Splenectomy and/or cyclophosphamide as salvage therapies in thrombotic thrombocytopenic purpura: the French TMA Reference Center experience

Beloncle, François; Buffet, M.; Coindre, Jean‐Philippe; Munoz‐Bongrand, Nicolas; Malot, Sandrine; Pène, Frédéric; Mira, Jean‐Paul; Galicier, Lionel; Guidet, Bertrand; Baudel, Jean-Luc; Subra, Jean‐François; Tanguy‐Schmidt, Aline; Pourrat, Jacques; Azoulay, Élie; Veyradier, Agnès; Coppo, Paul

doi:10.1111/j.1537-2995.2012.03578.x

Cited by 80 publications

(61 citation statements)

References 38 publications

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“…54,55 More recently, it has been used in patients who are refractory to rituximab, or used in combination with rituximab for TTP patients who are refractory to steroids and PEX. [56][57][58] In a recent case series of 5 patients with refractory TTP (refractory to PEX, steroids, along with vincristine or rituximab or both), who were then treated with 3 to 6 pulses of cyclophosphamide (500-750 mg/m 2 per pulse), a durable platelet recovery was seen at a median period of 10 days after the first cyclophosphamide pulse. 56 Side effects of cyclophosphamide include bone marrow suppression, infection risk, infertility, and a potential long-term risk of myelodysplastic syndrome/leukemia.…”

Section: Cyclophosphamide and Vincristinementioning

confidence: 99%

How I treat refractory thrombotic thrombocytopenic purpura

Sayani¹,

Abrams

2015

Blood

145

143

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Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and neurologic deficits. It is characterized by a deficiency of the von Willebrand factor (VWF) cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13), resulting in formation of microthrombi in the high sheer environment of the microvasculature. This causes microvascular occlusion, MAHA, and organ ischemia. Diagnosis is based on the presence of clinical symptoms, laboratory aberrations consistent with MAHA, decreased ADAMTS13 activity, and possibly presence of anti-ADAMTS13 autoantibodies. Upfront treatment of acute TTP includes plasma exchange and corticosteroids. A significant number of patients are refractory to this treatment and will require further interventions. There are limited data and consensus on the management of the refractory TTP patient. Management involves simultaneously ruling out other causes of thrombocytopenia and MAHA, while also considering other treatments. In this article, we describe our management of the patient with refractory TTP, and discuss use of rituximab, increased plasma exchange, splenectomy, and immunosuppressive options, including cyclophosphamide, vincristine, and cyclosporine. We also review recent evidence for the potential roles of bortezomib and N-acetylcysteine, and explore new therapeutic approaches, including recombinant ADAMTS13 and anti-VWF therapy. (Blood. 2015;125(25):3860-3867) Case A 25-year-old previously healthy woman presented with a 3-day history of fatigue, nausea, abdominal pain, and easy bruising. She was alert, oriented, afebrile, had mild abdominal tenderness, and purpura on her extremities. Her hemoglobin was 8.4 g/dL; platelets, 15 3 10 9 /L; creatinine, 1.1 mg/dL; and her lactate dehydrogenase and reticulocytes were increased. Schistocytes and nucleated red blood cells were easily seen on her peripheral blood smear. In the absence of other obvious precipitators of thrombocytopenia and microangiopathic hemolytic anemia (MAHA), she was diagnosed with acquired thrombotic thrombocytopenic purpura (TTP). Blood samples were sent for ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13) activity and inhibitor levels, and the patient was immediately started on plasma exchange (PEX) and prednisone 1 mg/kg per day. She responded well initially, and her platelets rose to 105 000/mL on day 4. However, on day 5, she was febrile and her platelets dropped to 40 000/mL. BackgroundAcquired TTP was initially characterized by thrombocytopenia, MAHA, renal failure, neurologic deficits, and fever. However, it is now well accepted that neither renal failure nor high fevers are key diagnostic features. Thrombocytopenia and MAHA are required for diagnosis when TTP is suspected. TTP is a hematologic emergency, with a mortality of 90% if untreated. Treatment with PEX and cortico...

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Section: Cyclophosphamide and Vincristinementioning

confidence: 99%

How I treat refractory thrombotic thrombocytopenic purpura

Sayani¹,

Abrams

2015

Blood

145

143

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“…Four patients experienced manageable infections. 23 Cyclophosphamide side effects include bone marrow suppression, infectious complications, decreased fertility and a long-term risk of malignancy, which may be considered as acceptable in the context of refractory, life-threatening TTP.…”

Section: Cyclophosphamidementioning

confidence: 99%

“…24 If a patient does not respond to standard TPE and prednisone, our current strategy is to sequentially increase the intensity of treatment depending on the clinical course ( Figure 1) by adding rituximab, followed by twice-daily TPE, pulses of cyclophosphamide and even splenectomy in the more severe cases (Beloncle et al 23 and Soucemarianadin, manuscript submitted).…”

Section: Cyclophosphamidementioning

confidence: 99%

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Treatment of thrombotic thrombocytopenic purpura beyond therapeutic plasma exchange

Coppo

Froissart

2015

Hematology

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Daily therapeutic plasma exchange (TPE) transformed the historically fatal prognosis of acquired, anti-ADAMTS13 antibody-mediated thrombotic thrombocytopenic purpura (TTP), leading to the current overall survival rates of 80%-85%. However, relapses occur in ϳ40% of patients and refractory disease with fatal outcomes still occurs. In this context, the introduction of rituximab has probably been the second major breakthrough in TTP management. Rituximab is now routinely recommended during the acute phase, typically in patients with a suboptimal response to treatment, or even as frontline therapy, with high response rates. In more severe patients, salvage strategies may include twice-daily TPE, pulses of cyclophosphamide, vincristine, as well as splenectomy in more desperate cases.In this life-threatening disease, relapse prevention represents a major goal. Persistent severe acquired ADAMTS13 deficiency in patients who are otherwise in remission is associated with a high risk of relapse and preemptive treatment with rituximab may be considered in this context.In the coming years, the TTP therapeutic landscape should be enriched by original strategies stemming from clinical experience and new agents that are currently being evaluated in large, ideally international, clinical trials. Promising agents under evaluation include N-acetylcysteine, bortezomib, recombinant ADAMTS13, and inhibitors of the glycoprotein-Ib/IX-von Willebrand factor axis. Learning Objectives• Patients with acquired TTP who experience a suboptimal response (refractoriness or disease exacerbation) with standard management need a more intensive treatment • Salvage therapies typically include rituximab, and in the more severe cases twice daily plasma exchange, boluses of cyclophosphamide, vincristine, and splenectomy • A persistent severe acquired ADAMTS13 deficiency during TTP remission should prompt consideration of preemptive rituximab to prevent relapses

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“…Esetismertetések, kis esetszámú tanulmányok szólnak e szerek hatásossága mellett. Leginkább a ciklofoszfamid ajánlható [44]. Optimális adagolási módja nem ismert, a szisztémás autoimmun kórképekben használt sémák alkalmazása javasolható.…”

Section: Immunszuppresszív Kezelés (Isu) [10]unclassified

Egészségügyi szakmai irányelv – A thromboticus thrombocytopeniás purpura (TTP) és a haemolyticus uraemiás syndroma (HUS) kezeléséről

…¹

2017

Orvosi Hetilap

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Splenectomy and/or cyclophosphamide as salvage therapies in thrombotic thrombocytopenic purpura: the French TMA Reference Center experience

Abstract: Cyclophosphamide and splenectomy provide comparable high remission rates in severe TTP with acceptable side effects and should be considered in the more severe patients who do not improve with other therapies.

Cited by 80 publications

References 38 publications

How I treat refractory thrombotic thrombocytopenic purpura

How I treat refractory thrombotic thrombocytopenic purpura

Treatment of thrombotic thrombocytopenic purpura beyond therapeutic plasma exchange

Egészségügyi szakmai irányelv – A thromboticus thrombocytopeniás purpura (TTP) és a haemolyticus uraemiás syndroma (HUS) kezeléséről

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