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Sirolumus’s merit for the Kasabach-Merritt phenomenon

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By Warren R. Heymann, MD
Oct. 8, 2018

KHE patient after 15 months of sirolimus therapy
KHE patient after 15 months of sirolimus therapy.
Credit: JAAD

Thrombopenic purpura associated with benign hemangioma is rare. In fact, we have not been able to find a record of a combination of these two conditions in the medical literature. We wish to report the following case of an extensive hemangioma of the skin associated with diffuse purpuric manifestations. The course and management of the condition, we believe, are of unusual interest.

In 1940, Drs. Haig Kasabach and Katherine Merritt reported the case of a 2 month-old boy with a large hemangioma involving the lower abdomen, scrotum, and left leg. The lesion became purpuric — this was accompanied by thrombocytopenia, an increased bleeding time, and anemia. A biopsy demonstrated lobules of fine capillaries, spindled cells, and mitoses. The child improved with radiation therapy. (1)

The Kasabach-Merritt phenomenon (KMP) is a consumptive coagulopathy associated with specific vascular tumors, notably Kaposiform hemangioendothelioma (KHE, which is the likely diagnosis in the original report) or tufted angioma (TA). KMP may affect up to 70% of all patients with KHE and up to 10% of patients with TA. KMP is characterized by profound thrombocytopenia, hypofibrinogenemia, elevated fibrin split products, rapid tumor growth, and can be life-threatening, with a mortality rate up to 30%. (2,3)

In their retrospective review of 146 patients with KHE, Ji et al reported that approximately 70% (102 patients) showed KMP. Patients with KMP were more likely to have major complications (compression of vital structures, bone destruction, decreased range of motion) than patients without KMP. Young age (< 6 months), truncal location, large lesion size and mixed lesion (cutaneous and deeper organ involvement) type were associated with KMP in a univariate analysis. In the multivariate analysis, only age [odds ratio (OR) 11.9], large lesion size (OR 5.08) and mixed lesion type (OR 2.96) were significantly associated with KMP. (4)

A curative treatment of KMP is defined as restoration of normal hemostasis and elimination of tumor cells. (5) Although surgical excision of KHE or TA would be curative, surgery is usually not an option given the extent of lesions and the risk during active KMP. The optimal therapy for KMP remains to be defined, although steroids and vincristine are currently considered first-line agents.

Blatt et al were the first to report the efficacy of sirolimus in a 2 month-old girl with KHE and KMP. Their hypothesis that sirolimus, an mTOR inhibitor, would be beneficial because of its anti-angiogenic activity proved to be prescient. (6) According to Cashell et al: “the use of m‐TOR inhibitors in vascular anomalies [is] based on the concept that patients have activation of the phosphatidylinositol 3‐kinase/AKT signaling pathway, controlled by mTOR. Accordingly, overexpression of AKT/protein kinase B, TIE2 receptor–activating mutations, and the loss of function mutations in the PTEN tumor suppressor gene have all been associated with the development of vascular anomalies in patients and laboratory models.” (7) Since Blatt et al, there have been approximately 50 manuscripts discussing sirolimus therapy for KMP, ranging from adjunctive treatment to monotherapy.

Despite its promise, because sirolimus is a potent immunosuppressant being administered during infancy for the KMP, caution is advised. Ying et al detailed 2 infants, 1 month-old, and 4.5 months-old, respectively. Both had KHE and KMP that improved with sirolimus, yet both developed fatal bronchopneumonia, with Mycoplasma pulmonis as the pathogen for the older infant. The authors suggested that antibiotic prophylaxis may be appropriate when using sirolimus in infants with immunological immaturity. (8)

Russell et al described the case of a 2 month-old boy with KHE and the KMP who developed Pneumocystis carinii pneumonia (PCP) while on sirolimus and a prednisolone taper, after lack of adequate response to prednisolone, propranolol, and vincristine. He had a prompt positive clinical and laboratory response to sirolimus, but 4 weeks after starting it, at the age of 4 months, he developed PCP. This led to respiratory failure, which required extracorporeal membrane oxygenation. Sirolimus was temporarily discontinued, and he was successfully treated for PCP with sulfamethoxazole-trimethoprim and methylprednisolone. He was restarted on sirolimus 3 weeks after discharge and given sulfamethoxazole-trimethoprim prophylaxis. At the age of 22 months, while still on sirolimus, the lesion continued to improve with test results revealing stable hemoglobin and platelet counts. The authors concluded that because PCP is a rare but life-threatening side effect of sirolimus therapy, especially in the setting of concurrent steroid treatment, Pneumocystis prophylaxis should be considered for patients receiving sirolimus. (9)

In a review of 61 patients with a variety of vascular anomalies (10 having KHE or TA with KMP) treated with sirolimus, grade 3 and higher toxicities attributable to sirolimus included blood/bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/laboratory toxicity in 3%. No toxicity-related deaths occurred. (10)

While there is merit in prescribing sirolimus for KHE (with or without KMP), I completely concur with Tower, in an editorial accompanying Ji et al, that future therapy will be based on a molecular understanding of KHE and KMP, with the development of targeted agents. (11)

Point to remember: Sirolimus may be a valuable drug, either alone, or in combination with other therapies (such as steroids or vincristine) for the management of the Kasabach-Merritt phenomenon.

1. Kasabach HH, Merritt KK. Capillary hemangioma with extensive purpura: Report of a case. Am J Dis Child 1940; 59: 1063-70.
2. Lewis D, Vaidya R. Kasabach Merritt syndrome. StatPearls [Internet] Treasure Island (FL): StatPearls Publishing, 2018-2018 Jul 27
3. Mahajan P, et al. Kasabach-Merritt phenomenon: Classic presentation and management options. Clin Med Insights Blood Disord 2017 Mar 16;10:1179545X17699849
4. Ji Y, et al. Kaposiform haemangioendothelioma: Clinical features, complications, and risk factors for Kasabach-Merritt phenomenon. Br J Dermatol 2018; 179: 457-63.
5. Lei HZ, et al. Retrospective study on the outcomes of infantile tufted angioma complicated by Kasabach-Merritt phenomenon. Clin Chim Acta 2018; 486: 199-204.
6. Blatt J, et al. Treatment of childhood Kaposiform hemangioendothelioma with sirolimus. Pediatr Blood Cancer 2010; 55: 1396-8.
7. Cashell J, et al. Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon in an infant: Successful treatment with prednisolone, vincristine, and addition of sirolimus. Pediatr Blood Cancer 2018; Aug 1 [Epub ahead of print].
8. Ying H, et al. A case report of 2 sirolimus-related deaths among infants with Kaposiform hemangioendotheliomas. Pediatrics 2018; 141 (Suppl 5): S425-9.
9. Russell TB, et al. Pneumocystis jirovecii pneumonia during sirolimus therapy for Kaposiform hemangioendothelioma. Pediatrics 2018; 141 (Suppl 5): S421-4.
10. Adams DM, et al. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics 2016; 137: 1-10.
11. Tower RL. Kaposiform haemangioendothelioma: New insights and old problems. Br J Dermatol 2018; 179: 253-4.

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