SEVERE HYPOFIBRINOGENEMIA ASSOCIATED WITH IMATINIB AND PREDNISONE THERAPY IN PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA
(Abstract release date: 05/18/17)
EHA Library. Sciumè M. 05/18/17; 182362; PB1648
Mariarita Sciumè
Contributions
Contributions
Abstract
Abstract: PB1648
Type: Publication Only
Background
Hypofibrinogenemia associated to acute lymphoblastic leukemia (ALL) is rare and usually due to L-asparaginase. Consumption coagulopathy or therapy-related hepatotoxicity are other possible explanations. Severe hypofibrinogenemia, not linked to the causes listed, was rarely reported and a role of steroid therapy on fibrinogen metabolism was suggested.
Aims
Our aim was to identify the incidence of severe hypofibrinogenemia during induction phase in a cohort of consecutive ALL patients and to assess its impact on clinical decision-making.
Methods
In order to avoid confounding factor due to L-asparaginase, we revised our cohort of Philadelphia chromosome–positive (Ph+) ALL that we treated according to pediatric-type therapy program (imatinib, intensive chemotherapy without L-asparaginase) for patients aged 18-65 years and through LAL0201-B protocol (imatinib, prednisone) for patients >65 years. We retrospectively analyzed coagulation tests on admission and during induction therapy of all Ph+ ALL patients diagnosed at our Institution from 2004.
Results
Twenty-one Ph+ ALL were identified; 17 patients were younger than 65 years, while the remaining 4 patients had a median age of 74 years (66-76). No alteration of plasma fibrinogen during induction was observed in younger patients. Severe hypofibrinogenemia (<100 mg/dl) was detected in 3 out of 4 Ph+ ALL over 65 years. In these patients induction consisted of prednisone 40 mg/m2/d from day 1 to 45 and imatinib at the fixed dose of 800 mg/d. On admission hemoglobin levels were >10 g/dl in all patients, leucocytes counts were 2x109/L (blasts 15%), 8x109/L (blasts 30%) and 18x109/L (blasts 61%), while platelet count was reduced in 2 cases (61x109/L and 65x109/L). Coagulation tests were normal (fibrinogen median level 380 mg/dl). Severe hypofibrinogenemia developed between 6 and 15 days after beginning treatment and lasted between 4 and 48 days. Fibrinogen nadir ranged from 47 to 100 mg/dL (median 61 mg/dL); reduced plasma fibrinogen levels at functional tests were also confirmed to immunological assays. During fibrinogen nadir, D-dimer was positive in all patients, but stable compared to the outset. Antithrombin, coagulation factors, activated partial thromboplastin and prothrombin time, common liver function tests remained in a normal range; platelet counts showed a trend to normalization. Early clearance of peripheral blood blasts was observed and when hypofibrinogenemia appeared no blast cells were detectable. At the end of induction bone-marrow evaluation demonstrated the absence of BCR-ABL transcript by qualitative RT-PCR. There were no bleeding events and only one patient received a prophylactic transfusion of fresh-frozen plasma (10 ml/kg) for fibrinogen <50 mg/dl on two occasions. Normal fibrinogen levels (>165 mg/dl) were recovered at the end of steroid therapy.
Conclusion
We observed severe hypofibrinogenemia in Ph+ ALL patients older than 65 years treated with imatinib and high-doses steroid, while normal fibrinogen levels were detected in younger Ph+ ALL during intensive chemotherapy plus imatinib. In our experience, hypofibrinogenemia was not associated to major bleeding events, although its clinical significance should be investigated in larger series. Fibrinogen may recognize multiple metabolic pathways, also unrelated to in vivo coagulation and fibrinolysis; the correspondence between steroid treatment and hypofibrinogenemia seems to suggest that glucocorticoids may alter some steps in fibrinogen kinetics and could be considered as a cause of acquired hypofibrinogenemia.
Session topic: 2. Acute lymphoblastic leukemia - Clinical
Keyword(s): Prednisone, Fibrinogen, Acute lymphoblastic leukemia
Abstract: PB1648
Type: Publication Only
Background
Hypofibrinogenemia associated to acute lymphoblastic leukemia (ALL) is rare and usually due to L-asparaginase. Consumption coagulopathy or therapy-related hepatotoxicity are other possible explanations. Severe hypofibrinogenemia, not linked to the causes listed, was rarely reported and a role of steroid therapy on fibrinogen metabolism was suggested.
Aims
Our aim was to identify the incidence of severe hypofibrinogenemia during induction phase in a cohort of consecutive ALL patients and to assess its impact on clinical decision-making.
Methods
In order to avoid confounding factor due to L-asparaginase, we revised our cohort of Philadelphia chromosome–positive (Ph+) ALL that we treated according to pediatric-type therapy program (imatinib, intensive chemotherapy without L-asparaginase) for patients aged 18-65 years and through LAL0201-B protocol (imatinib, prednisone) for patients >65 years. We retrospectively analyzed coagulation tests on admission and during induction therapy of all Ph+ ALL patients diagnosed at our Institution from 2004.
Results
Twenty-one Ph+ ALL were identified; 17 patients were younger than 65 years, while the remaining 4 patients had a median age of 74 years (66-76). No alteration of plasma fibrinogen during induction was observed in younger patients. Severe hypofibrinogenemia (<100 mg/dl) was detected in 3 out of 4 Ph+ ALL over 65 years. In these patients induction consisted of prednisone 40 mg/m2/d from day 1 to 45 and imatinib at the fixed dose of 800 mg/d. On admission hemoglobin levels were >10 g/dl in all patients, leucocytes counts were 2x109/L (blasts 15%), 8x109/L (blasts 30%) and 18x109/L (blasts 61%), while platelet count was reduced in 2 cases (61x109/L and 65x109/L). Coagulation tests were normal (fibrinogen median level 380 mg/dl). Severe hypofibrinogenemia developed between 6 and 15 days after beginning treatment and lasted between 4 and 48 days. Fibrinogen nadir ranged from 47 to 100 mg/dL (median 61 mg/dL); reduced plasma fibrinogen levels at functional tests were also confirmed to immunological assays. During fibrinogen nadir, D-dimer was positive in all patients, but stable compared to the outset. Antithrombin, coagulation factors, activated partial thromboplastin and prothrombin time, common liver function tests remained in a normal range; platelet counts showed a trend to normalization. Early clearance of peripheral blood blasts was observed and when hypofibrinogenemia appeared no blast cells were detectable. At the end of induction bone-marrow evaluation demonstrated the absence of BCR-ABL transcript by qualitative RT-PCR. There were no bleeding events and only one patient received a prophylactic transfusion of fresh-frozen plasma (10 ml/kg) for fibrinogen <50 mg/dl on two occasions. Normal fibrinogen levels (>165 mg/dl) were recovered at the end of steroid therapy.
Conclusion
We observed severe hypofibrinogenemia in Ph+ ALL patients older than 65 years treated with imatinib and high-doses steroid, while normal fibrinogen levels were detected in younger Ph+ ALL during intensive chemotherapy plus imatinib. In our experience, hypofibrinogenemia was not associated to major bleeding events, although its clinical significance should be investigated in larger series. Fibrinogen may recognize multiple metabolic pathways, also unrelated to in vivo coagulation and fibrinolysis; the correspondence between steroid treatment and hypofibrinogenemia seems to suggest that glucocorticoids may alter some steps in fibrinogen kinetics and could be considered as a cause of acquired hypofibrinogenemia.
Session topic: 2. Acute lymphoblastic leukemia - Clinical
Keyword(s): Prednisone, Fibrinogen, Acute lymphoblastic leukemia
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