Allogeneic hematopoietic stem cell transplantation for poor-risk CLL: dissecting immune-modulating strategies for disease eradication and treatment of relapse

Abstract

To elucidate factors contributing to the effectiveness of allogeneic hematopoietic stem cell transplantation (alloHCT) in high-risk CLL, immune interventions, GvHD and clinical outcome of 77 consecutive patients allografted for CLL were analyzed. Immune modulation (immunosuppression tapering, rituximab-augmented donor lymphocyte infusions) was guided by minimal residual disease (MRD) monitoring and commenced at a median of 91 (22-273) days after alloHCT, resulting in a probability of being event free and MRD-negative 1 year after transplant of 57% (84% in those encountering chronic GvHD). Patients who were event free and MRD-negative at the 12-month landmark had a 4-year PFS of 77% and largely remained durably MRD-negative if MRD clearance had occurred subsequent to immune modulation. Three-year overall survival, PFS, relapse incidence and non-relapse mortality of all 77 patients were 69, 57, 26 and 24%, respectively. Survival was not affected by EBMT risk category but by active disease at alloHCT, which could not be overcome by intensification of conditioning. Twenty-three patients who experienced relapse post alloHCT had a survival of 56% at 2 years after CLL recurrence. In conclusion, MRD-guided immune modulation after alloHCT for high-risk CLL can provide durable MRD clearance in more than half of the patients.

The addition of ofatumumab to the conditioning regimen does not improve the outcome of patients with high-risk CLL undergoing reduced intensity allogeneic haematopoietic cell transplantation: a pilot trial from the GETH and GELLC (CLL4 trial)

“…This NRM doubles what has been recently reported in similar studies of high-risk patients undergoing alloHCT, 5,[10][11][12] approaching what is usually accomplished with myeloablative regimens. 10,11,13 Indeed, both the PFS and the OS curves resemble those obtained with myeloablative regimens, with a very significant early attrition rate followed by a plateau. It is also worth mentioning that the severe toxicity observed in our study was not due to infusional reactions or mucositis, which were infrequent and mild, but to high infection and GvHD rates.…”

Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation

“…A few treatment options for salvage therapy after alloSCT have shown moderate efficacy, including monoclonal anti-CD20 antibodies, donor lymphocyte infusions, lenalidomide and standard chemotherapy. [16][17][18][19][20] Here, we report on the use of ibrutinib as treatment for relapsed CLL patients following alloSCT. In three out of five of our patients, ibrutinib was started after multiple lines of other treatment regimens following post-alloSCT relapse had failed.…”

Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial

“…12 As shown in the original publication and also in other studies, GVL activity is strongly associated with chronic GVHD in CLL. 7,10 Accordingly, the 2-year chronic GVHD incidence of 73% 7 observed in this trial was unevenly distributed between patients with and without a relapse event. If all patients with at least 1 prior chronic GVHD episode had been excluded, only 5 patients would have arrived event-free at the 6-year landmark, translating in to a 6-year GVHD-and relapse-free survival among all 90 patients of 8% (95% CI, 2% to 14%).…”

“…9 Indeed, coexistence of semiallogeneic cells in the same individual is already a well-recognized natural phenomenon (microchimerism) resulting from bidirectional maternal-fetal exchange during pregnancy with persistence in respective individuals decades later. 10 Naturally acquired microchimerism is found in healthy individuals, in organs and circulation, without apparent graft-versus-host reaction or graft rejection and has been associated with both health benefits and risks, pointing to functional capacity. 10,11 We hypothesized that a similar phenomenon also occurs after dCBT more commonly than would be suggested by estimates of mixedunit chimerism by standard clinical measures, with "occult" presence of cells derived from the losing unit in the clinical setting of complete single CB unit dominance after dCBT.…”

“…This observation is in keeping with a previous single-center study reporting long-term MRD-negative disease control in those patients who experienced immune-mediated MRD disappearance. 10 The 32 patients who were alive and event-free 6 years after allo-HCT did not differ from the whole trial population in terms of age, …”