Long-Term Study Confirms Durable Responses With Reduced-Intensity Conditioning AlloHCT in High-Risk CLL

Ten-year follow-up data from the prospective phase II CLL3X trial of the German CLL Study Group confirms that patients with high-risk chronic lymphocytic leukemia (CLL) can achieve durable responses with reduced-intensity conditioning allogeneic hematopoietic cell transplantation (alloHCT), according to a report published in Blood.

Isabel Krämer, from the Department of Medicine V at the University of Heidelberg in Germany, and co-authors also determined that much of this long-term benefit could be attributed to the graft-versus-leukemia (GVL)-mediated clearance of minimal residual disease (MRD).

“Patients who have achieved immune-induced MRD clearance one year after alloHCT have an 87 percent probability of remaining disease-free for at least 10 years,” the authors reported. “Late relapses do occur, but may benefit from strategies involving innovative pathway inhibitors.”

The researchers enrolled 100 patients (median age = 53 years; range = 27-65 years) between June 2001 and March 2007 from 16 sites, and 90 patients underwent alloHCT with stem cells from related (40%) or unrelated (60%) donors. Reduced-intensity conditioning regimens consisted of: fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 once-daily from day six to day two pre-transplant. Patients with unrelated donors also received antithymocyte globulin 10 mg/kg daily from day four to day one pre-transplant.

The CLL3X trial included adult patients (age range = 18-65 years old) with high-risk CLL (defined as refractoriness or early relapse [within 12 months] after treatment with a purine analogue-containing regimen; relapse after autologous HCT; or progressive disease in the presence of an unfavorable genetic constellation). Patients were excluded if they had Richter transformation. Twenty-four percent of patients were refractory to alloHCT, and 35 percent had a TP53 mutation.

Long-term results were available for 37 patients: five died because of complications of CLL (n=3), chronic graft-versus-host disease (GVHD; n=1), and secondary cancer (n=1). Three patients experienced disease recurrence at 6.9, 9.3, and 9.7 years following alloHCT.

At six years of follow-up, 37 of the 90 patients who received HCT (41%) had died, including nine of 12 patients who received in vivo T-cell depletion with alemtuzumab.

After a median follow-up of 9.7 years (range = 0.6-15.2 years), rates of 10-year overall survival (OS) and progression-free survival (PFS) for all 90 allografted patients were 51 percent (95% CI 40-62) and 34 percent (59% CI 23-44), respectively (see TABLE).

The authors identified the following as important risk factors for long-term outcomes:

  • refractory versus sensitive disease status at alloHCT (hazard ratio [HR] = 10.2 for non-relapse mortality [NRM; 97.5% CI 3.09-33.4] and 0.49 for relapse incidence [REL; 97.5% CI 0.18-1.32])
  • alemtuzumab ex vivo T-cell depletion (HR=5.81 for NRM [97.5% CI 1.79-18.8] and 1.13 for REL [95% CI 0.45-2.84])

For the 59 patients who had sensitive disease at the time of alloHCT and did not receive alemtuzumab T-cell depletion, 10-year outcomes were:

  • 9% for NRM (95% CI 2-23)
  • 51% for REL (95% CI 40-68)
  • 41% for PFS (95% CI 27-54)
  • 61% for OS (95% CI 47-75)

MRD-negative status at 12 months post-alloHCT was “highly prognostic for a reduced relapse risk,” the authors wrote (25% vs. 80%; p<0.0001). “The protective effect of MRD negativity at the 12-month landmark was even more pronounced if MRD clearance occurred only after immunosuppression withdrawal, suggesting effective GVL activity (10-year REL = 12%),” they added.

Thirty-nine patients relapsed during follow-up, and no relapses occurred after 10 years post-alloHCT. Five of the relapses occurred late (from 2011 to present), but all five patients were alive at a median of 28 months (range = 4-62 months) after the relapse event.

Three patients who relapsed achieved sustained disease control with ibrutinib, “[reflecting] the improved rescue options with ibrutinib and other pathway inhibitors that are available,” the authors wrote.

Earlier results from the CLL3X study indicated that GVL activity is strongly associated with the development of chronic GVHD, and the researchers reported a six-year GVHD- and relapse-free survival of 8 percent (95% CI 2-14) for the entire patient cohort. “However, it has to be taken into account that chronic GVHD is characterized by a large variance in clinical appearance and severity, and – most importantly – can calm down over time,” the authors wrote. Chronic GVHD and quality of life were not formally studied in this analysis.

The study is limited by its non-randomized design and limited number of patients with long-term follow-up. Because of the inclusion of only patients ≤65 years old, the results may not be generalizable to the full CLL population.

Dr. Krämer reported honoraria from Medical Specialties Distributors and travel grants from Gilead.


Reference

Krämer I, Stilgenbauer S, Dietrich S, et al. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 July 17. [Epub ahead of print]

TABLE. Long-Term Outcomes for Patients Receiving AlloHCT
  Overall 10-Year Follow-Up (n=32) Patients Alive and Event-Free at 6-Year Follow-Up (n=32)
Non-relapse mortality 20% (95% CI 15-36) 3.4% (95% CI 0-10)
Relapse incidence 46% (95% CI 43-67) 18% (95% CI 4-32)
Progression-free survival 34% (95% CI 23-44) 79% (95% CI 65-94)
Overall survival 51% (95% CI 40-62) 94% (95% CI 85-100)
alloHCT = allogeneic hematopoietic cell transplantation

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