Gemtuzumab Based Induction Chemotherapy Combined with Midostaurin for FLT3 Mutated Patients. Results from the Patient- Reported Outcome Measures from the NCRI AML19V2 ‘Midotarg Pilot’

Introduction: The AML19 v2 ‘midotarg’ pilot explored the safety and efficacy of Midostaurin in patients with a FLT3 mutation who had received DA chemotherapy combined with one or two doses of Gemtuzumab Ozogamicin (GO) in induction. The addition of Midostaurin to DAGO1 and DAGO2 chemotherapy was well tolerated and safe in both younger and older patients with FLT3mut AML with promising survival at 24 months. The full clinical outcomes of this study have been reported (Russell N, ASH 2023), and here we report the findings from the patient reported outcome measures (PROs) across treatment groups.

Methods: Patients with newly-diagnosed AML without known adverse karyotype were randomised to receive DA 3+10 plus either a single dose of GO or two doses. Patients with a FLT3-ITD or TKD could enter the “Midotarg” pilot and receive 50mg bd of Midostaurin (m) for 14 days following completion of chemotherapy, and following the second induction (DA 3+8 without GO) and 2 courses of HDAC consolidation and as maintenance for 12 cycles in non-transplanted patients.

Quality of Life (QoL) questionnaires were given to all new patients prior to starting treatment, prior to course 2 of treatment, and at 3, 6 (approximately post consolidation), 9 and 12 months post trial entry. The questionnaires included the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQC-30).

Scores were calculated following the EORTC scoring manual reporting mean values across domains. Data was analysed using a linear mixed model to compare scores across treatment groups. A more stringent p-value (0.0025) was set for this exploratory analysis to account for the multiplicity of testing. Consistent with current evidence a minimal clinically important difference (MCID) of ≥10 was set to measure deterioration across time points, using a logistic regression analysis to estimate the odds ratio of MCID.

Results: 196 patients with a median age of 50 (IQR 40-58) years were recruited to AML19 v2 between November 2020 to November 2021, of which 77 FLT3mut patients were enrolled into the Midotarg pilot receiving DAGO1m (n=39) or DAGO2m (n=38). 59 had a FLT3 ITD and 22 a FLT3-TKD (and 4 had both). The remaining, predominantly FLT3 WT, patients (n=119) received DAGO1 (n=59) or DAG02 (n=60) only.

Of these patients, 161 (82%) provided baseline PRO data, with completion of 120 (61%) at post course 2, 114 (58%) at 3 months, 105 (54%) at 6 months, 97 (49%) at 9 months and 91 (46%) at 12 months.

There were no statistically significant differences in global QOL between the DAGOm and DAGO treatment groups. Both groups followed the same trajectory of improvement, with an increase in global QOL scores from baseline to prior to course 2 (47 to 71 DAGOm, 54 to 71 DAGO) which was maintained through to 12 months. A significant treatment time interaction was observed on the individual domains for dyspnea at 6 months (Avg score DAGOm 19 (SE3.9), DAGO 32 (SE4.4); P = 0.001) and for insomnia at 6 months (Avg score DAGOm 21(SE4.3), DAGO 34 (SE4.8); P = 0.002) and 9 months (Avg score DAGOm 19 (SE3.4), DAGO 33 (SE5.0); P = 0.002). At 6 and 9 months DAGOm patients were on maintenance midostaurin whereas DAGO patients were off treatment which may account for this effect. At 12 months all patients were off treatment and there was no statistical difference across domains between treatment groups. No further statistically significant differences were observed between the treatment groups across any other scales. Additionally, there were no significant differences in the proportion of patients experiencing clinically meaningful deterioration at any time point between treatment groups.

Conclusion: The analysis of the PROs from this pilot study demonstrate that the promising clinical benefits previously reported are not accompanied by any clinically relevant adverse deterioration in patient’s overall QOL. This was an exploratory analysis that offers important insight for hypothesis generation for future studies in this patient group.