A quality‐adjusted survival time without symptoms or toxicities analysis of glasdegib plus low‐dose cytarabine versus low‐dose cytarabine as initial therapy for acute myeloid leukemia in patients who are not considered candidates for intensive chemotherapy

Abstract

Background In a randomized study, glasdegib (a hedgehog inhibitor) plus low‐dose cytarabine (LDAC) significantly prolonged survival in comparison with LDAC in patients with acute myeloid leukemia (AML). A quality‐adjusted time without symptoms of disease progression or toxicity (Q‐TWiST) approach was used to evaluate comparative quality‐adjusted survival. Methods Overall survival was partitioned into the following: time with any treatment‐emergent grade 3 or higher adverse events (TOX); time without symptoms of disease progression or toxicity (TWiST); and time after treatment discontinuation due to insufficient clinical response, relapse, or death time after progression (REL). Q‐TWiST was calculated by multiplying the restricted mean time in each state by respective utilities and then summing up the utility‐adjusted time. Results At 20 months of follow‐up, the survival probabilities for the glasdegib‐LDAC arm and the LDAC arm were 28.2% and 7.9%, respectively. Glasdegib‐LDAC patients (n = 78), in comparison with LDAC patients (n = 38), had significantly longer mean TWiST (+3.4 months; 95% confidence interval [CI], 1.8‐5.2 months) and TOX (+0.8 months; 95% CI, 0.1‐1.6 months) and longer but nonsignificant REL (+0.3 months; 95% CI, −1.9 to 2.3 months). Q‐TWiST was 4.0 months (95% CI, 2.1‐5.8 months) longer with glasdegib plus LDAC, and this translated into a 75% relative improvement in quality‐adjusted survival with respect to LDAC. Results were robust to the length of follow‐up (6‐24 months) and remained significant when all adverse events, regardless of grade, were included. Conclusions These results suggest that most of the survival benefit from glasdegib plus LDAC versus LDAC alone is TWiST, and this represents added time in relatively “good” health. These results support the clinical value of glasdegib plus LDAC as initial therapy for AML in patients for whom intensive chemotherapy is not an option.

Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML

“…The QuANTUM-R study of quizartinib versus salvage chemotherapy in adults aged ≥ 18 years with relapsed/refractory AML with a FLT3 internal tandem duplication showed a relative Q-TWiST gain of 20.3% [ 28 ]. In the BRIGHT AML 1003 study of glasdegib in combination with low-dose cytarabine versus low-dose cytarabine alone in adults aged ≥ 55 years with newly diagnosed AML who were not considered candidates for intensive induction therapy, the combination treatment provided a relative Q-TWiST gain of 75% [ 14 ].…”

“…Within each treatment arm, the mean time spent in each health state was calculated, and the means differences for each health state were determined as the difference in mean values between treatment arms. To calculate the Q-TWiST gain, the mean value for each treatment arm’s health state was first weighted by its respective assigned quality-of-life value per literature standards [ 12 , 14 ], represented by health utility (U; scale of 0.0 [indicates death] to 1.0 [indicates “perfect” health]). Q-TWiST was then calculated as follows for each treatment arm [ 12 , 13 ]: Q-TWiST = ( U TWiST × TWiST) + ( U TOX × TOX) + ( U REL × REL).…”