Literature Scan
Can Biomarkers Predict Treatment Outcomes in Hodgkin Lymphoma Where PET-Adapted Strategy Fails ?
For patients with Hodgkin lymphoma , early or interim fluorodeoxyglucose ( FDG )– PET scanning after two cycles of chemotherapy ( PET-2 ) has been shown to be an effective predictor of treatment response – and a marker of when treatment can safely be escalated or de-escalated . According to a study published in The Lancet Haematology , adding biomarker information to the PET-2 scan prognostic model could improve the predictive value of PET scanning and identify patients who may have treatment failure even with a PET-2 negative scan .
Claudio Agostinelli , MD , from the Bologna University School of Medicine in Italy , and authors found that , even though “ no other factor was better than a positive PET-2 scan in predicting treatment failure , the association of biomarkers with PET-2 increased the negative predictive value of PET-2 alone .”
The study included a training set of 208 patients with Hodgkin lymphoma treated with ABVD
( doxorubicin , bleomycin , vinblastine , and dacarbazine ) chemotherapy in whom factors predictive of treatment outcome were assessed ; the results in this cohort were then validated in a fully matched independent cohort of 102 patients with Hodgkin lymphoma ( validation set ).
For both sets , inclusion criteria were :
• the availability of a representative tissue sample collected at diagnosis
• treatment with ABVD with or without radiotherapy
• baseline staging and interim restaging after two ABVD courses with FDG – PET
• no treatment change based solely on interim PET result
• HIV-negative status
TABLE 2 . Results of Multivariate Analysis for Progression- Free and Overall Survival
N |
Hazard ratio ( 95 % CI ) |
p Value |
Progression-free survival |
Ann Arbour Stage |
I |
4 |
|
|
II |
70 |
1.0 |
0.01 |
III |
31 |
2 · 1 ( 1 · 7 – 2 · 5 ) |
0.01 |
IV |
24 |
3 · 6 ( 3 · 2 – 3 · 9 ) |
0.01 |
Low FOXP3 expression (< 55 / HPF ) |
35 |
|
|
High FOXP3 expression ( ≥55 / HPF ) |
94 |
0 · 3 ( 0 · 1 – 0 · 7 ) |
0.005 |
Low p53 expression (< 25 %) |
113 |
1.0 |
|
High p53 expression ( ≥25 %) |
16 |
2 · 6 ( 1 · 0 – 6 · 6 ) |
0.04 |
PET-2 negative |
108 |
1.0 |
|
PET-2 positive |
21 |
33 · 3 ( 13 · 6 – 83 · 3 ) |
< 0.0001 |
Symptoms *
129
··†
0.63
|
White blood cell count
129
··†
0.68
|
International Prognostic Score
129
··†
0.52
|
BCL2
129
··†
0.23
|
PD1
129
··†
0.27
|
Overall survival |
PET-2 negative |
108 |
1.0 |
|
PET-2 positive |
21 |
31 · 3 ( 3 · 7 – 58 · 9 ) |
0 · 002 |
Symptoms B *
129
··†
0.99
|
White blood cell count
129
··†
0.58
|
BCL2
129
··†
0.23
|
FOXP3
129
··†
0.070
|
HPF = high power field |
* Symptoms were presence of night sweats , unexplained fever of > 38 ° C , and weight loss of more than 10 % of ideal |
weight during the past 6 months . |
† Variables not entered in model . |
The investigators used Cox multivariate analysis classification and regression tree to compare the predictive values of tissue biomarkers in neoplastic and microenvironmental cells with that of PET-2 , as well as to assess the biomarkers ’ ability to correctly classify patients whose outcome was incorrectly predicted by PET-2 .
The biomarkers analyzed included BCL2 and p53 expression in Hodgkin Reed Sternberg cells ( HRSCs ) and FOXP3 and PD1 expression in microenvironmental cells .
Long-term treatment outcomes were similar between the training set and the validation set . In the training set , 31 ( 15 %) of 208 patients had disease progression and 18 ( 9 %) of 208 patients relapsed . In
“The algorithm correctly predicted the response to treatment in more than half of the patients who had a relapse or disease progression despite a negative scan .”
the validation set , 19 ( 19 %) of 102 patients had disease progression and three ( 3 %) of 102 patients relapsed .
Multivariate analyses revealed that PET-2 was the only factor that maintained prognostic significance for both progression-free survival ( PFS ; hazard ratio [ HR ] = 33.3 ; 95 % CI 13.6-83.3 ) and overall survival ( OS ; HR = 31.3 ; 95 % CI 3.7-58.9 ). Disease stage , FOXP3 expression , and p53 expression had significant associations only for PFS , with a better survival with FOXP3 and a worse survival with p53 . See TABLE 2 for full results of the multivariate analysis .
In the training set , no factor was better than positive PET-2 scan for predicting treatment failure , and no factor was able to correctly reclassify patients who , despite a negative PET-2 scan , ultimately had treatment failure .
Adding biomarker information to PET scan
— CLAUDIO AGOSTINELLI , MD
results also increased the sensitivity of a prognostic model compared with using PET-2 alone ( 78 % vs . 59 %). These findings were reproduced in the validation set , the authors noted . They added that tissue biomarker assessment was feasible , cost effective , and reproducible , with most of the antibodies included in the panel routinely used in pathology labs .
“ The algorithm correctly predicted the response to treatment in more than half of the patients who had a relapse or disease progression despite a negative PET-2 scan , thus increasing the negative predictive value of PET-2 ,” Dr . Agostinelli and authors reported . “ This finding keeps with the preliminary results in interim PET response-adapted clinical trials in advanced classic Hodgkin lymphoma , pointing toward a non-negligible proportion of treatment failures in the interim PET-negative group treated with standard ABVD .”
The authors noted the study ’ s retrospective nature as a potential limitation , and wrote that the results warrant prospective validation in future studies or clinical trials , and may lead to a “ more appropriate riskadapted treatment .” Other limitations include the generalizability of results and availability and reproducibility of biomarker testing .
REFERENCE
Agostinelli C , Gallamini A , Stracqualursi L , et al . The combined role of biomarkers and interim PET scan in prediction of treatment outcome in classical Hodgkin ’ s lymphoma : a retrospective , European , multicentre cohort study . Lancet Haematol . 2016 ; 3 : e467-79 .
70 ASH Clinical News December 2016