Page 179 - Haematologica Vol. 109 - July 2024

ARTICLE - ASCT in refractory or early relapsed DLBCL
A.M. Tun et al.
after frontline therapy, compared to those with refractory or relapse within 6 months, did not have a statistically significant improvement in PFS after ASCT (P=0.47), al- though PFS was numerically better in the former (median PFS 29.6 vs. 10.1 months). Additionally, there was a trend for improvement in OS in the univariate analysis (P=0.07), and a statistically significant improvement in OS, after adjustment for age at ASCT and sex, in the multivariate model (P=0.04). Therefore, after establishing the chemo- sensitivity of the disease, careful consideration between HDT followed by ASCT and CAR-T is warranted in such patients due to their favorable survival rate after ASCT (24-month PFS, 52%), although the findings from our study population, receiving care at the Mayo Clinic and the University of Iowa, may not be broadly generalizable. There remain logistical and financial barriers that prevent timely access to CAR-T therapy.30 Patients often need to wait weeks to months for frailty and fitness assessments, overcoming logistical and financial barriers, as well as CAR-T manufacturing (although a significantly shorter wait time is anticipated with the use of allogeneic CAR-T products).16,30,31 Moreover, patients with relapsed or progres- sive disease are often symptomatic requiring immediate intervention. Thus, it is reasonable to initiate ST, espe- cially in resource-limited settings. Those who achieve PR can consider proceeding with ASCT based on reasonable survival outcomes, and this practice is supported by the report from the CIBMTR favoring ASCT consolidation, as discussed earlier.12,28 For those achieving CR, ASCT consolidation seems favored over CAR-T in patients with early treatment failure, as per the recent study from the CIBMTR that reported a lower 2-year relapse rate (22.8% vs. 45.9%; P<0.001) and a superior 2-year PFS rate (70.9% vs. 48.3%; P<0.001), although it is difficult to draw defin- itive conclusions due to its retrospective study design.32 Similar survival outcomes were reported for patients who received CAR-T therapy while in CR, with a 2-year PFS rate of 44% in the MD Anderson Cancer Center cohort and a 1-year PFS rate of 59.6% in a study from eight academic centers in the USA.33,34 Notably, patients relapsing or pro- gressing after CAR-T therapy have unfavorable outcomes due to the limited availability and efficacy of subsequent ST.19 After CAR-T therapy, cytopenias and patients’ intoler- ance of intensified therapy and the potential of stem cell mobilization failure make ASCT less feasible.19,35 Although ASCT consolidation is generally favored in patients with established chemosensitive disease, post-ASCT outcomes of those with a MYC rearrangement are poor, despite them having chemosensitive disease, with a median PFS of only 3.1 months; CAR-T therapy may be preferred in such patients.36,37
It is, however, worth noting that only about half of patients with relapsed or refractory DLBCL treated with intensified therapy are able to proceed with ASCT consolidation, al- though higher response rates can be expected with the
incorporation of novel therapeutic agents.7,13,15,17,29,38,39 In the CORAL study, ~63% of patients achieved CR or PR to ST, namely RICE (rituximab, ifosfamide, carboplatin, and etoposide) and R-DHAP (rituximab, dexamethasone, high- dose cytarabine, and cisplatin), and ~53% of patients sub- sequently proceeded with ASCT. In NCIC-CTG LY.12, ~45% of patients had responses to the ST regimens GDP (gem- citabine, dexamethasone, and cisplatin) and DHAP.7,29 The real-world analysis of the Molecular Epidemiology Resource database found that 40% of patients treated aggressively with second-line ST for relapsed or refractory DLBCL were able to proceed with ASCT.13 In participants of the ZUMA-7 and TRANSFORM trials, who were then randomized to the ST group, ASCT consolidation was done in 38% and 46% of patients, respectively.15,17 However, response to ST can be improved with the incorporation of novel therapy; notably, polatuzumab vedotin added to RICE produced an overall response rate (i.e., CR or PR) of 92%, with an acceptable toxicity profile, in a multicenter phase II study.39 Response rates could also improve with incorporation of bispecif- ic CD20xCD3 monoclonal antibodies to ST,40,41 and these strategies are being evaluated by currently ongoing clinical studies such as those investigating glofitamab plus RICE (NCT05364424) and epcoritamab plus GDP (NCT05852717). The strengths of our study include systematic review of a large number of patients with relapsed or refractory DL- BCL following failure of frontline R-CHOP or R-CHOP-like immunochemotherapy who then underwent ASCT after the first, early relapse or in a refractory state, with the availability of long-term follow-up data. However, our study has limitations due to its retrospective study design with potential selection bias, geographical bias with limited generalizability, and lack of centralized histopathology review, as well as some missing information and a long study period that spans over two decades with potential heterogeneity in management approaches.
In conclusion, survival outcomes after ASCT are favorable in at least a subset of patients with primary refractory or early relapsed DLBCL. Post-ASCT survival outcomes are more favorable in patients who require only one line of ST and those who achieved CR to ST. Furthermore, survival outcomes after ASCT are excellent in patients achieving CR after one line of ST. In patients who relapse between 6 to 12 months after completing frontline therapy, the choice between CAR-T therapy and ST followed by HDT and ASCT should be considered carefully. These data support the role of ST and ASCT consolidation as a second-line treatment strategy in select patients with primary refractory or early relapsed DLBCL in an appropriate clinical context.
Disclosures
No conflicts of interest to disclose.
Contributions
AMT, YW, and PBJ conceived and designed the study and
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