T-ALL in CNS-3 status needs improvement

In this issue of Blood, Gossai et al¹ assessed the prognostic significance of central nervous system (CNS) leukemic involvement in 2164 children and young adults, aged 1 to 30 years, who were newly diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) and were¹ enrolled in 2 consecutive, phase 3 clinical trials (AALL0434, n = 1550 patients; AALL1231, n = 614 patients), from the Children’s Oncology Group (COG). Despite the differences in the 2 trials, the authors found that patients with CNS-1 or CNS-2 status at diagnosis had similar event-free survival (EFS) and overall survival (OS), and these outcomes were significantly better than those of patients with CNS-3 status, all of whom received cranial radiotherapy (CRT).

The CNS is the most important site of extramedullary disease in children and adults with acute lymphoblastic leukemia, with an incidence of CNS involvement at diagnosis ranging from 5% to 11%.² The diagnosis of CNS leukemia relies on microscopic examination of the cerebrospinal fluid after centrifugation, and a grading system generated by the COG (CNS-1, CNS-2, and CNS-3) is used to quantify the degree of CNS involvement.³ Multiparametric flow cytometry is more sensitive for detection of CNS leukemia than conventional cytology and could aid in identifying patients at higher risk of relapse and improving risk stratification for optimizing CNS-directed therapy.⁴ Risk factors for CNS involvement at the time of diagnosis include a high white-blood-cell count, a lactate dehydrogenase level > 3 times the upper limit of normal, adverse cytogenetics (including t[9;22] and t[4;11]), and T lineage. With modern prophylaxis techniques, rates of CNS leukemia relapse (either isolated or combined) range from 4% to 15%. Outcomes of children and adults after CNS leukemia relapse are poor, although the prognosis for an isolated CNS relapse is better than that for a combined CNS-and-marrow relapse, and the prognosis for late relapse is more favorable than that for early relapse.

Historically, CRT (usually as a dose of 18-24 Gy) and intrathecal therapy were the fundamental components of CNS prophylaxis. However, concerns over the delayed toxicity of CRT, including neurocognitive defects, endocrinopathy, and secondary cancers increased, leading to studies showing that CRT can be omitted from routine prophylaxis without compromising CNS leukemia relapse rates.⁵ Moreover, subsequent hematopoietic stem cell transplantation (in which total body irradiation–based conditioning may be used) for relapse or consolidation for high-risk disease could impact the total radiation dose given to a patient. Thus, strategies to avoid CRT using varying combinations of CNS-penetrating systemic agents plus other CNS-directed therapies were developed. Agents that cross the blood–brain barrier include methotrexate, cytarabine, dexamethasone, asparaginase, 6-mercaptopurine, dasatinib, and ponatinib. Regarding methotrexate, the COG study AALL0232 in children and young adults with B-cell acute lymphoblastic leukemia (B-ALL) showed that interim maintenance based on high-dose methotrexate (5000 mg/m²) yielded superior EFS, with CNS relapse rates below historical values (<5%).⁶ However, the parallel COG study, AALL0434, of T-ALL found that Capizzi escalating-dose methotrexate (C-MTX, 100-300 mg/m²) plus peg-aspargase interim maintenance provided superior disease-free survival and significantly fewer isolated CNS relapses compared with high-dose methotrexate (0.4% vs 3.0%).⁷ The CNS prophylaxis studies by the COG, assessing outcomes based on CNS status in B-ALL, showed worse survival for patients with CNS-3 status than those with CNS-2 status, which in turn was poorer than that for patients with CNS-1 status. Based on these findings, CNS-directed therapy was progressively intensified for CNS-2 and CNS-3 B-ALL. The study by Gossai et al examined whether the same approach could be applied for T-ALL patients. Except for patients with CNS-3 disease who received nelarabine in the AALL0434 study,⁸ EFS/OS for those with CNS-3 disease was inferior to that for patients with CNS-1 or CNS-2 disease. In contrast to B-ALL outcomes, those for CNS-1 and CNS-2 disease were similar in T-ALL patients. Therefore, CNS-2 patients with T-ALL can be treated similarly to CNS-1 patients, without additional intrathecal chemotherapy or the use of CRT.

The problem now is to determine the best treatment for T-ALL patients with CNS-3 disease. Nelarabine, C-MTX, and dexamethasone each have been shown to reduce the risk of CNS relapse. However, nelarabine mitigated the poor prognosis for patients with CNS-3 disease, using a regimen that included CRT. It is possible that the additional use of C-MTX and induction dexamethasone could eliminate the need for CRT in these patients. However, this combined strategy has not yet been evaluated. Would this approach be sufficient to overcome the poor prognosis of these patients, or are additional agents needed? Lessons learned from therapies used in relapsed or refractory (R/R) ALL patients have shown that some therapies, such as CD19-directed chimeric antigen receptor-modified (CAR) T-cells, are effective and safe for treatment of CNS leukemia (either with or without concurrent medullary relapse),⁹ and these therapies likely will be used as part of the treatment of newly diagnosed patients in the near future, providing an additional strategy of CNS therapy or high-risk prophylaxis. CAR T-cells directed against CD7 or CD5 are actively being investigated in R/R T-ALL and lymphoblastic lymphoma. Data from phase 1 and 2 trials show similar efficacy to that obtained with CD19 CAR T cells for R/R B-ALL, with the same possible implications for CNS prophylaxis or therapy in T-ALL.¹⁰ Apart from cellular therapies, other agents capable of penetrating the CNS (eg, MEK inhibitors or drugs targeting the PI3 kinase pathway, among others) are being actively investigated. Better approaches clearly are needed to treat CNS-3 T-ALL, especially if omission of CRT is a priority. Early intensive therapy to maximize eradication of CNS leukemia should help prevent future CNS disease relapses.

Conflict-of-interest disclosure: The author declares no competing financial interests.