Allogeneic Stem-Cell Transplantation for Relapsed/Refractory ALK-Positive Anaplastic Large-Cell Lymphoma: A Study from the Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire (SFGM-TC)
Authors: Grange Thomas , Jais Jean-Philippe , Sicre de Fontbrune Flore , Castilla-Llorente Cristina , Marçais Ambroise , Ghesquieres Herve , Devillier Raynier , Yakoub-Agha Ibrahim , Bilger Karin , Gros François-Xavier , Maillard Natacha , Huynh Anne , Méar Jean-Baptiste , Rubio Marie-Thérèse , Maertens Johan , Chevallier Patrice , Rialland Battisti Fanny , François Sylvie , Bulabois Claude-Éric , Villate Alban , Loschi Michael , Renard Cécile , Charbonnier Amandine , Bruno Bénédicte , Bay Jacques-Olivier , Devalck Christine , Cornillon Jérome , Poiré Xavier , Sterin Arthur , Gabellier Ludovic , Raus Nicole , Nguyen-Quoc Stéphanie , Rigaud Charlotte , Sibon David 
Published: December 2024

Introduction: Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) is a rare T-cell lymphoma that generally occurs in children and young adults. The disease is characterized by the presence of a translocation involving ALK on chromosome 2p23. In relapsed/refractory (R/R) ALK+ ALCL, a salvage treatment based on brentuximab vedotin or an ALK inhibitor is usually proposed, followed by allogeneic stem-cell transplantation (alloSCT) in eligible patients (pts) (Pro B, Blood 2017; Veleanu L, N Engl J Med 2024). However, data on alloSCT in this setting are scarce. To gain insight of alloSCT in R/R ALK+ ALCL, we conducted a registry study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Methods: This study included all pts who underwent an alloSCT for R/R ALK+ ALCL between January 2009 and December 2022 in France and Belgium. Pts who received two alloSCT were not included. Data were extracted from the SFGM-TC registry and centers were contacted for additional data and to update the follow-up. All pts or their legal representatives provided signed consent for inclusion in the registry and the collection and use of anonymized medical data. The endpoints examined were overall survival (OS), progression-free survival (PFS), graft versus host disease (GVHD)-free, relapse-free survival (GRFS), and cumulative incidence of relapse (CIR).

Results: 53 pts were included in the study. At the time of alloSCT, the median age was 29 years (range 3-61 years; 10 pts &lt; 20 years) and 64% of pts were male. The median number of prior treatment lines was 2 (range 1-4), 13 (25%) pts had previously failed autoSCT, and 18 (34%) pts had received an ALK inhibitor as a bridge to alloSCT. Before alloSCT, 79% of pts were in complete response (CR), 13% in partial response (PR) and 6% had a progressive disease (PD). Pre-alloSCT Karnofsky performance status (KPS) was 90-100 in 75% of pts and 80 in 25%. Conditioning regimen was myeloablative (MAC) in 26 (49%) pts (including total body irradiation in 15 pts). AlloSCT was performed from matched sibling donors (MSD) in 36% of the cases, matched unrelated donors 10/10 (MUD) in 34%, haploidentical donors (HD) in 13%, cord blood (CB) in 11% and mismatched unrelated donor in 6%. The stem cell source was peripheral blood (PB) in 70%, bone marrow (BM) in 19% and CB in 11% of the cases.

After a median follow-up of 5 years, 5-year OS, PFS and GRFS were 85%, 67% and 53%, respectively. Taking into account the competing risk of death, 5-year CIR, 5-year cumulative incidence of acute GVHD (aGVHD) and 5-year cumulative incidence of chronic GVHD (cGVHD) were 26%, 53% (grade &gt;2 in 13%) and 42% (extensive in 19%), respectively. Eight pts died after alloSCT, including 3 in the absence of lymphoma progression.

In multivariate analysis for OS, only aGVHD &gt; grade 2 and KPS &lt; 90 had a significant negative impact (p&lt;0.05 for both factors). The use of a MAC regimen was the main risk factor for aGVHD &gt; grade 2 (p=0.04). Stem cell source was the only factor significantly affecting PFS (improved PFS with PB vs BM, p=0.01). Regarding OS, PFS and CIR, there was no significant difference between CR and PR before alloSCT; between MAC and non-MAC regimens; and between MSD, MUD and HD. Of note, there was no independent impact of age (&lt; 20 years vs &gt;= 20 years) on OS, PFS or CIR.

To assess the influence of changes in alloSCT practice over time, patients were divided into two groups of equal size: alloSCT before (n=27) and after (n=26) September 1, 2017. The comparison of endpoints before vs after this date was as follows: 5-year OS 74% vs 100% (p=0.013), 5-year PFS 48% vs 92% (p=0.003) and 5-year CIR 41% vs 8% (p=0.012). The main differences in group characteristics were that pts transplanted after September 1, 2017 were all responders at the time of alloSCT (CR or PR, p=0.028) and tended to have received more often ALK inhibitors as a bridge to alloSCT (p=0.1).

Conclusion: This study, one of the largest assessing alloSCT in R/R ALK+ ALCL, showed overall good results, especially in recent years, with a potential cure in most patients. Selection of patients (responders with good KPS), appropriate conditioning regimen (no benefit of MAC over non-MAC regimens, and more aGVHD &gt; grade 2 with MAC) and stem cell source (PB rather than BM) should further improve alloSCT results in R/R ALK+ ALCL.