New Approaches Emerge for Treating ALL, Yet Challenges Remain

Dan Douer, MD

The treatment landscape for acute lymphoblastic leukemia (ALL) is changing, pointing to promising new approaches clinicians can use in practice. These include deploying pediatric regimens in the adult setting, recognizing genetic alterations beyond the Philadelphia chromosome that can be manipulated with targeted agents in “Philadelphia-like” disease, and modifying autologous T-cells with new treatment modalities.

This is all good news for patients, said Dan Douer, MD, in reviewing some of the latest ALL research at the 19th Annual Congress on Hematologic Malignancies. Douer, an attending physician in the Leukemia Service at Memorial Sloan Kettering Cancer Center, cautioned that while “best clinical practice is changing, what we think today also may change,” in a setting where the response rate is low in patients who relapse, and where there is still no standard classification of risk.

Some of the more provocative questions surrounding ALL treatment, he said, include whether it makes sense to shift standard of care at an age around puberty to 21 years, which he deemed “an administrative decision,” not grounded in the latest research.

Another question involves the use of heavily myelosuppressive, “AML-like” drugs. He argued that myelosuppression is a side effect and not a goal in ALL, noting that research has demonstrated no added benefit for anthracycline intensification and that non-myelosuppressive drugs, including steroids and vincristine, elicit a high response rate in adults with ALL.

Douer also explored the question of why asparaginase is underused in adult patients, a decision he attributed to the belief that it is more toxic in adults than in children where research has demonstrated increasing duration of asparaginase improves overall outcomes. “My concern is that this fear, this reluctance, has not gone away.”

Pediatric Protocols in Adults

Douer noted that adult ALL patients have a higher range of biologically unfavorable disease, presenting a particular challenge for clinicians. He reviewed studies conducted over the last several years utilizing “pediatric-inspired” regimens in adults, including early results from the US Intergroup Trial C10403 (CALGB 10403) which were presented at the 2014 ASH Annual Meeting in December.¹

This trial involved 296 newly diagnosed adolescent and young adult (AYA) patients (median age = 24 years, range 17-39), the majority (76%) of whom had B-precursor ALL. The study built on research from the successful Children's Oncology Group (COG) Study AALL0232.² For the AYA study reported at ASH, the experimental regimen was identical to the standard arm (Capizzi escalating methotrexate plus PEG asparaginase) used in the COG 0232 study.

When this intensive pediatric regimen was used in the AYA group, 2-year overall survival (OS) was 78%, and event-free survival was 66%. Toxicities in the AYA cohort were similar to those experienced by pediatric patients receiving the regimen in the COG 0232 study, including ALT elevation in approximately 50% of patients in both in the AYA and pediatric populations and hyperbilirubinemia (~25%).

Douer and colleagues adapted the COG 0232 regimen to reduce toxicities in a study involving 51 patients (median age = 32 years, range 18-57) who received six doses of intravenous pegaspargase at 2000 IU/m2 per dose.³ The approach involved longer intervals between doses, more rational synchronization with other chemotherapy drugs to prevent overlapping toxicities, and administration with steroids to reduce hypersensitivity. Complete remission was achieved in 96% of patients, and notably, said Douer, most patients entered complete remission after one cycle of therapy.

Investigators reported 7-year disease-free and OS rates of 58% and 51%, respectively. Douer added that for standard-risk patients, OS was 74% and for high-risk patients, 40%.

The most common grade 3/4 asparaginase-related toxicities were lengthy hyperbilirubinemia (31%) and transaminitis (63%), and these occasionally resulted in treatment delays.

“What’s really emerging now are the liver toxicities,” said Douer, prompting many physicians to discontinue use of the drug. He stressed that these toxicities occur mostly after the first dose and may last as long as 1 month, but, “if you continue giving the drug, the toxicity doesn’t necessarily recur after subsequent doses.”

Douer presented some potential strategies for addressing liver toxicity, including experimental data from a study of the effect of L-asparaginase on rat livers. The study determined that the therapy induced severe toxicity in fatty livers, but toxicity was low in normal livers. Moreover, l-carnitine had the potential to ameliorate L-asparaginase—induced hepatotoxicity in patients with preexisting liver disorders.⁴ “The most important thing is to know how to give asparaginase,” he said, administration guidelines exist, including premedication with hydrocortisone, early identification and treatment of pancreatitis, as well as treatment of thrombosis with oral anticoagulants and of hypertriglyceridemia with gemfibrozil.

Philadelphia+ and “Ph-like” ALL

Before the TKI era, there was no cure for Philadelphia+ (Ph+) ALL without transplant, Douer noted, and the TKI imatinib when combined with chemotherapy has shown efficacy in a number of studies. When patients are imatinib-intolerant or develop resistance, second- and third-generation TKIs can be used, eg, dasatinib, nilotinib, ponatinib. The ideal chemotherapy backbone is unclear, he added, and oncologists tend to use their own “favorite,” typically hyper-CVAD or BFM. Some studies show that prednisone with dasatinib has a high complete remission rate, and the question of allogenic BMT remains open.

“Ph-like” ALL has a gene expression profile similar to Ph+ ALL but without the chromosomal abnormalities. It increases with age and is characterized by a higher white blood cell count, a higher rate of minimal residual disease, and worse outcomes. Research published in The New England Journal of Medicine last fall identified a number of subgroups of kinase genetic alterations.⁵

“What’s important,” said Douer, “is that all of these can be targeted by FDA-approved drugs,” such as dasatinib, ruxolitinib, and crizotinib, and studies have demonstrated strong preclinical evidence and encouraging anecdotal clinical responses with this agents.

Blinatumomab and CAR-T Technology

The third breakthrough in ALL treatment involves modifying autologous T cells to kill B ALL cells. In a phase II study presented at the 2014 ASCO Annual Meeting, the efficacy of single-agent blinatumomab was confirmed in a difficult-to-treat population with relapsed/refractory ALL (NCT01466179).⁶ In this trial, 43% of patients achieved a complete response (CR) or CR with partial hematological recovery (CRh) within the first two cycles. “Although this is not a curable approach, you get a reasonably good overall survival,” Douer said, adding that one practical drawback of this therapy is that it is 24-hour infusion over 28 days.

A different way of modifying T cells is through chimeric antigen receptor (CAR)-T technology, and Douer highlighted two recent studies demonstrating the potential of this approach. The first, presented at ASH 2014, reported that CAR-T therapy achieved an 87% CR among the 28 patients enrolled in the study (median age 55, range 23-74 years) and an OS of 57% at 6 months.⁷ In the other trial, involving 30 patients (25 children and 5 adults), the overall CR was 90%, and 6-month OS was 78%.8 Douer noted that most of the responses in these two studies are “deep, with molecular remission.”

A principal concern with CAR-T therapy is cytokine release syndrome (CRS), and it is associated with the patient’s tumor burden, Douer explained. CRS is marked by fever for 3 or more days, significant cytokine elevation, and at least one clinical sign (eg, hypotension, hypoxia, neurologic changes [mental change, seizures]). Treatment involves intensive support, the I-6 inhibitor tocilizumab, and steroids.

In an overall assessment of the two therapies, Douer, said, “blinatumomab is not curative, CAR-T cell therapy may be, but the toxicity is much higher.”

References

1. Stock W, Luger SM, Anjali S, et al. Favorable outcomes for older adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL): early results of US Intergroup Trial C10403. Presented at: 2014 ASH Annual Meeting. Abstract 796.
2. Larsen EC, Salzer WL, Devidas M, et al. Comparison of high-dose methotrexate (HD-MTX) with Capizzi methotrexate (C-MTX) plus asparaginase (C-MTX/ASNase) in children and young adults with high-risk acute lymphoblastic leukemia (HR-ALL): A report from the Children’s Oncology Group Study AALL0232. Presented at: 2011 ASCO Annual Meeting. Abstract 3.
3. 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;32(9):905-911.
4. Rosemann A, Afify M, Panse J, et al. L-carnitine ameliorates L-asparaginase-induced acute liver toxicity in steatotic rat livers. Chemotherapy. 2013;59(3):167-175.
5. Roberts KG, Li Y, Paine-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005-1015.
6. Topp MS, Goekbuget N, Selwyn Stein A, et al. Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). Presented at: 2014 ASCO Annual Meeting. Abstract 7005.
7. Park JH, Riviere I, Wang X, et al. 382 CD19-Targeted 19-28z CAR Modified Autologous T Cells Induce High Rates of Complete Remission and Durable Responses in Adult Patients with Relapsed, Refractory B-Cell ALL. Presented at: 2014 ASH Annual Meeting. Abstract 382.
8. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517.

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