Background: Allogeneic stem cell transplantation (alloSCT) remains the only curative treatment option for patients with myelofibrosis (MF). The selective JAK2/IRAK1/ACVR1 inhibitor pacritinib (PAC) is effective in reducing spleen size and MF-related symptoms. We hypothesize that, because of its differential kinome profile, PAC pre-treatment before alloSCT improves outcomes in MF patients, potentially by diminishing NF-kB regulated inflammatory cytokine and graft-versus-host disease (GVHD) and by reducing the rate of primary (PGF) and secondary graft failure (SGF). Aims: Primary objective was to investigate the effect of pre-transplant PAC on the outcomes of alloSCT with uniform conditioning regimen in MF. Primary endpoint was the proportion of patients with a failure (PGF, SGF, grade 3-4 acute GVHD, and death of any cause) within 180 days post-transplant. Secondary endpoints included the safety profile of PAC, response rate, relapse and non-relapse mortality (NRM). Methods: MF patients (primary, post-ET, post-PV) aged 18-70 years with an intermediate-2 or high risk DIPSS Plus score and platelet count ≥25x109/L were included to receive 3-4 cycles of PAC (BID 200 mg, 1 cycle 28 days, stopped one day before conditioning) before proceeding to alloSCT with busulfan, fludarabine and anti-T lymphocyte globulin (Grafalon-Neovii) conditioning. Ruxolitinib treatment was allowed if it was stopped before initiation of PAC. Patients with disease progression or without a suitable HLA-identical sibling donor or 10/10 matched unrelated donor went off protocol before alloSCT. GVHD prophylaxis consisted of mycophenolate mofetil (day 0 to 28) and cyclosporine A (day -3 to 100, followed by tapering). Results: 61 eligible patients (64% JAK2 mutated and 62% JAK2-inhibitor naïve) were included, of whom 38 (62%) proceeded to alloSCT according to protocol and completed a minimum of 6-month post-transplant follow-up. 23 (38%) patients went off protocol before alloSCT (adverse events, not PAC related [n=4] and possibly PAC related [n=2], progressive disease [n=1], death [n=2], no suitable donor [n=7] or other reason [n=7]), of whom 2 (9%) continued PAC in follow-up and 20 (87%) still received an alloSCT (off protocol). Of the transplanted patients within the protocol, 6 (16%) had an event for the primary endpoint: one (3%) SGF and 5 (13%) deaths (all NRM). Three patients received a stem cell boost or donor lymphocyte infusion before an event at day 180 could have occurred. Figure 1 shows overall survival from inclusion and GVHD-free, relapse-free survival post-transplant after a median follow-up of 32.9 months (range, 9.4-52.7). The 1-year cumulative incidence of acute GVHD grade 3 or 4 was 3%, while moderate and severe chronic GVHD were 38% and 24% respectively. 3-4 cycles of PAC resulted in a symptom response (>50% reduction in MPN-SAF-TSS) before alloSCT in 31% of patients, and a reduction of spleen size below the lower costal margin from median 9 cm (interquartile range [IQR], 5-14) to median 4 cm (IQR, 3-10). PAC dose modification for hematological and gastro-intestinal toxicity was necessary in 9 (15%) and 2 (3%) patients, respectively; 39 (61%) patients were able to tolerate the 200 mg BID dose throughout the treatment period. Summary/Conclusion: Treatment with the JAK2/IRAK1/ACVR1 inhibitor PAC at a 200 mg BID dose is a safe and effective pre-transplant strategy for patients with MF. In this phase II HOVON-134 trial, we have shown a low incidence of 6-month post-transplant failure (including PGF, SGF, grade 3-4 acute GVHD and death) compared with historical controls.Keywords: Hematopoietic cell transplantation, Janus Kinase inhibitor, Reduced intensity transplantation, Myelofibrosis
Coronavirus disease 19 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can be associated with changes in platelet count [1, 2]. Thrombocytopenia has been reported in up to 40% of COVID-19 infections [3-5] and is an important marker for morbidity and mortality [1, 2, 5]. Hence, monitoring of platelet counts is important in diagnosis and treatment of COVID-19 patients. Thrombocytopenia can be a result of the COVID-19 infection itself (septicaemia), diffuse intravascular coagulation (DIC), medication or a COVID-19-associated immune thrombocytopenic purpura (ITP) [6]. A rare and often missed alternative explanation of thrombocytopenia is pseudothrombocytopenia [7]. Pseudothrombocytopenia or spurious thrombocytopenia is an in vitro phenomenon of platelet agglutination caused by an anticoagulant, usually ethylenediaminetetraacetic acid (EDTA), resulting in a falsely lowered automated platelet count [8]. The mechanism of pseudothrombocytopenia is not clearly defined, but it is suggested to be an immunologically mediated phenomenon of platelet clumping due to the formation of immune complexes between naturally occurring autoantibodies and cryptic epitopes of the glycoprotein IIb/IIIa complex on the platelet membrane that are exposed by the EDTA anticoagulant used for routine blood sample collections [9]. This phenomenon has been previously reported to be associated with autoimmune diseases and infections [10], such as hepatitis A [11], mononucleosis [12] and Plasmodium falciparum malaria [13]. It has a reported incidence between 0.03% and 0.27% among the general population [14]. Here, we report the first patient with pseudothrombocytopenia related to COVID-19 infection and its natural course. Our patient is a 54-year-old woman with a history of sarcoidosis diagnosed in October 2019, for which she was still being treated with daily prednisolone 7.5 mg (December 2019) and weekly methotrexate 12.5 mg (January 2020). She previously had a stable normocytic anaemia and normal platelet counts. Approximately 10 days after onset of respiratory symptoms, she presented with progressive respiratory failure (and a need for high-flow oxygen therapy) secondary to COVID-19 bilateral pneumonia with a positive SARS-CoV-2 polymerase chain reaction (PCR) test on day of presentation in our hospital. After a chest CT-angiography scan excluded pulmonary embolism, empirical treatment according to local protocol with dexamethasone (prednisolone was discontinued on admission), ceftriaxone, ciprofloxacin and prophylactic low-molecular weight heparin (nadroparin) was started. A full blood count on the day of presentation showed a stable haemoglobin level of 9.9 g/dl, with normal leukocyte (7.0 × 109/L) and platelet (236 × 109/L) counts. The following day, a marked fall in platelet count to 54 × 109/L was noted (measured with the Coulter impedance method on EDTA)—a trend that continued the following days to a nadir platelet count of 6 × 109/L on day 10 after presentation (Figure 1). On this day, dexamethasone and methotrexate were discontinued; the latter because a possible causal relationship with the thrombocytopenia was postulated. Further laboratory work showed a slightly elevated lactate dehydrogenase (427 U/L), normal haptoglobin, normal prothrombin (PT) and activated partial thromboplastin time (aPTT) and elevated D-dimers (3.50 mg/L), excluding a thrombotic microangiopathy. No further testing for diffuse intravascular coagulation (DIC) or heparin-induced thrombocytopenia (HIT) was performed at this time. HIV-serology test was negative. There were no clinical signs of bleeding or thrombosis. On day 10 after presentation, platelet count in a citrate blood sample was 129 × 109/L. Analysis of a peripheral blood film at the same moment showed platelet agglutination in EDTA as well as in citrate, although much less evident (Figure 2). Hence, the diagnosis of pseudothrombocytopenia was confirmed, which also marked the misdiagnosis of a true thrombocytopenia at first in this patient. In the following weeks, together with SARS-CoV-2 seroconversion and clinical recovery, we noted a positive trend in platelet counts (Figure 1): EDTA 28 × 109/L and citrate 217 × 109/L in week 6 after nadir, EDTA 99 × 109/L and citrate 249 × 109/L in week 8 after nadir. The phenomenon seems transient, as it was reported to be in the only other publication describing a similar case, although platelet transfusion was given in this case [7]. SARS-CoV-2 IgM and total antibodies were first measured, using the Wantai ELISA-test (WS-1196 and WS-1096), in week 7 after diagnosis of COVID-19 infection, already showing sufficient SARS-CoV-2 seroconversion. In COVID-19-related pseudothrombocytopenia, we suggest a possible link with SARS-CoV-2 IgM antibodies and hypothesize an EDTA-dependent immune-complex formation with cryptic platelet membrane epitopes. To test this, we incubated patient serum with EDTA-blood of a universal donor, but this did not induce platelet agglutination. Taken together, this may suggest that generation of cryptic epitopes is patient specific. In conclusion, we illustrate the importance of considering pseudothrombocytopenia in COVID-19-associated thrombocytopenia. This is the first case of COVID-19-associated pseudothrombocytopenia in which we also describe the transience of this diagnosis. It is essential to recognize this in vitro phenomenon, as this falsely lowered automated platelet count is not associated with a clinical bleeding tendency, does not have any therapeutic consequences (platelet transfusion nor discontinuation of essential medication) and is self-limiting, as shown in our patient. In the differential diagnosis of COVID-19-associated thrombocytopenia, exclusion of pseudothrombocytopenia is therefore critical. The authors declare that there is no conflict of interest. R. Van Dijck, M.N. Lauw and A.J.G. Jansen conceived the idea. R. Van Dijck wrote the manuscript. R. Van Dijck and H. Russcher provided Figures 1 and 2. A.J.G. Jansen, M.N. Lauw, M. Swinkels and H. Russcher reviewed and critically evaluated the manuscript. All authors approved the final version of the manuscript.
Primary central nervous system lymphoma (PCNSL) is a type of non-Hodgkin lymphoma limited to the central nervous system. It has a poor prognosis. Consensus has been reached on the treatment of newly diagnosed patients with high-dose methotrexate-based chemotherapy, but whether the addition of the monoclonal anti-CD20 antibody rituximab improves survival, as it does in systemic B-cell non-Hodgkin lymphoma, remains disputed. In this review, we reflect on the available evidence of the use of rituximab in PCNSL. Whether rituximab has any beneficial effect remains uncertain.
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