Early T cell precursor acute lymphoblastic leukemia (ETP-ALL), an uncommon subtype of T cell acute lymphoblastic leukemia (T-ALL), carries a poor prognosis and low response rate to traditional chemotherapy drugs. But a clinical trial of a targeted agent that shows promise against ETP-ALL will soon be enrolling patients at The University of Texas MD Anderson Cancer Center.
Few connections have been made between the biological features of T-ALL (which also presents as T cell lymphoblastic lymphoma) and patients’ clinical outcomes. The World Health Organization classifies T-ALL cases into subtypes based on leukemic cell biomarkers that correspond to four stages of T cell maturity: prethymic, prothymic, thymic, and mature. In practice, many researchers began combining the prothymic and prethymic stages into one class, “early.” But neither classification system nor any subtypes of T-ALL have demonstrated prognostic or predictive value—until the discovery of ETP-ALL.
A clinically relevant T-ALL subtype
ETP-ALL was first described in a 2009 study of pediatric T-ALL. By flow cytometry, the leukemic cells of some patients had an expression profile reminiscent of recent arrivals in the thymus from the bone marrow. These cells had a unique biomarker signature: the key immunophenotypic features of immature leukemic T cells—the absence of antigens CD1a, CD8, and CD5—along with the expression of one or more stem cell or myeloid antigens. Clinical assessment of the pediatric patients in that study showed that those with this subtype of T-ALL responded poorly to conventional T-ALL treatments.
Subsequent studies reported ETP-ALL in 11%–12% of childhood and 7%–8% of adult T-ALL cases and confirmed that children with ETP-ALL have significantly worse clinical outcomes.
However, studies of clinical outcomes in adults were largely inconclusive until a recent study by Joseph Khoury, M.D., an associate professor in the Department of Hemato pathology; Nitin Jain, M.D., an assistant professor in the Department of Leukemia; and colleagues.
The researchers retrospectively analyzed the records of 111 patients newly diagnosed with T-ALL at MD Anderson between 2000 and 2014. All patients had received frontline chemotherapy with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-
CVAD) or an augmented Berlin-Frankfurt-Münster regimen. Reassessment of the patients’ flow cytometry data identified 19 patients who met the criteria for ETP-ALL, and these patients experienced a significantly lower complete remission rate (73%) than did patients with non–ETP-ALL (91%). In fact, a multivariate analysis of 11 potential prognostic markers found only two to be significant: age and the ETP-ALL subtype.
The study was notable for its use of a single, large patient population, Dr. Khoury said. “The prognostic significance of this subtype is demonstrated now within a relatively well-controlled cohort of patients who received the same fundamental types of treatment,” he said. “We confirmed that clinical outcomes of adult ETP-ALL patients mirror those of pediatric ETP-ALL patients,” Dr. Jain said. “When treated uniformly with chemotherapy, patients with ETP-ALL have poor long-term outcomes.”
Targeting the ETP-ALL subtype
“Traditionally, patients with T-ALL are grouped within a single category from a therapeutic standpoint,” Dr. Khoury said. Whereas the more common B cell ALL cases are treated differently based on genetic markers such as the Philadelphia chromosome, all TALL cases are typically treated with the same chemotherapy regimens. “Based on our findings,” Dr. Khoury said, “patients with ETP-ALL need a different approach than those with non–ETP-ALL.”
“ETP-ALL affects a relatively small group of patients,” Dr. Jain said, “but these patients have a largely unmet medical need.” Drs. Jain and Khoury and their team are investigating how to address that need. One drug target they’ve recognized as promising is the apoptosis regulator Bcl-2. In recent years, studies by Marina Konopleva, M.D., Ph.D., a professor in the Department of Leukemia, and others have noted that T-ALL cells—and especially ETP-ALL cells—express high levels of Bcl-2. An oral inhibitor of Bcl-2, venetoclax (formerly called ABT-199), has demonstrated activity against chronic lymphocytic leukemia in clinical trials, and preclinical studies suggest that venetoclax may be effective against ETP-ALL. “ETP-ALL cells are preferentially sensitive to Bcl-2 antagonism in vitro and in mouse models,” Dr. Jain said, adding that he and others are optimistic about this strategy’s potential for patients with ETP-ALL.
In the next 3–5 months, Dr. Jain and researchers from the Departments of Leukemia and Hematopathology plan to open a single-arm, phase IB multiple ascending dose trial evaluating the safety of venetoclax in patients with ALL. Eligible patients must have untreated ALL (of any type), be over 50 years of age, have good organ function, and not be currently receiving treatment for other cancers. This will be the first trial of venetoclax in patients with ALL.
The trial, as planned, will pair venetoclax with a low-intensity chemotherapy regimen that the team calls “mini-hyper-CVD,” which is similar to hyper-CVAD but omits doxorubicin and uses much smaller doses of the other agents. Dr. Jain said the low-intensity chemotherapy regimen was designed to minimize the risks of tumor lysis syndrome and neutropenia, both of which have been associated with venetoclax treatment.
Another promising strategy against ETP-ALL is to target the Janus kinase (JAK) signaling pathway. Like Bcl-2 levels, JAK levels are especially high in ETP-ALL cells, suggesting that inhibitors of JAK may also be effective against this subtype. And in preclinical studies, the JAK1/JAK2 inhibitor ruxolitinib has shown activity against T-ALL cells. Dr. Jain said, “Ruxolitinib may be a future option for treating patients with T-ALL, including patients with the ETP-ALL subtype.” Drs. Jain and Khoury, along with other researchers from the Departments of Hematopathology and Leukemia, are studying the feasibility of JAK inhibition in experimental models.
Identifying the ETP-ALL subtype is a practical way to anticipate a poor response to traditional T-ALL treatment, Dr. Khoury said. Screening requires only flow cytometry, a standard diagnostic procedure already used in most clinical workups. Patients who screen positive for ETP-ALL may respond better to more intensive treatments or to chemotherapy using nonstandard agents.
Dr. Khoury and his team are calling for awareness of this subtype in research centers to find new treatments and in clinics for oncologists and patients to make informed treatment decisions. “It is important for oncologists to be aware that patients whose T-ALL is subtyped ETP-ALL will likely need a different approach,” he said.
For more information, Dr. Nitin Jain at 713-745-6080 or Dr. Joseph Khoury at 713-745-2387.
Jain N, Lamb A, O’Brien S, et al. Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype. Blood. 2016;127:1863–1869.
OncoLog, May 2016, Volume 61, Issue 5