Tailored Treatment of Immune Thrombotic Thrombocytopenic Purpura

Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening disease. iTTP develops due to autoantibodies to the ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) enzyme. These antibodies lead to functional deficiency of ADAMTS-13, which results in the circulation of ultra-large von Willebrand factor (VWF) multimers and leads to thrombocytopenia, hemolysis, and organ ischemia.[1] ADAMTS-13 autoantibodies can be triggered by certain antiplatelet drugs, immunosuppressive agents, human immunodeficiency virus (HIV), estrogen-containing contraceptives, and pregnancy. Initial iTTP treatment may include plasma exchange (PEX)[2] and immunosuppressive therapy (glucocorticoids and rituximab).[3] Such treatment increased the survival rate of patients with iTTP to 78%.[4] The introduction of caplacizumab has dramatically improved the results of iTTP treatment. Caplacizumab forms a part of so-called triplet therapy, which includes daily PEX from the first day until the platelet count is ≥150 × 10⁹/L, administration of immunosuppression (prednisolone 1 mg/kg and rituximab at a dose of 375 mg/m² intravenously on days 1, 4, 8 and 15) and caplacizumab. Caplacizumab is recommended for 30 days after cessation of PEX.[5] However, some patients may achieve remission earlier than the 30-day period, while others may require more than 30 days to reach an ADAMTS-13 activity level of ≥20%.

Between February 2021 and March 2024, 24 patients were diagnosed with iTTP based on clinical manifestations, thrombocytopenia, hemolytic anemia, ADAMTS-13 activity level of less than 10%, and presence of the ADAMTS-13 inhibitor ([Table 1]). Data presented as median and range (difference between lowest and highest values).

Table 1 Baseline disease characteristics of iTTP patients

Characteristic	Value
Age, y, median (range)	43 (18–68)
Female, n	18 (75%)
De novo iTTP, n	20 (83%)
iTTP relapse, n	4 (17%)
Clinical presentations
Neurological/mental disorders, n	15 (63%)
Thrombocytopenia, n	24 (100%)
Hemorrhagic syndrome, n	24 (100%)
Anemia, n	24 (100%)
ADAMTS-13 activity, %, median (range)	0 (0–3.1)
ADAMTS-13 inhibitor, BU, median (range)	2.5 (0.4–14.0)
Platelet count, ×109/L, median (range)	18 (1–59)
Hemoglobin, g/L, median (range)	81 (48–111)
Schistocyte count, % median (range)	1 (0–13)
LDH, U/L, median (range)	564 (281–3,025)
PEX from suspicion of TTP to triplet therapy
Number of patients, n	7/24
Number of PEX, median (range)	4 (1–8)
Total volume, mL, median (range)	8,000 (2,000–16,000)

Abbreviations: ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; iTTP, immune thrombotic thrombocytopenic purpura; LDH, lactate dehydrogenase; PEX, plasma exchange; TTP, thrombotic thrombocytopenic purpura.

After clinical suspicion of iTTP, prior to receiving the ADAMTS-13 activity results, 7 of 24 patients immediately underwent PEX procedures; however, these patients continued to exhibit thrombocytopenia, anemia, and clinical signs of iTTP before the start of the triplet therapy.

We therefore modified the triplet therapy and tailored it based on the ADAMTS-13 activity. The modification of the triplet therapy included the time of initiation of treatment with rituximab and duration of therapy with caplacizumab and rituximab.

After confirming the diagnosis of iTTP with ADAMTS-13/inhibitor testing, we initiated or continued treatment with daily PEX and started prednisolone (1 mg/kg/d) and caplacizumab. Patients received an intravenous loading dose of caplacizumab (10 mg) before the start of the first PEX. Subsequent doses (10 mg) were administered subcutaneously, once daily. Caplacizumab was provided free of charge via Sanofi's Managed Access Program. Sanofi was not involved in the design, collection, analysis, interpretation, or reporting of data, but was given the opportunity to review the publication prior to submission. The decision to submit for publication was made independently by the authors. We continued PEX until the platelet count increased to ≥150 × 10⁹/L, then we stopped PEX, but continued caplacizumab and prednisolone. Only after stopping PEX did we start rituximab (375 mg/m² intravenously once a weekly; [Fig. 1]). Caplacizumab was stopped only after the ADAMTS-13 activity reached ≥20% (partial ADAMTS-13 remission). Rituximab and prednisolone were continued until the ADAMTS-13 activity reached ≥40% (complete ADAMTS-13 remission), then rituximab was stopped and the dose of prednisolone was gradually tapered off.

Fig. 1 The treatment regimen. ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; iTTP, immune thrombotic thrombocytopenic purpura; PEX, plasma exchange.

In the week after the triplet therapy, neurological and cognitive disorders had regressed in all previously affected patients. The median time from the start of the triplet therapy to platelet count recovery to 150 × 10⁹/L was 4 (range: 3–7) days. The changes in platelet count followed a wave-like pattern. During the first 2 weeks of caplacizumab therapy, the platelet count rapidly increased to supra-normal levels, and then the platelet count normalized ([Fig. 2]). Before platelet recovery, patients required a median of 4 PEX (range: 4–7) with the median total volume of 10,768 (range: 4391–34,544) mL. Despite platelet recovery, all the patients still had an ADAMTS-13 activity of less than 20% ([Fig. 2]).

Fig. 2 Platelet count and ADAMTS-13 activity during treatment. ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.

The median duration of caplacizumab therapy was 24 (range: 6–63) days. After PEX cessation, the median duration of caplacizumab therapy was 20 (range: 1–59) days. Ten patients required caplacizumab therapy for only 1 to 12 days after PEX cessation. However, in five patients, the duration of caplacizumab therapy after PEX cessation exceeded 30 days.

Most patients achieved complete ADAMTS-13 remission during treatment, that is, ADAMTS-13 activity of ≥40% ([Fig. 2]). To achieve an ADAMTS-13 activity of ≥40%, four rituximab infusions were required for 19 patients, six rituximab infusions for 1 patient, and eight rituximab infusions for 2 patients. In two patients, the ADAMTS-13 activity was, respectively, 30 and 33% after eight rituximab infusions, that is, complete remission was not achieved despite normal platelet counts and lactate dehydrogenase levels. The median time to achieve an ADAMTS-13 activity of ≥40%, that is, complete remission, was 24 (range: 5–82) days, and the probability of achieving complete remission was 91.6% ([Fig. 3]).

Fig. 3 Probability of partial remission (PR) and complete remission (CR) in immune thrombotic thrombocytopenic purpura (iTTP) patients.

In the present study, the treatment regimen for iTTP was modified from the standard approach. “Sprint therapy” with PEX, glucocorticoids, and first of all caplacizumab has previously allowed quick cessation of the manifestations of iTTP.[3] However, caplacizumab itself does not increase the activity of ADAMTS-13. The increase in platelet count and disappearance of hemolysis are achieved by caplacizumab binding to the A1 domain of VWF.[6] An interesting phenomenon we observed was the wave-like increase in blood platelet count during treatment. The rapid rise in platelet count to above-normal levels in the first few days, followed by normalization later, can be explained by the fast release of platelets from existing platelet aggregates. However, if the ADAMTS-13 activity level is not increased by the time caplacizumab is discontinued, the clinical manifestations of iTTP may recur. According to the Hercules study,[7] caplacizumab is recommended alongside immunosuppressive therapy for 30 days after the last iTTP episode. However, within this time frame, in some patients the ADAMTS-13 activity may remain low and iTTP recurrences could happen. In the Hercules study,[7] 17 of 72 patients (26.3%) in the caplacizumab arm had an ADAMTS-13 activity of less than 10% after treatment cessation, and 6 of these 17 patients experienced a relapse of iTTP. Conversely, the ADAMTS-13 activity may increase in some patients more quickly than 30 days after cessation of PEX. An ADAMTS-13 threshold, above which caplacizumab therapy can be discontinued, remains to be defined, although there is evidence that a level greater than 20% is sufficient.[8] [9] In a German study, there were no iTTP recurrences when caplacizumab therapy was stopped in patients with an ADAMTS-13 activity of greater than 10%.[10] A retrospective observational study[11] analyzing caplacizumab use in 60 patients found that immunosuppressive therapy led to a greater than 10% increase in the ADAMTS-13 activity 1 to 191 days (median: 21 days) after PEX cessation. In 11 of 60 patients, caplacizumab was continued beyond day 30, and in 5 patients it was extended to day 58. Meanwhile, in 34 of 60 patients, caplacizumab was discontinued before day 30 because their ADAMTS-13 activity exceeded 10%. The median time to ADAMTS-13 recovery with caplacizumab use has been reported as 14 to 28 days after the end of PEX. Therefore, caplacizumab therapy should be tailored based on the ADAMTS-13 activity level.[11] Caplacizumab therapy was continued until the ADAMTS-13 activity increased to ≥20%, and the median duration of caplacizumab therapy after discontinuing PEX was 20 days. This was shorter than the 30-day duration reported in the Hercules study,[7] and in the caplacizumab therapy guidelines.[12] It was also shorter than the 32.5 (range: 9–204) days reported for the German patient cohort to achieve an ADAMTS-13 activity greater than 10% after TTP diagnosis, and 21 (range: 1–191) days after cessation of PEX.[10] However, cessation of caplacizumab therapy after an ADAMTS-13 activity of ≥20% in our study does not mean overall saving in cost of iTTP treatment, because 5 of 24 patients required longer therapy with caplacizumab than the recommended 30 days after PEX cessation.

Increment in the ADAMTS-13 activity during the initial short period is achieved through PEX and glucocorticoids, whereas in the long term, increment in the ADAMTS-13 activity is achieved through immunosuppressive therapy with glucocorticoids and rituximab.[3] Rituximab therapy was not considered decisive in acute phase of iTTP, and can be regarded as a “stayer therapy.” In a study of the efficacy of rituximab with PEX and steroids, but without caplacizumab, the median time to sustained normalization of the platelet count was 12 days and the ADAMTS-13 activity reached 15% only before the second rituximab infusion.[13] Additionally, concurrent treatment with PEX can decrease the serum concentration of rituximab. The median fall in serum rituximab level after PEX was 65%.[14] In our work, rituximab therapy was started only after platelet count increased to ≥150 × 10⁹/L and PEX procedures were stopped. Immunosuppressive therapy with glucocorticoids and rituximab was continued till the ADAMTS-13 activity increased to ≥40%. It was previously shown that in a once-weekly regimen of 375 mg/m² rituximab administered intravenously for four doses, 92.1% of patients achieved an ADAMTS-13 activity of greater than 30%, and 78.9% achieved ADAMTS-13 activity normalization.[15] In our study, the ADAMTS-13 activity of ≥40% was reached in 22 of 24 patients, although some patients required six to eight rituximab infusions.

In conclusion, ADAMTS-13 activity monitoring allows tailoring of the triplet therapy in iTTP patients. Initiation of caplacizumab early on allows for faster short-term recovery. PEX, corticosteroids and caplacizumab allow to increase platelet count, interrupt hemolysis, and relieve symptoms of iTTP. PEX should be stopped when platelet count increased to >150 x 109/L. Rituximab should be started after PEX cessation. Caplacizumab should be stopped when ADAMTS13 activity reached to >20%. Rituximab and glucocorticoids should be continued until the ADAMTS13 activity increased to >40%, after this, rituximab should be stopped and a dose reduction of corticosteroids initiated.

Publication History

Article published online:
17 October 2024

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