Lenalidomide and metronomic melphalan for CMML and higher risk MDS: A phase 2 clinical study with biomarkers of angiogenesis

AbstractMetronomic, low dose chemotherapy may have anti-angiogenic effects and augment the effects of lenalidomide in MDS and CMML. We evaluated the clinical efficacy, tolerability and anti-angiogenic effects of melphalan 2mg and lenalidomide 10mg for 21 days/28 in CMML (n=12) and higher risk MDS (n=8) patients in a prospective phase II study. The primary endpoint was overall response and secondary endpoints included survival, progression-free survival, toxicity and biomarkers of angiogenesis. The median age was 73 years, 55% were pretreated and transfusion dependent. The overall response rate was 3(15%) of 19 evaluable patients but 25% in CMML and 33% in pCMML. Dose reductions and/or delays were common due to myelosuppression. Transient spikes in circulating endothelial cells that declined below baseline were seen in responders and patients with CMML, suggesting anti-angiogenic activity. In conclusion, lenalidomide and metronomic low dose melphalan demonstrate signals of clinical and possible anti-angiogenic activity in patients with pCMML that require future validation. This trial was registered at clinicaltrial.gov under # NCT00744536

A Machine Learning Model of Response to Hypomethylating Agents in Myelodysplastic Syndromes

Hypomethylating agents (HMA) prolong survival and improve cytopenias in individuals with higher-risk myelodysplastic syndrome (MDS). Only 30-40% of patients, however, respond to HMAs, and responses may not occur for more than 6 months after HMA initiation. We developed a model to more rapidly assess HMA response by analyzing early changes in patients’ blood counts. Three institutions’ data were used to develop a model that assessed patients’ response to therapy 90 days after the initiation using serial blood counts. The model was developed with a training cohort of 424 patients from2 institutions and validated on an independent cohort of 90 patients. The final model achieved an area under the receiver operating characteristic curve (AUROC) of 0.79 in the train/test group and 0.84 in the validation group. The model provides cohort-wide and individual- level explanations for model predictions, and model certainty can be interrogated to gauge the reliability of a given prediction

Long-Term Follow-Up of a Large Active Surveillance Cohort of Patients With Prostate Cancer

Purpose Active surveillance is increasingly accepted as a treatment option for favorable-risk prostate cancer. Long-term follow-up has been lacking. In this study, we report the long-term outcome of a large active surveillance protocol in men with favorable-risk prostate cancer. Patients and Methods In a prospective single-arm cohort study carried out at a single academic health sciences center, 993 men with favorable- or intermediate-risk prostate cancer were managed with an initial expectant approach. Intervention was offered for a prostate-specific antigen (PSA) doubling time of less than 3 years, Gleason score progression, or unequivocal clinical progression. Main outcome measures were overall and disease-specific survival, rate of treatment, and PSA failure rate in the treated patients. Results Among the 819 survivors, the median follow-up time from the first biopsy is 6.4 years (range, 0.2 to 19.8 years). One hundred forty-nine (15%) of 993 patients died, and 844 patients are alive (censored rate, 85.0%). There were 15 deaths (1.5%) from prostate cancer. The 10- and 15-year actuarial cause-specific survival rates were 98.1% and 94.3%, respectively. An additional 13 patients (1.3%) developed metastatic disease and are alive with confirmed metastases (n = 9) or have died of other causes (n = 4). At 5, 10, and 15 years, 75.7%, 63.5%, and 55.0% of patients remained untreated and on surveillance. The cumulative hazard ratio for nonprostate-to-prostate cancer mortality was 9.2:1. Conclusion Active surveillance for favorable-risk prostate cancer is feasible and seems safe in the 15-year time frame. In our cohort, 2.8% of patients have developed metastatic disease, and 1.5% have died of prostate cancer. This mortality rate is consistent with expected mortality in favorable-risk patients managed with initial definitive intervention. </jats:sec

Gleason upgrading with time in a large, active surveillance cohort with long-term follow-up

1 Background: Active surveillance (AS) is an accepted management strategy for localized prostate cancer. However, the rate of pathological upgrading has not been well described in mature study cohorts. Furthermore, concern exists over the possibility of prostate cancer dedifferentiation with time in patients on AS. Methods: Patients in our prospectively collected AS database with at least one repeat prostate biopsy were included. Linear regression analysis was used to estimate the proportion of patients upgraded (Gleason 6 to 3+4 or higher, Gleason 3+4 to 4+3 or higher) with time from diagnostic biopsy. Results: 593 of 862 patients in our cohort had at least one repeat biopsy. Median follow-up was 6.4 years (max. 20.2 years). The total number of biopsies ranged from 2 to 6. 20% of patients were intermediate risk, 0.3 % high risk, all others low risk. 31.2% of patients were upgraded during active surveillance. The proportion of patients upgraded increased with time, suggesting prostate cancer dedifferentiation occurred at a rate of 1.0%/year (95%CI -0.12 to 2.16%/year). The estimated rate of increase was 2.5 times higher in patients with intermediate risk disease at diagnosis (rate 1.9%/year, 95%CI -0.7-4.6) compared with those with low risk disease (rate 0.75%/year, 95%CI -0.5-2.0). Further analysis is underway. 62% of upgraded patients (n=114) went on to have active treatment. Patients who were upgraded and treated had significantly greater PSA velocities (median 1.2 ng/ml/y vs 0.42 ng/ml/y, p=0.01) and significantly higher Gleason scores when upgraded, than those who remained on surveillance (21.8% vs 2.8% Gleason 8-10, p&lt;0.01). Conclusions: This is the largest re-biopsy cohort, with long-term follow-up, described to date, enabling the first estimates of prostate cancer dedifferentiation in patients on AS. Dedifferentiation rates appear higher in patients with intermediate risk prostate cancer compared with those who are low risk at baseline. </jats:p