Background:DUSP22- and TP63-rearranged ALK- ALCL are distinct genetic subtypes with unique disease phenotypes and reported variability in overall survival. The ECHELON-2 study established BV-CHP as the standard upfront therapy in for treating systemic anaplastic large cell lymphoma (sALCL). However, disease or patient features that predicted outcomes for patients (pts) with sALCL treated with CHOP/CHOEP may not apply for BV-CHP/CHEP-treated pts. We conducted a multicenter, retrospective analysis of pts with ALK-negative sALCL treated with BV-based multiagent chemotherapy (BV-CHP/CHEP) seeking to establish outcomes achieved and determine the impact of DUSP22 and/or TP63 rearrangements in this setting.

Methods: We identified all pts with ALK-negative sALCL receiving frontline BV-based multiagent chemotherapy from 2012 to 2024 at each center. Treatment may have occurred in a clinical trial or as standard-of-care. FISH testing for gene rearrangements and IHC testing for sALCL markers was performed at each site per standard procedures. We used descriptive statistics to characterize the population and Kaplan-Meier methods to calculate PFS and overall survival (OS) from date of diagnosis. Comparisons between survival trajectories and analysis of clinical/disease features (baseline age, stage III/IV, elevated LDH, IPI score, presence of cytotoxic marker(s), TP63/DUSP22 rearrangement status, and receipt of transplant) influencing PFS and OS were performed using the log-rank test.

Results: We identified 112 pts across 8 centers in the United States and Canada. The median age at diagnosis was 59 years (range, 26-86), 38% were female, 85% ECOG 0/1, and 70 (67%) had stage III or IV disease. 93/112 pts had all baseline IPI variables documented, of which 34 (37%) were IPI 0 or 1, 46 (50%) 2 or 3, and 13 (14%) 4 or 5. DUSP22 rearrangement was present in 25/90 (28%) cases, TP63 rearrangement in 6/82 (7%), and there were 3 cases with concurrent DUSP22/TP63 rearrangement. Relevant tumor markers included CD3+ in 59%, CD4+ in 76%, CD7+ in 23%, and CD8+ in 26%. The frequency of cytotoxic IHC marker positivity was as follows: TIA-1 in 43%, granzyme B in 38%, and perforin in 50%; 76 cases had at least one of these three markers tested and 37 (49%) were positive for ≥1 marker.

The initial treatment was predominantly BV-CHP (88%), less frequently BV-CHEP (12%). Ninety-six (86%) pts received 6 cycles, and the reasons for receiving <6 cycles were interim CR response in 7 pts, unknown in 4, progressive disease in 3, and toxicity in 2. The end-of-induction response rate was 89%, including 79% CR, and 34 (33%) pts underwent consolidative transplant (autoHCT, 32; alloHCT, 2). Twenty-one pts whose disease initially responded later experienced relapse.

With a median follow-up of 29 months (range, 0.5-150) among survivors, median PFS and OS were 67 months (95% CI: 37.7-NR) and 94 (95% CI: 91.2-NR), respectively. The 2-year PFS and OS rates were 66% (56-77) and 83% (76-92), respectively. The 2-year OS did not significantly differ by DUSP22 rearrangement: 94% present (95% CI: 84-100) vs. 86% absent (95% CI: 76-97). Pts whose ALCL harbored TP63 rearrangement had inferior 1- and 2-year PFS that did not reach the threshold for statistical significance: 50% vs. 82% and 50% vs. 64%, respectively (P = 0.2). One of the 3 pts with dual DUSP22/TP63-rearranged disease remains in remission, one died following relapse and one has just completed treatment. 25 of the pts who attained end-of-treatment CR underwent autoHCT and their 1-year and 2-year PFS rates were 83% (95% CI: 70-100) and 74% (95% CI: 58-95), respectively.

Considering predictors of PFS/OS, IPI 2-3 (P = 0.02), 4-5 (P = 0.0007), and stage III/IV (P = 0.02) conferred inferior PFS. Only IPI 2-3 (P = 0.05) and 4-5 (P = 0.006) associated with inferior OS.

Conclusions: This cohort, the largest of ALK- sALCL pts treated with frontline BV-based chemotherapy reported since the original publication of ECHELON 2, confirms the high activity of BV-based multiagent chemotherapy regimens. Pts with sALCL harboring TP63 rearrangement fared worse but the outcomes appeared better than previous reports in this subpopulation. Our data suggest that DUSP22 rearrangement status may not significantly affect outcomes in BV-CHP/CHEP-treated pts. High IPI score and advanced stage were associated with inferior PFS.

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2025
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