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T-Cell Acute Lymphoblastic Leukemia (T-ALL) | BMT

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. (Source –





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.

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. (Source –



Types of T-Cell Acute Lymphoblastic Leukemia (T-ALL) Bone Marrow Transplant


The main types of stem cell transplants are:

  • Allogeneic stem cell transplant, in which the stem cells come from someone else. This is the preferred type of transplant when treating ALL.
  • Autologous stem cell transplant, in which the patient gets back their own cells

Allogeneic transplant: A donor’s tissue type (also known as the HLA type) needs to closely match the patient’s tissue type to help prevent the risk of major problems with the transplant. The best donor is often a close relative, such as a brother or sister, if they have the same tissue type as the patient. If there are no siblings with a good match, the cells may come from an HLA-matched, unrelated donor – a stranger who has volunteered to donate their cells. Some patients cannot have this kind of transplant because a matching donor isn’t available.

The use of allogeneic transplant is also limited by its side effects, which are often too severe for people who are older or who have other health problems. One option that may help patients who can’t have an allogeneic transplant because of age or health issues is to use lower doses of chemo and radiation that don’t completely destroy the cells in their bone marrow. This is known as a non-myeloablative or reduced-intensity transplant. This kind of SCT relies on the donor cells to kill the leukemia cells, instead of the chemo and radiation. This is not a standard treatment for ALL, and is being studied to determine how useful it may be.

Autologous transplant: A patient’s own stem cells are removed from their bone marrow or blood. They are frozen and stored while the person gets treatment (high-dose chemotherapy and/or radiation). A process called purging may be used in the lab to try to remove any leukemia cells in the samples. The stem cells are then put back (reinfused) into the patient’s blood after treatment.

An autologous transplant may be an option for patients who can’t have an allogeneic transplant because they don’t have a matched donor, or for some other reason. One problem with autologous transplants is that leukemia is a disease of the bone marrow and blood, so even after purging, there is a danger of giving the patient back leukemia cells with the stem cells.

Another reason that allogeneic transplants are preferred is because of the graft-versus-leukemia effect. When the donor immune cells are infused into the body, they may recognize any remaining leukemia cells as being foreign to them and attack them. This effect doesn’t happen with an autologous SCT. (Source)



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