Laetitia Languille

Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program

Romiplostim, a thrombopoietic agent with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, was recently licensed for adults with chronic ITP. Only France has allowed romiplostim compassionate use since January 2008. ITP patients could receive romiplostim when they failed to respond to successive corticosteroids, intravenous immunoglobulins, rituximab, and splenectomy, or when splenectomy was not indicated. We included the first 80 patients enrolled in this program with at least 2 years of follow-up. Primary platelet response (platelet count ≥ 50 × 10(9)/L and double baseline) was observed in 74% of all patients. Long-term responses (2 years) were observed in 47 (65%) patients, 37 (79%) had sustained platelet responses with a median platelet count of 106 × 10(9)/L (interquartile range, 75-167 × 10(9)/L), and 10 (21%) were still taking romiplostim, despite a median platelet count of 38 × 10(9)/L (interquartile range, 35-44 × 10(9)/L), but with clinical benefit (lower dose and/or fewer concomitant treatment(s) and/or diminished bleeding signs). A high bleeding score and use of concomitant ITP therapy were baseline factors predicting romiplostim failure. The most frequently reported adverse events were: arthralgias (26%), fatigue (13%), and nausea (7%). Our results confirmed that romiplostim use in clinical practice is effective and safe for severe chronic ITP. This trial was registered at www.clinicaltrials.gov as #NCT01013181.

Characteristics and outcome of warm autoimmune hemolytic anemia in adults: New insights based on a single-center experience with 60 patients.

Warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disease with poorly known natural history and management remaining mainly empirical. To better describe the characteristics and outcome of wAIHA in adults, we performed a single‐center cohort study of patients diagnosed with wAIIHA from 2001 to 2012 in our center. Sixty patients (50% women) were included, the mean age at the time of wAIHA onset was 54 ± 23 years. wAIHA was considered “primary” for 21 patients (35%) and was associated with an underlying disorder in 39 (65%), including mainly lymphoproliferative disorders and systemic lupus. All patients but two needed treatment and received corticosteroids, with an overall initial response rate of 87%. However, 63% of the patients were corticosteroid‐dependent and 56% required at least one second‐line treatment including mainly rituximab (n = 19). At the time of analysis, after a mean follow‐up of 46 months, 28 patients (47%) were in remission and off treatment and 5 (8%) had died. The presence of an underlying lymphoproliferative disorder was associated with reduced response to corticosteroids and increased need for second‐line therapy. In conclusion, in the last decade and compared to a previous series from our center, the rate of secondary wAIHA has increased and the use of rituximab has emerged as the preferred second‐line treatment and corticosteroid‐sparing strategy; the overall mortality has significantly decreased (8 vs. 18%). Am. J. Hematol. 89:E150–E155, 2014.

A retrospective pilot evaluation of switching thrombopoietic receptor-agonists in immune thrombocytopenia

Romiplostim and eltrombopag, the first thrombopoietic receptor-agonists with demonstrated efficacy against immune thrombocytopenia in prospective controlled studies, were recently authorized in most countries for adults with chronic immune thrombocytopenia. So far, no data are available about the potential contribution of switching from romiplostim to eltrombopag or vice versa in terms of efficacy or tolerance. Efficacies and tolerance profiles were evaluated for 46 patients who sequentially received both drugs, switching from one to the other. The reasons for switching were: lack of efficacy for 23 patients, platelet-count fluctuations for 11, side effects for 4, and 8 patients’ preferences. For 50–80% of the patients, switching from romiplostim to eltrombopag or eltrombopag to romiplostim effectively impacted the platelet count, with fluctuations disappearing in 54% and side effects resolved in 100%. In 80% of the patients, the 2 thrombopoietic receptor-agonists achieved similar response patterns. Our results confirmed that switching from one thrombopoietic receptor-agonist to the other could be beneficial in clinical practice for patients with severe chronic immune thrombopenia who failed to respond or experienced adverse events to the first. (Clinical Trials.gov identifier: NCT01618734).

Characteristics and outcome of immune thrombocytopenia in elderly: Results from a single center case‐controlled study

The management of ITP in elderly raises several questions that have not been fully addressed in the literature. To assess the impact of ITP in elderly, a case‐control study was performed. The main characteristics at onset and the outcome of ITP in 55 patients aged of 70 years and above (cases) were compared with those of 97 younger adults (controls) seen at the same tertiary referral institution. The mean age at diagnosis was respectively 77.8±6.1 years (cases) and 40.3±14.9 years (controls). While the median platelet count at time of diagnosis was not significantly different in cases and controls (6×109/L, range: 2–26 versus 12×109/L: 5–21.5), bleeding symptoms were more frequent in cases (82%) than in the controls (68%, p=0.07), and the median bleeding score was significantly higher in elderly (p=0.001). The rate of treatment‐related adverse events was more than twofold higher in elderly patients and the mean cumulative duration of hospital stay for ITP during the follow‐up period was much longer when compared to the controls (p<0.0001). Three ITP‐related deaths (5.4%) including 1 from intracranial hemorrhage occurred in the cases but none in the controls. In conclusion, this study confirms that at equivalent platelet count, ITP has a greater impact in elderly. Am. J. Hematol. 2011.

Effect of pregnancy on the course of immune thrombocytopenia: a retrospective study of 118 pregnancies in 82 women

In women with pre‐existing immune thrombocytopenic purpura (ITP), the effect of pregnancy on the course of the disease is poorly known. We performed a dual‐centre retrospective cohort study of 118 pregnancies in 82 women with primary ITP. In early pregnancy, the platelet count was <100 × 109/l in 35·6% of pregnancies. During pregnancy the median platelet count nadir was 66 × 109/l (25th–75th percentile: 42–117), with platelet count <30 × 109/l for 26 pregnancies (22%). In 49% of pregnancies, a significant decrease of the platelet count required treatment at least transiently in preparation for delivery. At the time of delivery, the median platelet count was 110 × 109/l (77–155). Compared to before pregnancy, at 3 months post‐partum, only 11% of pregnancies [95% confidence interval (95% CI): 6·8–20·2] showed disease worsening. Previous splenectomy was the only factor significantly associated with ITP worsening after pregnancy (53·9% vs. 10·3%, P < 0·001). For 8·3% of the pregnancies (95% CI: 3·8–15·1), neonatal thrombocytopenia required treatment, especially in case of previous maternal splenectomy (adjusted odds ratio 16·7, 95% CI: 2·61–106). The overall risk of exacerbation of ITP and severe thrombocytopenia during pregnancy is acceptable.

Long-term complications of splenectomy in adult immune thrombocytopenia

AbstractThe recent large decrease in splenectomy use for chronic immune thrombocytopenia (ITP) is partly due to still-unsolved questions about long-term safety. We performed the first single-center exposed/unexposed cohort study evaluating the long-term incidence of splenectomy complications in patients with primary ITP. Overall, 83 patients who underwent splenectomy more than 10 years ago (exposed) were matched with 83 nonsplenectomized patients (unexposed) on the date of ITP diagnosis ±5 years, age and gender. After a median follow-up of 192 months (range 0.5–528), 43 patients (52%) achieved overall response after splenectomy. Splenectomized patients experienced more venous thromboembolism (VTE) than controls (n = 13 vs n = 2, P = 0.005). On multivariate analysis, splenectomy was an independent risk factor of VTE (hazard ratio = 4.006, P = 0.032 [95% confidence interval: 1.13–14.21]). Splenectomized patients presented more severe infections on long-term follow-up: all required hospitalization, and 5/26 (19%) infections led to severe sepsis or septic shock and to death for 3 cases (none in controls). However, the incidence of malignancy was similar in both groups, as was cardiovascular risk, which appeared to be related more to ITP than splenectomy. Finally, splenectomy did not significantly decrease overall survival. Despite the risk of thrombosis and severe sepsis, splenectomy remains an effective and curative treatment for ITP.

Hydroxychloroquine is a good second‐line treatment for adults with immune thrombocytopenia and positive antinuclear antibodies

Treatment of patients with lupus‐associated thrombocytopenia (SLE‐ITP) is not standardized. We report data on efficacy and safety of hydroxychloroquine (HCQ) in this setting and in ITP patients with positive antinuclear antibodies (ANA) without definite SLE. Inclusion criteria were: definite diagnosis of ITP with a platelet count (PLT) <50 × 109/L, ANA ≥ 1/160 on Hep2 cells with or without a definite diagnosis of SLE, and no sustained response to at least one previous treatment‐line and treatment with HCQ. Response criteria were Complete Response (CR) for PLT ≥ 100 × 109/L and Response (R) for PLT ≥30 × 109/L and at least twice the initial value. Forty patients (32 females) with a mean age of 35 ± 17 years and PLT at ITP diagnosis of 14 ± 13 × 109/L were analyzed. Twelve (30%) patients had a SLE‐ITP, 28 patients had only positive ANA. All the patients failed to respond to oral prednisone with a median of two treatment‐lines (1–5) before HCQ which was initially given in combination with another ITP treatment in 36 patients. Overall response rate was 60% (24/40) including 18 lasting CR and six lasting R maintained with a median follow‐up of 64 months (6–146), in ¾ of cases with only HCQ and no concomitant ITP treatment. The response rate (CR+R) was higher in the SLE group vs ANA‐positive group (83% vs 50%, P < 0.05). No patient stopped HCQ because of a side‐effect. HCQ appears to be a safe and effective second line treatment for patients with SLE‐ITP or ITP and high titer of ANA. This trial was registered at www.clinicaltrials.gov as # NCT01549184. Am. J. Hematol. 89:194–198, 2014.

Cutaneous rash and dapsone-induced hypersensitivity syndrome a common manifestation in adult immune thrombocytopenia. Presentation and outcome in 16 cases.

To the Editor: The successful use of dapsone for primary or secondary immune thrombocytopenia (ITP) was first reported 25 years ago [1,2]. Although the mechanism of action remains poorly understood, several uncontrolled studies have assessed the efficacy of dapsone for ITP [1–4] with an overall response rate of 40%. Dapsone is proposed as possible second-line treatment for ITP as suggested by international consensus in the guidelines recently published by the American Society of Haematology. A multitude of drug hypersensitivity definitions exist in the literature. Dapsoneinduced hypersensitivity syndrome (DHS), sometimes called dapsone or sulfone syndrome, was originally described in leprosy and combines a generalized skin eruption with one or more of the following: (1) fever, (2) lymphadenopathy, or (3) hepatitis [5]. DHS prevalence is estimated to be about 1.4% (95% confidence interval, 1.2–1.7%) [5]. Prognosis can be severe, with life-threatening visceral involvement and high mortality (9.9%) [5]. A recent genome-wide association study in China demonstrated a strong association of HLA-B*13:01 polymorphism and risk of DHS among patients of Indian origin receiving dapsone for leprosy [6]. As the incidence and clinical outcome of DHS in ITP patients receiving dapsone have never been reported, we report our experience in a large monocentric study. Over an 11-year period (2002–2013), we identified 231 patients with ITP who received dapsone in our institution. In total, 17 (7.3%) presented a dapsone-induced cutaneous reaction. One patient was excluded from the final analysis because of missing data or lost to follow-up. Baseline characteristics of the 16 patients with primary ITP are summarized in Supporting Information Table 1. All patients, except two Asians, were of Caucasian or African origin. The median platelet count at the onset of dapsone treatment was 21 g/L (range, 2–50 g/L). In all, 14 patients also received steroid therapy (prednisolone: 1 mg/kg) as second-line therapy. No other drugs had been newly introduced in the previous 3 months. Overall, the response rate to dapsone was 62.5% (10/16), that is, 7/16 (44%) CR and 3/16 (18%) R. All 16 patients presented generalized skin rash within 3 months after dapsone initiation (median, 24 days; range, 2–52 days) (Table I). The skin rash was usually described as urticated erythematous papules and plaques (Supporting Information Fig. 1). The median platelet count at the time of skin rash was 112 g/L (range, 23–293 g/L). In all 16 cases, dapsone was withdrawn within 48 hr. No severe hemolysis was observed (median decrease in hemoglobin level, 1.35 g/dL, n5 7). Skin rash was associated with fever in five patients (31%), hepatitis in three patients (18.7%), and lymphadenopathy in one patient (6.3%). In all, 6 out of the 231 patients fulfilled the DHS criteria (2.6%); three were referred to the hospital. One patient met DHS criteria and presented moderate cytolysis hepatitis (with no liver failure). Two other patients did not fulfill DHS criteria; one presented generalized rash; a skin biopsy showed an inflammatory infiltrate. At the time of skin eruption, 14 patients were still on a short course of steroids. Steroids were discontinued during the week after the skin manifestations in all patients. After daspone discontinuation, cutaneous and systemic manifestations disappeared in all patients, without any treatment. Two patients showed sustained CR after the discontinuation of treatment, at 5and 8-month follow-up. The other patients showed relapse and required therapy. The 11 patients with a DNA sample did not show HLA-B*13:01 polymorphism. Dapsone is an inexpensive therapeutic option for treating ITP in children and adults but has not been well studied as compared with other more costly alternatives. The drug is largely used in France, Italy, Turkey, and India, with an overall response rate of 40% [1–4]. DHS is the most severe adverse event with the treatment, but until now, its incidence in ITP was not reported. In our analysis of 16 patients with ITP, cutaneous reaction to dapsone was a common adverse event (7.3%) and occurred in the weeks after the start of treatment. In 40% of these patients, skin rash was associated with systemic manifestations consistent with the diagnosis of DHS, and hence the incidence of definite DHS (2.6%) was similar to that in other diseases [5]. We found a good prognosis with dapsone-induced reactions in ITP. In contrast with the severe outcomes reported for DHS in other settings, with a mortality of almost 10%, we observed no life-threatening visceral involvement, no systemic symptoms, or biological manifestations (hepatitis, eosinophilia) in most patients; only three had to be referred to the hospital but showed rapid recovery. One hypothesis to explain this good prognosis is that a short course of steroids (<3 weeks) was almost systematically combined with dapsone. The anti-inflammatory and/or immune modulation induced by steroid therapy may attenuate the systemic manifestations. In view of the potential severity of DHS, our practice is now to systematically associate a short course of steroid therapy (<3 weeks) with the initiation of dapsone. An alternative explanation could be the rapid withdrawal of dapsone in all cases. The physicians in our group are aware of dapsone-related adverse events. Patients are systematically informed that dapsone should be immediately stopped if any skin symptom occurs. The pathophysiological mechanism and risk factors of dapsone-related skin and systemic symptoms remain unknown. A strong association of HLA-B*13:01 polymorphism and risk of DHS (odds ratio, 20.53) has been reported earlier [6]. We confirm that this haplotype is largely absent in European and African patients. All of our patients, who were tested, including two Asians, were negative for the polymorphism. At least in Europe, HLA genotyping is not useful before dapsone treatment. To conclude, skin rash is a common manifestation of dapsone treatment for ITP. However, the incidence of DHS does not differ from that with other indications. Conversely, DHS in ITP is characterized by good prognosis, possibly because of concomitant steroid therapy. In this cohort, the risk of hypersensitivity reaction did not limit the use

Systematic detection of portal or splenic vein thrombosis after splenectomy for immune cytopenia

To the Editor: In many countries, splenectomy remains the gold standard treatment for severe immune thrombocytopenia (ITP) and a second-line treatment for warm antibody autoimmune hemolytic anemia (wAIHA). Splenectomy is an independent risk factor of venous thromboembolism throughout life. Postulated mechanisms include thrombocytosis and circulation of damaged cells or microvesicles due to the removal of the blood filter. Splenectomy also favors portal or splenic vein thrombosis (PSVT) in the early postoperative period. Local factors such as inflammation, decreased portal flow during peritoneal exsufflation and stasis in the splenic stump may play a role. Whereas symptomatic PSVT is rare (2% of patients undergoing splenectomy regardless of the indication), systematic CT-scan has revealed PSVT in up to 55% of patients after splenectomy. In contrast, few clinical complications of PSVT are reported on long-term follow-up of such patients (3 portal cavernomas reported in 83 patients splenectomized for ITP), which raises the question of the clinical significance of asymptomatic PSVT. Complications such as portal cavernoma and mesenteric venous ischemia are respectively associated with extrahepatic portal vein thrombosis (ePVT) and proximal splenic vein thrombosis (pSVT) but the significance of thrombosis occurring in intrahepatic branches or distal splenic vein is uncertain. The natural history of postoperative PSVT is unclear, and thus no guidelines are established about their screening and treatment. We conducted a retrospective study to assess the incidence, sites and outcome of PSVT in ITP and wAIHA patients who underwent systematic enhanced CT-scan after splenectomy. The study was performed in accordance with the Helsinki Declaration and conducted between January 2009 and April 2015 in Henri Mondor Hospital (Creteil, France), a tertiary-care national referral center for adult immune cytopenias, where abdominal enhanced CT-scan was systematically performed between days 3 and 7 after splenectomy. Adult patients splenectomized for ITP or wAIHA were consecutively included. Patients with immune cytopenia secondary to hematologic malignancy were excluded. Most patients had undergone a preoperative CT-scan; none showed PSVT. The postoperative CT-scan was assessed by an independent senior radiologist. SVT was defined as pSVT when located between the superior and inferior mesenteric vein (SMV and IMV) or within 2 cm from the SMV junction; otherwise, it was defined as distal SVT (dSVT). PVT was classified as intrahepatic or extrahepatic. Patients received postoperative thromboprophylaxis by low molecular weight heparin. In case of PSVT the physician was free to initiate an anticoagulation therapy or to keep the patient on prophylactic regimen. Doppler ultrasonography or enhanced CT-scan was performed within the 6 months after PSVT. The response to splenectomy was defined according to international criteria for ITP and as hemoglobin>10 g/dL for wAIHA. Thirty nine patients (20 women characteritics described in Supporting Information Table S1) were included among 43 patients screened; splenectomy was mainly performed by laparoscopy (n538) for patients with ITP (n530) or wAIHA (n59). The median time from diagnosis of cytopenia to splenectomy was 18 months [IQR: 10–56]. The median age of the patients was 43 years [IQR: 33–55]. Eight patients were positive for antinuclear antibodies, including 2 with systemic lupus erythematosus. Lupus anticoagulant or anticardiolipin antibody was detected in 5/39 patients without definite antiphospholipid syndrome. Patients had received a median of 4 lines [IQR: 3–5] of treatment. In the month before splenectomy, 22/30 (75%) ITP patients received corticosteroids, 13/30 (43%) intravenous immunoglobulins (IVIg) and 12/30 (40%) thrombopoietin receptor agonists (TPO-RAs); the median preoperative platelet count was 733 10/L [IQR: 31–139]. 63% of ITP patients and 89% of wAIHA responded to splenectomy; the relapse rate was 13% in ITP and 44% in wAIHA. CT-scan was performed at a median of 5 days [IQR: 4–6] after splenectomy. The overall incidence of PSVT was 74% (29/39), without significant difference between ITP and wAIHA (P5 .79). The characteristics of PSVT are in Figure 1 and in Supporting Information Table S2. Most of the SVT cases were distal (n522/28). Most of the PVT cases were intrahepatic (n514/15); 3 involved the left or right portal branch. One ePVT occurred in a patient with history of recurrent pulmonary embolism. Only 5 patients had clinical symptoms at the time of the PSVT [i.e., abdominal pain (5/5) and fever (1/5)]; symptomatic PSVT cases were iPVT associated with dSVT (n53) and isolated dSVT (n52). We found no association between PSVT occurrence and the age, sex, positivity for antinuclear antibodies, use of TPO-RAs or IVIg, corticosteroids dose, preoperative or postoperative platelet count, which may be explained by the small number of patients. In accordance with other studies, spleen weight was higher in patients with PSVT (mean 206 vs 102 g, P5 .14). According to the physician decision, 13/25 patients received anticoagulation therapy for a median of 8 weeks [range: 4–18] and 12/25 patients (including 2 pSVT, 10 dSVT, 4 segmental iPVT) received standard thromboprophylaxis. Radiological follow-up was performed at a median of 6 weeks [IQR: 2–26], mostly by CT-scan (17/25). Eight patients (62%) who received curative anticoagulation showed complete resolution of the thrombus, as did all 12 untreated patients. Portal cavernoma developed in a woman with wAIHA despite curative