SAN FRANCISCO – “The best opportunity to improve acute lymphoblastic leukemia (ALL) outcomes is to make the best evidence-based choices early at the time of diagnosis or early at the time of relapse. This is a disease where early choices are irrevocable, and if you make the wrong choices, patients suffer,” Dr. Joseph C. Alvarnas asserted at the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
Hematologists must also stay up on novel agents being added to the ALL treatment armamentarium, he stressed. “The state of the art is one that evolves over the course of months, not over the course of years. So maintaining current [knowledge] in this is essential. And many of these patients benefit from being referred quickly to an expert institution,” he said.
Susan London/Frontline Medical News
Dr. Joseph C. Alvarnas
Cytogenetics and genomics help risk-adapt therapy
“Cytogenetic, molecular, and genomic data are essential to making great early choices,” maintained Dr. Alvarnas, who is an associate clinical professor in the department of hematology & hematopoietic cell transplantation, and director of Value Based Analytics, at the City of Hope Comprehensive Cancer Center in Duarte, California.
Patients with Philadelphia chromosome (Ph)-positive ALL should receive tyrosine kinase inhibitors (TKIs) concomitantly with age-adapted induction and consolidation therapy, he recommended. In those with a poor response, a mutational analysis is key to guiding next steps.
“While in the young pediatric population – we are talking ages 5-10 years – there is a trend away from offering transplant to patients with Ph-positive disease because some of them are actually cured through the combination of induction pediatric regimens followed by TKI-based therapy, for adults, the standard of care until demonstrated otherwise is prompt referral for transplant,” he said.
Indeed, long-term survival is nearly doubled for Ph-positive patients if they have a transplant in a first complete remission versus later (54% vs 29%) (Blood. 2008;112;903-9).
Patients with the high-risk MLL rearrangement are likely to fare poorly and should also be considered for early transplant in first complete remission, according to Dr. Alvarnas.
A novel genetic subtype of ALL identified by looking at networks of genes – Ph-like ALL – has a poor prognosis, especially when affected patients are young adults as compared with children or adolescents (N Engl J Med. 2014;371:1005-15). Analyses have identified the presence of a cluster of genetic abnormalities involving ABL, JAK2, and RAS, among others.
“If you think strategically about how we might be able to better treat these patients … targeted agents like ruxolitinib (Jakafi), dasatinib (Sprycel), and crizotinib (Xalkori) may all play a role,” he said. “Now this is not ready for prime time yet – I’m not ready to advocate that you begin treating patients with targeted therapies. I think in fact this patient population should be referred to an academic cancer center for treatment on protocol. But as we look at what’s likely to change over the next year to 5 years, genomic alterations may make these patients better candidates for treatment with TKIs.”
Demographics can guide treatment choices as well
Patient demographics, especially age, should also be used to risk-adapt ALL therapy, according to Dr. Alvarnas. The adolescent and young adult (AYA) subset of patients – aged 15-39 – tend to be fitter and can therefore benefit from pediatric or pediatric-inspired regimens.
“These regimens don’t use novel therapeutics, for the most part; they increase the dose density or dose intensity of existing agents, particularly L-asparaginase. And a lot of adult doctors used to treating older patients don’t like L-asparaginase because of the significant morbidities, particularly pancreatitis, that can arise with this agent,” he said. “But when you get a younger, fitter group of patients, you can use very intensive doses of L-asparaginase not only with impunity, but with greater cure rates.”
AYA patients have superior event-free and overall survival when treated with a pediatric or pediatric-inspired regimen than when treated with an adult regimen (Blood. 2008;112:1646-54).
“So think of it this way: patients 15-39 years of age are receiving inferior therapy if they are receiving adult regimens,” Dr. Alvarnas said. “Now the caveat there is they have to be … physiologically fit, and there may be specific contraindications to these pediatric regimens. But this should be an opt out, not an opt in. The pediatric-inspired regimens are, I would say, the standard care for this population.”
At the other end of the age spectrum, patients 65 years and older with ALL have poorer outcomes, which may be due to both biology of disease and physiology. “We need to be very mindful and think carefully of how best to treat these patients in a patient-centric fashion,” he said.