Bortezomib in the treatment of refractory thrombotic thrombocytopenic purpura

Abstract

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening condition caused by autoantibody-mediated inhibition of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type-1 motif, 13). Therapeutic plasma exchange (TPE) improves survival, but disease may be refractory despite therapy. Management and treatment response of refractory TTP is variable, with rituximab and other immunosuppression often being used. Case reports have suggested a benefit of the proteasome inhibitor, bortezomib, possibly due to elimination of the autoreactive plasma cells producing anti-ADAMTS13 antibodies. We evaluated the effect of bortezomib in a series of primary refractory TTP patients unresponsive to intensive therapy. Bortezomib-treated patients were identified from consecutive cases managed at two UK referral centres. Demographic and clinical data were extracted from hospital records. ADAMTS13 activity was measured using a fluorescence resonance energy transfer VWF73 assay, and anti-ADAMTS13 IgG using enzyme-linked immunosorbent asssay. We identified six bortezomib-treated patients out of 51 consecutive cases of acute, acquired TTP. All patients received TPE, methylprednisolone and rituximab. Five of the six achieved complete remission with bortezomib, and one died of cardiac arrest due to underlying disease. No treatment-related adverse events were observed. Mean follow-up time after hospital discharge was 17 months (range: 3-33). Bortezomib appears effective in the treatment of a subgroup of cases with severe, refractory TTP. Prospective trials are required to further investigate this effect.

Bortezomib-based antibody depletion for refractory autoimmune hematological diseases

“…Although absolute numbers are low, the apparent high response rate in TTP is consistent with a recent series of 6 consecutive cases from UK referral centers where 5 patients achieved remission. 16 Although formal prospective evaluation of proteasome inhibition in ultra-rare diseases like TTP is unlikely to be feasible, more common presentations such as refractory AIHA should be amenable to trial development. Registry data may also prove invaluable for capturing disease-specific response rates and safety end points.…”

“…7 On this basis, bortezomib has been prospectively evaluated as an adjunct to rituximab and plasma exchange (PEX) as a means to deplete alloantibodies in solid organ transplant recipients. 8 Moreover, reports of activity in autoimmune diseases including AIHA, 9,10 immune thrombocytopenia, 11 and TTP [12][13][14][15][16] are emerging. Following our initial success utilizing bortezomib in a patient with refractory TTP, 12 we now report our cumulative experience using this treatment approach in a series of patients with refractory antibody-mediated autoimmune hematological diseases.…”

Remission of Severe, Relapsed, and Refractory TTP after Multiple Cycles of Bortezomib

“…However, they could not demonstrate if the response was secondary to rituximab or bortezomib [7]. Similarly, Patriquin et al reported a series of six refractory TTP patients all of whom received PEX, methylprednisolone, and rituximab besides bortezomib [11]. Bortezomib was given very early in the disease process (range 6–22 days) which is understandable given the often aggressive nature of TTP and hence the resultant desperate therapy alterations.…”

Novel therapies in thrombotic thrombocytopenic purpura

“…However, NAC as a single therapy, was unable to reverse TTP signs nor dissolve preexisting VWF‐rich thrombi 32. Case reports have shown successful use of NAC in patients with refractory TTP as evidenced by normalization of platelet function and ADAMTS13 activity in four patients33, 34 but was unsuccessful in three others 35, 36, 37. A pilot study to evaluate the use of NAC in suspected TTP is underway (NCT01808521).…”

“…Its mechanism of action in TTP is thought to be due to the elimination of plasma cells that produce the autoantibodies against ADAMTS13. The evidence for the use of this drug is still limited to case reports35, 40, 41, 42, 43, 44, 45 and a case series37 that reported 14 cases of TTP that were refractory to PEX, steroids, and rituximab. All but one patient recovered from their acute episode of TTP.…”