Treatment outcomes of patients with B-cell acute lymphocytic leukemia (B-ALL) vary according to age, with adult patients experiencing a poorer prognosis than pediatric patients. In a report published in Blood, Nitin Jain, MD, from the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, and authors examined the incidence and clinical and genomic features of Philadelphia (Ph)-like ALL – a subtype of ALL for which there are limited and conflicting data – to determine which factors might predispose older patients to worse outcomes.
“The inferior outcome of older patients has been linked to several factors, both disease-related and patient-related,” Dr. Jain and authors wrote, meaning “genomic characterization of Ph-like ALL has significant therapeutic implications with the emerging use of kinase inhibitors in this patient population.”
This analysis included 148 patients (median age = 38 years; range = 15-84 years) with newly diagnosed B-ALL who underwent genomic testing as part of a larger multicenter study defining the genomics of Ph-like ALL. All patients received induction chemotherapy at the MD Anderson Cancer Center, either with hyper-CVAD–based regimen (consisting of cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine; n=124) or with an augmented Berlin-Frankfurt-Münster regimen (consisting of vincristine, prednisone, L-asparaginase, daunorubicin, cytarabine, and methotrexate; administered to patients <40 years of age; n=24).
Patients were categorized as:
- Ph-like ALL (n=49; 33.1%)
- Ph-positive (Ph+) ALL (n=46; 31.1%)
- B-other (not Ph-like, not Ph+) ALL (n=53; 35.8%)
Patients with Ph-like ALL were younger (median age = 33.5 years), compared with patients with B-other and Ph+ ALL (median age = 38 years [p=0.23] and 49 years [p=0.001], respectively). The incidence of Ph-like ALL was highest in the youngest group of patients (<40 years; 42%), compared with 24 percent in those ≥40 years old (p=0.02). Among these older patients, the incidence of Ph-like ALL was comparable in those 40 to 59 years old and those ≥60 years old (22% vs. 26%, respectively).
There also were significantly more men in the Ph-like ALL group (66% in Ph-like vs. 48% Ph+ vs. 36% B-other ALL; p=0.006). “Sixty-eight percent of the patients with Ph-like ALL were of Hispanic ethnicity,” the authors noted, which was significantly higher than the other disease groups (35% in Ph+ ALL and 30% in B-other ALL; p<0.001).
Response rates were similar among all three disease subgroups, with at least 89 percent of patients experiencing complete remission (CR) or CR with incomplete platelet recovery (TABLE). While patients with Ph-like ALL were significantly less likely to achieve minimal residual disease (MRD)-negative remission, as assessed by flow cytometry, MRD-negative status at the time of morphologic remission was not associated with inferior long-term outcomes for these patients (median overall survival [OS] = 26.2 months vs. 23.0 months for MRD-positive patients; p=0.318).
Overall, patients with Ph-like ALL had significantly worse OS, event-free survival (EFS), and remission duration, compared with the other disease subgroups. “The five-year survival for Ph-like ALL was markedly inferior to B-other ALL (23% vs. 59%, respectively; p=0.006),” the researchers wrote. “This was despite the fact that the patients with Ph-like ALL were younger, compared with those in the B-other group.”
The presence of the CRLF2 mutation – the most common mutation in this patient population (appearing in 61% of patients with Ph-like ALL) – was associated with worse outcome, including inferior OS, EFS, and remission duration. “Five-year survival in the CRLF2+ group was <20 percent,” Dr. Jain and researchers wrote. Also, the authors observed that a “striking” majority of patients in the CRLF2+ group were Hispanic (78%).
All of the patients with a CRLF2+ mutation (n=30) had an IKZF1 aberration, and 14 patients (44%) had a JAK2 mutation. Though the presence of the IKZF1 mutation did not influence OS, patients with a JAK2 mutation had a worse median OS (18.8 months vs. 26.9 months for patients with wild-type JAK2; p=0.012).
Dr. Jain and authors also identified the following variables as significant predictors of poorer survival: age >60 years (hazard ratio [HR] = 3.3; p<0.001); white blood cell count (HR=1.9; p=0.017); platelet count (HR=7.4; p=0.005); and Ph-like ALL (HR=1.8, p=0.03).
“Since the majority of patients with Ph-like ALL received hyper-CVAD–based treatment (an intensive regimen), we believe further intensification of chemotherapy treatment is unlikely to benefit adult patients with Ph-like ALL,” Dr. Jain and authors concluded. “It remains to be determined if [the] addition of novel monoclonal antibodies (such as inotuzumab ozogamicin) or bispecific antibodies (such as blinatumomab) could improve the outcomes of this group of patients.”
The study is limited by its small patient population and single-center design. Also, though the authors did not find any evidence that the treatment regimen affected patient outcome, they noted that the study was not powered to address this question.
Jain N, Roberts KG, Jabbour E, et al. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood. 2016 December 5. [Epub ahead of print]
|TABLE. Responses in Ph-Like ALL, Ph+ ALL, and B-Other ALL|
|p Value (all groups)||p Value (Ph-Like vs. B-Other ALL)|
|MRD assessed at CR (n=98)|
|Ph = Philadelphia; ALL = acute lymphocytic leukemia; CR = complete remission; CRi = complete remission with incomplete platelet recovery; MRD = minimal-residual disease; N/A = not applicable|