Successful Treatment of Acquired Thrombotic Thrombocytopenic Purpura With Caplacizumab Combined With Plasma Exchanges and Immune Suppression in 3 Children.

Acquired thrombotic thrombocytopenic (aTTP) purpura is a life-threatening condition that can lead to devastating thromboembolic events. Recently, caplacizumab has been shown to rapidly restore platelet numbers and reduce the risk of severe end-organ damage when added to plasma exchanges (PEXs) and immunosuppression (IST). Here, we report the outcomes in 3 children with aTTP who were treated with caplacizumab in combination with PEXs and IST. In all 3 patients, platelet count increased to >15,000/mm 3 in 24 h and normalized on day 4, whereas normalization of ADAMTS13 activity >50% and elimination of the inhibitor was achieved after 18 to 89 days. Epistaxis was observed in 2 patients and was the only side effect related to caplacizumab. Caplacizumab is a promising agent for first-line treatment of children with aTTP.

Vemurafenib combined with cladribine and cytarabine results in durable remission of pediatric BRAF V600E-positive LCH.

Langerhans cell histiocytosis (LCH) is a disorder with a variety of clinical signs. The most severe forms affect risk organs (RO). The established role of the BRAF V600E mutation in LCH led to a targeted approach. However, targeted therapy cannot cure the disease, and cessation leads to quick relapses. Here, we combined cytosine-arabinoside (Ara-C) and 2'-chlorodeoxyadenosine (2-CdA) with targeted therapy to achieve stable remission. Nineteen children were enrolled in the study: 13 were RO-positive (RO+) and 6 RO-negative (RO-). Five patients received the therapy upfront, whereas the other 14 received it as a second or third line. The protocol starts with 28 days of vemurafenib (20 mg/kg), which is followed by 3 courses of Ara-C and 2-CdA (100 mg/m2 every 12 h, 6 mg/m2 per day, days 1-5) with concomitant vemurafenib therapy. After that, vemurafenib therapy was stopped, and 3 courses of mono 2-CdA followed. All patients rapidly responded to vemurafenib: the median disease activity score decreased from 13 to 2 points in the RO+ group and from 4.5 to 0 points in the RO- group on day 28. All patients except 1 received complete protocol treatment, and 15 of them did not have disease progression. The 2-year reactivation/progression-free survival (RFS) for RO+ was 76.9% with a median follow-up of 21 months and 83.3% with a median follow-up of 29 months for RO-. Overall survival is 100%. Importantly, 1 patient experienced secondary myelodysplastic syndrome after 14 months from vemurafenib cessation. Our study demonstrates that combined vemurafenib plus 2-CdA and Ara-C is effective in a cohort of children with LCH, and the toxicity is manageable. This trial is registered at www.clinicaltrials.gov as NCT03585686.

Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia.

We compared the efficacy and safety of eltrombopag (ELTR) combined with immunosuppressive therapy (IST) and IST alone in treatment-naïve children with severe (SAA) and very severe (vSAA) aplastic anemia. Ninety-eight pediatric patients were randomized to receive horse antithymocyte globulin (hATG) and cyclosporin A (CsA) with (n = 49) or without (n = 49) ELTR. The primary endpoint was the overall response rate (ORR) at 4 months. After 4 months, nonresponders were crossed over to the alternative group. In all patients, the ORR in ELTR + IST and IST groups was similar (65% vs 53%; P = .218); however, the complete response (CR) rate was significantly higher in the ELTR + IST group (31% vs 12%; P = .027). In severity subgroups, the ORR was 89% vs 57% (P = .028) in favor of IST + ELTR in SAA, but it did not differ in patients with vSAA (52% vs 50%; P = .902). At 6 months after the crossover, 61% of initial ELTR(-) patients achieved a response compared with 17% of initial ELTR(+) patients (P = .016). No significant difference in ELTR + IST and IST groups was observed in the 3-year overall survival (OS) (89% vs 91%; P = .673) or the 3-year event-free survival (EFS) (53% vs 41%; P = .326). There was no unexpected toxicity related to ELTR. Adding ELTR to standard IST was well tolerated and increased the CR rate. The greatest benefit from ELTR combined with IST was observed in patients with SAA but not in those with vSAA. The second course of IST resulted in a high ORR in initial ELTR(-) patients who added ELTR and had limited efficacy among patients who received ELTR upfront. This trial was registered at Clinicaltrials.gov as #NCT03413306.

Platelet function and bleeding at different phases of childhood immune thrombocytopenia.

Immune thrombocytopenia (ITP) is believed to be associated with platelet function defects. However, their mechanisms are poorly understood, in particular with regard to differences between ITP phases, patient age, and therapy. We investigated platelet function and bleeding in children with either persistent or chronic ITP, with or without romiplostim therapy. The study included 151 children with ITP, of whom 56 had disease duration less than 12 months (grouped together as acute/persistent) and 95 were chronic. Samples of 57 healthy children were used as controls, while 5 patients with leukemia, 5 with aplastic anemia, 4 with MYH9-associated thrombocytopenia, and 7 with Wiskott-Aldrich syndrome were used as non-ITP thrombocytopenia controls. Whole blood flow cytometry revealed that platelets in both acute/persistent and chronic ITP were increased in size compared with healthy donors. They were also pre-activated as assessed by PAC1, CD62p, cytosolic calcium, and procoagulant platelet levels. This pattern was not observed in other childhood thrombocytopenias. Pre-activation by CD62p was higher in the bleeding group in the chronic ITP cohort only. Romiplostim treatment decreased size and pre-activation of the patient platelets, but not calcium. Our data suggest that increased size, pre-activation, and cytosolic calcium are common for all ITP platelets, but their association with bleeding could depend on the disease phase.

Bleeding tendency and platelet function during treatment with romiplostim in children with severe immune thrombocytopenic purpura.

It has been suggested that platelet function in chronic immune thrombocytopenic purpura (ITP) may be abnormal. Thrombopoietin mimetics used for treatment can affect it, but the data remain limited. We investigated platelet function of 20 children diagnosed with severe ITP (aged 1-16 years, 12 females and eight males). Platelet functional activity in whole blood was characterized by flow cytometry before and after stimulation with SFLLRN plus collagen-related peptide. Levels of CD42b, PAC1, and CD62P, but not CD61 or annexin V, were significantly increased (P < 0.05) in resting platelets of patients before treatment compared with healthy donors. On average, PAC1 and CD62P in patients after activation were also significantly elevated, although some patients failed to activate integrins. Romiplostim (1-15 µg/kg/week s.c.) was prescribed to seven patients, with clinical improvement in six. Interestingly, one patient had clinical improvement without platelet count increase. Eltrombopag (25-75 mg/day p.o.) was given to four patients, with positive response in one. Others switched to romiplostim, with one stable positive response, one unstable positive response, and one non-responding. Platelet quality improved with romiplostim treatment, and their parameters approached the normal values. Our results suggest that platelets in children with severe ITP are pre-activated and abnormal, but improve with treatment.