Precision Therapy Versus Standard Therapy in AML and MDS in Elderly

This is a randomized clinical trial that randomizes between treatment principles. The study will investigate if precision therapy determined by a tumour board is better than standard treatment for acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) in elderly. The tumour board will decide the precision therapy based on identified genetic changes that can guide customized therapy. There are currently 40-50 targeted therapies approved for various cancers in Norway. The precision therapy will be given in addition to the standard treatment.

The primary study objective will be to evaluate the cost-effectiveness of a precision therapy strategy compared with standard treatment. Other objectives will mesaure efficacy and satety of the treatment, and impact on life quality of the patients.

Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) in the elderly are not curable since elderly patients usually do not tolerate intensive chemotherapy and allogeneic stemcell transplantation. Next generation sequencing (NGS) of DNA can find changes in tumor DNA that can be targeted by new drugs, so called "precision therapy". Precision therapy drugs are usually less toxic than standard treatment, and thus may be particularly well suited for elderly. Precision therapy is principally different from today's standard therapy since it will be individualized based on NGS from the tumor, while in standard therapy all patients receive the same treatment. It is unknown how a precision therapy strategy will perform compared with standard therapy in AML and high-risk MDS in the elderly. A Clinical Tumour Board will decide on the precision therapy.

Study design:

This is a prospective, open label, single centre, randomized phase II clinical trial. The study randomizes between standard treatment and precision therapy in unfit elderly patients with AML and high-risk MDS. Importantly, this study design is not a randomization between treatments as in a traditional clinical trial, but a randomization between treatment principles. This means that patients in the standard treatment arm will receive the same treatment, while patients in the precision arm will receive different treatments based on the profiling of the tumor cells. Since most of the precision therapies will be experimental, the study is designed so that the patients in both arms receive a period of standard treatment before randomization. This is to reduce the risk of patients not receiving effective treatment, so that the precision therapy can be tested safely. The standard treatment for AML and high-risk MDS in elderly may change during the study, therefore "standard treatment" is defined as the recommended treatment in Norway at any time point. This means that MDS patients and AML patients may have different standard therapy.

Diagnostic sampling and genomic profiling will be done on the bone marrow of all included patients before start of treatment and compared with germline DNA from buccal swab taken at the bone-marrow. Treatment with hydroxyurea prior to the initial standard treatment is allowed to get leukocytes below 30.

While the patient receive two initial 28 day cycles of standard treatment, NGS of the bone marrow samples are done and assessed in the diagnostic pipeline, followed by bioinformatics analysis. The information is then interpreted by a Clinical Tumour Board consisting of pathologists, haematologists, oncologists, molecular biologists and bioinformatician, the treating hematologist and study nurse. The Clinical Tumour Board makes the decision on targeted treatment.

After initial standard therapy bone marrow samples will be evaluated for response to treatment. Patients with progressive disease as defined by the European Leukemia Net will go out of the study and receive treatment according to investigators choice. Notably, the results from the Clinical Tumour Board will be available for these patients to provide best possible treatment.

Patients without disease progression are randomized in a stratified manner 2:1 after the initial treatment with standard therapy to either precision therapy advised by the Clinical Tumour Board or continuous standard therapy.

Eligibility Criteria:
Inclusion Criteria:

* Patients with a diagnosis of AML and related precursor neoplasms according to WHO 2016 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease and therapy-related AML (not if they have received antileukemic/mds treatment)), or
* acute leukemias of ambiguous lineage according to WHO 2016 or a diagnosis of myelodysplastic syndrome (MDS) with IPSS-R \> 4.5.1
* Patients 60 years and older.
* Patients must NOT be eligible for intensive chemotherapy or allogeneic stem cell therapy (See Chapter 23.3)
* WBC ≤ 25 x109/L (prior hydroxyurea allowed for a maximum of 14 days, stopped before start of treatment)
* Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:
* WHO performance status 0, 1 or 2 for subjects ≥ 75 years of age OR 0 to 3 for subjects ≥ 60 to 74 years of age.
* Life-expectancy above 3 months
* Signed Informed Conscent
* Male Subjects Only: Male subjects who are sexually active, must agree, from Study Day 1 through at least 90 days after the last dose of study drug, to practice contraception with condom. Male subjects must agree to refrain from sperm donation from initial study drug administration until at least 90 days after the last dose of study drug.

Exclusion Criteria:

* Acute promyelocytic leukemia.
* AML with favourable cytogenetic or genetic changes in patients who are fit for intensive chemotherapy. Favourable genetics are: t(8;21)(q22;q22.1); RUNX1-RUNX1T1; inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11; mutated NPM1 without FLT3-ITD or with FLT3-ITDlow†; Biallelic mutated CEBPA
* Patients previously treated for AML or MDS (any antileukemic therapy or MDS treatment including investigational agents).
* Patients where it is not possible to get bone-marrow for NGS, i.e., "dry tap".
* Diagnosis of any previous or concomitant malignancy is an exclusion criterion: except when the patient completed successfully treatment (chemotherapy and/or surgery and/or radiotherapy) with curative intent for this malignancy at least 6 months prior to randomization.
* Blast crisis of chronic myeloid leukemia.
* Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.)
* Cardiac dysfunction as defined by:

  * Unstable angina or
  * New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue,palpitations, dyspnea, or angina pain or
  * Unstable cardiac arrhythmias
* Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance with the study protocol and follow-up schedule.
* Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.
* Patients who do not understand the Written Informed Consent (e.g., language problems)
* Current concomitant chemotherapy, radiation therapy, or immunotherapy; other than hydroxyurea.
* Subject is known to be positive for HIV (HIV testing is not required).
* Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load within 3 months. (Hepatitis B or C testing is not required).
* AML subjects that has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of venetoclax treatment.
* Subject has a malabsorption syndrome or other condition that precludes enteral route of administration. Additional exclusion criteria at the time of randomization
* WHO performance status \> 2 for subjects ≥ 75 years of age OR \> 3 for subjects ≥ 60 to 74 years of age.
* Progressive disease according to ELN criteria (see chapter 12 Response evaluation)
* Initial treatment has made the patient eligible for allogeneic stemcell transplantation
* In addition, it will be specific exclusion criteria for the patients receiving targeted therapies related to the Summary of Product Characteristics (SPC) of each drug.