The goal of this clinical trial is to learn if drugs (fludarabine and melphalan) combinated with a targeted irradiation (in bone marrow and in lymphoid tissue) works to treat blood cancers (high risk myelodysplastic syndrome or acute myeloid leukemia) in adults. It will also learn about the safety of this combination of drugs and irradiation. The main questions it aims to answer are:

• Does this combined therapy result in an improved survival and decreased relapse/progression rate after a bone marrow transplant?
• What toxicities or complications do participants have when taking this combined therapy?

Researchers will use this combined therapy to see if it works to treat high risk myelodysplastic syndrome or acute myeloid leukemia through the evaluation of the length of time (during the treatment and 2 years after the treatment) that a patient lives with the disease but it does not get worse (progression-free survival).

Participants will:

• Receive the combined therapy (study treatment) one week before the bone marrow transplant.
• Receive too post-transplant medication as per usual clinical practice.

Patients will have to attend medical visits (checkups and tests) for 2 years.

This is a single-arm, single center phase II trial to evaluate the antileukemic activity and safety of the AHSCT TMLI/Flu/Mel conditioning regimen in patients with high-risk myelodysplastic syndrome or acute myeloid leukemia. A patient safety-lead phase will be carried out to ensure there are no unexpected toxicities. Ultimately, a total of 34 patients will be treated at the TMLI/Flu/Mel dose level deemed safe as determined during the introductory patient safety segment of this study.

Up to three dose levels can be studied. A 3+3 de-escalation design comprising a patient safety-lead phase will be applied in successive patient cohorts to evaluate the safety of the TMLI schedule and identify the optimal treatment dose:

Initially, 3 patients will be treated at the starting TMLI dose (Dose Level 1, 1200 cGy). If 0 or 1 DLT is observed among the first 6 patients at Dose Level 1, then 28 additional patients will be treated at this dose level (allowing for the evaluation of 34 patients treated at the target dose level). If ≥2/6 patients experience a DLT at Dose Level 1, then the MTD has been exceeded and the next lower TMLI dose (Dose Level -1, 1100 cGy) will be expanded to up to 6 patients. If 0 or 1 patient out of 6 experiences a DLT, this dose level will be further evaluated (n=28 additional patients). If ≥2/6 patients experience a DLT, the next lower dose (Dose Level -2, 1000 cGy) level will be expanded applying the same criteria. No further dose level reductions will be allowed beyond Dose Level -2.

No more than 3 patients may be <30 days after stem cell infusion at any time during patient safety introduction. The tacrolimus dose and MMF dose will remain fixed for all defined dose levels and will not be reduced at any time.

Considering this proposed design, the expected sample size of the study will be n=34 patients, with a potential minimum and maximum size of n=34 and n=46, respectively.

Inclusion Criteria:

• The participant has the ability and willingness to sign the informed consent document. (For adults, only participants with mild cognitive abilities may use a legally authorized representative).
• Documented (signed) informed consent. The patient, family member, and doctor of the transplant staff (doctor, nurse, and social worker) meet at least once before the transplant procedure begins. During this meeting, all relevant information regarding the risks and benefits to the donor and recipient will be presented. Alternative treatment modalities will be discussed. The risks are explained in detail in the attached consent forms.
• Age: ≥ 50 years or Haematopoietic Cell Transplantation-Comorbidity Index pre-transplant score ≥ 3 or any other condition that precludes the use of a fully myeloablative conditioning regimen.
• Karnofsky's performance status ≥ 70%.
• Patients with myelodysplastic syndrome/acute myeloid leukemia or acute myeloid leukemia with relapsed/refractory active disease (i.e. ≥5% bone marrow blasts), or in complete remission or morphologic leukemia-free state with evidence of measurable residual disease as assessed by multiparameter flow cytometry (≥ 0,1%) or next-generation sequencing (in the case of fms-like tyrosine kinase-3 internal tandem duplication-mutated AML).
• All candidates for this study must have an 8/8 human leukocyte antigens-identical (A, B, C, DR) sibling donor or an unrelated donor with at least 8/8 human leukocyte antigens matching. A single allele mismatch in A, B, C, DR or dq and a kir mismatch in C shall be allowed. All combinations of donor/recipient "abo" blood types are acceptable; as even major "abo" compatibilities can be treated using a variety of techniques (red blood cell exchange or plasma exchange).
• The time elapsed since the end of the last induction or re-induction cycle must be greater than or equal to 14 days.
• Total bilirubin ≤ 1.5 mg/dL x Upper Limit of Normality OR 3 x upper limit of normal for Gilbert's disease.
• Serum glutamate oxaloacetate transaminase & serum glutamate pyruvate transaminase ≤ 5 x Upper Limit of Normality.
• Serum creatinine ≤ 1.3 mg/dL or creatinine clearance measured ≥ 80 mL/min for 24 hours of urine collection.
• Women of childbearing age only: Negative urine or serum pregnancy test.
• Men AND women of childbearing potential agree to use appropriate contraceptives (hormonal or barrier contraception or abstinence) prior to study entry and for six months following the duration of study participation. If a woman becomes pregnant or suspects she is pregnant while participating in the trial, she should inform her treating physician immediately.
• Pulmonary function tests: forced expiratory volume in one second (FEV1) and Carbon Monoxide Diffusion Capacity (DLCO) (adjusted for Hb) ≥ 50% from expected normal value.
• Patients should undergo cardiac evaluation with an electrocardiogram showing no ischemic changes or clinically relevant arrhythmia, and a ≥50% ejection fraction established by multigated acquisition scan or echocardiogram.
• ECG showing no ischemic changes or clinically significant arrhythmia.
• The time elapsed since the end of the last induction or reinduction cycle must be greater than or equal to 14 days.

Exclusion Criteria:

• Patients who have received a previous autologous (within the last year) or allogeneic transplant (at any time) are excluded.
• Previous radiation therapy which would preclude the use of TMLI.
• Plans during the trial to receive any other investigational (non-trial-related) agents.
• Uncontrolled disease, including ongoing or active infection.
• History of allergic reactions attributed to compounds of chemical or biological composition similar to cyclophosphamide or etoposide.
• Patients with other active malignancies are not eligible for this study, other than the malignancies discussed.
• Patients with a psychological or medical condition that the patient's physician deems unacceptable to proceed with allogeneic hematopoietic stem cell transplantation.
• Women who plan to become pregnant or breastfeed during the trial.
• Patients who do not agree to practice effective forms of contraception.
• Subjects who, in the opinion of the investigator, may not be able to meet the safety control requirements of the study.