Background
Unlike the traditional method of overall survival prediction in patients with cancer, conditional survival predicts the survival of patients dynamically throughout the course of disease, identifying how a prognosis evolves over time.
Methods
The authors assessed 815 consecutive patients with multiple myeloma through the German Study Group on Multiple Myeloma (Deutsche Studiengruppe Multiples Myelom; DSMM) incentive. Over 10 variables, including patient‐specific and multiple myeloma–specific parameters, were analyzed at the time of initial diagnosis and repeatedly during follow‐up. The probability of survival for another 5 years was calculated according to disease‐related and host‐related risks. Multivariate Cox models were used to determine baseline and updated prognostic factors for survival.
Results
The median follow‐up and overall survival were 10.3 years and 5.1 years, respectively. When comparing 5‐year conditional survival probabilities from the data derived at the time of initial diagnosis with those updated over time, substantially differing prognoses were observed when follow‐up data were used. Multivariate Cox regression models for cohorts surviving 0 to 5 years demonstrated hazard ratios (HRs) for patients aged <60 years, 60 to 69 years, and >70 years of 1, 1.68, and 3.17, respectively. These HRs for age were found to decline for patients surviving 5 years, as well as for those with advanced stages of disease (II/III) and unfavorable cytogenetics, whereas progressive disease remained an important factor in patients surviving 1 year, 3 years, and 5 years, with HRs of 1.85, 2.11, and 2.14, respectively.
Conclusions
To the authors' knowledge, the current study is the first analysis of conditional survival in patients with multiple myeloma using both baseline and follow‐up risk parameters, demonstrating that regular risk assessment throughout the course of disease and complete follow‐up provide a more reliable conditional survival estimation than baseline assessment alone.
Previous gene therapy trials for X-linked chronic granulomatous disease (X-CGD) lacked long-term engraftment of corrected hematopoietic stem and progenitor cells (HSPCs). Chronic inflammation and high levels of interleukin-1 beta (IL1B) might have caused aberrant cell cycling in X-CGD HSPCs with a concurrent loss of their long-term repopulating potential. Thus, we performed a targeted CRISPR-Cas9-based sgRNA screen to identify candidate genes that counteract the decreased repopulating capacity of HSPCs during gene therapy. The candidates were validated in a competitive transplantation assay and tested in a disease context using IL1B-challenged or X-CGD HSPCs. The sgRNA screen identified Mapk14 (p38) as a potential target to increase HSPC engraftment. Knockout of p38 prior to transplantation was sufficient to induce a selective advantage. Inhibition of p38 increased expression of the HSC homing factor CXCR4 and reduced apoptosis and proliferation in HSPCs. For potential clinical translation, treatment of IL1B-challenged or X-CGD HSPCs with a p38 inhibitor led to a 1.5-fold increase of donor cell engraftment. In summary, our findings demonstrate that p38 may serve as a potential druggable target to restore engraftment of HSPCs in the context of X-CGD gene therapy.
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