Delayed response to Cablivi often tied to other causes, new study finds
Missed doses, infections among factors behind delayed platelet recovery
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A lack or delayed response to Cablivi (caplacizumab-yhdp), when used alongside standard therapy to treat acute episodes of immune-mediated thrombotic thrombocytopenic purpura (iTTP), was linked to clinical factors rather than clear drug resistance in a new study.
Researchers found that issues such as missed doses or serious infections — rather than true treatment resistance — explained cases where platelet counts did not recover as expected.
“In clinical practice, persistent [low platelet counts] during ongoing [Cablivi] treatment should prompt a careful reassessment for potential confounding factors, rather than an escalation of iTTP treatment,” the researchers wrote.
The study, “Revisiting Clinical Response and Refractoriness in Immune Thrombotic Thrombocytopenic Purpura,” was published in Blood.
How Cablivi works to prevent clot formation in iTTP
Cablivi is approved for iTTP patients, ages 12 and older, in combination with plasma exchange and immunosuppressive therapy. It’s designed to prevent the formation of tiny blood clots that occur when an immune attack disrupts ADAMTS13, an enzyme that normally prevents platelets (cell fragments that help blood clot) from forming clots when they aren’t needed.
In clinical trials, most iTTP patients achieved clinical remission when Cablivi was added to standard treatment, typically defined by normalization of platelet counts and a reduction in LDH, a marker of red blood cell breakdown. Still, in some cases, platelet count recovery was delayed, raising concerns about iTTP refractoriness, meaning a lack of adequate treatment response.
A team led by scientists at the University of Cologne in Germany sought to determine whether delayed clinical responses during Cablivi treatment reflected true refractoriness or were due to other factors.
“The lack of clinical response in iTTP patients is a particular challenge for physicians, as they must balance the decision to intensify iTTP therapy … with the possibility of alternative diagnoses for thrombocytopenia (low platelet counts), that may call for additional treatments,” the scientists wrote.
The researchers collected clinical data on acute iTTP episodes occurring in 204 adult patients (67.2% women). The data were drawn from the German REACT-2020 (NCT04985318) and Austrian ATMAR registries.
Study examines treatment response in real-world iTTP cases
All patients received Cablivi, which was used as a first-line treatment (within three days) in most cases (79%). Most patients also received plasma exchange (80%), along with corticosteroids (99.5%) and rituximab (88%). About one-fifth (20%) were treated with a regimen that did not include plasma exchange.
Refractoriness was assessed using two different definitions. The 2017 IWG defined refractory iTTP as persistent thrombocytopenia, a lack of a sustained platelet count increase, or a platelet count of less than 50 x 109/L, along with persistently elevated LDH despite five days of plasma exchange. The French CNR-MAT defined refractoriness as the absence of platelet count doubling after four days of standard-of-care treatment, with LDH remaining above the upper limit of the normal range.
According to efficacy data, most patients (83.8%) achieved a clinical response, defined as normalization of platelet counts (greater than 150 x 109/L), within five days of starting Cablivi. The remaining patients (16.2%) also experienced meaningful improvement, with platelet counts doubling or more.
When the team assessed refractoriness, three of the 204 patients (1.5%) met the criteria of either refractory definition. Of these, one patient (0.5%) met both criteria. All three patients had received treatment with Cablivi and plasma exchange, along with immunosuppression using rituximab and corticosteroids.
In all three cases, alternative causes of sustained thrombocytopenia were identified: missed Cablivi doses in one case and serious infections in two cases. Eventually, all three patients achieved clinical remission.
“Not a single case in our cohort could be classified as truly refractory in the absence of a clear confounding factor,” the team noted.
Other medical factors linked to delayed platelet recovery
The researchers also assessed eight patients (3.9%) with a markedly prolonged time to clinical response, taking 10 days or longer to achieve platelet count normalization. In all cases, other factors contributed to the delayed response. These included infections, cancer, multiple platelet transfusions before iTTP diagnosis or treatment, a major bleeding event that interrupted Cablivi therapy, and missed Cablivi doses.
In the final analysis, having another identifiable medical cause was the only factor linked to slower platelet recovery. Other characteristics — including age, sex, body mass index (a measure of body fat based on height and weight), LDH levels before treatment, level of consciousness, and whether the episode was a first occurrence or a relapse — were not associated with delayed recovery.
“True iTTP refractoriness — when strictly defined — was exceedingly rare in this caplacizumab [Cablivi]-treated cohort, and most cases of delayed recovery were attributable to identifiable alternative causes,” the team wrote. “These findings support a structured clinical reassessment when platelet recovery is delayed, helping to avoid unnecessary interventions while ensuring timely management of underlying confounding conditions.”
