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The presence or absence of minimal residual disease predicted progression-free and, to a lesser degree, overall survival among chronic lymphocytic leukemia (CLL) patients who achieved complete or partial remission with six courses of chemoimmunotherapy, based on two randomized phase III trials.
These findings underscore the value of measuring minimal residual disease (MRD) in patients who respond to a defined period of CLL therapy, Dr. Gabor Kovacs of the University of Cologne (Germany) and his associates wrote Aug. 29 in the Journal of Clinical Oncology.
The investigators examined the predictive value of measuring MRD in peripheral blood by using four-color flow cytometry at a threshold of 10-4 by analyzing data from 554 adult CLL patients who achieved complete or partial remission during two phase III trials – one (CLL8) comparing fludarabine and cyclophosphamide with fludarabine, cyclophosphamide, and rituximab (FCR) and a second (CLL10) comparing FCR with bendamustine plus rituximab (J Clin Oncol. 2016 Aug 29. doi:10.1200/JCO.2016.67.1305).
The median progression-free survival (PFS) after the end of treatment was 61 months for the 34% (186 patients) who attained MRD-negative complete remission (CR), 54 months for the 29% of patients who attained MRD-negative partial remission (PR), 35 months for the 7% of patients who attained MRD-positive CR, and 21 months for the 30% of patients who attained MRD-positive PR. Progression-free survival did not differ significantly between MRD-negative CR and MRD-negative PR patients, but was significantly longer for MRD-negative PR patients than for MRD-positive CR patients (P = .048).
Progression-free survival was even more distinct for MRD-positive CR patients, compared with those who attained MRD-positive PR (P = .002). Overall survival was significantly shorter only when patients had MRD-positive PR rather than MRD-negative CR (72 months vs. not reached, P = .001).
Among the MRD-negative PR patients, 16% had only residual lymphadenopathy, 11% had only bone marrow involvement, 48% had only splenomegaly, and 25% had more than one organ system affected, the researchers noted. Importantly, PFS for MRD-negative PR with residual splenomegaly (63 months) was similar to that for MRD-negative CR (61 months, P = .354).
In contrast, patients with MRD-negative PR and residual lymphadenopathy had shorter PFS than did MRD-negative CR patients (31 months, P = .001). “We hypothesize that residual splenomegaly after chemoimmunotherapy often represents tissue that does not contribute to a subsequent clinical progression,” the researchers commented.
They also noted an important caveat – their findings are only valid for patients who received a defined period of CLL treatment followed by observation (without maintenance), not for patients who are treated indefinitely until progression.
The CLL8 and CLL10 trials were funded by Roche, Mundipharma, and the German Federal Ministry of Education and Research. Dr. Kavocs disclosed support for travel, accommodations, and expenses from Roche and Celgene.
The report by Kovacs et al. is important because it further establishes minimal residual disease–free status as a meaningful clinical endpoint. Today, MRD-free remission as a treatment endpoint is most relevant for clinical trials as a means to demonstrate improved outcomes; MRD status is not yet a standard of care for patients with chronic lymphocytic leukemia. Data such as that reported by Kovacs et al. confirm the correlation of MRD-free status at the end of treatment with time-to-event endpoints (progression-free survival and overall survival), which require years of follow-up.
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Dr. William G. Wierda |
MRD status as a surrogate endpoint may allow for earlier determination of more effective therapy and, in work by the German CLL Study Group, was used to model PFS hazard ratios in randomized trials. The role of MRD status in maintained remission, such as with small-molecule inhibitors, will likely be to identify opportunities for treatment-free intervals. In addition, it will certainly be a useful tool in developing curative strategies, such as in pediatric acute lymphocytic leukemia; it is unlikely that cure will be possible without an MRD-negative remission in CLL. MRD status is an important and meaningful clinical endpoint that will likely guide future clinical trials and developments for patients with CLL.
Dr. William G. Wierda is at the University of Texas MD Anderson Cancer Center, Houston. He disclosed ties to Sanofi, Genentech, Pharmacyclics, Celgene, Gilead Sciences, Novartis, Abbvie, and several other companies. These comments are from his editorial (J Clin Oncol. 2016 Aug 29. doi:10.1200/JCO.2016.69.1972).
The report by Kovacs et al. is important because it further establishes minimal residual disease–free status as a meaningful clinical endpoint. Today, MRD-free remission as a treatment endpoint is most relevant for clinical trials as a means to demonstrate improved outcomes; MRD status is not yet a standard of care for patients with chronic lymphocytic leukemia. Data such as that reported by Kovacs et al. confirm the correlation of MRD-free status at the end of treatment with time-to-event endpoints (progression-free survival and overall survival), which require years of follow-up.
|
Dr. William G. Wierda |
MRD status as a surrogate endpoint may allow for earlier determination of more effective therapy and, in work by the German CLL Study Group, was used to model PFS hazard ratios in randomized trials. The role of MRD status in maintained remission, such as with small-molecule inhibitors, will likely be to identify opportunities for treatment-free intervals. In addition, it will certainly be a useful tool in developing curative strategies, such as in pediatric acute lymphocytic leukemia; it is unlikely that cure will be possible without an MRD-negative remission in CLL. MRD status is an important and meaningful clinical endpoint that will likely guide future clinical trials and developments for patients with CLL.
Dr. William G. Wierda is at the University of Texas MD Anderson Cancer Center, Houston. He disclosed ties to Sanofi, Genentech, Pharmacyclics, Celgene, Gilead Sciences, Novartis, Abbvie, and several other companies. These comments are from his editorial (J Clin Oncol. 2016 Aug 29. doi:10.1200/JCO.2016.69.1972).
The report by Kovacs et al. is important because it further establishes minimal residual disease–free status as a meaningful clinical endpoint. Today, MRD-free remission as a treatment endpoint is most relevant for clinical trials as a means to demonstrate improved outcomes; MRD status is not yet a standard of care for patients with chronic lymphocytic leukemia. Data such as that reported by Kovacs et al. confirm the correlation of MRD-free status at the end of treatment with time-to-event endpoints (progression-free survival and overall survival), which require years of follow-up.
|
Dr. William G. Wierda |
MRD status as a surrogate endpoint may allow for earlier determination of more effective therapy and, in work by the German CLL Study Group, was used to model PFS hazard ratios in randomized trials. The role of MRD status in maintained remission, such as with small-molecule inhibitors, will likely be to identify opportunities for treatment-free intervals. In addition, it will certainly be a useful tool in developing curative strategies, such as in pediatric acute lymphocytic leukemia; it is unlikely that cure will be possible without an MRD-negative remission in CLL. MRD status is an important and meaningful clinical endpoint that will likely guide future clinical trials and developments for patients with CLL.
Dr. William G. Wierda is at the University of Texas MD Anderson Cancer Center, Houston. He disclosed ties to Sanofi, Genentech, Pharmacyclics, Celgene, Gilead Sciences, Novartis, Abbvie, and several other companies. These comments are from his editorial (J Clin Oncol. 2016 Aug 29. doi:10.1200/JCO.2016.69.1972).
The presence or absence of minimal residual disease predicted progression-free and, to a lesser degree, overall survival among chronic lymphocytic leukemia (CLL) patients who achieved complete or partial remission with six courses of chemoimmunotherapy, based on two randomized phase III trials.
These findings underscore the value of measuring minimal residual disease (MRD) in patients who respond to a defined period of CLL therapy, Dr. Gabor Kovacs of the University of Cologne (Germany) and his associates wrote Aug. 29 in the Journal of Clinical Oncology.
The investigators examined the predictive value of measuring MRD in peripheral blood by using four-color flow cytometry at a threshold of 10-4 by analyzing data from 554 adult CLL patients who achieved complete or partial remission during two phase III trials – one (CLL8) comparing fludarabine and cyclophosphamide with fludarabine, cyclophosphamide, and rituximab (FCR) and a second (CLL10) comparing FCR with bendamustine plus rituximab (J Clin Oncol. 2016 Aug 29. doi:10.1200/JCO.2016.67.1305).
The median progression-free survival (PFS) after the end of treatment was 61 months for the 34% (186 patients) who attained MRD-negative complete remission (CR), 54 months for the 29% of patients who attained MRD-negative partial remission (PR), 35 months for the 7% of patients who attained MRD-positive CR, and 21 months for the 30% of patients who attained MRD-positive PR. Progression-free survival did not differ significantly between MRD-negative CR and MRD-negative PR patients, but was significantly longer for MRD-negative PR patients than for MRD-positive CR patients (P = .048).
Progression-free survival was even more distinct for MRD-positive CR patients, compared with those who attained MRD-positive PR (P = .002). Overall survival was significantly shorter only when patients had MRD-positive PR rather than MRD-negative CR (72 months vs. not reached, P = .001).
Among the MRD-negative PR patients, 16% had only residual lymphadenopathy, 11% had only bone marrow involvement, 48% had only splenomegaly, and 25% had more than one organ system affected, the researchers noted. Importantly, PFS for MRD-negative PR with residual splenomegaly (63 months) was similar to that for MRD-negative CR (61 months, P = .354).
In contrast, patients with MRD-negative PR and residual lymphadenopathy had shorter PFS than did MRD-negative CR patients (31 months, P = .001). “We hypothesize that residual splenomegaly after chemoimmunotherapy often represents tissue that does not contribute to a subsequent clinical progression,” the researchers commented.
They also noted an important caveat – their findings are only valid for patients who received a defined period of CLL treatment followed by observation (without maintenance), not for patients who are treated indefinitely until progression.
The CLL8 and CLL10 trials were funded by Roche, Mundipharma, and the German Federal Ministry of Education and Research. Dr. Kavocs disclosed support for travel, accommodations, and expenses from Roche and Celgene.
The presence or absence of minimal residual disease predicted progression-free and, to a lesser degree, overall survival among chronic lymphocytic leukemia (CLL) patients who achieved complete or partial remission with six courses of chemoimmunotherapy, based on two randomized phase III trials.
These findings underscore the value of measuring minimal residual disease (MRD) in patients who respond to a defined period of CLL therapy, Dr. Gabor Kovacs of the University of Cologne (Germany) and his associates wrote Aug. 29 in the Journal of Clinical Oncology.
The investigators examined the predictive value of measuring MRD in peripheral blood by using four-color flow cytometry at a threshold of 10-4 by analyzing data from 554 adult CLL patients who achieved complete or partial remission during two phase III trials – one (CLL8) comparing fludarabine and cyclophosphamide with fludarabine, cyclophosphamide, and rituximab (FCR) and a second (CLL10) comparing FCR with bendamustine plus rituximab (J Clin Oncol. 2016 Aug 29. doi:10.1200/JCO.2016.67.1305).
The median progression-free survival (PFS) after the end of treatment was 61 months for the 34% (186 patients) who attained MRD-negative complete remission (CR), 54 months for the 29% of patients who attained MRD-negative partial remission (PR), 35 months for the 7% of patients who attained MRD-positive CR, and 21 months for the 30% of patients who attained MRD-positive PR. Progression-free survival did not differ significantly between MRD-negative CR and MRD-negative PR patients, but was significantly longer for MRD-negative PR patients than for MRD-positive CR patients (P = .048).
Progression-free survival was even more distinct for MRD-positive CR patients, compared with those who attained MRD-positive PR (P = .002). Overall survival was significantly shorter only when patients had MRD-positive PR rather than MRD-negative CR (72 months vs. not reached, P = .001).
Among the MRD-negative PR patients, 16% had only residual lymphadenopathy, 11% had only bone marrow involvement, 48% had only splenomegaly, and 25% had more than one organ system affected, the researchers noted. Importantly, PFS for MRD-negative PR with residual splenomegaly (63 months) was similar to that for MRD-negative CR (61 months, P = .354).
In contrast, patients with MRD-negative PR and residual lymphadenopathy had shorter PFS than did MRD-negative CR patients (31 months, P = .001). “We hypothesize that residual splenomegaly after chemoimmunotherapy often represents tissue that does not contribute to a subsequent clinical progression,” the researchers commented.
They also noted an important caveat – their findings are only valid for patients who received a defined period of CLL treatment followed by observation (without maintenance), not for patients who are treated indefinitely until progression.
The CLL8 and CLL10 trials were funded by Roche, Mundipharma, and the German Federal Ministry of Education and Research. Dr. Kavocs disclosed support for travel, accommodations, and expenses from Roche and Celgene.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Quantifying minimum residual disease significantly improved the accuracy of progression-free survival estimates in patients with chronic lymphocytic leukemia who achieved complete or partial remission after a defined period of chemoimmunotherapy.
Major finding: Progression-free survival was significantly longer for MRD-negative partially remitted patients, compared with MRD-positive completely remitted patients (P = .048), and was even more distinct for MRD-positive completely remitted patients, compared with MRD-positive partially remitted patients (P = .002).
Data source: An analysis of 554 patients achieving complete or partial remission during two randomized phase III trials (CLL8 and CLL10).Disclosures: The CLL8 and CLL10 trials were funded by Roche, Mundipharma, and the German Ministry of Education and Research. Dr. Kavocs disclosed support for travel, accommodations, and expenses from Roche and Celgene.
