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PAPER SPOTLIGHT

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 %).

TABLE . Responses in Ph-Like ALL , Ph + ALL , and B-Other ALL

Ph-Like ALL ( n = 49 )

Ph + ALL ( n = 46 )

B-ALL Categories

B-Other ALL ( n = 53 ) p value ( all groups ) p value ( Ph-Like vs . B-Other ALL )

CR / CRi 89 % 93 % 94 % 0.57 0.34

Ph = Philadelphia ; ALL = acute lymphocytic leukemia ; CR = complete remission ; CRi = complete remission with incomplete platelet recovery ; MRD = minimal-residual disease ; N / A = not applicable

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 wildtype 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 .

REFERENCE

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 ]

14 ASH Clinical News January 2017 Annual Meeting Edition