Novel Agents Change the Treatment of Acute Lymphoblastic Leukemia

Christina T. Loguidice
Published: Tuesday, May 29, 2018
Mark R. Litzow, MD
Mark R. Litzow, MD
Significant advances continue to improve the outcome for patients aged 40 years and older with acute lymphoblastic leukemia (ALL). During an OncLive Peer Exchange® moderated by Mark R. Litzow, MD, a panel of experts discussed the latest data on several novel agents for ALL and provided insights on how to align these treatments in challenging settings.

ALL (also called acute lymphocytic leukemia) is a rare cancer, with an estimated 5960 new cases anticipated in 2018.1 It is most common in children, adolescents, and young adults (aged 15-39 years), with a median age of onset of 15 years.1 Cure rates are high for children, with 98% of pediatric patients achieving remission; approximately 85% of those aged 1 to 18 years with newly diagnosed ALL can expect to become long-term event-free survivors.2 However, patients aged 60 years or older with ALL continue to have poor survival rates, and there is a gray area for how to treat patients aged 40 to 60 years.

Tyrosine Kinase Inhibitors in Frontline Ph+ ALL

From 20% to 30% of adult patients have Philadelphia chromosome–positive (Ph+) ALL, which has been associated with a poorer prognosis than Philadelphia chromosome–negative (Ph-) ALL.3 “The game changers in the treatment of this subtype of ALL have been the tyrosine kinase inhibitors [TKIs],” Litzow said. “Certainly, imatinib [Gleevec] has been the first agent that was tested in this subset of patients, but most of the tyrosine kinase inhibitors have now been tested in 1 form or another.” The panelists noted that more potent TKIs, such as dasatinib (Sprycel) and ponatinib (Iclusig), are now preferred over imatinib because of their superior response rates.

Allogeneic stem cell transplantation (ASCT) and chemotherapy are other cornerstones of Ph+ ALL therapy, but not all patients are candidates, such as the elderly or otherwise frail or unfit patients, who are at greater risk of treatment- related complications and toxicities. Recent evidence suggests that ASCT or chemotherapy could be avoided under certain circumstances without significantly worse outcomes.

“Our pediatric colleagues have relied primarily on the use of imatinib, and some of their studies have suggested that if pediatric patients with Ph+ ALL achieve MRD [minimal residual disease] negativity, becoming BCR-ABL–negative, they don’t appear to need a transplant, and their outcomes are similar to what’s seen with either a matched related or unrelated donor,” Litzow said. He noted that similar findings have yet to be definitively demonstrated in adults.

Chemotherapy for Ph+ ALL often uses a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen, with a TKI added, but Italian researchers have shown that using a TKI with corticosteroids and central nervous system prophylaxis can achieve a high rate of complete hematologic response, although complete molecular response (CMR) is lower without chemotherapy. In an initial study that used dasatinib, there was a CMR of about 20%, Litzow said.

More recently, the same investigators reported the results of their multicenter phase II study that assessed the safety and efficacy of steroids plus ponatinib alone for elderly or unfit patients with Ph+ ALL.4 The primary endpoint of complete hematologic response (CHR) was prematurely reached, with 40 of 42 patients (95.2%) achieving CHR after 1 treatment course. After 8 courses, 38 patients (90.5%) were in CHR. The remaining 4 patients dropped out of the study because of disease relapse (n = 1), excessive toxicity (n = 1), or medical reasons (n = 2). A CMR was observed in 11 of 24 patients at 24 weeks (45.8%), with the remaining 14 of 38 patients being unevaluable.

“Ponatinib seems to have particularly robust activity in ALL,” Aaron C. Logan, MD, PhD, said. He discussed an MD Anderson Cancer Center study that added ponatinib to hyper-CVAD.5 The 3-year continued remission and overall survival (OS) rates with this regimen were 79% and 76%, respectively. Furthermore, analysis at 4 months showed that cytogenetic response duration and OS did not differ significantly in patients with or without ASCT. “If we can add [ponatinib] to backbones like hyper-CVAD and other regimens and get outcomes that rival those that we see in children, then perhaps we don’t need to transplant the Ph+ population anymore,” Logan said.

The panelists concluded that using TKI inhibitors with steroids alone is most appropriate for frail, elderly patients and others who may not be fit for transplant, because they are better able to tolerate such treatments, which could help them achieve hematological remission. For more robust patients, hyper-CVAD or transplantation remain important options, with a goal to achieve a CMR.

Moving Ponatinib to the Frontline

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