Early T-precursor Research Articles

Clinical Characteristics and Outcomes of Newly Diagnosed Patients with Adult T-Cell Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LL) with Hypercvad Based Regimens

Introduction: T-cell ALL and T-LL are considered as different spectra of the same neoplastic clone. In various clinical trials of adult ALL, patients with T-ALL and T-LL were combined when analyzing treatment responses and survival outcomes. We have previously reported the results with HCVAD-based regimens in patients with adult ALL. In this study we addressed whether the initial presentation, treatment response, and survival outcomes of adults with T-LL and T-ALL differed when patients were uniformly treated with frontline HCVAD-based regimens at a single institution.Methods: One hundred and fifty previously untreated patients with T-LL (n=54) and T-ALL (n=96) who were treated with HCVAD-based regimens (1992-2016) were included in this analysis. Patient charts were reviewed for initial characteristics, treatment responses including minimal residual disease (MRD) status and survival outcomes; event free (EFS) and overall survival (OS) were analysed.Results: Among 150 patients with previously untreated adult T-ALL/LL, we identified 54 patients (36%) with T-LL and 96 (64 %) with T-ALL. Among patients with available immunophenotype data (n=104), early T precursor (ETP) phenotype was significantly more frequent among patients with T-ALL compared to patients with T-LL (44% vs 19%; p=0.006). The proportion of early, cortical and mature immunophenotype were 2% vs 6%, 31% vs 49% and 16% vs 12% in T-ALL versus T-LL, respectively. The clinical characteristics, response to therapy and outcomes of patients in T-LL versus T-ALL were compared (Table 1 and Figure-1).Patients with T-ALL were slightly older at presentation (median age 37 years [18-67] versus 31 years [17-78]; p=0.07). Patients with T-ALL had significantly higher white blood cell counts, peripheral blood blasts %, bone marrow blasts %, and serum LDH as compared to patients with T-LL. Distribution of chromosomal aberrations was significantly different among the two groups: Diploid karyotype was more commonly encountered in patients with T-LL while patients with T-ALL had more hyperdiploidy and hypodiploidy. Among patients evaluable for response, complete remission (CR) rates were 85% and 95% (p=0.002) in T-LL and T-ALL, respectively. Overall the median follow up times were 72 months (range, 5-243) and 61 months (range, 1-267). Thirty nine (72%) patients with T-LL and 43 (45%) with T-ALL were alive at the time of last follow-up. Patients with T-LL had better outcomes than patients with T-ALL. The 3-year EFS and OS rates were 78% and 74% in patients with T-LLand 53% (p=0.005) and 50% (p=0.001) in patients with T-ALL (Figure 1).Conclusions: In summary, adult patients with T-LL have better outcomes than patient with T-ALL after treatment with HCVAD-based regimens. Additional studies to characterize the genomic profile in tumoral tissues, as well as the pattern of relapses in patients with adult T-LL and T-ALL are ongoing. [Display omitted] [Display omitted] DisclosuresKonopleva:Calithera: Research Funding; Cellectis: Research Funding. Jain:Incyte: Research Funding; Servier: Consultancy, Honoraria; Seattle Genetics: Research Funding; Infinity: Research Funding; Novimmune: Consultancy, Honoraria; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Genentech: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Wierda:Acerta: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

How Genomic Data Are Changing the Leukemia Treatment Landscape

How Genomic Data Are Changing the Leukemia Treatment Landscape

Clinical profile and outcome of early T-precursor (ETP) acute lymphoblastic leukemia (ALL) in a tertiary care cancer centre

Clinical profile and outcome of early T-precursor (ETP) acute lymphoblastic leukemia (ALL) in a tertiary care cancer centre

Interleukin-3 receptor α chain (CD123) is preferentially expressed in immature T-ALL and may not associate with outcomes of chemotherapy.

Interleukin-3 (IL-3) receptor α chain (CD123) plays an essential role in regulating the proliferation of hematopoietic stem cells. In the hematopoietic malignancies, CD123 expression has been found in acute myeloid leukemia (AML), B-precursor acute lymphoblastic leukemia (B-ALL), as well as dendritic cell malignancies. However, whether CD123 is also expressed in T-acute lymphoblastic leukemia (T-ALL) remains unknown. Using multi-parameter flow cytometry, we analyzed CD123 expression in 160 consecutive diagnostic T-ALL patients, including 88 pediatric T-ALL cases and 72 adult T-ALL cases. The minimal residual disease (MRD) was detected after one course of induction therapy to evaluate the treatment effects. CD123 expression was detected in 24 out of 88 (27%) pediatric T-ALLs and 30 out of 72 (42%) adult T-ALLs. Further analysis revealed that CD123 expression is associated with the maturation stage of T-ALLs. The frequencies of CD123-positive cases decreased from 83 to 40% and 21% in early T-precursor ALLs, T-precursor ALLs, and mature T-ALLs, respectively. Interestingly, we detected the CD4+CD8+ double-positive leukemic cells in 22 immature and 34 mature T-ALL patients. Of note, only 4% of these patients expressed CD123. In addition, we found that 79% of CD33+ and 64% of CD117+ immature T-ALL patients also expressed CD123. However, CD123 expression did not predict the outcomes of the first course of induction therapy in T-ALL patients. In conclusion, we found that CD123 is preferentially expressed in immature T-ALL. Moreover, CD123 expression is strongly associated with cross-lineage expression of myeloid markers in early T-precursor ALL.

PI3K pan-inhibition impairs more efficiently proliferation and survival of T-cell acute lymphoblastic leukemia cell lines when compared to isoform-selective PI3K inhibitors.

Class I phosphatidylinositol 3-kinases (PI3Ks) are frequently activated in T-cell acute lymphoblastic leukemia (T-ALL), mainly due to the loss of PTEN function. Therefore, targeting PI3Ks is a promising innovative approach for T-ALL treatment, however at present no definitive evidence indicated which is the better therapeutic strategy between pan or selective isoform inhibition, as all the four catalytic subunits might participate in leukemogenesis. Here, we demonstrated that in both PTEN deleted and PTEN non deleted T-ALL cell lines, PI3K pan-inhibition exerted the highest cytotoxic effects when compared to both selective isoform inhibition or dual p110γ/δ inhibition. Intriguingly, the dual p110γ/δ inhibitor IPI-145 was effective in Loucy cells, which are representative of early T-precursor (ETP)-ALL, a T-ALL subtype associated with a poor outcome. PTEN gene deletion did not confer a peculiar reliance of T-ALL cells on PI3K activity for their proliferation/survival, as PTEN was inactivated in PTEN non deleted cells, due to posttranslational mechanisms. PI3K pan-inhibition suppressed Akt activation and induced caspase-independent apoptosis. We further demonstrated that in some T-ALL cell lines, autophagy could exert a protective role against PI3K inhibition. Our findings strongly support clinical application of class I PI3K pan-inhibitors in T-ALL treatment, with the possible exception of ETP-ALL cases.

Outcome for children and young people with Early T‐cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003

We investigated the outcome for children and young people with Early T-precursor acute lymphoblastic leukaemia (ETP-ALL), a recently described poor prognosis sub-group of T-ALL, treated on a contemporary protocol, UKALL 2003. After a median follow-up of 4 years and 10 months, the ETP sub-group, representing 16% of T-ALL patients, had non-significantly inferior 5-year event-free survival (76·7% vs. 84·6%, P = 0·2) and overall survival (82·4% vs. 90·9%, P = 0·1), and a higher relapse rate (18·6% vs. 9·6%, P = 0·1) compared to typical T-ALL. ETP-ALL has an intermediate risk outcome, which does not warrant experimental treatment or first remission allogeneic transplant for the group universally.

Mixed phenotype acute leukemia

Mixed phenotype acute leukemia

Poor Response to Standard Chemotherapy in Early T-precursor (ETP)-ALL: A Subtype of T-ALL Associated with Unfavourable Outcome: A Brief Report.

Early T-precursor (ETP)-ALL, a type of T-ALL, is a new pathobiologic entity with distinct immunophenotype (CD1a(-), CD8(-), CD5(weak/absent) with stem-cell/myeloid markers) and genetic expression, poor response to standard intensive chemotherapy and very high risk of relapse. The genetic mutations typically associated with the pathogenesis of acute myeloid leukemia are seen with increased prevalence in ETP-ALL. No Indian data exists regarding this rare entity. Recently we have seen six cases of ETP-ALL and hereby reporting their clinical characteristics and treatment outcome. All patients were given induction chemotherapy according to standard protocols. Only one out of six patients could achieve remission after induction therapy. Rest five patients died because of their leukemia. This reflects the aggressive biology of this disease and its poor response to standard chemotherapy regimens generally used in T-ALL. The limited experience with ETP-ALL reflects whether rarity of this condition or failure to recognize this is not clear at this time. More studies are required to understand the basic biology of this disease and new therapeutic strategies need to be devised.

Characteristics and Outcome Of Children and Young Adults With Early T-Precusor (ETP) ALL Treated On UKALL 2003

Early T-precursor (ETP) ALL is a recently described poor prognostic sub-group of childhood T-ALL identified by a distinctive gene expression profile and immunophenotype (CD1a-, CD5 weak, CD8- and presence of myeloid or stem cell markers). It accounts for around 12% of T-ALL and is associated with a poor outcome in retrospective US and Italian studies with a 5 year event-free survival (EFS) of less than 50% on historical treatment protocols. We sought to determine the outcome for this sub-group on a contemporary MRD stratified treatment protocol, UKALL 2003.As full immunophenotype data was not collected centrally, individual centres were asked to provide individual patient data retrospectively. Of 387 T-ALL cases in the trial, immunophenotype data to classify ETP status was not available for 148 patients. Of the remaining 239 cases, 35 (15%) were classified as definite/probable (CD8 and 1a neg with stem cell or myeloid antigen expression) and 17 (7%) as possible (CD8 neg and stem cell or myeloid antigen expression, 1a not available) ETP. The definite, probable and possible ETP groups had similar patient characteristics and outcomes and have, therefore, been analysed together. Compared to those without an ETP phenotype, ETP patients were more likely to present with a low (<50x109/l) white cell count (56% vs 26%, p<0.0001) but were less likely to be morphological rapid early responders at day 8/15 (63% vs 83% p =0.002) or MRD low risk at the end of induction (4% vs 27%, p = 0.008). Unlike previous reports, the risk of induction failure was not significantly higher in the ETP group (n= 2 vs 1 among non-ETP cases).With a median follow-up of 4 years 10 months (range 1 year 4 months - 9 years), the ETP sub-group have a non-significantly inferior EFS (76.0% (95% CI: 64.0-88.0%) vs 84.6% (79.3-89.9%) at 5 years, p = 0.2) and OS (84.1% (73.9-94.3%) vs 90.9% (86.6-95.2%), p = 0.08) compared to the non-ETP sub-group, due primarily to a non-significantly higher relapse rate (17.7% (6.5-28.9%) vs 9.6% (5.1-14.1%), p = 0.1). Although MRD risk group was a determinant of outcome in the non-ETP group (p=0.05), its significance within the ETP group could not be reliably determined since only 2 patients were MRD low risk, of whom 1 suffered a relapse. Interestingly, of the 8 relapses in the ETP group, 7 were isolated marrow relapses and there was one isolated testicular relapse, whereas 12 of the 17 relapses in the non-ETP group involved the CNS (5 isolated and 7 combined).Although ETP ALL is associated with an adverse outcome compared with non-ETP T-ALL, a 5 year EFS of 76% on a contemporary MRD stratified protocol is not sufficiently poor to warrant experimental treatment or first remission allogeneic transplant for the group universally. Disclosures:No relevant conflicts of interest to declare.

Mutational Spectrum Of Adult T-ALL

IntroductionT-cell acute lymphoblastic leukemia (T-ALL) in adults represents a disease with a rather unfavourable prognosis. Despite the fact that treatment stratification and minimal residual disease (MRD) monitoring have improved survival, there is still need to improve outcome by the development of novel targeted therapies. Therefore, molecular alterations are in the focus of on-going research. Until recently only few candidates were identified as recurringly mutated genes including NOTCH1, FBXW7, PTEN. The development of next generation sequencing (NGS) significantly enlarged this spectrum and identified alterations in additional genes (BCL11B, PHF6, DNM2, CNOT3, KRAS, NRAS, DNMT3A). Whereas a number of putative driver mutations have been characterized, the spectrum of recurring alterations in larger cohorts and their relevance in different leukemic subgroups remains unexplored. To unravel relevant recurring alterations in a large cohort of adult T-ALL and to explore potential target genes for novel therapeutic strategies, we performed targeted high throughput NGS of 88 candidates in 81 T-ALL samples. Patients and methodsWe investigated 67 adult T-ALL patients enrolled in the trial 07/2003 of the German Acute Lymphoblastic Leukemia Multicenter Study Group (GMALL). In addition, 14 patients with early T-precursor ALL (ETP-ALL) from other GMALL trials were analysed. Customized biotinylated RNA oligo pools (SureSelect, Agilent) were used to select the targeted regions. We performed 76-bp paired-end sequencing on an Illumina Genome Analyzer IIx platform and reads were mapped to NCBI hg19 RefSeq. For a variant call we required at least a read depth of 20, an allele frequency of 20% and an average base calling quality of Q13. Polymorphisms annotated in dbSNP 135 were excluded. The targeted region comprised 88 genes known to be frequently mutated in ALL, acute myeloid leukemia, myelodysplastic syndrome as well as genes associated with epigenetic regulation, splicing, DNA mismatch repair, and the NOTCHpathway. ResultsWe obtained an average of 1.2 Mbp sequence for each sample, resulting in an average coverage of 120 reads for the target region. 79% of the targeted region was covered with a minimum of 20 reads. After exclusion of polymorphism annotated in dbSNP135, 473 single nucleotide variations (SNV) and small indels were identified, 294 of those resulted in changes on the protein level. On average three (3.1) genes per patient were mutated, and 66 (77%) of the 88 genes were mutated in at least one patient. As expected, the highest mutation rate with 53% was found for NOTCH1, with a higher frequency in thymic T-ALL (67.5%) than in early T-ALL (33.3%). Mutation frequencies of FBXW7 (10%), WT1 (10%), JAK3 (12%), and BCL11B (10%) were in the range of reported frequencies. Recently identified novel alterations in DNM2 (17%), PHF6 (11%), DNMT3A (5%) or RELN (5%) were confirmed in our cohort. Interestingly, genes that had not been described in T-ALL included recurring mutations in the histone methyl-transferase MLL2 (11%), frequently mutated in B-cell lymphomas. Like in lymphoma and in the Kabuki syndrome, MLL2 mutations were distributed over the entire gene without any obvious hot spot region. Also the protocadherins FAT1 (15%) and FAT3 (12%) were recurringly altered. FAT1and its inactivation by mutations were recently linked to activation of the WNT pathway in solid tumours.Affected pathways significantly differed in leukemic subgroups: whereas mutations involving the NOTCH pathway were predominately enriched in the thymic subgroup (75%) and less relevant in early T-ALL (33%, P=0.004), chromatin modifiying genes (17% vs. 5%, P=0.22) and signalling genes (42% vs. 15%, P=0.09) were more frequently mutated in early T-ALL. Spliceosome mutations described in myeloid and mature lymphoid malignancies were present only in a minority (7.4%) of T-ALL. ConclusionAdult T-ALL reveals a highly heterogeneous spectrum of candidate gene mutations. Here we provide an original and comprehensive overview of recurring mutations that unravel preferentially pathways altered in specific leukemic subgroups. In addition, we identified novel candidate genes with potential therapeutic implications (FAT1, EZH2, DNMT3A). These mutations have to be validated in a larger cohort with a focus on clinical implications accompanied by functional assays regarding their use as therapeutic targets. Disclosures:Krebs:Illumina: Honoraria. Greif:Illumina: Honoraria.

Myeloid/T-Cell Acute Lymphoblastic Leukemia in Children and Adults

Until recently, few molecular aberrations were recognized in T-cell acute lymphoblastic leukemia (T-ALL) and they were restricted to aberrations involving the T-cell receptor (TCR). The introduction of powerful technologies has allowed to identify novel rearrangements. In this context, we have performed a gene expression profiling analysis on a relatively large cohort (n=69) of adult patients with a diagnosis of T-ALL. By unsupervised clustering, we identified 5 subgroups. Of these, one branch included 7 patients (10%) whose gene expression profile resembled that of AML. These cases were characterized by the overexpression of a large set of myeloid-related genes, as well as of miR-223. Finally, these patients appear to have an unfavorable clinical course. This newly identified subset of T-ALL cases partly resembles the so-called ETP (early T-precursor) pediatric subgroup: both age groups have in fact a peculiar gene expression profile, an unfavorable outcome and an incidence of about 10%.