Randomised controlled phase-2 trial to determinate the efficacy of adoptive immunotherapy with haploidentical natural killer cells in high-risk acute myeloid leukemia (HINKL)
Final Report Abstract
Treatment outcome in acute myeloid leukemia (AML) is still unsatisfying, especially in cases with high-risk disease. The only curative treatment option is allogeneic hematopoietic cell transplantation (HCT). Give the high extramedullary toxicity of this approach, its use is currently still restricted to patients at younger age with a good performance status. In addition, successful allogeneic HCT requires a significant reduction in disease burden within induction therapy which is often not achievable in high-risk patients. Therefore, only a minor proportion of patients with high-risk AML qualifies for allogeneic HCT. At the same time, several preclinical and clinical studies could demonstrate that the adoptive transfer of HLA-partially matched (haploidentical) Natural Killer cells (NK cells) from sibling donors after immunosuppressive pretreatment can contribute to control of the underlying disease as NK cells are able to attack and eradicate myeloid neoplasms, Until now, no controlled prospective trial has confirmed the efficacy of this approach within a randoimzed trial design. The HINKL trial was supposed to be the first randomized clinical trial of its kind, comparing the adoptive transfer of NK cells from a haploidentical donor with conventional cyatabine-based post-remission therapy in older patients with high-risk AML. The trial had been powered to detect a 2-year survival difference between the cell therapy arm and the respective copntrol intervention. Unfortunately, the prolonged process of licensure of the investigational cell product and the 18 months it took for the trial to be approved by the competent authorities in Germany, a significant delay in trial activation occurred. As german drug and ATMP regulation is not handled centrally but differently in each federal state, the coordination between the local authorities (Regierungspräsidium/Landesdirektion) and the federal authority (PEI) takes an enormous amount of time and bureaucracy, especially if the cellular product or ATMP is new to the local authorities. The local authority often is not able to assess the ‚Investigational compound’ and to confirm manufacturing license and waits for the PEI to give advice, although the trial protocol has not been formally submitted with the PEI yet. In this process, the PI has no chance to intervene or to get feedback in which field the ball currently is located. Of course, a shortage in personel at the regulating bodies is another reason for that agonizing procedure. Therefore, multicentric approaches are difficult to handle without a professionel sponsor even when federal funding (BMBF/DFG) is available. In general, academic centres and sponsors have only a limited personel and financial equipment which does not allow to constantly lobby various regulators and exert contstant pressure on these. The prolongation in trial initiation leads to a demotivation of staff and participating centres and medical standards may have changed during 1-2 years of waiting for final approval which then makes successful acrrual almost impossible. In order to improve this, a mechanism of central submission for ATMP or cell-based clinical trials at PEI needs to be in place with final decisions being made within 3-4 months and federal authorities being just informed but not actively involved. PEI of course needs to be staffed adequately to be able to compete with other European countries. Although, the first site could be initiated, only three patients were screened and only one patient could be randomized to the control intervention. In the meantime, the potential superiority of novel therapies, e.g. hypomethylating agents, bcl2-anatagonists and the increasing use of haploidentical allogeneic HCT even in older patients decreased the adherence of referal centres to the protocol. Accordingly, the trial had to be closed due to slow accrual. The speed of recruitment made the successful inclusion of 56 planned patients highly unlikely. Both the sponsor and the funding bodies were involved in the decision and agreed to close the trial and to finalize the follow-up of the included patient who unfortunately relapsed early and died from recurring AML. In summary, the trial team had to realize that the high regulatory burden and the delays which have to be foreseen within academic investigator initiated trials make the execution of such a demanding trial difficult without involving pharmaceutical industry, at least in Germany. Current developments in the area of chimeric antigen receptor T cells (CAR T cells) confirm the notion that licensure of such an approach can only be achieved by larger internationally active pharmaceutical companies, mainly recruiting patients outside Germany.
Publications
- 2013. Azacytidine impairs NK cell activity in AML and MDS patients undergoing MRD-based pre-emptive treatment after allogeneic stem cell transplantation. Blood Cancer J 3:e136
Schonefeldt C, Sockel K, Wehner R, Sopper S, Wolf D, Wermke M, Thiede C, Oelschlagel U, Ehninger G, Bornhäuser M, Platzbecker U, Schmitz M
(See online at https://doi.org/10.1038/bcj.2013.35) - 2014. KIR haplotype B donors but not KIR-ligand mismatch result in a reduced incidence of relapse after haploidentical transplantation using reduced intensity conditioning and CD3/CD19-depleted grafts. Ann Hematol 93:1579–1586
Michaelis SU, Mezger M, Bornhäuser M, Trenschel R, Stuhler G, Federmann B, Oevermann L, Kanz L, Handgretinger R, Bethge WA
(See online at https://doi.org/10.1007/s00277-014-2084-2)
