Page 89 - 2018_10-Haematologica-web

Everolimus added to consolidation therapy for AML
There is plausible pre-clinical evidence both in vitro and in vivo that mTOR inhibition could be beneficial in AML. mTOR is a serine/threonine protein kinase that is predom- inantly modulated by PI3K-AKT-dependent mechanisms and acts as a central regulator of cellular metabolism, growth and survival.4 Dysregulation of the mTOR path- way is closely associated with cancers including AML,5,6 and other human diseases. Part of the rationale is the evi- dence of constitutive activation of the PI3K-AKT pathway in 90% of AML samples and the demonstration that this activation is central to the survival of AML blasts but not to that of normal CD34+ cells.7 The concept that everolimus may have the potential to eliminate leukemia- initiating stem cells while sparing normal hematopoietic stem cells is also appealing. In vivo evidence in NOD/SCID mice has suggested that mTOR regulates a critical cell sur- vival pathway in AML stem cells.8,9 In preliminary unran- domized clinical trial, the mTOR inhibitor sirolimus was administered as a single agent to nine relapsed, refractory or poor-risk AML patients for 28 days resulting in partial responses in four, and stable disease in a fifth patient.10 Dephosphorylation of downstream effectors of mTOR was demonstrated. In an ongoing UK trial, 11 elderly patients with primary, relapsed AML have been treated with the combination of low-dose Ara-C and sirolimus. Following a single 28-day course of treatment, of the seven patients eligible for analysis, one had achieved a complete remission, four had obtained a partial remission, one had profoundly hypocellular bone marrow and one patient was a non-responder (Das Gupta, unpublished data). Patients in this trial reliably maintained trough sirolimus levels of 8-16 ng/mL, which are consistent with the published concentrations required to inhibit AML cell growth in vitro. The feasibility of combining mTOR inhi- bition (sirolimus) with intensive chemotherapy had also been assessed in AML patients in conjunction with the more intensive MEC (mitoxantrone, etoposide and cytara- bine) chemotherapy regimen in a phase I dose escalation study and reported in abstract form. In this study standard renal transplant doses of sirolimus were well tolerated and did not increase the non-hematologic toxicity of MEC chemotherapy with a median time to neutrophil recovery of 27 days.11 Based on this background information, the NCRI AML17 trial included the option for eligible patients to be randomized to receive, or not, the mTOR inhibitor everolimus daily between consolidation chemotherapy courses.
Methods
The UK NCRI AML 17 trial (ISRNCTN 55675535) was a large, prospective, phase 3, multicenter trial for patients with newly- diagnosed AML or high-risk myelodysplastic syndrome (>10% marrow blasts), generally under the age of 60 years, open from April 2009 to December 2014 in more than 130 centers in the United Kingdom, Denmark and New Zealand. Through random- ization of the participants, it addressed several issues (Online Supplementary Figure S1). Between October 2009 and October 2012, 499 adult patients who did not have acute promyelocytic leukemia had received a first induction course of treatment: those who did not have core-binding factor leukemia, high-risk disease (defined using a multifactorial score12) and were not in the lestau- rtinib randomization for patients with FLT3 mutations, could be randomized to receive everolimus, or not, in a 2:1 ratio, between
subsequent consolidation chemotherapy courses. The treatment schedules have been set out elsewhere.13 Allogeneic stem cell transplantation was permitted for patients with intermediate- or poor-risk disease with a recommendation of myelo-ablative con- ditioning for patients aged <35 years and reduced intensity condi- tioning for intermediate-risk patients aged >45 years, with inves- tigators able to choose an ablative or reduced intensity approach for patients between 35 and 45 years.
Of all adult patients entering the AML17 trial while the everolimus randomization was available, 34% were eligible for such randomization. These patients were randomized to receive, or not, oral everolimus (10 mg daily from 2 days after each chemotherapy course for up to 28 days or until 2 days before the start of the subsequent course, whichever was shorter) between each course of consolidation chemotherapy. In patients allocated three courses of treatment, a final 28-day course of everolimus was given after a 1-week break. In patients with side effects thought to be due to everolimus, subsequent daily doses could be reduced by 50%. If this did not improve tolerability, dosing could be further reduced to alternate days; if these reduced doses were not tolerated, subsequent doses were to be omitted. After 65% (n=146) of the patients randomized to everolimus had been assessed, the independent data monitoring committee recom- mended, because of increased side effects and reduced compli- ance, that the starting daily dose of everolimus be reduced to 5 mg with the option to increase to 10 mg if well-tolerated.
Extensive Sanger sequencing (111 genes) was undertaken in 123 patients; NPM1 status was available in 302 patients.
Patients were requested to provide a trough blood sample taken immediately prior to everolimus dosing on day 14 of each treat- ment course to measure the level of mTOR inhibitory activity in their plasma. The methods for measuring this activity are summa- rized in Online Supplementary Figure S2 and will be reported more fully elsewhere.
Statistical considerations
All analyses are on an intention-to-treat basis. Categorical end- points were compared using Mantel-Haenszel tests, giving Peto odds ratios and confidence intervals. Continuous/scale variables were analyzed by Wilcoxon rank sum tests and time-to-event out- comes using the log-rank test, with Kaplan-Meier survival curves. Odds/hazard ratios (OR/HR) <1 indicate benefit for everolimus. All survival percentages refer to 5 years unless otherwise stated.
Stratified analyses were performed with suitable tests for inter- action14 and interpreted cautiously.
It was planned to recruit 600 patients to the everolimus ran- domization, which would have given 85% power to detect a 12.5% difference in the primary endpoint of relapse-free survival, from 50% to 62.5% (HR 0.68). Follow-up is complete until March 1st, 2016 [median follow-up from diagnosis 53.5 months (range, 4.3 – 76.8 months)].
The trial was conducted in accordance with the Declaration of Helsinki, sponsored by Cardiff University and approved by Wales REC3 on behalf of all UK investigators, by the Danish Medicines Agency for sites in Denmark, and by MEDSAFE for sites in New Zealand.
Results
Patients’ characteristics
The randomization opened in October 2009. In 2012, the independent data monitoring committee recommend- ed closure of the randomization because of an excess of early mortality in remission with everolimus and no asso-
haematologica | 2018; 103(10)
1655