ALK-positive anaplastic large-cell lymphoma in adults: an individual patient data pooled analysis of 263 patients

Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) comprises 0.5% of adult lymphomas. In many prior retrospective adult series, despite clear differences in outcome, ALK-positive ALCL has been pooled with ALK-negative ALCL, impairing the exploration of prognostic factors and impact of different treatments for ALK-positive ALCL. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/CHOP-like regimen remains the standard treatment of ALK-positive ALCL, with a 5-year overall survival (OS) rate of 70-90%. Most patients are young (median age 35 years) with some studies suggesting this is the predominant reason outcomes are generally more favorable than in ALK-negative ALCL. A retrospective study from the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) and a population-based study from the Danish and Swedish lymphoma registries suggested a possible benefit from the integration of etoposide in the front-line therapy, but definitive conclusions are lacking, and the role of etoposide is still a matter of debate. Herein, we conducted a pooled analysis of individual patient data (IPD) from six studies of first-line therapy in adult ALK-positive ALCL to identify the key prognostic factors and treatment impact. IPD were collected and pooled from six previously published studies: two from the Lymphoma Study Association (LYSA), one from the DSHNHL, one from Japan, one from the International Peripheral T-Cell Lymphoma Project (IPTCLP), and one from the Mayo Clinic. Patients recruited to the six studies met criteria for diagnosis of ALK-positive ALCL by the REAL (The Revised European American Lymphoma Classification)/World Health Organization classification with a centralized pathologic review. Eligibility criteria and statistical analyses are available in the Online Supplementary Methods. In total, there were 263 patients diagnosed between 1985 and 2008, 136 (52%) of which had been enrolled in clinical trials (Online Supplementary Table S1). Given the small number of patients included from one of the LYSA studies (n=10) and from the Mayo Clinic (n=9), the six studies were subsequently grouped in four cohorts (LYSA [two studies]), DSHNHL, Japan and [IPTCLP+Mayo Clinic]). Table 1 lists the main clinical, biologic and immunohistochemical characteristics. The median followup was 4.9 years (range, 0.1 to 20.4 years). The treatment details are available in the Online Supplementary Table S2. For the 255 patients evaluable for a response at the end of treatment, the reported CR/CRu, PR and SD/PD (complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), or progressive disease (PD)) rates to the first-line therapy were 85%, 5% and 10%, respectively. For all 263 patients, the 5-year progression-free survival (PFS) and OS rates were 69% (95% CI, 64% to 75%) and 81% (95% CI, 76% to 86%), respectively (Online Supplementary Figure S1). Importantly, the PFS was not significantly different between cohorts (5-year PFS from 60% to 76%, P=0.110). For patients >60 years (n=31, 11.8%), compared to those ≤60 years (n=232, 88.2%), 5-year PFS (55% vs. 71%, P<0.01, hazard ratio (HR) 2.077) and OS (64% vs. 83%, P<0.001, HR 3.041) rates were inferior (Figure 1 A-B) (Online Supplementary Table S3). All individual international prognostic index (IPI) factors significantly affected the PFS and OS rates, with the number of extranodal sites >1 conferring the highest risk and with no significant heterogeneity between cohorts (Online Supplementary Figure S2). In a multivariate analysis, only the number of extranodal sites >1 and age >60 years impacted the PFS and OS rates (Online Supplementary Table S4), and finally, the IPI score had a better predictive value for the OS than the prognostic index for peripheral T-cell lymphoma, not oth-