Implementing DPYD*2A Genotyping in Clinical Practice: The Quebec, Canada, Experience.

BACKGROUND: Fluoropyrimidines are used in chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. DPYD*2A polymorphism is one of the most studied variants. The study objective was to document the impact of implementing this test in routine clinical practice. METHODS: We retrospectively performed chart reviews of all patients who tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec, Canada. RESULTS: During a period of 17 months, 2,617 patients were tested: 25 patients tested positive. All were White. Twenty-four of the 25 patients were heterozygous (0.92%), and one was homozygous (0.038%). Data were available for 20 patients: 15 were tested upfront, whereas five were identified after severe toxicities. Of the five patients confirmed after toxicities, all had grade 4 cytopenias, 80% grade ≥3 mucositis, 20% grade 3 rash, and 20% grade 3 diarrhea. Eight patients identified with DPYD*2A mutation prior to treatment received fluoropyrimidine-based chemotherapy at reduced initial doses. The average fluoropyrimidine dose intensity during chemotherapy was 50%. No grade ≥3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation. CONCLUSION: Upfront genotyping before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A. IMPLICATIONS FOR PRACTICE: Fluoropyrimidines are part of chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. This retrospective analysis demonstrates that upfront genotyping of DPYD before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. This approach was reported previously, but insufficient data concerning its application in real practice are available. This is likely the first reported experience of systematic DPYD genotyping all over Canada and North America as well.

Romiplostim efficacy in an acute myeloid leukemia patient with transfusion refractory thrombocytopenia.

BACKGROUND: Refractoriness to platelet (PLT) transfusion is a feared, life-threatening complication in hematology-oncology patients. Despite increased PLT requirement and treatment costs, the clinical management is difficult and these patients had less favorable outcomes. CASE REPORT: We report on the efficacy of the thrombopoietic agent romiplostim in a patient with acute myeloid leukemia with chemotherapy-induced transfusion-refractory thrombocytopenia. CONCLUSION: Romiplostim could be very helpfull in the management of AML patients with transfusion refractory thrombocytopenia.

Bone Marrow Immunohistochemistry and Flow Cytometry in the Diagnosis of Malignant Hematologic Diseases With Emphasis on Lymphomas: A Comparative Retrospective Study.

We aim to evaluate the degree of agreement between immunohistochemistry (IHC) and flow cytometry (FC) in the diagnosis of malignant hematologic diseases, mainly lymphomas. A total of 260 bone marrow biopsies, 255 bone marrow aspirates, and 5 other suspensions of 260 patients used for diagnosis of a hematologic malignancy between 2009 and 2012 with both, IHC and FC, were retrospectively analyzed. Overall there is a substantial degree of agreement (κ=0.69) between IHC and FC. Chronic lymphocytic leukemia/small lymphocytic lymphoma, mature T-cell neoplasms, acute leukemias, and myelodysplastic syndromes had the highest concurrence rates (>80%). In nonconcordant cases, an IHC provided diagnosis in 25.4%, and an FC in 4.6%. Lymphomas were diagnosed by an IHC only in 51% of the cases. Both methods have good concurrence rates and are complementary. An IHC has the advantage of combining markers, morphology, and tissue immunoarchitecture, which is beneficial in the diagnosis of lymphomas. An FC is required in leukemias as it is faster and plays an important role in minimal residual disease.

Retrospective Study of High Hemoglobin Levels in 56 Young Adults.

BACKGROUND: Erythrocytosis is a frequent request for consultation in the hematologic field. The diagnostic approach is well established in the general population but in a young adult, finding the etiology of erythrocytosis can be a real diagnostic challenge. METHODS: This is an observational retrospective unicentric study made at the Sherbrooke University Hospital Center, over a period of 20 years (1995 - 2015). Every patient aged between 16 and 35 years old with a significant elevation of hemoglobin or hematocrit was included (hemoglobin > 185 g/L and/or hematocrit > 0.52 in men; hemoglobin > 165 g/L and/or hematocrit > 0.48 in women). RESULTS: Totally, 426 patients met the inclusion criteria (over a total of 113,453 complete blood counts) but only 56 entered the study for investigations. The majority of patients were of male gender, 43% of the patients were obese, 59% were smokers and 38% used excess alcohol or recreational drugs. Twenty-five patients had the diagnosis of absolute erythrocytosis. Seven patients had the diagnosis of relative erythrocytosis and no cause could be identified in 24 patients. No primary erythrocytosis was found in this cohort. Among the 25 patients with secondary erythrocytosis, hypoxia was the most frequent etiology identified. Less than half of the patients in the cohort had long term follow-up. Search for JAK2 mutation and serum EPO dosage were performed in 17.9% and 23.2% of cases respectively. Seven patients were treated with aspirin and five patients had phlebotomies. CONCLUSIONS: This retrospective study reveals an actual clinical management that is often discordant with the current recommendations and a frequent lack of follow-up after initial investigations. Harmonization of management of erythrocytosis appears to be highly desirable.

Pressure Infusion Cuff and Blood Warmer during Massive Transfusion: An Experimental Study About Hemolysis and Hypothermia.

BACKGROUND: Blood warmers were developed to reduce the risk of hypothermia associated with the infusion of cold blood products. During massive transfusion, these devices are used with compression sleeve, which induce a major stress to red blood cells. In this setting, the combination of blood warmer and compression sleeve could generate hemolysis and harm the patient. We conducted this study to compare the impact of different pressure rates on the hemolysis of packed red blood cells and on the outlet temperature when a blood warmer set at 41.5°C is used. METHODS: Pressure rates tested were 150 and 300 mmHg. Ten packed red blood cells units were provided by Héma-Québec and each unit was sequentially tested. RESULTS: We found no increase in hemolysis either at 150 or 300 mmHg. By cons, we found that the blood warmer was not effective at warming the red blood cells at the specified temperature. At 150 mmHg, the outlet temperature reached 37.1°C and at 300 mmHg, the temperature was 33.7°C. CONCLUSION: To use a blood warmer set at 41.5°C in conjunction with a compression sleeve at 150 or 300 mmHg does not generate hemolysis. At 300 mmHg a blood warmer set at 41.5°C does not totally avoid a risk of hypothermia.

A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer.

INTRODUCTION: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. METHODS: Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75mg/m(2) IV every 21days) with or without PX-866 (8mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. RESULTS: 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P=0.13). Median PFS was 92days in Arm A and 82days in Arm B (P=0.42). There was no difference in OS between the two arms (263 vs. 195days; P=0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed. CONCLUSION: The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.