ASH Clinical News Advances in Hematology Research & Patient Care: Hi | Page 22

CLINICAL NEWS
controls (all with standard-risk ALL), then tested the findings for
replication in 817 children with high-risk ALL.
Within the discovery cohort, the top-ranked variants associated
with osteonecrosis were rs76599360 and rs77556622 (p=1.13x10-9;
odds ratio [OR]=22.0; 95% CI 8.15-59.6). These variants were located
near bone morphogenic protein 7 (BMP7).
The top replicated non-synonymous SNP, rs34144324, was in a
glutamate receptor gene (GRID2): p=8.65x10-6 (OR=3.46; 95% CI
2.00-5.98) and p=0.0136 (OR=10.8; 95% CI 1.63-71.4) in the discovery and replication cohorts, respectively. “Genotyping of this variant
was verified in the whole-exome sequencing data,” the authors noted,
with the GWAS results further supported by pathway and enhancer
enrichment analyses.
Glutamate receptor signaling was the top enriched pathway
(p=9.91x10-4) with six genes present; the adipogenesis pathway was
the only other non-overlapping pathway (p=0.02), with seven genes
present (including BMP7).

“Variants in genes important to bone and fat differentiation from
mesenchymal stem cells were associated with osteonecrosis in children
younger than 10 years old,” Dr. Karol and colleagues concluded,
suggesting that the balance of bone and fat may be important in these
patients and affect osteonecrosis through an effect on cholesterol levels.
“Recent pediatric ALL trials have been amended to decrease
osteonecrosis,” Dr. Karol noted, “precluding us from using more
intensive regimens involving steroids and asparaginase — drugs that
have acute toxicities but have fewer long-term side effects than many
of our other alternatives.” The results of the current study increase the
understanding of the development of osteonecrosis, which may lead
to better treatments in the future, he added.
Reference
Karol SE, Yang W, Mattano LA, et al. Genetic risk factors for the development of
osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia.
Abstract #250. Presented at the 2015 ASH Annual Meeting, December 6, 2015;
Orlando, Florida.

RESONATE-2: Ibrutinib Safe, Effective in Older Patients with
CLL/SLL
Chlorambucil is considered a standard therapy for older patients with chronic lymphocytic leukemia (CLL) but, according to results from the RESONATE-2 trial presented at the
2015 ASH Annual Meeting, ibrutinib could take over as standard, first-line treatment in older patients with this disease.
The recent randomized, open-label, phase III trial evaluated
the safety and efficacy of single-agent ibrutinib compared
with chlorambucil in treatment-naïve patients age ≥65 years
who had CLL and/or small lymphocytic lymphoma (SLL).
“This is one of the first steps toward a chemotherapy-free regimen,”
Alessandra Tedeschi, MD, of the Azienda Ospedale Niguarda Cà
Granda in Milan, Italy, who presented the results, told ASH Clinical
News. “A chemotherapy-free approach would be important for all
patients, but particularly elderly patients who have many comorbidities.
Immunochemotherapy may be too toxic for this population, so it would
be important for these patients to receive a chemotherapy-free approach
as first-line treatment.”
Ibrutinib is currently approved by the U.S. FDA for use in patients
with CLL who have received one or more prior therapies and for those
with the deletion of the 17p13 chromosomal region (del17p) mutation.
A total of 269 patients were randomized 1:1 to receive:
• Ibrutinib 420 mg daily until progression
• Chlorambucil 0.5 mg/kg (up to maximum 0.8 mg/kg) on days 1
and 15 of a 28-day cycle for up to 12 cycles
Patients with del17p were excluded from the study.
Median patient age was 73 years, with 70 percent of patients
≥70 years old. Progression-free survival was the study’s primary
endpoint; secondary endpoints included overall survival (OS),
overall response rate (ORR), event-free survival, rate of hematologic
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2015 ASH Annual Meeting

improvement, and safety.
The median duration of treatment was 17.4 months with ibrutinib compared with 7.1 months with chlorambucil.
After a median follow-up of 18.4 months, the investigators
found that ibrutinib significantly prolonged PFS compared with
chlorambucil (median = not reached vs. 18.9 months; hazard ratio
[HR] = 0.16; 95% CI 0.09-0.28; p<0.0001). Treatment with ibrutinib
almost doubled the rate of PFS at 18 months (93.9% vs. 44.8%), and
reduced the risk of disease progression or death by 91 percent compared with chlorambucil (HR=0.09; 95% CI 0.03-0.17; p<0.0001).
Similarly, the ORR rate among patients receiving ibrutinib was
substantially higher than among those receiving chlorambucil (86%
versus 35.3%).
Ibrutinib significantly prolonged OS compared with chlorambucil (median = not reached for either arm; HR=0.16; 95% CI
0.05-0.56), and more patients receiving ibrutinib were alive two
years after starting therapy compared with the chlorambucil cohort
(97.8% vs. 85.3%, respectively).
“We didn’t achieve a very high rate of complete remission,
even though PFS was so high,” Dr. Tedeschi said, “suggesti