Hematological malignancies (HM) are rare cancers that affect the blood and lymph system and can only be cured with transplantation of donor stem cells; namely allogeneic hematopoietic cell transplantation (HCT). While advancements have improved outcomes for younger and otherwise healthy patients, HCT can have devastating effects on the health-related quality of life (HRQOL) for older and medically infirm (vulnerable) patients with HM. We were the first to develop an HCT-specific comorbidity index (HCT-CI) that specifically showed that those with high scores can suffer from significant impairments in HRQOL and higher rates of morbidity and mortality after HCT compared to patients with lower comorbidity scores. Guided by our and others’ preliminary studies, we propose here to randomize those vulnerable patients between supportive and palliative care, clinical management targeting specific comorbidities, both approaches combined, vs. standard of care (SOC) to see which intervention can improve HRQOL of those patients after HCT. OBJECTIVES: (1) Evaluate in a randomized phase II study the effectiveness of the four approaches mentioned above in improving day-90 HRQOL for vulnerable recipients of allogeneic HCT; (2) determine in a phase III study whether the winner arm from phase II definitively improves HRQOL vs. SOC; and (3) compare the interventions with respect to survival, additional patient-reported outcomes, and the use of resources. METHODS: We will conduct a multi-center seamless phase II/III randomized clinical trial in five large transplant centers. The seamless feature means patients used in the phase II analysis will be included in the phase III analysis but that will only happen if phase II produces an intervention with a clear advantage over SOC. In Aim 1, we will enroll 300 patients who either have age of ≥65 years, HCT-CI scores of ≥3, and/or slow walk speed as indication of frailty, two weeks before they start their allogeneic HCT. Each intervention arm will be implemented over 10 weeks period, 2 weeks before and 8 weeks after HCT, to achieve the maximum benefit in preparing patients for HCT and guiding them through the early phases of the procedure. Patients will be randomly assigned to one of the four arms described above. If there is an intervention arm from phase II that improves HRQOL, then we will continue to test that arm only against SOC in a phase III study. We will only need an additional 300 vulnerable patients for phase III (total of 600 for phase II/III). In Aim 3, we will see if any of the interventions can improve survival, other patient-reported outcomes, and/or the use of resources. PATIENT OUTCOMES: This proposal is the first to compare these peri-transplant interventions in vulnerable HM patients given HCT. Results can minimize the suffering and, if possible, prolong the lives of similar patients in the future and world-wide. Results could also encourage physicians to offer transplants to more vulnerable patients, who are currently being denied the procedure for fear of its morbidity and mortality risks. Finally, the national overall use of healthcare resources could be improved for the benefit of other patients.