Negative MRD Status Predicts Longer Progression-Free Survival and Overall Survival in Relapsed/Refractory Chronic Lymphocytic Leukemia

Patients with chronic lymphocytic leukemia (CLL) who achieved a complete remission after treatment with chemoimmunotherapy may still have residual disease that could lead to disease relapse. Post-treatment minimal residual disease (MRD) negativity has been demonstrated to have prognostic significance in these patients, but the long-term benefit of MRD-negative status and its relevance in the relapsed/refractory setting is unclear.

In a retrospective study published in Blood, Marwan Kwok, MD, of the Hematological Malignancy Diagnostic Service in the Department of Haematology at St. James’ University Hospital in Leeds, United Kingdom, and authors assessed the long-term prognostic value of MRD status across different therapeutic settings in 133 patients with CLL. According to the results, MRD negativity was associated with both prolonged progression-free survival (PFS) and overall survival (OS).

“Our results demonstrate the long-term benefit of achieving MRD negativity, regardless of the therapeutic setting and treatment modality, and support its use as a prognostic marker for long-term PFS and as a potential therapeutic goal in CLL,” the authors wrote.

Dr. Kwok and colleagues enrolled patients who completed treatment for CLL between 1996 and 2007 at St. James’ University Hospital, achieved at least a partial response (PR), and received a bone marrow MRD assessment within six months of treatment completion. Patients were excluded from the analysis if they failed to respond or died before treatment completion or received an allogeneic hematopoietic cell transplant (as graft-versus-leukemia effect can lead to continued elimination of residual disease). MRD was assessed via multiparameter flow cytometry.

Of the 133 patients included in the analysis, 67 received combination chemotherapy or chemoimmunotherapy, 31 received single-agent chemotherapy, seven underwent autologous hematopoietic cell transplantation, and 28 received chemotherapy-free regimens, mostly with monoclonal antibody therapy. Fifty-seven patients had not previously received treatment for CLL, while the remaining 76 patients had received a range of one to seven prior therapies.

Forty-one percent of patients (n=55) were MRD-negative post-treatment (defined as <1 CLL cell detectable per 104 leukocytes, or <0.01%), including 46 with complete remission with incomplete blood count recovery (CRi) and nine with PR/nodular PR.

After a median follow-up of 10.1 years (range = 7.8-18.6 years), the median PFS was (p<0.001):

  • 7.6 years for MRD-negative patients
  • 3.3 years for patients with 0.01-1% MRD positivity
  • 2 years for patients with >1% MRD positivity

The median OS was also higher in patients who achieved MRD-negative status (p<0.001):

  • 10.6 years for MRD-negative patients
  • 5.3 years for patients with 0.01-1% MRD positivity
  • 3.6 years for patients with >1% MRD positivity

When MRD response was considered together with established prognostic factors including age, Binet stage, cytopenias, prior treatment, adverse cytogenetics evaluated at the time of treatment, treatment modality, and International Workshop on CLL response, MRD negativity was the only factor to predict both longer PFS (hazard ratio [HR] = 2.07; 95% CI 1.59-2.69; p<0.001) and OS (HR=1.39; 95% CI 1.13-1.70; p=0.002).

For patients who achieved MRD-negativity, adverse cytogenetics was predictive of longer PFS (HR=2.00; 95% CI 1.16-3.45; p=0.013); age (HR=2.41; 95% CI 1.45-4.00; p=0.001); disease stage (A or B vs. C; HR=2.23; 95% CI 1.14-4.33; p=0.018); and prior treatment (yes or no; HR=2.61; 95% CI 1.61-4/23; p<0.001) were predictive of OS.”

Overall, Dr. Kwok and co-authors found that patients receiving both frontline and subsequent treatments derived a significant survival benefit from achieving MRD-negative status. However, they added that greater long-term benefit was observed when MRD negativity was achieved upfront. For patients who achieved MRD-negative status with the first agent they received, 10-year PFS was 65 percent, versus 10 percent for those who were still MRD-positive (p<0.001), and 10-year OS was 70 percent versus 30 percent (p<0.001), respectively. In the relapsed/refractory setting, 10-year PFS was 30 percent versus 0 percent, respectively, and 10-year OS was 74 percent versus 11 percent, respectively (p values not provided).

For the 23 patients who achieved upfront MRD negativity, the PFS curve appeared to plateau at 7.7 years, and no clinical relapse was observed among the 52 percent (n=12) who remained in remission.

The authors also found that patients with del(17p) and del(11q) mutations who achieved MRD negativity appeared to partially overcome the poor prognosis of these mutations, “suggesting that targeting MRD may potentially be of value in this patient group,” they wrote.

“At present, MRD negativity is achieved predominantly through chemotherapy-containing regimens with considerable toxicity, thus precluding its use in frailer CLL patients,” Dr. Kwok and colleagues concluded. “Newer agents such as venetoclax can also produce MRD negativity in substantial proportions of CLL patients, including in individuals with del(17p).”

The study is limited by its retrospective design, and the need to validate prospectively the prognostic significance of MRD with novel treatments. In addition, MRD assessment would need to be standardized. “In the future, chemotherapy-free combinations may potentially allow MRD eradication with minimal toxicity, making MRD negativity a feasible therapeutic goal,” the authors concluded.


Reference

Kwok M, Rawstron AC, Varaghese A, et al. Minimal residual disease is an independent predictor for 10-year progression-free and overall survival in CLL. Blood. 2016 October 3. [Epub ahead of print]

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