Trial Information

Clinical Practice in the Prophylaxis and Treatment of Arterial and Venous Thromboembolism in Patients With hEmatological NEoplasms and LOw PlatElets (PENELOPE Observational Study)

Illness treatment overview The incidence of venous thromboembolism (VTE) among patients with
haematological malignancies has been recently reviewed (1). For patients with lymphoma, the
incidence of VTE ranged from 1.5 to 14.6% and is 59% in patients with central nervous system
lymphoma. The incidence of VTE in patients with acute leukaemia varies with time, being
between 1.4 and 9.6% at diagnosis and between 1.7 and 12% during induction therapy. Notably,
the highest rates of VTE were reported in patients with acute promyelocytic leukaemia, with
values between 6 and 16% in the largest series. In patients with multiple myeloma who did
not receive antithrombotic prophylaxis, the rate of VTE increased to 26% in those undergoing
treatment regimens including immumodulatory drugs (thalidomide and lenalidomide) (1).
Moreover, in patients who have undergone autologous or allogeneic haematopoietic stem cell
transplantation (HSCT), the rate of VTE is between 2.9 to 9.9%, and was central venous
catheter (CVC)-associated in the majority of cases (2-4). VTE has been shown to occur even
during periods of severe thrombocytopenia; one-third of the events from a patient series
occurred when the platelet count was <50 x109/L (3). Patients with acute leukaemia have a
high risk of haemorrhage, mostly related to thrombocytopenia as a result of haematological
disease and/or chemotherapy, such that the administration of anticoagulant drugs in this
setting is problematic. No randomised controlled trials have addressed the issue of VTE
treatment in patients with acute leukaemia, and the management of these cases is based only
on small groups of patient series or experts' opinion. Five reports have described in detail
cases of paediatric or adult patients with malignancies and thrombocytopenia who have been
treated with heparin as a result of a VTE (5-9). Out of a total of 54 cases, 32 had
haematological malignancies and a platelet nadir <50 x109/L (reviewed in ref. 10). The
majority of patients (22 of 32) had CVC-related thrombosis. A full dose of low molecular
weight heparin (LMWH) bid was administered to the majority of the patients with CVC-related
thrombosis and to the totality of patients for whom the thrombosis was not CVC-related. All
patients received platelet transfusions if the platelet count fell below <20-40 x109/L, and
the dose of LMWH was halved when the platelet count was <20 x109/L in one report. None of
the patients had major bleeding. Rethrombosis occurred in three of 32 (9.3%) patients (6,7).
In a large series of 379 patients with acute leukaemia, treatment for 20 patients who had
one (n=16) or two (n= 4) VTE events was essentially based on the administration of
enoxaparin 100 U/kg bid; in the case of a platelet count <50 x109/L or in the clinical
suspicion of bleeding risk the dose was reduced to 100 U/kg qd or 50 U/kg bid.
Alternatively, the patients received a continuous i.v. infusion of unfractionated heparin
(UFH) to obtain aPTTs in the lower therapeutic range (1.5 times greater than the basal
value). Secondary prophylaxis after acute VTE was based on the administration of enoxaparin
100 U/kg qd in the case of ongoing chemotherapy or vitamin K-antagonists (VKA) (INR between
2 and 3) otherwise. In general, the length of secondary prophylaxis was reported to be not
longer than six months (11). The safety of therapeutic anticoagulation treatment for the
management of thrombocytopenic patients was also evaluated in two series of patients
receiving HSCT (12,13). In 10 patients with multiple myeloma who had received autologous
HSCT, anticoagulation was required following pre-transplant CVC-related subclavian vein
thrombosis (n= 8), pulmonary embolism two months prior to transplant (n= 1), or a history of
acute intermittent atrial fibrillation that was complicated by an arterial embolus to the
leg (n= 1). Beginning on the first day of high-dose chemotherapy, the 10 patients received
therapeutic UFH (a 5,000 U i.v. bolus followed by 1,000 U per h) to maintain aPTTs between
50 and 70 seconds and were switched to VKA treatment when their conditions stabilised. UFH
treatment was interrupted once the VKA administration produced a therapeutic INR >2 for two
consecutive days. Heparinised patients received platelet transfusions to maintain counts >30
x109/L. Three patients developed bleeding (haematuria, haematemesis, mucosal bleeding) that
did not not require transfusion, and no thrombotic events occurred (12). In another series
of 26 patients with HSCT who were given enoxaparin for the treatment of VTE, 21 patients had
haematological malignancies. There were 25 VTE events recorded (four patients had two events
at different sites) and 11 cases had upper extremity CVC-related deep venous thrombosis.
During periods of thrombocytopenia (<55 x109/L), enoxaparin administration was reduced to a
median value of 49 U/kg/day (range 34-75) and was withdrawn in some instances when the
platelet count fell below 20 x109/L. Two major bleeding events (8%) occurred, in one case
fatal (13). The aforementioned data are insufficient for the production of evidence-based
guidelines. Experts and the AIEOP (Associazione Italiana di Ematologia e Oncologia
Pediatrica) have suggested that the first two weeks of treatment should consist of the
administration of full-dose LMWH (anti-factor Xa level 0.5-1 U/ml), maintaining the
platelet count above 50 x109/L. After the first two weeks, halving the dose is recommended
if the platelet count is between 20 and 50 x109/L. If the platelet count is below 20 x109/L,
it is advised that the LMWH therapy be discontinued until the platelet count recovers to
greater than 20 x109/L (14-16). Recent guidelines of the SISET (Società Italiana per lo
Studio dell'Emostasi e della Trombosi) also suggested that in patients with haematological
malignancies and VTE LMWH should be preferred over VKA either for the first six months or a
longer time (17). Arterial thrombosis has been rarely reported in patients with acute
leukemia as heralding manifestation or complicating the course of disease (18-21). However,
details concerning antithrombotic treatment and the platelet count at the time of the event
are lacking in the majority of the reported cases. There have been no published studies
concerning the use of novel antithrombotic agents such fondaparinux, direct thrombin or
factor Xa inhibitors, in patients with haematological malignancies or thrombocytopaenia.
However, in vitro experiments that have been performed on plasma from children with ALL and
antithrombin deficiency as a result of the administration of asparaginase have demonstrated
that the direct thrombin inhibitor melagatran generates a consistent anticoagulant response
that is independent of the antithrombin level. Therefore, this drug class may have important
potential for use in this field (22).

Rationale Data about treatment of arterial or venous thromboembolism in patients with
haematological malignancies and thrombocytopenia are mainly anecdotal. The very limited
knowledge in this setting does not allow to plan a randomized controlled trial, lacking a
standard of care and being quite uncertain the benefits and risks of different strategies.
Therefore we planned an observational study either retrospective and prospective to gain
information about efficacy and safety of different therapeutic strategies in patients with
hematologic neoplasms and platelet count <50 x109/L having had diagnosis of arterial or
venous thromboembolism.