Caplacizumab (CPLZ) is indicated, in combination with therapeutic plasma exchange (TPE) and immunosuppressive therapy (IST), for the treatment of immune-mediated TTP (iTTP). TPE is a mainstay of iTTP ...treatment but is burdensome and associated with complications. Real-world data suggest efficacy of TPE-free CPLZ regimens in iTTP, but clinical trial data is unavailable. This trial evaluates the efficacy and safety of CPLZ with IST without first-line TPE in adults with iTTP.
MAYARI (NCT05468320) is a Phase 3 multicenter study. Adults with a clinical diagnosis of initial/recurrent iTTP are eligible pending ADAMTS13 activity level confirmation within 48 hours of enrollment. Participants will receive CPLZ and IST. CPLZ treatment will be continued until ADAMTS13 activity level of ≥50% at 2 consecutive visits after platelet count normalization or for up to 12 weeks, whichever occurs first; follow-up period is 12 weeks. TPE may be started after 24 hours if indicated.
The primary endpoint is the proportion of participants achieving remission without requiring TPE during the overall study period (Table). Revised outcomes definitions from the International Working Group for iTTP will be utilized (Cuker et al. Blood. 2021;13714:1855-1861). An adequate number of participants will be enrolled to ensure ≥55 participants with ADAMTS13 activity levels <10% at baseline are available for primary endpoint analysis; around 61 participants are expected to be enrolled.
The current standard of care in patients with iTTP includes a combination of TPE, IST, and CPLZ. This novel study will define the efficacy and safety of CPLZ and IST without first-line TPE in adults with iTTP. This regimen would avert the risks for substantial complications associated with TPE and represents a paradigm shift in the frontline management of iTTP. This content was first presented at ASH 2022 (abstract #1174).
The management of exacerbations and disease relapse is important for patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP). Severe ADAMTS13 (a disintegrin and metalloproteinase ...with a thrombospondin type 1 motif, member 13) deficiency during clinical remission is associated with risk of relapse and may guide prophylactic immune-modulatory therapy. We evaluated ADAMTS13 activity as a potential biomarker of exacerbation or relapse risk in the HERCULES and post-HERCULES studies.
This is a post hoc analysis of integrated data from the modified intent-to-treat (mITT) population of the Phase 3 HERCULES trial (NCT02553317) comparing caplacizumab and placebo (both plus standard-of-care treatment) in patients (pts) with iTTP and the 3-year follow-up post-HERCULES study (NCT02878603). ADAMTS13 activity was determined at baseline, weekly during treatment (post-TPE) and twice during follow-up. Recurrence risk was assessed according to ADAMTS13 activity, using TTP adverse event codes.
49/144 (34%) pts in the HERCULES mITT had a recurrence during HERCULES or post-HERCULES. 140/144 pts had follow-up data after treatment end. Of these, 39 pts (28%) had a recurrence after treatment end; mean SD ADAMTS13 activity was 20.5% (28.7) in pts with recurrence vs 54.0% (34.9) in pts without; P<0.0001). ADAMTS13 activity was <20% at treatment end in 69.2% (27/39) and 27.1% (26/96) pts with/without recurrence (P<0.0001). Similar trends were seen across both treatment groups (Table).
Regardless of the treatment received (caplacizumab or placebo), lower ADAMTS13 activity levels at end of treatment were associated with a higher risk of recurrence in the HERCULES and post-HERCULES studies. These data highlight the predictive value of ADAMTS13 levels on the risk of recurrence and may assist clinical decision-making in the treatment of iTTP. This content was first presented at ASH 2022 (abstract #2493).
Abstract Heavy menstrual bleeding (HMB) is a common symptom in patients who present to the obstetrician-gynecologist or adolescent medicine specialist and might result from an underlying inherited ...bleeding disorder. Whereas relatively common bleeding disorders such as von Willebrand disease are often included in standard laboratory assessments, rarer platelet function disorders can be challenging to diagnose. Additionally, HMB can be a particularly difficult symptom to manage in adolescents with platelet function disorders, and it is associated with decreased quality of life. We review the diagnostic and management issues of patients with platelet function disorders through the presentation of 2 patient case reports, with a focus on a diagnosis of Glanzmann thrombasthenia, an inherited qualitative disorder that affects platelet function. Whereas the first patient presented to the emergency department before the diagnosis of a bleeding disorder and required a hematologic referral and extensive laboratory assessments, the second patient had been diagnosed with Glanzmann thrombasthenia as a child but experienced severe management challenges at the onset of menarche. In both patients, collaboration between the obstetrician-gynecologist or adolescent medicine specialist and the hematologist was critical for achieving acute management of the bleeding symptoms and for ensuring optimal long-term disease management. Together, these cases highlight the importance of properly identifying females with HMB who might have an undiagnosed bleeding disorder and of consulting with a hematologist to determine an appropriate management plan throughout all life stages.
Objective: The efficacy and safety of caplacizumab (CPLZ) for patients (pts) with immune-mediated thrombotic thrombocytopenic purpura (iTTP; also known as acquired TTP) were demonstrated in the Phase ...3 HERCULES trial, with a 28-day follow-up period after end of treatment. Post-HERCULES (NCT02878603) evaluated the long-term outcomes of pts with iTTP treated with CPLZ during HERCULES, and the safety and efficacy of repeated CPLZ use for iTTP recurrence. Methodology: Over 3 years’ follow-up, pts could receive CPLZ with therapeutic plasma exchange (TPE) and immunosuppressive therapy (IST) for iTTP recurrence. Safety was assessed during the overall study period in the intention-to-observe (ITO) population; TTP-related events (TTP-related mortality, recurrence, or major thromboembolic events) were assessed in pts without recurrence in HERCULES or prior to post-HERCULES (efficacy ITO population). Safety and efficacy were also evaluated during recurrences. Results: Of 104 pts enrolled, incidences of adverse events (AEs) were similar between pts treated with CPLZ+TPE+IST during HERCULES (n=75) and pts treated with TPE+IST only (n=29). TTP-related events occurred in 4/49 pts (8%) randomized to CPLZ vs 11/29 pts (38%) randomized to placebo. The first recurrence episode was resolved/resolving for all 13 pts treated with CPLZ for recurrence, including 9 pts with repeat CPLZ. The safety profile of CPLZ for recurrence was consistent with HERCULES. Conclusion: Over long-term follow-up, the safety profile of patients treated with CPLZ in combination with TPE+IST was generally similar to those who received IST+TPE only, with no observed increases in iTTP recurrence. Repeat use of CPLZ was efficacious, with no new safety concerns.
Children often present to emergency departments (EDs) with uncontrollable nose bleeding. Although usually due to benign etiologies, epistaxis may be the presenting symptom of an inherited bleeding ...disorder. Whereas most bleeding disorders are detected through standard hematologic assessments, diagnosing rare platelet function disorders may be challenging. Here we present two case reports and review diagnostic and management challenges of platelet function disorders with a focus on Glanzmann’s thrombasthenia (GT). Patient 1 was a 4-year-old boy with uncontrolled epistaxis. His medical history included frequent and easy bruising. Previous laboratory evaluation revealed only mild microcytic anemia. An otolaryngologist stopped the bleeding, and referral to a pediatric hematologist led to the definitive diagnosis of GT. Patient 2 was a 2.5-year-old girl with severe epistaxis and a history of milder recurrent epistaxis. She had a bruise on her abdomen with a palpable hematoma and many scattered petechiae. Previous assessments revealed no demonstrable hemostatic anomalies. Platelet aggregation studies were performed following referral to a pediatric hematologist, leading to the diagnosis of GT. As evidenced by these cases, the ED physician may often be the first to evaluate severe or recurrent epistaxis and should recognize indications for coagulation testing and hematology consultation/referral for advanced hematologic assessments.
PUPs A-LONG evaluated safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, Phase 3 study enrolled ...male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at study start, 20 (19%) had family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval CI: 21.8%–41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI: 8.8%–24.7%). The median (range) time to high-titer inhibitor development was 9 (4–14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 non–treatment-related death due to intracranial hemorrhage (onset prior to first rFVIIIFc dose). The overall median (interquartile range) ABR was 1.49 (0.00–4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within expected range, although high-titer inhibitor development was on the low end of the range reported in literature. rFVIIIFc was well-tolerated and effective as prophylaxis and for treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).
Summary
This United States community study evaluated the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone (D‐VCd) in newly diagnosed multiple myeloma (NDMM) and relapsed ...multiple myeloma (RMM). Patients received 4–8 induction cycles of bortezomib 1·5 mg/m2, cyclophosphamide 300 mg/m2 and dexamethasone 40 mg weekly. Intravenous daratumumab 16 mg/kg was administered as approved except for a split‐first dose in Cycle 1. Eligible patients underwent autologous stem cell transplantation. All patients received ≤12 daratumumab maintenance doses monthly. Eighty‐six NDMM and 14 RMM patients received ≥1 treatment dose. In NDMM patients, very good partial response or better (≥VGPR) and overall response rates after 4 induction cycles were 44% (primary endpoint) and 79%, respectively, and 56% and 81% at end of induction. The 12‐month progression‐free survival (PFS) rate was 87%. Efficacy was also observed in RMM patients. Fatigue (59%) and neutropenia (13%) were the most frequent treatment‐emergent adverse event (TEAE) and grade 3/4 TEAE, respectively. Infusion reactions occurred in 54% of patients, primarily during the first dose, and were mild (2% grade 3). The first 2 daratumumab infusions were 4·5 and 3·8 h (median). Overall, D‐VCd was well tolerated, split‐first daratumumab dosing was feasible, the ≥VGPR rate after 4 cycles was 44% and the 1‐year PFS rate was 87%.
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