TITLE:

Prospective observational study to determine bleeding risk and platelet transfusion requirements in haematological malignancies.

INTODUCTION AND BACKGROUND

Patients presenting with haematological malignancies are at a high risk of bleeding, both due to the disease and its treatment. Anemia, deranged coagulation profile, underlying infection, febrile neutropenia, hyperleukocytosis are some of the known risk factors that in addition to thrombocytopenia contribute to the heightened risk of bleeding in these group of patients.

A recent cochrane review dated September 2015, titled ‘Platelet transfusion to treat bleeding compared with platelet transfusion to prevent bleeding in people with blood cancers receiving intensive treatment’, has reviewed 6 studies and concluded that prophylactic transfusions reduce bleediing and therapeutic transfusion reduces the total number of blood products transfused, but no increased risk of death or adverse events in the therapeutically treated group. Although the author has exercised caution by saying that the quality of evidence was low to moderate and none of these studies reported on the quality of life. [1]

Recent data indicate that platelet transfusions may have an effect both on inflammatory reactions and modulate the immune system so as to have a potentially negative impact on the prognosis of malignant diseases. [2]

Also an original paper published in Cancer Microenvironment (2014), titled – ‘Platelets Promote Mitochondrial Uncoupling and Resistance to Apoptosis in Leukemia cells: A novel Paradigm for the bone marrow microenvironment’, reported that leukemia cell lines and primary and primary CD34+ leukemic blasts exposed to platelet rich plasma or platelet lysates display increased resistance to apoptosis induced by mitochondrial targeted agents  ABT-737 and CDDO-Me. [3]

Given this background, are a few widely debated topic in the treatment of hematological malignancies of therapeutic versus prophylactic use of platelets and who gets them, at what platelet triggers and at what dose. [4] [5] [6]

With the aim of correlating platelet counts with clinical decisions, the authors of the article, ‘The Bleeding Risk Index’, developed a clinical prediction rule to guide the prophylactic use of platelet transfusions among patients with lymphomas or solid tumors.In this study factors that were predictive of bleeding included any prior episode of bleeding, treatment with a drug affecting platelet function, bone marrow metastases, a baseline platelet count ˂ 75,000 per µL, genitourinary or gynecologic malignancy, a Zubrod performance status score ˃ 2 and treatment with agents that were highly toxic to the bone marrow. Compared with 20,000 and 10,000 platelet threshold

strategies, theBRI-based strategy provided the best trade-off between sensitivity for major bleeding episodes (80%) and specificity for any bleeding (84%).[7]

Also the authors of the study, ‘A Risk Model for Thrombocytopenia Requiring Platelet Transfusion After Cytotoxic Chemotherapy’ did a univariate and multivariate analysis of risk factors for chemotherapy-induced thrombocytopenia requiring platelet transfusions on the cohort of the 1,051 patients (CLB 1996 ) treated with chemotherapy in the Department of Medicine of the Centre Leon Berard (CLB) in 1996. In univariate analysis, performance status (PS) greater than 1, platelet count ˂ 150,000/µL at day 1 (d1) before the initiation of chemotherapy, d1 lymphocyte count I700/µL, d1 polymorphonuclear leukocyte count ˂ 1,500/µL, and the type of chemotherapy (high risk v others) were significantly associated (P ˂ .01) with an increased risk of severe thrombocytopenia requiring platelet transfusions. Using logistic regression, d1 platelet count less than 150,000/µL, d1 lymphocyte counts ˂ I700/µL, the type of chemotherapy, and PS greater than 1 were identified as independent risk factors for platelet transfusions. The observed incidences of platelet transfusions were 45%, 13%, 7%, and 1.5% for patients with ≥ 3, 2, 1, or 0 risk factors, respectively. This model was then tested in 3 groups of patients treated with chemotherapy used as validation samples: (1) the series of 340 patients treated in the CLB in the first 6 months of 1997, (2) the prospective multicentric cohort of 321 patients of the ELYPSE 1 study, and (3) the series of 149 patients with non-Hodgkin’s lymphoma treated in the CLB within prospective phase III trials (1987 to 1995). In these 3 groups, the observed incidences of platelet transfusions in the above defined risk groups did not differ significantly (P ˃ .1) from those calculated in themodel. This risk index could be useful to identify patients at high risk for chemotherapy-induced thrombocytopenia requiring platelet transfusions. [8]

AIMS AND OBJECTIVES:

Primary

To determine the factors predicting bleeding risk in hematological malignancies and thereby to arrive at a ‘bleeding risk index’.

Secondary

1) To revisit the prophylactic thresholds for various co morbidities, namely: febrile neutropenia, fungal pneumonia, oral mucositis in adults and sepsis.

2) % of outpatients with stable thrombocytopenia and platelet count above 20k/µl, who were given platelets.

3)% of inpatients with stable thrombocytopenia and platelet count above 10k/µl, who were given platelets.

4) To correlate all bleeding episodes with coagulation profile (when available on EMR) in addition to the platelet count and other contributory factors.

5) To correlate the grade of bleeding (WHO grades) and the platelet counts at which they occurred.

STUDY DESIGNS AND METHODS:

TARGET POPULATION/INCLUSION CRITERIA:

Patients between age 8 and 60 years presenting to TMH, Parel with de novo hematological malignancy (newly diagnosed and not having received chemotherapy outside) and who will be treated with curative intent.

EXCLUSION CRITERIA:

1) Those will myelodysplastric syndromes.

2) Those with secondary leukemias.

3) Those who have received prior chemotherapy.

Material and Methods:

Approximately 100newly diagnosed patients (a convenient number for follow up) equally divided among the adult and pediatric population will be part of the observational study based on the above criteria. These patients will be primarily followed primarily from the EMR and when required information will be sought from the treating doctors. Individual patient assessment form will be filled up for each new patient who is a part of the observational study and will be followed for two chemotherapy phases i.e induction and the phase following it.

Patient assessment form will include a brief history during admission, which will be obtained from the EMR and will include the duration of illness at the time of presentation and any transfusion history during that period.

Also the performance status during at the time of admission in the form of ECOG score will be noted from the EMR.

Diagnostic findings at time of admission will be obtained from EMR and include the baseline CBC and a look for underlying infections esp. fungal pneumonia (based on chest CT or X ray findings). Serum creatinine and serum albumin (as a marker of liver function and nutritional status), will be noted from EMR.

Type of leukemia will be documented from the diagnostic studies performed.

Any transfusion requirements before commencement of induction phase will be noted.

All occasions requiring a transfusion during induction and the subsequent phase will be noted for the indication and lab investigations available at that time (Hb, WBC count, Plt count, PT/INR & D-dimer) from EMR. The indication if not mentioned on the request form will be sought from the treating doctor.