T-cell immunophenotype of acute lymphoblastic leukemia (T-ALL) is an uncommon aggressive leukemia that can present with leukemic and/or lymphomatous manifestations. Molecular studies are enhancing our understanding of the pathogenesis of T-ALL, and the discovery of activating mutations of NOTCH1 and FBXW7 in a majority of patients has been a seminal observation. The use of pediatric intensive combination chemotherapy regimens in adolescents and young adults has significantly improved the outcome of patients with T-ALL. The use of nelarabine for relapsed and refractory T-ALL results in responses in a substantial minority of patients. Allogeneic hematopoietic cell transplantation (HCT) still plays a key role in patients with high-risk or relapsed/refractory disease. γ-Secretase inhibitors hold promise for the treatment of patients with NOTCH1 mutations, and the results of clinical trials with these agents are eagerly awaited. It is recommended that younger patients receive a pediatric-intensive regimen. Older and unfit patients can receive suitable multiagent chemotherapy and be allocated to HCT based on their response, risk factors, and comorbidities. Although advances in the treatment of T-ALL have lagged behind those of B-cell ALL, it is hoped that the molecular revolution will enhance our understanding of the pathogenesis and treatment of this aggressive lymphoid malignancy.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant neoplasm of the bone marrow. It accounts for ∼20% of all cases of ALL and is somewhat more common in adults than children, although the incidence diminishes with older age.1  Its clinical presentation can include hyperleukocytosis with extramedullary involvement of lymph nodes and other organs, including frequent central nervous system infiltration and the presence of a mediastinal mass, arising from the thymus. T-ALL is a precursor lymphoid neoplasm according to the World Health Organization (WHO) classification and is a distinct entity from adult T-cell leukemia/lymphoma, which is a malignancy of mature T cells caused by human T-cell lymphotropic virus type I.2 

The WHO defines lymphoblasts in T-ALL as TdT positive with variable expression of CD1a, CD2, CD3, CD4, CD5, CD7, and CD8. Cytoplasmic CD3 and CD7 are often positive. T-ALL can be subdivided into different stages by intrathymic differentiation, including pro-T, pre-T, cortical T, and medullary T.3,4  The immunophenotypes of these subtypes are listed in Table 1.

Table 1

Immunologic classification of T-ALL

cCD3CD7CD28CD1aCD34CD4CD8
Pro-T − − +/− − − 
Pre-T − +/− − − 
Cortical T − 
Mature T* (medullary) − − +/− +/− 
cCD3CD7CD28CD1aCD34CD4CD8
Pro-T − − +/− − − 
Pre-T − +/− − − 
Cortical T − 
Mature T* (medullary) − − +/− +/− 

cCD3, cytoplasmic CD3.

*

Also surface (membrane) CD3+.

Microarray gene expression studies have established a close association between differentiation arrest gene expression signatures, immunophenotype, and activation of oncogenic pathways, enriching our understanding of T-ALL heterogeneity from that gained from immunophenotype-only–based classifications.5,6  Supervised analysis of microarray data based on expression of T-ALL transcription factor oncogenes activated by chromosomal translocations distinguished different major groups of T-ALL: early T-cell precursor (ETP) ALL or immature T-ALLs (related to pro-T and pre-T immunophenotypic groups), TLX tumors with expression of high levels of CD1 genes and transcriptionally related to early cortical thymocytes (related to cortical T ALLs), and TAL1-associated leukemias, which showed a gene expression signature, reflecting an arrest in the late stages of thymocyte differentiation characterized by upregulation of CD3 and TCR genes (related to the medullary-T immunophenotypic group).5,6  In this context, the poorly understood ETP group has received much attention lately.

In children, ETP ALL accounts for 15% of all T-ALL, whereas in adults, the incidence has been variably reported but seems to be significantly higher than in the pediatric population.7-9  The transcriptional profile of ETP ALL shows similarities to immature myeloid progenitors and hematopoietic stem cells, suggesting these tumors may be part of a spectrum of stem cell–like leukemias.7  ETP ALL was originally defined by the absence of expression of CD1a, CD8, and CD5 and aberrant expression of myeloid and stem cell markers.9,10  ETP ALL may be immunophenotypically,11  genetically,8  and biologically heterogeneous.12  Of note, gene expression profiling studies suggest that early immature leukemias transcriptionally related to ETPs may account for up to 50% of T-ALLs in some series.8 

The WHO classifies T-ALL and T-cell lymphoblastic lymphoma (T-LL) together despite differences in clinical presentation.3  Lymphoblastic lymphoma accounts for 1% to 2% of non-Hodgkin lymphoma and is of T-cell origin in 90% of cases with frequent presence of a large mediastinal mass. It is distinguished from T-ALL somewhat arbitrarily by the presence of <20% marrow blasts. Studies of gene expression profiling have shown differential expression of genes involved in chemotactic responses and angiogenesis, suggesting a role in tumor cell localization, which may explain the differences in clinical expression.13,14 

T-cell transformation involves the cooperative effect of oncogenes and tumor suppressors, which deregulate the mechanisms controlling normal T-cell proliferation, differentiation, and survival during thymopoiesis, as recently reviewed by Van Vlierberghe et al15  (Figure 1). Among these, constitutive activation of the NOTCH1 gene plays a key role. NOTCH1 was first discovered as a partner gene in the t(7;9)(q34;q34) chromosomal translocation16  and was later implicated in the pathogenesis of up to 60% of T-ALL, harboring activating mutations, involving negative regulatory domains responsible for the control of initiation and termination of NOTCH signaling.17,18  Additionally, it was found that mutations in the FBXW7 gene are present in 15% of T-ALL cases, and these interfere with the proteasomal degradation of activated NOTCH1 protein.18-21  In addition to NOTCH1 mutations, T-ALLs frequently show T-cell receptor gene chromosomal translocations, resulting in aberrant expression of transcription factor oncogenes, such as TAL1, LMO1, LMO2, TLX1, and TLX3.15  Furthermore, mutations in the IL7R, JAK1, and JAK3 genes activate the IL7R/JAK-STAT pathway, and loss of the PTEN tumor suppressor gene drives aberrant phosphatidylinositol 3-kinase (PI3K)-AKT signaling.15  The genetic landscape of T-ALL also includes loss of transcription factors (eg, WT1, LEF1, RUNX1, ETV6, and BCL11B), epigenetic (eg, EZH2, SUZ12, and PHF6) tumor suppressors, cell-cycle inhibitors (eg, CDKN2A, RB, and CDKN1B), gains of oncogenes (eg, MYB), and chromosomal rearrangements that can result in fusion products, including CALM-AF10, MLL1-ENL, and NUP214-ABL1.15  Of note, the genetics of ETP ALL are closely related to that of myeloid leukemias with a low frequency of NOTCH-activating mutations and deletions in the CDKN2A/B loci, otherwise present in 70% of T-ALLs, and a higher prevalence of mutations activating cytokine receptor and RAS signaling, including N-RAS, K-RAS, FLT3, IL7R, JAK3, JAK1, SH2B3, and BRAF, and inactivating hematopoietic transcription factors, such as GATA3, ETV6, RUNX1, IKZF1, and epigenetic factors, such as EZH2, EED, SUZ12, SETD2, and EP300.7,22,23 

Figure 1

The landscape of genetic alterations in T-ALL. Schematic representation of the most common genes targeted by chromosomal translocations, deletions, and mutations in T-ALL. Font size is indicative of the relative prevalence of these alterations, with highly prevalent targeted genes shown in in larger font sizes and less frequently altered loci shown in smaller font size.

Figure 1

The landscape of genetic alterations in T-ALL. Schematic representation of the most common genes targeted by chromosomal translocations, deletions, and mutations in T-ALL. Font size is indicative of the relative prevalence of these alterations, with highly prevalent targeted genes shown in in larger font sizes and less frequently altered loci shown in smaller font size.

Close modal

Chemotherapy

The remarkable success of pediatric ALL treatment has not been achieved in adults, although outcomes in pediatric T-ALL have been inferior to pediatric B-cell ALL (B-ALL).24,25  For the last several decades, the treatment of adults with ALL has resulted in survivals of ∼40%. However, multiple studies have now demonstrated that adolescents and young adults (AYAs) treated with pediatric-intensive chemotherapy regimens fare better than AYAs treated with adult-intensive chemotherapy regimens. This was first reported in a retrospective comparison of 321 AYAs who were treated in several trials, either by the Children’s Cancer Group (CCG) or the Cancer and Leukemia Group B (CALGB), from 1988 to 2001.26  The complete remission (CR) rates between the pediatric and adult cohorts were the same, but the AYAs treated by the CCG had a 67% overall survival (OS) at 7 years in contrast to 46% for the AYAs in the CALGB trials. No significant differences in outcome were noted between the B-ALL and T-ALL subsets in either cohort.26  Comparisons from pediatric and adult groups in other countries have shown similar results.27  These studies have generally focused on patients under the age of 21 years. In T-ALL, a randomized pediatric study showed that the addition of high-dose methotrexate improved event-free survival and OS.28 

Based on these retrospective comparisons, several prospective studies using pediatric-intensive regimens in AYAs in different countries have uniformly shown favorable outcomes, with OS in the 60% to 70% range.29-31  These studies included patients with B-ALL and T-ALL. However, a Canadian study has reported their retrospective experience with pediatric-intensive regimens in patients with T-ALL and has reported similar results, with a 75% survival at 5 years.32  Similarly, the French Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) assessed the results of young adults treated with T-ALL and has seen favorable outcomes, with an OS at 3 years of 58%.33  The upper age limit for administration of a pediatric-intensive regimen is not well defined. Some studies have used these regimens in patients up to age 50 to 60 years and shown feasibility, though toxicity and treatment-related mortality (TRM) are higher in older adults.29,34,35 

On the basis of these studies, it is our recommendation that AYA patients with T-ALL be treated with a pediatric-intensive regimen at diagnosis to achieve remission and potentially cure them.

More challenging is the optimal approach to the treatment of older patients with T-ALL. Studies have demonstrated that these patients do not tolerate pediatric-intensive regimens as well as AYAs.29  The large combined trial of adults with ALL from the Medical Research Council (MRC) in Great Britain and the Eastern Cooperative Oncology Group (ECOG) in the United States, UKALLXII/E2993, has reported the outcomes of a subset of 356 patients with T-ALL up to age 60 years. This trial showed that the outcome of T-ALL is equivalent to or superior to that of B-ALL1  (Figure 2).

Figure 2

OS from the diagnosis of patients with B- vs T-ALL in the UKALLXII/E2993 trial.

Figure 2

OS from the diagnosis of patients with B- vs T-ALL in the UKALLXII/E2993 trial.

Close modal

There are few data on the role of positron emission tomography in the diagnosis and follow-up of patients with T-ALL. In one series, the use of positron emission tomography did not predict the risk of relapse.36  In this study, however, the addition of mediastinal irradiation appeared to result in prolonged time to progression compared with patients who only received chemotherapy. However, the role of mediastinal radiation in patients with T-ALL is not well defined, and we do not recommend its routine use.

Another regimen to consider is the hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone alternating with high dose methotrexate and cytarabine) regimen. Although intensive, this regimen is reasonably well tolerated in fit older individuals. However, in a small series of T-ALL patients, although a high CR rate was seen with the hyper-CVAD regimen, and it was safely administered, there was a high risk of relapse after achievement of remission.37 

In 2009, the German ALL Group (GMALL) reported their experience with 744 T-ALL patients between the ages of 15 and 55 years. The CR rate was 86%, with OS at 10 years of 47%. OS at 5 years improved from 44% to 56% with the addition of pegaspargase in induction and high-dose methotrexate with pegaspargase in consolidation in latter trials.38  The treatment of older adults with ALL has also been reviewed in this “How I Treat” series in 2013.39 

An important therapeutic agent in the management of T-ALL is nelarabine, a prodrug of guanine arabinoside, with increased solubility.40 

Nelarabine has been combined with chemotherapy in the front-line setting in both pediatric and adult patients.41  In adults, nelarabine has been combined with hyper-CVAD as initial therapy. Of 40 patients with T-ALL or T-LL, the CR rate was 89% in T-ALL and 94% in T-LL. OS at 3 years was 63%.42  Nelarabine is being further tested in a phase 2 randomized trial in Great Britain, comparing its addition as consolidation therapy in patients with T- ALL (NCT01085617).

The management of T-ALL has evolved from the use of standard lymphoma regimens to the use of ALL regimens, incorporating induction, consolidation, delayed intensification, and maintenance with CNS prophylaxis with high-dose chemotherapy and intrathecal therapy. Although no randomized trials have been done, outcomes with ALL-type regimens appear superior to the use of lymphoma regimens, as has been recently reviewed.43 

Hematopoietic cell transplantation

Given the poor outcome of older adults with ALL, the question has been raised as to whether they could benefit from an allogeneic hematopoietic cell transplantation (HCT) with a reduced-intensity conditioning (RIC) regimen. A retrospective analysis from the European Society for Blood and Marrow Transplant (EBMT) assessed the outcome of 576 adult ALL patients over the age of 45 years who were transplanted and received either an RIC (n = 127) or a myeloablative conditioning regimen (n = 449) from HLA-identical siblings in first or second remission. The number of patients with T-ALL was not specified; therefore, results from this study should be interpreted with caution. Patients receiving the RIC regimen had a median age of 56 years (range 45-73), with a TRM of 21% and OS of 48% vs the myeloablative conditioning regimen patients, who had median age of 50 years (45-68, P < .0004), and TRM was 29% (P = .03) and OS 45% (P = .56). Patients over the age of 60 years had a survival rate of 32% with an RIC transplant.44  Similar results were seen in a study by the Center for International Blood and Marrow Transplant Research (CIBMTR).45  Thus, serious consideration should be given to RIC allogeneic HCT for older adults with ALL.

The role of autologous HCT in T-ALL is limited. The MRC/ECOG trial showed that 5-year OS of the 99 patients randomized between autologous HCT and chemotherapy was 51% in both arms (P = .09).1  A retrospective report from Russia showed that, in a group of 72 patients, 18 patients proceeded to autologous HCT with carmustine (BCNU), etoposide, cytarabine (ara-C), and methotrexate (BEAM) conditioning, followed by prolonged maintenance, and had 100% disease-free survival with no relapses, compared with 53% disease-free survival for patients who received chemotherapy only.46  Based on this small study, it is difficult to recommend autologous HCT as standard practice in light of the MRC/ECOG trial results, but one wonders what role prolonged maintenance therapy played in lessening relapse in the Russian study.

Prognostic factors are less clear in patients with T-ALL than in patients with B-ALL. In the series of T-ALL patients treated in the MRC/ECOG trial, the traditional prognostic factor of a leukocyte count >100 × 109/L resulted in a poorer OS at 5 years, compared with patients with a leukocyte count <100 × 109/L. Patients with a complex cytogenetic karyotype (≥5 chromosomal abnormalities) had a significantly lower OS at 5 years, compared with patients with simple or normal karyotypes (19% vs 51%, P = .006), and this impact was not affected by a higher leukocyte count or age. Patients with activating mutations of NOTCH1 and/or FBXW7 had a higher event-free survival of 51% compared with 27% without these abnormalities, although this difference did not reach statistical significance.1  Multiple studies in both pediatric and adult patients have shown that mutations in NOTCH1 and FBXW7 are associated with an improved early treatment response and increased sensitivity to corticosteroid therapy.47-51  However, not all these studies show that the early benefits seen translate into improved survival. Activated NOTCH1 expression can impair glucocorticoid-induced cell death in thymocytes,52  and it has been shown that blocking NOTCH1 signaling with γ-secretase inhibitors can reverse glucocorticoid resistance in some T-ALLs.53  Further studies of patients with NOTCH1/FBXW7 mutations have shown that patients within these subgroups who have K-RAS, N-RAS, and PTEN mutations or deletions have a poorer prognosis than patients who are NOTCH1 and/or FBXW7 mutated without mutations in these other genes.54  This refined classification may explain why some patients with NOTCH1/FBXW7 mutations do poorly.

By immunophenotype, patients who were CD1a positive in the MRC/ECOG trial had an OS at 5 years of 64% (95% CI, 48%-80%) vs 39% (26%-52%) in CD1a-negative patients (P = .01). This appeared to be caused by a higher risk of relapse in CD1a-negative patients (50%; 36%-65%) at 5 years compared with 23% (8%-38%) in CD1a-positive patients (P = .02).1  The GMALL study of 744 patients identified patients with early T-ALL and mature T-ALL as high risk as defined by their criteria noted in the previous section above.38 

ETP ALL were originally described as a high-risk group associated with poor response to therapy and dismal prognosis10,55,56 ; however, this group seems to be heterogeneous and not always associated with poor prognosis.12  In adult T-ALL, a comprehensive analysis integrating immunophenotype, gene expression profiling, chromosomal alterations, and mutation profiling of 53 patients treated in the UKALLXII/E2993 trial identified an ETP gene expression signature as a marker of poor prognosis.7,8,15  In addition, the absence of biallelic TCRG deletion,57  CD13 surface expression, heterozygous deletions of the short arm of chromosome 17, and mutations in IDH1 or IDH2 and DNMT3A genes were also associated with poor prognosis, whereas homozygous deletion of CDKN2A/CDKN2B, NOTCH1 and/or FBXW7 mutations, and mutations or deletions in the BCL11B tumor suppressor gene were associated with favorable outcomes.8  Looking at recent data from a large trial of 1144 children with T-ALL, the Children’s Oncology Group has shown a higher rate of induction failure of patients with ETP ALL but similar survivals.58  Thus, we would not currently recommend different management of adult patients with ETP ALL.

In a donor/no-donor analysis in the MRC/ECOG trial, there was less relapse in those with a donor at 25% vs 51% relapse in those without a donor (P < .001). Nonrelapse mortality was increased in the donor group (22% vs 12% at 5 years, P = .006). Survival was 57% with a donor compared with 42% without a donor (P = .07).1 

The strongest prognostic factor emerging for patients with ALL is the assessment of minimal residual disease (MRD) by flow cytometry, clonal immunoglobulin, or T-cell receptor gene rearrangements. Despite the high remission rates, many patients still relapse, indicating that many patients harbor residual disease. In adult ALL, the GMALL has shown that patients with standard-risk ALL (T-ALL in 33% of patients) who have a rapid decline in measurement of MRD within the first month of therapy had no relapses at 3 years.59  A more recent GMALL study of 1648 newly diagnosed patients (T-ALL 35%), of whom 580 (T-ALL 34%) were evaluable for molecular response, showed that T-ALL patients reached a significantly higher rate of molecular negativity by day 71 of therapy compared with B-ALL (79% vs 66%, P = .001). Patients who achieved molecular negativity had improved OS (80% vs 42%, P = .0001), and molecular response was the only variable with significant prognostic impact in multivariate analysis.60 

A recent study from the GRAALL group has elegantly combined MRD assessment with genetic markers to assess prognosis in 423 of the 860 patients who achieved CR and had MRD analysis done. Of these, 260 were B-ALL and 163 T-ALL patients. A higher risk of relapse was seen in the T-ALL patients who had MRD level ≥10−4, if they lacked NOTCH1/FBXW7 or had N/K-RAS mutation and/or PTEN gene alteration. A high-risk group containing either high MRD levels and/or adverse genetics represented 59% of the T-ALL patients, and the hazard ratio for their cumulative incidence of relapse was 5.31 (95% CI, 2.00-14.07; P = .001) with OS at 5 years from CR of 91% for standard-risk patients and 62% for high-risk patients61  (Figure 3).

Figure 3

Relapse-free survival and OS from CR according to the new risk classification of Beldjord et al. (A) Relapse-free survival in T-ALL patients (86% vs 52% at 5 years; hazard ratio [HR], 4.20; 95% CI, 1.85-9.51; P = .001). (B) OS from CR in T-ALL patients (91% vs 62% at 5 years; HR, 4.14; 95% CI, 1.58-10.83; P = .004). High risk includes MRD-positive and or adverse genetics including no NOTCH1/FBXW7 mutation or presence of N/K-RAS mutation and/or PTEN gene alteration.

Figure 3

Relapse-free survival and OS from CR according to the new risk classification of Beldjord et al. (A) Relapse-free survival in T-ALL patients (86% vs 52% at 5 years; hazard ratio [HR], 4.20; 95% CI, 1.85-9.51; P = .001). (B) OS from CR in T-ALL patients (91% vs 62% at 5 years; HR, 4.14; 95% CI, 1.58-10.83; P = .004). High risk includes MRD-positive and or adverse genetics including no NOTCH1/FBXW7 mutation or presence of N/K-RAS mutation and/or PTEN gene alteration.

Close modal

Decision-making with T-ALL requires an assessment of prognostic factors to determine whether to continue consolidation and maintenance chemotherapy or to consider allogeneic HCT. The presence of MRD postinduction would be a strong indication to consider HCT. Other adverse prognostic factors, predominantly the genetic markers mentioned in the previous paragraph (if available), should be assessed in the context of the patient’s physiologic status and comorbidities along with discussions with the patient regarding the risks and benefits of chemotherapy vs allogeneic HCT. It is recognized that these genetic markers are not yet widely available for use, but likely will be in the near future.

Case presentation

A 25-year-old male presented with a mediastinal mass. A bone marrow biopsy showed 31% blasts that expressed CD2, CD5, CD17, cytoplasmic CD3, CD10, weak CD4, and TdT. Cytogenetics were normal, and cerebrospinal fluid examination was negative. He was treated with hyper-CVAD and completed 5 cycles of therapy. He achieved a complete remission, but with his sixth cycle of therapy, he developed Escherichia coli septic shock and went into multiorgan failure with development of ischemic skin necrosis in all four extremities. He required bilateral above-the-elbow and below-the-knee amputations. No further chemotherapy was given.

A year later, he presented with a leukocyte count of 356 × 109/L and was treated with high-dose cytarabine and idarubicin without response. He was subsequently salvaged with 2 cycles of nelarabine with achievement of a CR. He then had a myeloablative matched sibling-related allogeneic HCT with a conditioning regimen of cyclophosphamide and total body irradiation and subsequent development of chronic graft-versus-host disease. Four years later, he relapsed with an ischial mass. Fluorescent in situ hybridization from the biopsy specimen revealed a t(5;14) (TLX3; BCL11B) in 96% of nuclei and a +22q11.2 in 73% of nuclei. Cytogenetics showed a complex monosomal karyotype with monosomies 7 and 21. Bone marrow biopsy showed <5% atypical blasts. Bone marrow fluorescent in situ hybridization analysis showed a TLX3-BCL11B rearrangement.62  He received radiation therapy to the left ischial area and then 4 cycles of nelarabine followed by 2 donor lymphocyte infusions 2 months apart, which resulted in oral chronic graft-versus-host disease. The patient has remained in remission and is currently attending undergraduate school.

Nelarabine for relapsed/refractory T-ALL

Patients who relapse have a poor prognosis. In the MRC/ECOG trial, 123 of 356 patients (37%) relapsed. Twenty-seven underwent an allogeneic HCT, but only 8 survived at a median of 5.2 years, confirming the dismal outcome of these patients.1 

Nelarabine was initially studied in 93 patients with refractory hematologic malignancies in a daily 1-hour IV infusion for 5 days. The maximum tolerated dose based on neurotoxicity was 40 mg/kg per day in adults and 60 mg/kg per day in children.63 

In adults with relapsed/refractory T-cell ALL, a regimen of 1.5 g/m2 per day on days 1, 3, and 5 was administered in multiple cycles every 22 days. The complete remission rate was 31%, overall response rate 41%, and OS at 1 year was 28%.64  GMALL reported on 126 patients with the same schedule. Forty-five patients achieved a complete remission (36%) and 12 a partial remission. Of the CR patients, 80% were able to proceed to a stem cell transplant (SCT). The OS was 24% at 1 year and 11% at 6 years, with SCT patients achieving an OS of 31% at 3 years.65 

HCT

The use of allogeneic HCT in T-cell ALL in both first CR and beyond has been reported. A study from Saudi Arabia reported 53 patients, 32 (60%) in first CR, 18 (34%) in second or later CR, and 3 (6%) in relapse. The TRM at 5 years was 22.5%, and relapse was 36%. OS and disease-free survival at 5 years were 44% and 42%, respectively.66 

The EBMT has reported the outcome of 886 patients with T-cell ALL who had undergone allogeneic HCT. Four-year OS and leukemia-free survival were 58% and 55%, respectively, whereas 4-year TRM and relapse incidence were 19% and 26%, respectively. The use of total body irradiation in the conditioning regimen was associated with improved outcomes.67 

There is an emerging experience with the use of umbilical cord blood HCT. A report from the CIBMTR of 116 mismatched single- or double-cord HCT compared with 546 unrelated donor peripheral blood HCT and 140 bone marrow HCT in B- and T-ALL patients in the first or second remission showed no difference in 3-year probabilities of survival between recipients of cord blood, matched adult donors, and mismatched adult donors at 44%, 44%, and 43%, respectively.68  Thus, donor choice in the allogeneic HCT setting is similar to other hematologic malignancies, where a matched sibling donor is the first choice and an unrelated donor is the second choice, depending on the degree of matching, cell dose, and urgency of proceeding to transplant. Umbilical cord blood also represents a viable donor option for transplantation for T-ALL, but experience is more limited with this donor source.

The development of new agents for the treatment of T-ALL has lagged behind developments in B-ALL, where multiple monoclonal antibody constructs have shown significant success.69  Other conventional chemotherapy drugs for the treatment of ALL can be considered for patients with relapsed T-ALL. Although not tested exclusively in T-ALL, clofarabine with or without other agents demonstrated modest responses in T-ALL.70 

The high frequency of NOTCH1/FBXW7 mutations in T-ALL suggests the potential for therapeutic targeting. The NOTCH1 receptor is a class I transmembrane protein. Its activation is mediated by a transmembrane proteolytic cleavage catalyzed by the γ-secretase complex, which is involved in the deposition of amyloid fibrils in the brains of patients with Alzheimer disease and has been the focus of research, resulting in the development of highly active small-molecule γ-secretase inhibitor (GSI) drugs. In preclinical models, inhibition by GSI of NOTCH1 receptor activation resulted in G0/G1 cell-cycle arrest and decreased proliferation.17  Several GSIs are in clinical development for the treatment of T-ALL. One such agent, MK-0752, disappointingly showed significant gastrointestinal toxicity with only 1 transient clinical response.71  However, other GSIs show promising clinical activity. Recently, data from a phase 1 trial of a novel GSI inhibitor, BMS-906024, were presented. Eight of 25 evaluable patients showed a 50% or more reduction in bone marrow blasts, with 1 partial remission, 3 patients with 98% to 100% clearance of blasts, and 1 CR. Minimal diarrhea was noted.72  Studies in cell lines and patient samples showed that combining GSIs and glucocorticoids can induce apoptotic cell death in glucocorticoid-resistant T-ALL cells while simultaneously abrogating the gastrointestinal toxicity seen in experimental mice and rats.73-76 

The NUP214-ABL1 rearrangement, present in ∼5% of T-ALL, may serve as a biomarker for cases that may benefit from ABL1-directed tyrosine kinase inhibitor therapies.77,78  Moreover, targeted inhibition of JAK-STAT signaling with tyrosine kinase inhibitor, such as tofacitinib, has been proposed for the treatment of T-ALL with activating JAK3 mutations79  and could also benefit cases harboring IL7R-activating lesions. Also, inhibition of the PI3K-signaling pathway, using inhibitors of PI3K,80  AKT,81,82  mTOR,83  or dual PI3K-mTOR inhibitors,84  offers an attractive therapeutic avenue with or without glucocorticoids85,86  for the treatment of high-risk PTEN-null T-ALL cases.

Finally, preclinical evaluation of a BCL2 inhibitor, ABT-199, in a cell-line model of ETP ALL showed strong antileukemic effects and synergism with glucocorticoids, doxorubicin, as well as l-asparaginase, and analysis of primary patient samples identified highly sensitive T-ALL cases, primarily among ETP leukemias, which are characterized by higher levels of BCL2 expression.87,88 

The diagnosis and treatment of T-ALL remains a challenge with its uncommon and aggressive presentation. Further characterization of subtypes of T-ALL, such as ETP ALL, is reframing our ability to prognosticate in these patients. The discovery of the activating mutations of NOTCH1 and FBXW7 in a majority of patients with T-ALL has been a seminal observation that will hopefully result in the development of effective targeted therapies.

The use of pediatric, intensive chemotherapy regimens in AYAs is showing improved outcomes. Nelarabine for relapsed and refractory disease can result in significant responses. Allogeneic SCT remains an important component of the treatment of T-ALL for patients with high-risk or relapsed/refractory disease. A suggested approach to the management of T-ALL is outlined in Figure 4 and summarized below:

  • Suitable patients should receive a pediatric-intensive regimen of multiagent chemotherapy and, if they have no adverse genetic factors and are MRD negative, can continue treatment on this regimen. Patients with adverse genetic factors and/or who are MRD positive should be considered for allogeneic HCT from a matched-related, unrelated, or cord blood donor(s).

  • Patients not suited for a pediatric-intensive regimen should receive a multiagent chemotherapy regimen of the clinician’s choice, as the ideal regimen has not been determined. Based on response, MRD status, adverse genetic features, and suitability for HCT, a determination can be made as to whether to treat the patient with further chemotherapy or HCT.

Figure 4

Algorithm for management of newly diagnosed T-ALL. MA, myeloablative. *Adverse genetics include no NOTCH1/FBXW7 mutation or presence of N/K-RAS mutation and/or PTEN gene alteration. #Assess comorbidities and determine suitability for HCT.

Figure 4

Algorithm for management of newly diagnosed T-ALL. MA, myeloablative. *Adverse genetics include no NOTCH1/FBXW7 mutation or presence of N/K-RAS mutation and/or PTEN gene alteration. #Assess comorbidities and determine suitability for HCT.

Close modal

The authors thank Ms Denise Chase for transcription of the manuscript.

Contribution: M.R.L. and A.A.F. wrote the paper.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Mark R. Litzow, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: litzow.mark@mayo.edu.

1
Marks
 
DI
Paietta
 
EM
Moorman
 
AV
et al. 
T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993).
Blood
2009
, vol. 
114
 
25
(pg. 
5136
-
5145
)
2
Bazarbachi
 
A
Suarez
 
F
Fields
 
P
Hermine
 
O
How I treat adult T-cell leukemia/lymphoma.
Blood
2011
, vol. 
118
 
7
(pg. 
1736
-
1745
)
3
Borowitz
 
MJ
Chan
 
JKC
 
T-lymphoblastic leukaemia/lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues: World Health Organization Classification of Tumours. Lyon, France: International Agency for Research on Cancer (IARC); 2008:176-178
4
Bene
 
MC
Castoldi
 
G
Knapp
 
W
et al. 
 
Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia. 1995;9(10):1783-1786
5
Ferrando
 
AA
Neuberg
 
DS
Staunton
 
J
et al. 
Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia.
Cancer Cell
2002
, vol. 
1
 
1
(pg. 
75
-
87
)
6
Soulier
 
J
Clappier
 
E
Cayuela
 
JM
et al. 
HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL).
Blood
2005
, vol. 
106
 
1
(pg. 
274
-
286
)
7
Van Vlierberghe
 
P
Ambesi-Impiombato
 
A
Perez-Garcia
 
A
et al. 
ETV6 mutations in early immature human T cell leukemias.
J Exp Med
2011
, vol. 
208
 
13
(pg. 
2571
-
2579
)
8
Van Vlierberghe
 
P
Ambesi-Impiombato
 
A
De Keersmaecker
 
K
et al. 
Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia.
Blood
2013
, vol. 
122
 
1
(pg. 
74
-
82
)
9
Haydu
 
JE
Ferrando
 
AA
Early T-cell precursor acute lymphoblastic leukaemia.
Curr Opin Hematol
2013
, vol. 
20
 
4
(pg. 
369
-
373
)
10
Coustan-Smith
 
E
Mullighan
 
CG
Onciu
 
M
et al. 
Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia.
Lancet Oncol
2009
, vol. 
10
 
2
(pg. 
147
-
156
)
11
Chopra
 
A
Bakhshi
 
S
Pramanik
 
SK
et al. 
Immunophenotypic analysis of T-acute lymphoblastic leukemia. A CD5-based ETP-ALL perspective of non-ETP T-ALL.
Eur J Haematol
2014
, vol. 
92
 
3
(pg. 
211
-
218
)
12
Patrick
 
K
Wade
 
R
Goulden
 
N
et al. 
Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003.
Br J Haematol
2014
, vol. 
166
 
3
(pg. 
421
-
424
)
13
Basso
 
K
Mussolin
 
L
Lettieri
 
A
et al. 
T-cell lymphoblastic lymphoma shows differences and similarities with T-cell acute lymphoblastic leukemia by genomic and gene expression analyses.
Genes Chromosomes Cancer
2011
, vol. 
50
 
12
(pg. 
1063
-
1075
)
14
Raetz
 
EA
Perkins
 
SL
Bhojwani
 
D
et al. 
Gene expression profiling reveals intrinsic differences between T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.
Pediatr Blood Cancer
2006
, vol. 
47
 
2
(pg. 
130
-
140
)
15
Van Vlierberghe
 
P
Ferrando
 
A
The molecular basis of T cell acute lymphoblastic leukemia.
J Clin Invest
2012
, vol. 
122
 
10
(pg. 
3398
-
3406
)
16
Ellisen
 
LW
Bird
 
J
West
 
DC
et al. 
 
TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991;66(4):649-661
17
Weng
 
AP
Ferrando
 
AA
Lee
 
W
et al. 
Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia.
Science
2004
, vol. 
306
 
5694
(pg. 
269
-
271
)
18
Tzoneva
 
G
Ferrando
 
AA
Recent advances on NOTCH signaling in T-ALL.
Curr Top Microbiol Immunol
2012
, vol. 
360
 (pg. 
163
-
182
)
19
Malyukova
 
A
Dohda
 
T
von der Lehr
 
N
et al. 
The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling.
Cancer Res
2007
, vol. 
67
 
12
(pg. 
5611
-
5616
)
20
Thompson
 
BJ
Buonamici
 
S
Sulis
 
ML
et al. 
The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia.
J Exp Med
2007
, vol. 
204
 
8
(pg. 
1825
-
1835
)
21
O’Neil
 
J
Grim
 
J
Strack
 
P
et al. 
FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.
J Exp Med
2007
, vol. 
204
 
8
(pg. 
1813
-
1824
)
22
Mullighan
 
CG
Genome sequencing of lymphoid malignancies.
Blood
2013
, vol. 
122
 
24
(pg. 
3899
-
3907
)
23
Zhang
 
J
Ding
 
L
Holmfeldt
 
L
et al. 
The genetic basis of early T-cell precursor acute lymphoblastic leukaemia.
Nature
2012
, vol. 
481
 
7380
(pg. 
157
-
163
)
24
Hunger
 
SP
Lu
 
X
Devidas
 
M
et al. 
Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group.
J Clin Oncol
2012
, vol. 
30
 
14
(pg. 
1663
-
1669
)
25
Pui
 
CH
Evans
 
WE
A 50-year journey to cure childhood acute lymphoblastic leukemia.
Semin Hematol
2013
, vol. 
50
 
3
(pg. 
185
-
196
)
26
Stock
 
W
La
 
M
Sanford
 
B
et al. 
Children’s Cancer Group; Cancer and Leukemia Group B studies
What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies.
Blood
2008
, vol. 
112
 
5
(pg. 
1646
-
1654
)
27
Ramanujachar
 
R
Richards
 
S
Hann
 
I
Webb
 
D
Adolescents with acute lymphoblastic leukaemia: emerging from the shadow of paediatric and adult treatment protocols.
Pediatr Blood Cancer
2006
, vol. 
47
 
6
(pg. 
748
-
756
)
28
Asselin
 
BL
Devidas
 
M
Wang
 
C
et al. 
Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children’s Oncology Group (POG 9404).
Blood
2011
, vol. 
118
 
4
(pg. 
874
-
883
)
29
Huguet
 
F
Leguay
 
T
Raffoux
 
E
et al. 
Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study.
J Clin Oncol
2009
, vol. 
27
 
6
(pg. 
911
-
918
)
30
Ribera
 
JM
Oriol
 
A
Sanz
 
MA
et al. 
Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the Programa Español de Tratamiento en Hematología pediatric-based protocol ALL-96.
J Clin Oncol
2008
, vol. 
26
 
11
(pg. 
1843
-
1849
)
31
Storring
 
JM
Minden
 
MD
Kao
 
S
et al. 
Treatment of adults with BCR-ABL negative acute lymphoblastic leukaemia with a modified paediatric regimen.
Br J Haematol
2009
, vol. 
146
 
1
(pg. 
76
-
85
)
32
Al-Khabori
 
M
Minden
 
MD
Yee
 
KW
et al. 
Improved survival using an intensive, pediatric-based chemotherapy regimen in adults with T-cell acute lymphoblastic leukemia.
Leuk Lymphoma
2010
, vol. 
51
 
1
(pg. 
61
-
65
)
33
Ben Abdelali
 
R
Asnafi
 
V
Leguay
 
T
et al. 
Group for Research on Adult Acute Lymphoblastic Leukemia
Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study.
Blood
2011
, vol. 
118
 
19
(pg. 
5099
-
5107
)
34
DeAngelo
 
DJ
Dahlberg
 
S
Silverman
 
LB
et al. 
 
A multicenter phase ii study using a dose intensified pediatric regimen in adults with untreated acute lymphoblastic leukemia [abstract]. Blood. 2007;110(11). Abstract 587
35
Douer
 
D
Aldoss
 
I
Lunning
 
MA
et al. 
Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia.
J Clin Oncol
2014
, vol. 
32
 
9
(pg. 
905
-
911
)
36
Ellin
 
F
Jerkeman
 
M
Hagberg
 
H
Relander
 
T
Treatment outcome in T-cell lymphoblastic lymphoma in adults - a population-based study from the Swedish Lymphoma Registry.
Acta Oncol
2014
, vol. 
53
 
7
(pg. 
927
-
934
)
37
Kozlowski
 
P
Åström
 
M
Ahlberg
 
L
et al. 
Swedish Adult ALL Group
High relapse rate of T cell acute lymphoblastic leukemia in adults treated with hyper-CVAD chemotherapy in Sweden.
Eur J Haematol
2014
, vol. 
92
 
5
(pg. 
377
-
381
)
38
Hoelzer
 
D
Thiel
 
E
Arnold
 
R
et al. 
 
Successful subtype oriented treatment strategies in adult t-all; results of 744 patients treated in three consecutive GMALL studies [abstract]. Blood. 2009;114(22). Abstract 324
39
Gökbuget
 
N
How I treat older patients with ALL.
Blood
2013
, vol. 
122
 
8
(pg. 
1366
-
1375
)
40
Kurtzberg
 
J
The long and winding road of the clinical development of Nelarabine.
Leuk Lymphoma
2007
, vol. 
48
 
1
(pg. 
1
-
2
)
41
Dunsmore
 
KP
Devidas
 
M
Linda
 
SB
et al. 
Pilot study of nelarabine in combination with intensive chemotherapy in high-risk T-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group.
J Clin Oncol
2012
, vol. 
30
 
22
(pg. 
2753
-
2759
)
42
Jain
 
P
Kantarjian
 
H
Ravandi
 
F
et al. 
The combination of hyper-CVAD plus nelarabine as frontline therapy in adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma: MD Anderson Cancer Center experience.
Leukemia
2014
, vol. 
28
 
4
(pg. 
973
-
975
)
43
Portell
 
CA
Sweetenham
 
JW
Adult lymphoblastic lymphoma.
Cancer J
2012
, vol. 
18
 
5
(pg. 
432
-
438
)
44
Mohty
 
M
Labopin
 
M
Volin
 
L
et al. 
Acute Leukemia Working Party of EBMT
Reduced-intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation.
Blood
2010
, vol. 
116
 
22
(pg. 
4439
-
4443
)
45
Marks
 
DI
Wang
 
T
Pérez
 
WS
et al. 
The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission.
Blood
2010
, vol. 
116
 
3
(pg. 
366
-
374
)
46
Parovichnikova
 
E
Kuzmina
 
L
Mendeleeva
 
L
et al. 
Autologous hematopoietic stem cell transplantation followed by prolonged maintenance provides survival benefit over only chemothearpy in T-cell acute lymphoblastic leukemia: results of the RALL Study Group.
Bone Marrow Transplant
2014
, vol. 
49
 (pg. 
S6
-
S7
)
47
Asnafi
 
V
Buzyn
 
A
Le Noir
 
S
et al. 
NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study.
Blood
2009
, vol. 
113
 
17
(pg. 
3918
-
3924
)
48
Breit
 
S
Stanulla
 
M
Flohr
 
T
et al. 
Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia.
Blood
2006
, vol. 
108
 
4
(pg. 
1151
-
1157
)
49
Clappier
 
E
Collette
 
S
Grardel
 
N
et al. 
EORTC-CLG
NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951.
Leukemia
2010
, vol. 
24
 
12
(pg. 
2023
-
2031
)
50
Mansour
 
MR
Sulis
 
ML
Duke
 
V
et al. 
Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol.
J Clin Oncol
2009
, vol. 
27
 
26
(pg. 
4352
-
4356
)
51
Zuurbier
 
L
Homminga
 
I
Calvert
 
V
et al. 
NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols.
Leukemia
2010
, vol. 
24
 
12
(pg. 
2014
-
2022
)
52
Deftos
 
ML
He
 
YW
Ojala
 
EW
Bevan
 
MJ
Correlating notch signaling with thymocyte maturation.
Immunity
1998
, vol. 
9
 
6
(pg. 
777
-
786
)
53
Real
 
PJ
Ferrando
 
AA
NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia.
Leukemia
2009
, vol. 
23
 
8
(pg. 
1374
-
1377
)
54
Trinquand
 
A
Tanguy-Schmidt
 
A
Ben Abdelali
 
R
et al. 
Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study.
J Clin Oncol
2013
, vol. 
31
 
34
(pg. 
4333
-
4342
)
55
Inukai
 
T
Kiyokawa
 
N
Campana
 
D
et al. 
Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children’s Cancer Study Group Study L99-15.
Br J Haematol
2012
, vol. 
156
 
3
(pg. 
358
-
365
)
56
Ma
 
M
Wang
 
X
Tang
 
J
et al. 
Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia.
Fr Medecine
2012
, vol. 
6
 
4
(pg. 
416
-
420
)
57
Gutierrez
 
A
Dahlberg
 
SE
Neuberg
 
DS
et al. 
Absence of biallelic TCRgamma deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia.
J Clin Oncol
2010
, vol. 
28
 
24
(pg. 
3816
-
3823
)
58
Wood
 
BL
Winter
 
SS
Dunsmore
 
KP
et al. 
 
T-lymphoblastic leukemia (T-ALL) shows excellent outcome, lack of significance of the early thymic precursor (ETP) Immunophenotype, and validation of the prognostic value of end-induction minimal residual disease (MRD) in Children’s Oncology Group (COG) Study AALL0434 [abstract]. Blood. 2014;124(21). Abstract 1
59
Brüggemann
 
M
Raff
 
T
Flohr
 
T
et al. 
German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia
Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia.
Blood
2006
, vol. 
107
 
3
(pg. 
1116
-
1123
)
60
Gökbuget
 
N
Kneba
 
M
Raff
 
T
et al. 
German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia
Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies.
Blood
2012
, vol. 
120
 
9
(pg. 
1868
-
1876
)
61
Beldjord
 
K
Chevret
 
S
Asnafi
 
V
et al. 
Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)
Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.
Blood
2014
, vol. 
123
 
24
(pg. 
3739
-
3749
)
62
Bernard
 
OA
Busson-LeConiat
 
M
Ballerini
 
P
et al. 
A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia.
Leukemia
2001
, vol. 
15
 
10
(pg. 
1495
-
1504
)
63
Kurtzberg
 
J
Ernst
 
TJ
Keating
 
MJ
et al. 
Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies.
J Clin Oncol
2005
, vol. 
23
 
15
(pg. 
3396
-
3403
)
64
DeAngelo
 
DJ
Yu
 
D
Johnson
 
JL
et al. 
Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801.
Blood
2007
, vol. 
109
 
12
(pg. 
5136
-
5142
)
65
Gökbuget
 
N
Basara
 
N
Baurmann
 
H
et al. 
High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation.
Blood
2011
, vol. 
118
 
13
(pg. 
3504
-
3511
)
66
Bakr
 
M
Rasheed
 
W
Mohamed
 
SY
et al. 
Allogeneic hematopoietic stem cell transplantation in adolescent and adult patients with high-risk T cell acute lymphoblastic leukemia.
Biol Blood Marrow Transplant
2012
, vol. 
18
 
12
(pg. 
1897
-
1904
)
67
Cahu
 
X
Labopin
 
M
Giebel
 
S
et al. 
 
Myeloablative allogeneic hematopoietic stem cell transplantation for adult patients with T-cell acute lymphoblastic leukemia: a survey from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) [abstract]. Blood. 2012;120(21). Abstract 356
68
Marks
 
DI
Woo
 
KA
Zhong
 
X
et al. 
Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors.
Haematologica
2014
, vol. 
99
 
2
(pg. 
322
-
328
)
69
Kantarjian
 
H
Thomas
 
D
Wayne
 
AS
O’Brien
 
S
Monoclonal antibody-based therapies: a new dawn in the treatment of acute lymphoblastic leukemia.
J Clin Oncol
2012
, vol. 
30
 
31
(pg. 
3876
-
3883
)
70
Huguet
 
F
Leguay
 
T
Raffoux
 
E
et al. 
Clofarabine for the treatment of adult acute lymphoid leukemia: a review article by the GRAALL intergroup.
Leuk Lymphoma
2014
, vol. 
56
 
4
(pg. 
847
-
857
)
71
Deangelo
 
D
Stone
 
R
Silverman
 
L
et al. 
 
A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias [abstract]. J Clin Oncol. 2006;24(185). Abstract 6585
72
Zweidler-McKay
 
PA
DeAngelo
 
DJ
Douer
 
D
et al. 
 
The safety and activity of BMS-906024, a gamma secretase inhibitor (GSI) with anti-notch activity, in patients with relapsed T-cell acute lymphoblastic leukemia (T-ALL): initial results of a phase 1 trial [abstract]. Blood. 2014;124. Abstract 968
73
Aguirre
 
SA
Liu
 
L
Hosea
 
NA
et al. 
Intermittent oral coadministration of a gamma secretase inhibitor with dexamethasone mitigates intestinal goblet cell hyperplasia in rats.
Toxicol Pathol
2014
, vol. 
42
 
2
(pg. 
422
-
434
)
74
Real
 
PJ
Tosello
 
V
Palomero
 
T
et al. 
Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.
Nat Med
2009
, vol. 
15
 
1
(pg. 
50
-
58
)
75
Samon
 
JB
Castillo-Martin
 
M
Hadler
 
M
et al. 
Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia.
Mol Cancer Ther
2012
, vol. 
11
 
7
(pg. 
1565
-
1575
)
76
Wei
 
P
Walls
 
M
Qiu
 
M
et al. 
Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design.
Mol Cancer Ther
2010
, vol. 
9
 
6
(pg. 
1618
-
1628
)
77
Clarke
 
S
O’Reilly
 
J
Romeo
 
G
Cooney
 
J
NUP214-ABL1 positive T-cell acute lymphoblastic leukemia patient shows an initial favorable response to imatinib therapy post relapse.
Leuk Res
2011
, vol. 
35
 
7
(pg. 
e131
-
e133
)
78
Quintás-Cardama
 
A
Tong
 
W
Manshouri
 
T
et al. 
Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies.
Leukemia
2008
, vol. 
22
 
6
(pg. 
1117
-
1124
)
79
Degryse
 
S
de Bock
 
CE
Cox
 
L
et al. 
JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model.
Blood
2014
, vol. 
124
 
20
(pg. 
3092
-
3100
)
80
Subramaniam
 
PS
Whye
 
DW
Efimenko
 
E
et al. 
Targeting nonclassical oncogenes for therapy in T-ALL.
Cancer Cell
2012
, vol. 
21
 
4
(pg. 
459
-
472
)
81
Falà
 
F
Blalock
 
WL
Tazzari
 
PL
et al. 
Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor (2S)-1-(1H-Indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan2-amine (A443654) in T-cell acute lymphoblastic leukemia.
Mol Pharmacol
2008
, vol. 
74
 
3
(pg. 
884
-
895
)
82
Chiarini
 
F
Del Sole
 
M
Mongiorgi
 
S
et al. 
The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism.
Leukemia
2008
, vol. 
22
 
6
(pg. 
1106
-
1116
)
83
Evangelisti
 
C
Evangelisti
 
C
Chiarini
 
F
et al. 
Therapeutic potential of targeting mTOR in T-cell acute lymphoblastic leukemia (review).
 
[review] Int J Oncol. 2014;45(3):909-918
84
Martelli
 
AM
Chiarini
 
F
Evangelisti
 
C
et al. 
 
Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment. Oncotarget. 2012;3(4):371-394
85
Piovan
 
E
Yu
 
J
Tosello
 
V
et al. 
Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia.
Cancer Cell
2013
, vol. 
24
 
6
(pg. 
766
-
776
)
86
Wei
 
G
Twomey
 
D
Lamb
 
J
et al. 
Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance.
Cancer Cell
2006
, vol. 
10
 
4
(pg. 
331
-
342
)
87
Peirs
 
S
Matthijssens
 
F
Goossens
 
S
et al. 
ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia.
Blood
2014
, vol. 
124
 
25
(pg. 
3738
-
3747
)
88
Chonghaile
 
TN
Roderick
 
JE
Glenfield
 
C
et al. 
Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199.
Cancer Discov
2014
, vol. 
4
 
9
(pg. 
1074
-
1087
)
Sign in via your Institution