CLL), while Group B comprised patients with acute lymphoblastic leukemia/lymphoma (ALL). The primary endpoint was safety and toxicity assessment, along with the identification of the recommended phase 2 dose in each clinical group. Secondary endpoints included efficacy evaluation. Dose escalation in each group followed a “3 + 3” phase I study design, with three dose levels: 5e5 CAR-T cells/kg, 1e6 CAR-T cells/kg, and 2e6 CAR-T cells/kg. Lymphodepletion consisted of cyclophosphamide 60mg/kg on day -6 and Fludarabine 25mg/m2/day on days -5 to -3. Dose-limiting toxicities included prolonged CRS grade 3 or higher, ICANS grade ≥ 3, and grade ≥ 3 non hematologic toxicities with the exception of self-limited (<7 days) laboratory abnormalities without associated symptoms or clinical consequences. Results: As of 7/1/2023, a total of 13 patients were enrolled in Group A (NHL), and two patients were enrolled in Group B (B-ALL). Three patients in Group A withdrew consent or were withdrawn at the investigator's discretion due to new comorbid conditions before cell collection. Additionally, three patients were unable to receive CAR-T cell infusions due to disease progression, including two with Burkitt lymphoma. Among the remaining patients, 7 in NHL and 2 in B-ALL, received CART cells. The average age was 59 (range: 40-73), and 2 patients were female. In the NHL group, diseases treated included CLL (3), mantle cell lymphoma (2), follicular lymphoma (1), and Waldenstrom's (1). The median number of prior treatments was 4 (range: 3-10). CAR-T cell product manufacturing was successful in all patients to achieve the target dose, with a mean transduction efficiency of 43.8% (29.7% - 54.6%). One potential dose-limiting toxicity, nodular regenerative hyperplasia of the liver, considered possibly related to CAR-T cells, was observed in the NHL group at the 1e6 cells/kg dose level, leading to an expansion of this dose level. Other observed toxicities were as expected and manageable. Six patients experienced CRS, with grades 1-2 in the NHL group. Both patients in the B-ALL arm experienced CRS, one grade 1 and one grade e, with observed severity congruent with known disease burden before receiving CAR-T cells. Two cases of CRS required no intervention, while the remaining cases received tocilizumab (n=4), steroids (n=2), and/or anakinra (n1). There were three occurrences of ICANS, two in Group A and one in Group B. Treatments included corticosteroids (n=3) and anakinra (n=2). Among the 7 NHL patients evaluable for response, 2 achieved complete remission (follicular, mantel cell), three had a partial response (CLL), and one exhibited stable disease (Waldenstrom's). Two NHL patients (CLL and Mantel Cell) had subsequent disease progression. One B-ALL patient evaluable for response achieved a CR but experienced disease progression at one year and subsequently died. Discussion: In this parallel-group phase 1 study, fully human Hu19-CD841BBZ CAR-T cells with a 4-1BB costimulatory domain were successfully manufactured in all patients undergoing leukapheresis. Human CAR-T cells demonstrated preliminary safety and clinical activity in the setting of heavily pre-treated patients with R/R B cell malignancies. A platform of point-of-care manufacture permits access to novel CAR-T cell products, and may facilitate the development of novel immune effector cell products.

Treatment outcomes of adult acute lymphoblastic leukaemia in Auckland, New Zealand.

Acute lymphoblastic leukaemia/lymphoma (ALL) is a rare disease that requires an intensive chemotherapy regimen for successful treatment. This is a single-centre retrospective audit to assess the treatment outcomes in the largest ALL centre in New Zealand. Data such as survival and adverse events of patients with de novo ALL referred to Auckland City Hospital for treatment were included in this audit. Sub-group analyses were also performed. Sixty-five patients aged from 18 upwards with ALL were included in this audit. The median survival of all patients was 37.6 months. Adolescent and young adults (AYA) treated on the COG (paediatric) protocols had a mean survival of 48.3 months (median not reached), while adults treated with the UKALL14 protocol had a median survival of 37.6 months. In the UKALL14 sub-group, Māori/Pacific Islanders had an inferior EFS that was statistically significant. Overall AYA outcomes are comparable to international standards. Our adult outcomes may be poorer than the original UKALL14 trial, with Māori/Pacific Island patients having shorter survival.

Outcomes of adult patients with early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) and non-ETP T-ALL.

Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) is generally considered to be a high-risk subtype. We retrospectively analyzed the clinical outcomes of adult patients diagnosed with ETP-ALL or other T-cell ALL (non-ETP T-ALL). The subjects were 82 patients (ETP-ALL: n = 18, non-ETP T-ALL: n = 64) for whom relevant immunophenotype data needed for classification were available. ETP-ALL patients were older (median age, 50.5 vs. 33.5years, P = 0.042) and had less mediastinal involvement (27.8 vs. 73.4%, P < 0.001). The rate of complete remission (CR) with the first induction therapy was significantly lower in the ETP group (33.3 vs. 64.0%, P = 0.03), but the CR rate within 2 cycles of chemotherapy did not differ significantly (61.1 vs. 76.6%, P = 0.232). The 3-year overall survival (OS) rate was also similar in both groups (43.2 vs. 45.8%, P = 0.992). The ETP phenotype had no impact on survival in the transplant group or the non-transplant group. A multivariate analysis identified the male sex as a poor prognostic factor (HR: 4.43, P < 0.01), but not the immunophenotype of ETP. The prognosis for adult patients with ETP-ALL was comparable to that of non-ETP T-ALL patients. However, further studies aimed at improving the remission rate for ETP-ALL are needed.

United Arab Emirates Population-Based Acute Leukaemia Registry: Acute Lymphoblastic Leukaemia Real-World Data

Population-based registries may provide data useful for clinical decisions in patients' populations not well presented by clinical studies, which is essential to establish recommendations for the management of patients in the real world. The aim of the first Sheikh Shakhbout Medical City (SSMC) ongoing acute leukaemia registry is to obtain information about the demography, clinical presentation, genetic markers, risk stratification and disease response of patients with diverse ethnicities and backgrounds .The registry includes newly diagnosed adults with acute leukaemia, admitted to SSMC from June 2021 onward. SSMC acute leukaemia registry is an observational retrospective and prospective study. Electrical medical records were used to collect data, and coding was used for each variable based on the 2017 European leukaemia network (ELN) and the 2016 European society for medical oncology (ESMO) clinical practice guidelines. A total of 41 patients were registered between June 2021 and May 2022. Eighteen patients with Acute Lymphoblastic leukaemia/Lymphoma (ALL) and 1 patient mixed-lineage leukaemia (MLL). Of the 18 patients with ALL, 6 patients with T-cell ALL, one of them with antecedent Chronic myeloid leukaemia (CML), and 12 patients with B-cell ALL. Seventy four percent of patients are males (n=14) and 26% (n=5) are females, 58% (n=11) are younger than 40 years of age, and 42% (n=8) are between 40 and 65 years old, with median age of 37 years at the time of diagnosis. Forty Seven percent of patients are Arabs, 26% are South Asian, 11% are Southeast Asian, 11% are African, and 5% are from other ethnicities (Table 1). Seventy four percent (n=14) of patients have adverse prognosis as per Hoelzer D et al., (2016). Of the 12 patients with B-cell ALL, 5 patients with Philadelphia chromosome-positive, accounts for 41% of patients which is higher compared to the 31% reported percentage in other clinical trials (Gupta R et al., 2018), 3 patients with Philadelphia-like chromosome positive, accounts for 25% of patients which is within the reported percentage range in other trial canters (Hoelzer D et al., 2016; National Comprehensive Cancer Network [NCCN], 2022) Induction regimens included paediatric protocols (n=3), hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose methotrexate, and cytarabine (HyperCVAD) (n=14), and 2 patients did not receive induction chemotherapy due to refusal of therapy and loss of follow up. As per the NCCN (2022), 6 patients achieved complete remission (CR) post induction,4 of which have negative minimal residual disease (MRD), 1 patient has positive MRD and 1 patients has failed MRD test. One patient achieved CR with incomplete hematologic recovery (CRi), 4 patients had partial remission, 2 patients were evaluated as treatment refractory, and 6 patients had no disease assessment post induction due to death or loss of follow up. Waca SSMC is one of the major leukaemia centres in Abu Dhabi, United Arab Emirates (UAE), where petroleum and natural gas are the main industry. UAE population consists of mixed ethnicities with different socioeconomic backgrounds where consanguinity is common and air pollution exposure at home countries is a big possibility. Despite the fact that our patient population is small, and statistically significant analysis might not be possible at this stage, we believe that our patient population demographics and genetic markers are not well-reflected in the standard guidelines. With longer observation and time the SSMC acute leukaemia registry promises to provide interesting data that may shed important input for better treatment algorithms. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

AKR1C3 expression in T acute lymphoblastic leukemia/lymphoma for clinical use as a biomarker

To investigate aldo–keto reductase 1C3 (AKR1C3) expression in T and B acute lymphoblastic leukemia/lymphoma (ALL) patients. Three commercial antibodies were evaluated for AKR1C3 immunohistochemistry (IHC) staining performance: Polyclonal Thermofisher scientific (Clone#PA523667), rabbit monoclonal Abcam [EPR16726] (ab209899) and Sigma/Millipore anti-AKR1C3 antibody, mouse monoclonal, clone NP6.G6.A6, purified from hybridoma cell culture. Initial optimization was performed on cell line controls: HCT116 (negative control); genetically modified cell line HCT116 with AKR1C3 overexpression; Nalm and TF1 cell lines. Twenty normal bone marrows from archival B and T-ALL patient samples were subsequently examined. AKR1C3 expression levels in these samples were evaluated by immunohistochemistry, Protein Wes and quantitative RT-PCR. Sigma/Millipore Anti-AKR1C3 antibody (mouse monoclonal, clone NP6.G6.A6) showed higher specificity compared to rabbit polyclonal antibody by immunohistochemistry. H-score was used to quantify percent of nuclear immunoreactivity for AKR1C3 with varying disease involvement. T-ALL samples had a higher H-score (172–190) compared to B-ALL cases (H-score, 30–160). The AKR1C3 expression in peripheral blood by Protein Wes and RT-qPCR showed concordance in relapsed/refractory and/or minimal residual T-ALL cases. Sigma/Millipore Anti-AKR1C3 antibody and mouse monoclonal, clone NP6.G6.A6 can be used to aid in AKR1C expression of T-ALL and in cases of relapsed/refractory and/or minimal residual disease.

Reduced-Intensity Therapy with Dose-Adjusted Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin (DA-EPOCH) Yields Durable Remissions in Adults with Newly-Diagnosed Acute Lymphoblastic Leukemia/Lymphoma (ALL): Final Results of a Phase II Trial

Reduced-Intensity Therapy with Dose-Adjusted Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin (DA-EPOCH) Yields Durable Remissions in Adults with Newly-Diagnosed Acute Lymphoblastic Leukemia/Lymphoma (ALL): Final Results of a Phase II Trial

Acute Lymphoblastic Leukemia/Lymphoma in the Elderly: The Mayo Clinic Experience

IntroductionElderly patients (≥60 years of age) with acute lymphoblastic leukemia/lymphoma (ALL) have a poor prognosis compared to younger adults. This is thought to be due to comorbidities, treatment-related mortality, adverse disease biology, low rates of complete remission (CR), high risk of relapse, and ineligibility for allogeneic hematopoietic stem cell transplantation (HSCT). Since it is unclear how all these factors play into the poor prognosis of elderly ALL, we sought to describe the presentation, treatment outcomes, and predictors of survival at our multi-site institution.MethodsAfter IRB approval, we performed a retrospective study of patients (pts) ≥60 years old diagnosed with ALL from 2000-2017 at Mayo Clinic Rochester, Arizona, and Florida. Statistical analysis was performed using JMP 10.0 software.ResultsBaseline characteristicsWe identified 124 consecutive pts with elderly ALL. The median age at time of diagnosis was 67 (60-86) and 74 (60%) were male. Median time of follow-up was 15.6 months (range 0.2-132). 77 (62%) were deceased at the time of last follow-up: 37 deaths related to disease, 24 due to infection or other causes, and 16 unknown.At time of diagnosis, 108 (87%) pts had B-cell ALL, of which 40 (37%) were Philadelphia chromosome positive (Ph+). Only 16 (13%) pts had T-cell ALL. Overall, 24 (19%) had an ECOG performance status (PS) ≥2, and 22 (18%) had a Charlson Comorbidity Index (CCI) ≥3. Further baseline characteristics including cytogenetics and FISH studies are detailed in Table 1.Treatment and Outcomes102/124 (82%) elected to undergo induction. Of these, 19 (19%) had an up-front dose reduction. The most common induction regimen was Hyper-CVAD, which was used in 62 (61%), concomitantly with rituximab in 21, and tyrosine kinase inhibitors (TKIs) in 17. Asparaginase-based chemotherapy was used in 27 (26%) pts. The remaining 13 (13%) received other regimens. Complete remission (CR/CRi) was achieved in 92 (90%) pts. 11 (11%) had primary refractory disease, of which 7 were refractory to multiple lines of therapy. Median time to CR was 30 days (range 10-352), requiring a median of 1 cycle (range 1-8) of chemotherapy. 5 (5%) died within 60 days of starting treatment, and by Day 100 there were a total of 10 (10%) deaths; these were related to subdural hematoma (3), infection (2), treatment discontinuation (1), and unknown causes (4).Palliative therapy up-front was chosen in 22/124 (18%), which included chemotherapy (e.g. vincristine and steroids), TKIs or hospice. 7 (32%) of these pts achieved CR within a median time of 54 days (range 23-128). The median overall survival (mOS) in the palliative group was 5.7 months (interquartile range [IQR] 1.7-12.1).Relapse occurred in 42 (42%) pts within a median time of 9.9 months (range 0-71.5); 10 (24%) of these pts had an extramedullary relapse, including 3 with CNS leukemia. 31 (74%) were treated with salvage chemotherapy, while 10 (21%) chose palliative care. Median survival from the time of relapse was 5.7 months (IQR 2-18).Overall, 34 (27%) underwent HSCT: allogeneic HSCT in 33, and autologous HSCT in 1. Of these, 29 (85%) were in CR1, and 5 (15%) were in CR2. The median age at time of HSCT was 65 (range 60-73). 3 (9%) died within 100 days of HSCT, due to early relapse (2; both were in CR1) and acute graft-versus-host disease (1). 11 (31%) relapsed after HSCT, within a median time of 9 months (range 1-30). Median survival after HSCT was 27.4 months (IQR 0.7-not reached [NR]).Predictors of SurvivalElderly ALL across the three Mayo Clinic campuses had a mOS of 20.8 months (IQR 9.4-87.3), which was inferior compared to our adult ALL (age 18-59) cohort in Rochester, who had a mOS of 51.1 months (IQR 15.3-NR) (Figure 1). In univariate analysis, which included the presenting variables shown in Table 1, only age, ECOG PS, CCI, and LDH negatively influenced survival (P <0.05). These factors continued to significantly predict for poor survival in multivariate analysis (Table 2).ConclusionsALL has worse outcomes in elderly pts compared to younger adults. However, treatment-related mortality was relatively low in our cohort even though the majority of pts underwent induction. Interestingly, we found that survival was influenced by age, ECOG PS, CCI, and LDH at time of diagnosis, rather than by cytogenetics or other biological features. Our data needs to be verified in a larger cohort. Nevertheless, this could be the first step toward a prognostic model in elderly ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Incidence of Invasive Fungal Infections in Children, Adolescents and Young Adults with Acute Lymphoblastic Leukaemia/Lymphoma Treated with the UKALL2011 Protocol: a Multicentre Retrospective Study

▪Introduction: While it is well-recognised that invasive fungal infections (IFIs) are a major cause of morbidity and mortality in haematological malignancies, epidemiological data in paediatric acute lymphoblastic leukaemia/lymphoma (ALL) is scarce (Groll et al. Lancet Oncology 2014). The incidence of IFI in paediatric ALL is difficult to estimate as differing chemotherapy protocols, patient populations, diagnostic strategies and IFI definitions preclude direct comparisons. Assessment is also limited by major practice variations in the use of prophylactic and empiric systemic antifungals. Despite the lack of published data, there is a concern that IFIs impact on disease outcome and survival, either directly due to infection-related mortality or secondary to chemotherapy omissions, dose reductions and changes to subsequent therapy. To determine the incidence and outcome of IFIs in paediatric, adolescent and young adult patients treated with the UKALL2011 protocol, we conducted a retrospective study in two large London tertiary referral centres over a 4 year period.Methods: All patients diagnosed and treated with ALL at Great Ormond Street Hospital (GOSH) and University College London Hospital (UCLH) between January 1st 2013 and January 1st 2017 were included in the study. Data on IFIs were collected during the following phases of the UKALL2011 protocol: Induction, consolidation, interim maintenance and delayed intensification. Medical records and online databases were used to collate the data. IFIs were classified as proven, probable and possible according to revised EORTC criteria (De Pauw et al. Clinical Infectious Diseases 2008).Results: Between January 1st 2013 and January 1st 2017 296 patients (M=160, F=136) with a median age of 5 years (range 10 months -24 years) were treated for ALL (B-lineage n=249, T lineage n=43, NA n=4) at GOSH (n=233) and UCLH (n=63). Cytogenetic risk profile for B-ALL was classified as good (n=133), intermediate (n=86), poor (n=20) or NA (n=10) (Moorman AV et al. Lancet Oncology 2010).A small cohort of young adult patients aged 20 to 24 years (n=16) received anti-fungal prophylaxis during induction and consolidation in the form of oral itraconazole when the neutrophil count was less than 1.5×109/L. This was substituted with liposomal amphotericin B when vinca alkaloids were scheduled. Routine anti-fungal prophylaxis was not implemented in the remaining cases (n=280)Over a 4 year period the incidence of proven, probable and possible IFI was 2% (n=6), 1.6% (n=5) and 4% (n=12) respectively. Positive mycological results were available in 7 cases: Candida spp in 5, Aspergillus spp in 1 and Scedosporium spp in 1. Disseminated disease (including CNS disease n=2) occurred in 4 cases, all during induction (Table 1).IFIs resulted in a treatment delay of a median of 3 weeks (range 1-15) in 16 cases. Omission of chemotherapy and significant dose reductions occurred in 2 and 4 cases respectively.Follow-up data is available in 22 of the 23 patients diagnosed with a proven, probable or possible IFI during the UKALL2011 protocol (lost to follow-up n=1).With a median follow up of 16 months (range 4-39), 20 patients are alive and in ongoing remission. Three patients proceeded to haematopoietic stem cell transplant (HSCT). Two of these patients died of complications of HSCT. IFI recurrence (candida utilis bacteraemia) was a contributing factor in one case.Conclusions: The incidence of IFIs is low in ALL patients treated with UKALL2011 protocol, with a low risk of mortality but the potential to compromise timely delivery of chemotherapy. The risk appears to be highest in induction. This data does not support the routine administration of prophylactic anti-fungal therapy in children and young people undergoing chemotherapy for ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Recurrent somatic mutations and low germline predisposition mutations in Korean ALL patients

In addition to somatic mutations, germline genetic predisposition to hematologic malignancies is currently emerging as an area attracting high research interest. In this study, we investigated genetic alterations in Korean acute lymphoblastic leukemia/lymphoma (ALL) patients using targeted gene panel sequencing. To this end, a gene panel consisting of 81 genes that are known to be associated with 23 predisposition syndromes was investigated. In addition to sequence variants, gene-level copy number variations (CNVs) were investigated as well. We identified 197 somatic sequence variants and 223 somatic CNVs. The IKZF1 alteration was found to have an adverse effect on overall survival (OS) and relapse-free survival (RFS) in childhood ALL. We found recurrent somatic alterations in Korean ALL patients similar to previous studies on both prevalence and prognostic impact. Six patients were found to be carriers of variants in six genes associated with primary immunodeficiency disorder (PID). Of the 81 genes associated with 23 predisposition syndromes, this study found only one predisposition germline mutation (TP53) (1.1%). Altogether, our study demonstrated a low probability of germline mutation predisposition to ALL in Korean ALL patients.

Early T precursor acute lymphoblastic leukaemia/lymphoma shows differential immunophenotypic characteristics including frequent CD33 expression and in vitro response to targeted CD33 therapy.

The differential immunophenotypic characteristics of early T precursor (ETP) acute lymphoblastic leukaemia/lymphoma (ALL) remain incompletely characterized. The study group (n=142) included 106 (74·7%) men and 36 (25·3%) women with a median age of 34·9years (range, 2-79) at diagnosis. Patients were subtyped by flow cytometry immunophenotyping as follows: 33 (23·2%) ETP; 32 (22·5%) early non-ETP; 60 (42·2%) thymic; and 17 (12·1%) mature. Excepting definitional markers, there was a significant differential expression of the markers CD2, CD10, CD33 and TdT between ETP-ALL and non-ETP-ALL. Positive CD33 expression (≥20% of leukaemic blasts) was detected in 21/33 (63%) ETP-ALL compared with 17/95 (17·9%) non-ETP-ALL (P<0·001). Notably, targeted anti-CD33 therapy with IMGN779 resulted in significant growth inhibition and increased apoptosis in ETP-ALL cells in vitro. An 11-marker T-ALL immunophenotype score discriminated reliably between ETP and non-ETP ALL. Longitudinal analysis of ETP-ALL cases in this study demonstrated that the immunophenotype may be occasionally dynamic but is largely stable over the disease course. In summary, identification of ETP-ALL might be enhanced by using an 11-marker T-ALL immunophenotype score. CD33 expression is frequent in ETP-ALL, and in vitro data suggest that exploring anti-CD33 therapy in ETP-ALL is warranted.

Dose-Adjusted Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin (DA-EPOCH) Is Active and Well-Tolerated in Adults with Newly-Diagnosed Acute Lymphoblastic Leukemia/Lymphoma (ALL): Initial Results of a Phase II Trial

BACKGROUND: HyperCVAD is used commonly in adult ALL but can be difficult for older or infirm patients (pts) to tolerate (JCO 2000, p. 547; Cancer 2008, p. 2097). At our center, only 50% who receive it reach a minimal residual disease negative (MRD-) state within 90 days (Am J Hematol 2018, p. 546). Lower-intensity options with ABL tyrosine kinase inhibitors (TKIs) yield high response rates in Philadelphia chromosome (Ph)+ disease, but long-term efficacy may be limited (Blood 2016, p. 774; ASH 2017, #99). DA-EPOCH is effective and relatively well-tolerated in high-grade lymphomas (NEJM 2013, p. 1915; Blood 2014, p. 2354). This prompted us to study DA-EPOCH as initial treatment of adult ALL. METHODS: Pts ≥ 18 years old with newly-diagnosed ALL were eligible if they were not a candidate for pediatric-inspired therapy (e.g., Ph+, age ≥ 40) and had adequate liver and kidney function. All pts signed IRB-approved consent forms. This single-center trial is registered on clinicaltrials.gov (NCT03023046) and supported by NCI 5P30 CA015704-41. DA-EPOCH was given as initially described (Blood 2002, p. 2685). Doses of myelosuppressive agents were adjusted based on the hematologic nadir after the previous cycle, but pts could start the next cycle before day 21 once ANC ≥ 1K/μL and platelets (plt) ≥ 50K/μL, and (after 1st 5 pts treated) dose-reduction was deferred if cytopenias reflected ALL. If Ph+, imatinib (IM) 600 mg or dasatinib (DAS) 100 mg daily on Days 1-14 of each cycle was added. If CD20+, rituximab (R) 375 mg/m2 was given once per cycle. All pts received G-CSF and intrathecal prophylaxis. Response was determined by morphology (morph), multiparameter flow cytometry (MFC) and (for Ph+) BCR-ABL RT-PCR on bone marrow aspirate (BMA). When MRD- by MFC (MFC-), high-throughput sequencing (HTS)-based MRD testing was performed as described previously (Clin Cancer Res 2014, p. 4540). BMA was performed after cycle 1, then repeated as needed to confirm MFC- or persistence. Up to 8 cycles could be given followed by maintenance (POMP ± TKI) or hematopoietic cell transplant (HCT) at physician9s discretion, though morph CR after ≤ 2 cycles was needed to continue. The primary endpoint was rate of MFC- after ≤ 4 cycles (i.e., RESULTS: 18 pts have received ≥ 1 cycle (Table). 15 (83%) achieved morph CR after ≤ 2 cycles. 8 of 14 (57%; 95% CI 0.29-0.82) evaluable for the primary endpoint were MFC- after ≤ 4 cycles; 3 pts remain too early to evaluate; 1 pt was removed after 2 cycles to continue DA-EPOCH closer to home. 2 Ph+ pts received IM, and 10 received DAS. 7 of 9 (78%) evaluable Ph+ pts were MFC- after ≤ 4 cycles, 3 after 1 cycle. 6 Ph+ pts (5 p190 and 1 p210; 67%) were MRD- by PCR after ≤ 4 cycles. 1 of 5 evaluable Ph- pts (20%) reached MFC- after 1 cycle. MRD by HTS was sought in 5 MFC- patients: clonal sequence was identifiable pre-treatment in 4, and 3 (75%) achieved MRD- by HTS, including 2 after only 1 cycle (both Ph+). 16 (89%) pts developed Grade (Gr) 3+ non-hematologic toxicity at some point throughout treatment, with febrile neutropenia (7 Gr 3), hypofibrinogenemia (4 Gr 3), and GI bleed (2 Gr 3, 1 Gr 5) the most common. 1 pt (6%) died in morph CR after Cycle 3; no other pts stopped due to toxicity. Median cycle length was 21 days (range: 16-27). Once beyond Cycle 2, only 7 of 28 total cycles (25%) yielded ANC 5 pts (28%) have undergone HCT, 3 of whom were in CR1 after DA-EPOCH (all Ph+). 5 in CR after DA-EPOCH have relapsed (33%), 1 of whom was post-HCT. No deaths from ALL have occurred. Median and 6-mo EFS are 8 mo and 61% (respectively). Median OS is not reached, and 6-mo OS is 94% (Figure). CONCLUSIONS: DA-EPOCH yields deep remissions (including by HTS) in newly-diagnosed ALL, particularly with TKI for Ph+ disease. Toxicity is manageable and rarely leads to discontinuation or delay. Because of the relatively high rate of early MFC-, the interim stopping rule for efficacy was not met, and enrollment continues. Updated results (including genomic profiling by RNAseq) will be presented. Disclosures Cassaday:Kite Pharma: Research Funding; Pfizer: Consultancy, Research Funding; Merck: Research Funding; Amgen: Consultancy, Research Funding; Incyte: Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy; Seattle Genetics: Other: Spouse Employment, Research Funding. Shustov:Seattle Genetics: Research Funding. Becker:GlycoMimetics: Research Funding. Radich:TwinStrand Biosciences: Research Funding.

Genome-Wide Single-Nucleotide Polymorphism Array Analysis Improves Prognostication of Acute Lymphoblastic Leukemia/Lymphoma

Chromosomal abnormalities are important for the risk stratification of acute lymphoblastic leukemia/lymphoma (ALL). However, approximately 30% of pediatric and 50% of adult patients lack abnormalities with clinical relevance by traditional cytogenetic analysis. We integrated cytogenetic, fluorescence in situ hybridization, and whole-genome single-nucleotide polymorphism array results from 60 consecutive clinical ALL cases. By cytogenetic and/or fluorescence in situ hybridization analyses, recurring abnormalities with clinical relevance were observed in 33 B-cell ALL (B-ALL), including t(9;22), hyperdiploidy, KMT2A translocation, ETV6-RUNX1, intrachromosomal amplification of chromosome 21, near haploidy or low hypodiploidy, and t(8;22). Single-nucleotide polymorphism array analysis found additional aberrations with prognostic or therapeutic implication in 21 B-ALL and two T-cell ALL, including IKZF1 deletion, intrachromosomal amplification of chromosome 21 (one case with a normal karyotype), low hypodiploidy (two cases with a normal karyotype), and one case each with fusion genes ETV6-NTRK3, CRLF2-P2RY8, NUP214-ABL1, and SET-NUP214. IKZF1 deletion was noted in nine B-ALL with t(9;22), one B-ALL with t(4;11), five B-ALL with a normal karyotype, and three B-ALL with nonrecurring karyotypic abnormalities. Combining single-nucleotide polymorphism array with chromosome and fluorescence in situ hybridization assays, the detection rate for clinically significant abnormal results increased from 56% to 75%. Whole-genome single-nucleotide polymorphism array analysis detects cytogenetically undetectable clinicallysignificant aberrations and should be routinely applied at diagnosis of ALL.

Early T-Cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) Is a High-Risk Subtype in Adults

Background: Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) is a recently recognized high-risk T-ALL subgroup. The optimal therapeutic approaches to adult patients with ETP-ALL are poorly characterized. In this study, we compared the outcomes of adults with ETP-ALL who received treatment on frontline regimens to those of patients with other T-ALL immunophenotypic subtypes.Methods: Patients with newly-diagnosed T-ALL who received frontline chemotherapy between the years 2000 and 2014 at The University of Texas MD Anderson Cancer Center (MDACC) were identified and immunophenotypically categorized into early, thymic, and mature per the European Group for the Immunologic Classification of Leukemia (EGIL)/WHO classification. Patients with ETP-ALL were identified on the basis of the following immunophenotype: CD1a(-), CD8(-), CD5(-/dim), and positivity for one or more stem cell or myeloid antigens. Patients received frontline treatment with the following chemotherapy regimens: hyper-CVAD alone (n=43), hyper-CVAD + nelarabine (n=44) or augmented BFM regimen (n=24).Results: A total of 111 patients with T-ALL with adequate immunophenotype data were identified. There was no difference in the outcomes of patients based on the EGIL/WHO subtypes (Fig 1). A total of 19 patients (17%) had ETP-ALL. The complete remission rate (CR)/CR with incomplete platelet recovery (CRp) rate in patients with ETP-ALL was significantly lower than that of non-ETP-ALL patients (73% vs. 91%; p=0.03). The median overall survival for patients with ETP-ALL was 20 months vs. not reached for the non-ETP-ALL patients (p = 0.008) (Fig 2). ETP-ALL remained a high-risk subgroup within the WHO 'Early' group (Fig 3). A subset of patients with early T-ALL had an immunophenotype that resembled that of ETP-ALL except for having ≥75% CD5 expression (ETP+CD5). The OS of patients with ETP+CD5 (n=19) was similar to that of non-ETP-ALL patients and differed from that of ETP-ALL patients (p=0.059).By univariate analysis, the following variables were significant for survival: age, WBC count (<50 vs. ≥50 x109 /L), platelet count (<100 vs. ≥100 x109 /L), LDH (<600 vs. ≥600 IU/L) and ETP-ALL (Table 1). By multivariate analysis, only age (HR: 2.862; 95%CI: 1.140-7.183; p=0.025) and ETP-ALL (HR: 2.275; 95%CI: 1.117-4.631; p=0.023) were significant.Conclusions: ETP-ALL represents a high-risk disease subtype of adult ALL. Allogeneic stem cell transplant in CR1 should be considered. Novel treatment strategies are needed to improve treatment outcomes in this T-ALL subset.Table 1Univariate and multivariate analysis for survivalParameterSurvivalUVAMVAPPHR95%CIAge ≥600.0130.0252.8621.140-7.183Gender0.24---Diagnosis (ALL vs. LBL)0.13---WBC < 50.0 (x 109 /L)0.009---Hemoglobin <10 (g/dL)0.36---Platelet <100 (x 109 /L)0.036---LDH <600 (IU/L)0.045---CNS involvement at Dx0.18---WHO classification (early, thymic, mature)0.101---ETP-ALL0.0080.0232.2751.117-4.631Treatment received0.43--- [Display omitted] [Display omitted] [Display omitted] DisclosuresKonopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Cortes:Astellas: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Teva: Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) in Adults: A High-Risk Subtype

Background: Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL) is a recently recognized high-risk T-ALL subgroup. The optimal therapeutic approaches to adult patients with ETP-ALL are poorly characterized. In this study, we compared the outcomes of adults with ETP-ALL who received treatment on frontline regimens to those of patients with other T-ALL immunophenotypic subtypes. Methods: Patients with newly-diagnosed T-ALL who received frontline chemotherapy between the years 2000 and 2014 at The University of Texas MD Anderson Cancer Center (MDACC) were identified and immunophenotypically categorized into early, thymic, and mature per the EGIL/WHO classification. Patients with ETP-ALL were identified on the basis of the following immunophenotype: CD1a(-), CD8(-), CD5(-/dim), and positivity for one or more stem cell or myeloid antigens. Results: A total of 111 patients with T-ALL with adequate immunophenotype data were identified. There was no difference in the outcomes of patients based on the EGIL/WHO subtypes. A total of 19patients (17%)hadETP-ALL.The completeremission rate(CR)/ CR with incomplete platelet recovery (CRp) rate in patients with ETP-ALL wassignificantly lowerthanthatofnon-ETP-ALL patients (73% vs. 91%; p¼0.03). The median overall survival for ETP-ALL patientswas20monthsvs.notreachedforthenon-ETP-ALLpatients (p ¼ 0.008). Conclusions: ETP-ALL represents a high-risk disease subtype of adult ALL. Allogeneic stem cell transplant in CR1 should be considered. Novel treatment strategies are needed to improve treatment outcomes in this T-ALL subset. Keywords: Acute leukemia, Lymphoblastic Leukemia, T-cell, Immunophenotype, Hyper-CVAD Chemotherapy, Flow Cytometry.