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Anemia, Refractory

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Acute Promyelocytic Leukemia

Martin Tallman, MD

Guido Marcucci, MD

Alan Burnett, MD

Hartmut Doehner, MD

Bob Lowenberg, MD

This clinical study will demonstrate the accuracy of the chromosomal aberration and gene mutation markers of the AMLProfiler molecular diagnostic assay and generate clinical performance data to support a Pre-Market Approval (PMA) submission to the Food and Drug Administration for in vitro diagnostic use within the United States of America.

The objective is to demonstrate the positive and negative percent agreement of each marker by comparing AMLProfiler results from multiple clinical participating sites with data generated using a laboratory developed bi-directional sequencing method generated at the molecular diagnostic reference lab.

The AMLProfiler assay is a qualitative in vitro diagnostic test for the detection of AML or APL specific chromosomal aberrations (specific recurrent translocations and inversions), as well as expression of specific genetic markers in RNA extracted from bone marrow aspirates of patients with Acute Myeloid Leukemia.

RNA from bone marrow samples will be retained.

Accuracy Testing of the Chromosomal Aberration and Gene Mutation Markers of the AMLProfiler

The acceptance criteria based on lower level of the 95% CI of the positive or negative percent agreement for all markers.

Illumina, Inc.

Skyline Diagnostics BV

Immune System Diseases

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Lymphosarcoma

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

All Drugs and Chemicals

Chrysarobin

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.

Red blood cell transfusion

Amy DeZern, MD, MHS

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.

Red Cell Transfusion Goals in Patients With Acute Leukemias

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

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

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.

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.

Median number of red cell and platelet transfusions given per participant.

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

Number of grade 3-4 bleeding events as defined by CTCAE 4.0.

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 deaths attributed to induction chemotherapy.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Accuracy Testing of the Chromosomal Aberration and Gene Mutation Markers of the AMLProfiler	NCT01463410	Acute Myeloid L... Acute Promyeloc... Refractory Anem...		18 Years -	Skyline Diagnostics BV
Accuracy Testing of the Chromosomal Aberration and Gene Mutation Markers of the AMLProfiler	NCT01463410	Acute Myeloid L... Acute Promyeloc... Refractory Anem...		18 Years -	Skyline Diagnostics BV
Red Cell Transfusion Goals in Patients With Acute Leukemias	NCT02086773	Acute Lymphobla... Acute Lymphocyt... Acute Myelogeno... Acute Promyeloc...	Red blood cell ...	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Red Cell Transfusion Goals in Patients With Acute Leukemias	NCT02086773	Acute Lymphobla... Acute Lymphocyt... Acute Myelogeno... Acute Promyeloc...	Red blood cell ...	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Spots Global Cancer Trial Database for acute promyelocytic leukemia (apl)