Long-Term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Chronic Lymphocytic Leukemia (CLL): 10-Year Follow-up of the Gcllsg CLL3X Trial

Abstract

PURPOSE of this analysis was to provide 10-year follow-up of the GCLLSG CLL3X trial which aimed at evaluating reduced-intensity conditioning (RIC) HSCT in patients with poor-risk CLL. DESIGN: The CLL3X trial included 100 patients (median age 53 (27-65) years), of whom 90 patients were allografted with blood stem cells from related (40%) or unrelated donors (60%) using fludarabine-alkylator-based RIC regimens. 24% had refractory CLL at HSCT, and 37% had a TP53 deletion and/or mutation. The 6-year follow-up of the trial including the observation that genetic risk factors such as TP53 lesions and SF3B1 and NOTCH1 mutations had no prognostic impact has been previously reported (Blood 2013;119:4851). Survival and relapse information was requested for all patients who underwent HSCT within the CLL3X trial in 9 German centres (the Canadian centre was unavailable for follow-up) and were alive at the 6-year follow-up. RESULTS: Follow-up information was received for 33/44 patients (75%) alive at the 6-year follow-up. Of these, 2 patients had experienced non-relapse mortality (NRM; 1 chronic GVHD, 1 secondary cancer) and another 2 had CLL recurrence 9.3 and 9.7 years post HSCT, respectively. With a median follow-up of survivors of 9.3 (0.6-15.5) years, 10-year NRM, relapse incidence (REL) event-free survival (EFS), and overall survival (OS) of all 90 patients allografted was 26%, 57%, 32%, and 51%, respectively. Absence of minimal residual disease (MRD) at the 12-month landmark post HSCT was highly predictive for an increased relapse risk (10-year REL 25% vs 80% if MRD was present at the 12-month landmark, p <0.0001), in particular if MRD eradication occurred only after immunosuppression withdrawal, suggesting of effective graft-versus-leukemia activity (GVL; 10-year REL 12%). In the 33 patients who were event-free at the 6-year landmark, NRM, REL, EFS, and OS 4 years after the 6-year landmark was 4%, 24%, 74%, and 93% (median follow-up after 6-year landmark 4.1 (0.1-8.5) years) without any effect of TP53 lesions on relapse risk. Notably, no relapse event occurred beyond 10 years post HSCT. Only one out of 33 patients included in the 6-year landmark analysis died from CLL, 4 relapsed patients are currently responding to pathway inhibitors, and the remaining patient with CLL recurrence still does not need treatment. CONCLUSIONS: Long-term observation of patients allografted in the CLL3X trial confirms that RIC HSCT can provide GVL-mediated sustained disease control in a sizable proportion of patients with poor-risk CLL independent of the TP53 status. Patients who are in MRD-negative remission one year after HSCT have a 75% probability of remaining disease-free at least for 10 years. However, late relapses do occur but may benefit from strategies involving innovative pathway inhibitors. Disclosures Krämer: Gilead: Other: Travel grants; MSD: Honoraria. Stilgenbauer:AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding. Böttcher:Hoffmann-LaRoche: Honoraria, Other: Travel grants, Research Funding; Celgene: Research Funding; AbbVie: Honoraria, Research Funding. Ritgen:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hegenbart:Jansen Cilag: Honoraria, Other: financial support of conference participation. Hallek:F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Kneba:Amgen: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants, Research Funding; Glaxo-SmithKline: Other: Travel grants; Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants; Janssen-Cilag: Consultancy, Honoraria, Other: Travel grants. Dreger:Gilead: Consultancy; Novartis: Consultancy; Gilead: Speakers Bureau; Novartis: Speakers Bureau; Janssen: Consultancy; Roche: Consultancy.

Ibrutinib for bridging to allogeneic hematopoietic cell transplantation in patients with chronic lymphocytic leukemia or mantle cell lymphoma: a study by the EBMT Chronic Malignancies and Lymphoma Working Parties

“…In contrast, with 30% at 1 year the cumulative incidence of early relapse events in the CLL group of the present analysis seems to be higher than the RI known from ibrutinib-naive CLL alloHCT series [26][27][28][29]. For instance, in the prospective CLL3X trial of German CLL Study Group the 12-month RI was 16% [13], and in a recent large registry study of the EBMT it was 14% (95%CI, 13-15%) [14]. Even in the ibrutinib-sensitive patients of the present study the 24% 12-month RI appears unusually high.…”

“…As expected, GRFS was considerably lower than PFS in both CLL and MCL transplants. This may reflect the fact that chronic GVHD (which is the main driver of GRFS) is closely associated with GVL in particular in CLL [13,34]. However, it has to be taken into account that chronic GVHD is characterized by a large variance in clinical appearance and severity, and can resolve or decrease over time.…”

“…All other patients engrafted with a median time to reach neutrophils of >0.5/nl and platelets of >20/nl of 16 (9-68) and 13 (5-36) days post transplant, respectively. Time to engraftment was not significantly different between patients who had withdrawn ibrutinib within 14 days prior to transplant and those who stopped ibrutinib earlier (neutrophils > 0.5/nl 17 (9-16) days vs. 16 (10-68) days, P = 0.57; platelets > 20/nl 14 (6-36) days vs. 13 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) days, P = 0.56).…”

“…It is well acknowledged that alloHCT can provide durable disease clearance in a sizable proportion of patients These authors contributed equally: Peter Dreger, Mauricette Michallet. with both R/R high-risk CLL and R/R MCL, mediated by graft-versus-leukemia (GVL) effects [11,[13][14][15][16][17]. Little is known, however, about the feasibility of alloHCT in patients with CLL/MCL who have been bridged to transplant with ibrutinib.…”

Is There a Role for Cellular Therapy in Chronic Lymphocytic Leukemia?

“…The introduction of reduced intensity conditioning finally permitted proof that Mathe's concept of graft-versus-leukemia activity indeed is the crucial contributor to disease eradication by alloHCT in CLL 4 . This has been illustrated most convincingly by studies of minimal residual disease (MRD) kinetics, demonstrating that MRD clearance posttransplant coincides with immune interventions, such as immunosuppression tapering and donor lymphocyte infusions 5–8 …”