Caplacizumab as Second-­Line Treatment for Refractory Thrombotic Thrombocytopenic Purpura

Monal Patel, DO 1;; Chad Morreale, DO 1;; Shaina Rozell, MD 2

1 UIC / Advocate Christ Medical Center, Dept. of Medicine, Oak Lawn, IL2 Advocate Christ Medical Center, Division of Hematology Oncology, Oak Lawn, IL

Background Discussion

Case Summary

Objective

• Thrombotic Thrombocytopenic Purpura (TTP) is a life-­threatening, multisystem disease characterized by:

§ Thrombocytopenia§ Microangiopathic hemolytic anemia§ Fever§ Neurologic changes § Renal abnormalities

• Refractory TTP is defined as recurrent episode(s) of thrombocytopenia, microangiopathic hemolysis, and ADAMTS13 levels <10% following remission from the initial TTP episode.

• Describe the diagnostic approach to TTP• Understand the current standard of treatment • Review alternative treatment options for relapsing and refractory TTP

History of Present Illness• A healthy 24 year old African American female presented for headaches, slurred speech, and right upper extremity parasthesias

• No PMH / PSH

Work-­up• Hemolytic anemia

§ Hemoglobin 5.8 g/dL, LDH 970 u/L§ Haptoglobin <6 mg/dL

• Thrombocytopenia: 43,000/microL• ADAMTS13 activity level <5%• ADAMTS13 antibody negative • CT head w/o contrast: no acute abnormalities

Hospital Course• Plasmapheresis (PLEX) daily for 6 days • Steroids: methylprednisolone 125 mg daily• Rituximab 375 mg/m2 weekly x 4 weeks

Relapse• After 6 days of PLEX:

§ Platelets: 411,000/microL§ Hemoglobin: 8.1 g/dL§ ADAMTS13 activity level: 50%

• 3 days after last PLEX session, platelets ↓ by 50% daily with ↑ LDH

§ Daily PLEX resumed for another 7 days, followed by every-­other-­day

§ Weekly Rituximab infusions continued • Following remission from her initial TTP episode, she remained in refractory TTP, ultimately requiring every-­other-­day PLEX as outpatient for 1 month.

• Eventually started on Caplacizumab 11mg SubQ daily for 30 days with remission achieved in 3 days.

• Gold standard of treatment is plasmapheresis § removes the von Willebrand factor (vWF) multimers § replaces the missing ADAMTS13 enzyme

• Rituximab, anti-­CD 20 antibody, which prevents B cells from producing antibodies

§ used for either upfront or refractory TTP treatment• Glucocorticoids to suppress antibody production • Second-­line treatment options used based on clinician’s discretion

§ Cyclosporine§ Vincristine§ Cyclophosphamide

• Caplacizumab, an anti–von Willebrand factor humanized, bivalent variable-­domain-­only immunoglobulin fragment, inhibits interaction between von Willebrand factor multimers and platelets

• HERCULES and TITAN clinical trial § Double-­blind controlled trial, 145 patients § Placebo vs. Caplacizumab (10 mg IV loading dose, 10 mg SubQ daily)

§ Administered during PLEX and 30 days thereafter• HERCULES and TITAN trials results:

§ Faster normalization of platelet count § Lower incidence of composite TTP related deaths§ Lower recurrence of TTP

Conclusion

Figure 1. Peripheral smear which shows schistocytes (circled above), common sign of red blood cell hemolysis.

• Thrombotic Thrombocytopenic Purpura is a diagnosis with a very high mortality rate

• PLEX is initiated immediately if there is clinical suspicion for TTP• Rituximab is usually used as adjunct therapy for TTP remission • Despite using PLEX, Rituximab and glucocorticoids our patient had refractory TTP

• Caplacizumab which is an anti-­vWF immunoglobulin has ongoing clinical trials that prove it efficacy for treatment of TTP.

• In our patient Caplacizumab (11mg SubQ daily) helped achieve remission within 3 days of initiation.