Red Cell Transfusion Goals in Patients With Acute Leukemias

Prospective Randomized Clinical Feasibility Study of Red Cell Transfusion Goals in Patients With Acute Leukemias

The purpose of this study to determine if a lower hemoglobin transfusion threshold, 7 g/dL, has a safety profile similar to that of the current standard transfusion threshold of 8 g/dL.

Transfusion of red blood cells (RBCs) is vitally important for the care of patients undergoing myelosuppressive therapy for acute leukemia. The therapeutic approach to this disease involves the use of high doses of chemotherapy to treat the blood cancers and bone marrow disorders; but it damages the marrow and blood system. Malignant and healthy stem cells are affected by the chemotherapy, and even when the malignant cells are killed, it can take weeks for the healthy cells to reconstitute the marrow. At diagnosis and before bone marrow recovery post treatment, RBCs are needed to support the patient. Current practices at major comprehensive cancer centers all utilize liberal hemoglobin transfusions triggers of 8-9 g/dL or higher. Higher hemoglobin levels in these high risk patients may have benefits such as better energy and organ function. However, research in a variety of clinical settings, suggests that a higher hemoglobin transfusion threshold is associated with the same or even higher mortality rates compared to lower hemoglobin thresholds (7-8 g/dL). These other settings include prospective randomized trials in high-risk orthopedic surgery patients, critically ill adult and pediatric ICU patients, acute GI bleed patients, and patients undergoing cardiac surgery. One clinical scenario where the ideal transfusion threshold is unknown is in patients receiving chemotherapy for hematologic malignancies. Transfusion requirements and triggers have not been systematically studied in acute leukemia or other cancers. Acute leukemia carries a high mortality; any unnecessary increase in morbidity or mortality is not acceptable. Without a clear benefit of higher transfusion thresholds, the added risks and costs of transfusion may be substantial and unnecessary. The investigators plan to study this issue in this pilot and feasibility study by randomly assigning patients treated for acute leukemia to be transfused with RBCs at either a higher or lower hemoglobin concentration trigger point. In this way, the investigators will be able to accurately determine if there is benefit or harms to having a lower or higher red cell count during the induction treatment and recovery period for patients with acute leukemias. This study will also collect information evaluating the advantages and disadvantages of the two transfusion thresholds and the feasibility of expanding the study to a large randomized trial.This safety data will serve as a platform for a larger mortality study in leukemia and possibly additional studies in solid tumors.

Acute Lymphoblastic Leukemia, Acute Lymphocytic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Acute Promyelocytic Leukemia (APL)

Patients receive red blood cell transfusions with a transfusion threshold of 7 g/dL hemoglobin (Hb). Transfusions will not be given on schedule but will be given whenever Hb dips below the threshold.

Patients receive red blood cell transfusions with a transfusion threshold of 8 g/dL hemoglobin (Hb). Transfusions will not be given on schedule but will be given whenever Hb dips below the threshold.

Tolerance of low transfusion threshold as assessed by the percentage of participants who crossed over from the low arm to the high arm.

Safety of low vs. high transfusion threshold as assessed by total difference in number of transfusions given per participant

Overall safety is determined by the total difference between arms for the number of transfusions given per participant

Safety of low vs. high transfusion threshold as assessed by number of participants experiencing neutropenic infections

Overall safety is determined by the total difference between arms for number of participants experiencing neutropenic infections, where neutropenia is defined as absolute neutrophil count < 500/mcL.

Safety of low vs. high transfusion threshold as assessed by number of grade 3-4 bleeding events as defined by CTCAE 4.0

Safety of low vs. high transfusion threshold as assessed by number of deaths attributed to induction chemotherapy

Safety of low vs. high transfusion threshold as assessed by number of participants with at least one grade 3-5 non-hematological toxicity by CTCAE 4.0.

As per protocol-defined criteria, the transfusion strategy being tested would be deemed feasible if all of the following criteria are met: 1) More than 50% of eligible patients could be consented; 2) More than 75% of participants randomized to the low arm tolerated the 7 g/dL transfusion threshold; 3) Fewer than 15% of participants crossed over from the low arm to the high arm; 4) The study was not paused for safety concerns.

As per protocol-defined criteria, the transfusion strategy being tested would be deemed feasible if all of the following criteria are met: 1) More than 50% of eligible patients could be consented; 2) More than 75% of participants randomized to the low arm tolerated the 7 g/dL transfusion threshold; 3) Fewer than 15% of participants crossed over from the low arm to the high arm; 4) The study was not paused for safety concerns.

Feasibility as determined by percentage of participants who crossed over from the low arm to the high arm

As per protocol-defined criteria, the transfusion strategy being tested would be deemed feasible if all of the following criteria are met: 1) More than 50% of eligible patients could be consented; 2) More than 75% of participants randomized to the low arm tolerated the 7 g/dL transfusion threshold; 3) Fewer than 15% of participants crossed over from the low arm to the high arm; 4) The study was not paused for safety concerns.

Number of participants in each arm experiencing neutropenic infections, where neutropenia is defined as absolute neutrophil count < 500/mcL.

Median length of inpatient stay in days. This is for the initial inpatient stay for induction chemotherapy only (chemotherapy itself was not part of this protocol).

Number of participants with at least one grade 3-5 nonhematological toxicity as defined by CTCAE 4.0.

Number of participants with Eastern Cooperative Oncology Group (ECOG) performance status < 2. The ECOG scale is rated from 0 to 5, where 0 is best health and 5 is dead.

Number of participants who crossed over from the low to the high arm due to symptomatic anemia (defined as Hb < 8 g/dL with symptoms).

Estimated per-patient cost savings of the low transfusion threshold compared to the high transfusion threshold.

Median difference in fatigue scores as graded on the National Cancer Institute Fatigue Scale. Scores are from 0 to 10, where 0 is no fatigue and 10 is the worst possible fatigue.

Inclusion Criteria: Acute leukemia patients (AML, ALL, APL, treatment-related myeloid neoplasm, high grade MDS) Admitted with plans for inpatient myelosuppressive chemotherapy (with standard of care or protocol regimens) Exclusion Criteria: Age less than 18 years Acute coronary syndrome as defined by active chest pain, dynamic ECG changes, troponin greater than 2.5 Active blood loss Receiving erythropoietin stimulating agents prior to admission Chronic Renal Failure in Renal Replacement Therapy Documented wish against transfusion for personal or religious beliefs

DeZern AE, Williams K, Zahurak M, Hand W, Stephens RS, King KE, Frank SM, Ness PM. Red blood cell transfusion triggers in acute leukemia: a randomized pilot study. Transfusion. 2016 Jul;56(7):1750-7. doi: 10.1111/trf.13658. Epub 2016 May 20. Erratum In: Transfusion. 2016 Dec;56(12 ):3150.

Carson JL, Stanworth SJ, Dennis JA, Trivella M, Roubinian N, Fergusson DA, Triulzi D, Doree C, Hebert PC. Transfusion thresholds for guiding red blood cell transfusion. Cochrane Database Syst Rev. 2021 Dec 21;12(12):CD002042. doi: 10.1002/14651858.CD002042.pub5.