Pediatr Blood Cancer 2015;62:551–552
HIGHLIGHT
by Francine Blei, MD, MBA*
Kaposiform Hemangioendothelioma: Therapeutic Efficacy for an Enigmatic Diagnosis
I
n 1997, Sarkar et al. and Enjolras et al. independently reported that Kasabach–Merritt Phenomenon is not associated with common hemangiomas of infancy but with Kaposiform Hemangioendotheliomas or Tufted Angioma [1,2]. Kaposiform Hemangioendothelioma (KHE) has long been the bane of physicians due to the fastidious nature of this disorder, with variability in presentation and response to therapy. The hematologic association of Kasabach Merritt Phenomenon (KMP) with profound thrombocytopenia/ hypofibrinogenemia/coagulopathy add complexity to the management. An excellent review of KHE and risk factors for development of KMP is provided by Croteau and colleagues [3]. Historically, patients have been treated with what seemed like a random array of therapies, including steroids, interferon, chemotherapy, blood products, with variable response. Since then, we have gradually learned how to tame the lion of KHE, however each new case is often humbling to even experienced practitioners in this field. Corticosteroids had been the mainstay of treatment, along with antifibrinolytics, antiplatelet agents and other therapies. Interferon alfa at one time seemed promising, however it has since been replaced by other agents due to concerns about toxicity. Propranolol, which has been successful for treating hemangiomas of infancy, has not consistently been effective for KHE/KMP. In 2002, Haisley-Royster et al. published data on 15 patients with KMP associated with KHE or Tufted Angioma, treated at several centers on different continents. All patients had improvement in platelet count and fibrinogen within about1 month, average normalization of platelet count 5 weeks, and average length of treatment 21.5 weeks. Most of the patients (13/15) showed visual clinical improvement in the vascular mass. Four patients required a second course of vincristine. The authors were optimistic about their findings and concluded that vincristine should be considered as a therapy for these disorders [4]. In 2013, a consensus-derived recommendation for the management of KHE was published, reflecting opinions of physicians from 24 vascular anomalies programs. Case scenarios were presented and treatment modalities voted upon. For the case with KHE and KMP, steroids and vincristine (with weaning of steroids once patient stabilized) was the preferred first line treatment modality. Typical duration of therapy for vincristine was stated to be 20–24 weeks [5]. Now in 2014, m-Tor inhibitors are gaining favor for the treatment of these disorders. M-Tor activation in vascular anomalies was observed in vivo, and mTor inhibition suggested as a therapeutic target by Arbiser and colleagues [6]. A large clinical trial demonstrated effectiveness of sirolimus for lymphangioleiomyomatosis [7]. Based on a clinical trial assessing sirolimus C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25365 Published online 5 January 2015 in Wiley Online Library (wileyonlinelibrary.com).
treatment for patients with a variety complex vascular anomalies, this agent seemed to be effective for KHE [8]. Based on this observation, sirolimus is now becoming a medication that is being utilized more routinely for patients with this disorder. In fact, the authors of this highlighted article describing their experience with vincristine [9] recently published their experience with sirolimus for a 4 month old with KHE and KMP who had failed propranolol, methylprednisolone and vincristine therapy. Hematologic improvement was seen at week 3 after initiation of sirolimus [10]. In “Steroid-resistant Kaposiform hemangioendothelioma: A restrospective study of 37 patients treated with vincristine and long-term follow-up” [9] the authors review 37 cases of KHE treated with vincristine over a 10 year period. The age of diagnosis newborn to 10 months. The majority of these infants (37/39) had not responded well to corticosteroid steroids. Most of the patients responded well to vincristine, with a wide time range for hematologic (platelet count) normalization. The average length of treatment was 31.2 þ/ 5.9 weeks. Eight patients failed to respond to vincristine. Follow-up was not truly long-term. It is known that KHE often leaves residual fibrosis and other sequelae [11]. Interestingly, the same authors published in March of this year a series of six cases of KHE refractory to “other therapies,” which responded to sirolimus. These infants were younger on average than those in the vincristine series, and time to respond to therapy was remarkably quicker with a shorter duration of therapy, which has not been replicated in other studies [12]. In many other reports, sirolimus is being used after failure of other therapies. However, it seems to be gaining favor as a first line therapy. The negatives of vincristine (necessity for a central line, potential toxicities) versus sirolimus (frequent phlebotomy and monitoring blood levels, potential long term toxicity) need to be balanced against the positives oral versus intravenous activity, suggestion of quicker response and potential shorter duration of full dose therapy. Thus, a review of steroid-resistant KHE treated with vincristine has historic interest yet it is already anachronistic, since mTor inhibitors (sirolimus or an analogue) may finally offer monotherapy for a disease that has traditionally required multiple treatments. Vascular Anomalies Program of Lenox Hill Hospital, New York, New York Conflict of interest: Nothing to declare. Correspondence to: Francine Blei, Vascular Anomalies Program of Lenox Hill Hospital, New York. E-mail: [email protected]
Received 6 October 2014; Accepted 14 October 2014
552
Blei
REFERENCES 6. 1. Sarkar M,Mulliken JB, Kozakewich HP, Robertson RL, Burrows PE. Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg 1997;100:1377–1386. 2. Enjolras O, Wassef M, Mazoyer E, Frieden IJ, Rieu PN, Drouet L, Taı¨eb A, Stalder JF, Escande JP. Infants with Kasabach-Merritt syndrome do not have “true” hemangiomas. J Pediatr 1997;130:631–640. 3. Croteau SE, Liang MG, Kozakewich HP, Alomari AI, Fishman SJ, Mulliken JB, Trenor CC III. Kaposiform hemangioendothelioma: Atypical features and risks of Kasabach–Merritt phenomenon in 107 referrals. J Pediatr 2013;162:142–147. doi:10.1016/j.jpeds.2012.06.044. Epub 2012 Aug 4. 4. Haisley-Royster C, Enjolras O, Frieden IJ, Garzon M, Lee M, Oranje A, de Laat PC, Madern GC, Gonzalez F, Frangoul H, Le Moine P, Prose NS, Adams DM. Kasabach–Merritt phenomenon: A retrospective study of treatment with vincristine. J Pediatr Hematol Oncol 2002;24:459–462. Erratum in J Pediatr Hematol Oncol 2002 Dec;24(9):794. 5. Drolet BA, Trenor CC III, Branda˜o LR, Chiu YE, Chun RH, Dasgupta R, Garzon MC, Hammill AM, Johnson CM, Tlougan B, Blei F, David M, Elluru R, Frieden IJ, Friedlander SF, Iacobas I, Jensen JN, King DM, Lee MT, Nelson S, Patel M, Pope E, Powell J, Seefeldt M, Siegel DH, Kelly M, Adams DM.
Pediatr Blood Cancer DOI 10.1002/pbc
7. 8.
9. 10. 11.
12.
Consensus-derived practice standards plan for complicated Kaposiform hemangioendothelioma. J Pediatr 2013;163:285–291. doi:10.1016/j.jpeds.2013.03.080. Shirazi F, Cohen C, Fried L, Arbiser JL. Mammalian target of rapamycin (mTOR) is activated in cutaneous vascular malformations in vivo. Lymphat Res Biol 2007;5:233–236. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011;364:1595–1606. Hammill AM, Wentzel M, Gupta A, Nelson S, Lucky A, Elluru R, Dasgupta R, Azizkhan RG, Adams DM. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 2011;57:1018–1024. doi:10.1002/pbc.23124. Epub 2011 Mar 28. Wang Z. Steroid-resistant kaposiform hemangioendothelioma: A retrospective study of 37 patients treated with vincristine and long-term follow-up. Pediatr Blood Cancer 2014;14–0208. Wang Z, Li K, Dong K, Xiao X, Zheng S. Successful treatment of Kasabach–Merritt phenomenon arising from Kaposiform hemangioendothelioma by sirolimus. J Pediatr Hematol Oncol 2013;37:72–73. Enjolras O, Mulliken JB, Wassef M, Frieden IJ, Rieu PN, Burrows PE, Salhi A, Le´aute´-Labreze C, Kozakewich HP. Residual lesions after Kasabach-Merritt phenomenon in 41 patients. J Am Acad Dermatol 2000;42:225–235. Kai L, Wang Z, Yao W, Dong K, Xiao X. Sirolimus, a promising treatment for refractory Kaposiform hemangioendothelioma. J Cancer Res Clin Oncol 2014;140:471–476.
HIGHLIGHT
by Francine Blei, MD, MBA*
Kaposiform Hemangioendothelioma: Therapeutic Efficacy for an Enigmatic Diagnosis
I
n 1997, Sarkar et al. and Enjolras et al. independently reported that Kasabach–Merritt Phenomenon is not associated with common hemangiomas of infancy but with Kaposiform Hemangioendotheliomas or Tufted Angioma [1,2]. Kaposiform Hemangioendothelioma (KHE) has long been the bane of physicians due to the fastidious nature of this disorder, with variability in presentation and response to therapy. The hematologic association of Kasabach Merritt Phenomenon (KMP) with profound thrombocytopenia/ hypofibrinogenemia/coagulopathy add complexity to the management. An excellent review of KHE and risk factors for development of KMP is provided by Croteau and colleagues [3]. Historically, patients have been treated with what seemed like a random array of therapies, including steroids, interferon, chemotherapy, blood products, with variable response. Since then, we have gradually learned how to tame the lion of KHE, however each new case is often humbling to even experienced practitioners in this field. Corticosteroids had been the mainstay of treatment, along with antifibrinolytics, antiplatelet agents and other therapies. Interferon alfa at one time seemed promising, however it has since been replaced by other agents due to concerns about toxicity. Propranolol, which has been successful for treating hemangiomas of infancy, has not consistently been effective for KHE/KMP. In 2002, Haisley-Royster et al. published data on 15 patients with KMP associated with KHE or Tufted Angioma, treated at several centers on different continents. All patients had improvement in platelet count and fibrinogen within about1 month, average normalization of platelet count 5 weeks, and average length of treatment 21.5 weeks. Most of the patients (13/15) showed visual clinical improvement in the vascular mass. Four patients required a second course of vincristine. The authors were optimistic about their findings and concluded that vincristine should be considered as a therapy for these disorders [4]. In 2013, a consensus-derived recommendation for the management of KHE was published, reflecting opinions of physicians from 24 vascular anomalies programs. Case scenarios were presented and treatment modalities voted upon. For the case with KHE and KMP, steroids and vincristine (with weaning of steroids once patient stabilized) was the preferred first line treatment modality. Typical duration of therapy for vincristine was stated to be 20–24 weeks [5]. Now in 2014, m-Tor inhibitors are gaining favor for the treatment of these disorders. M-Tor activation in vascular anomalies was observed in vivo, and mTor inhibition suggested as a therapeutic target by Arbiser and colleagues [6]. A large clinical trial demonstrated effectiveness of sirolimus for lymphangioleiomyomatosis [7]. Based on a clinical trial assessing sirolimus C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25365 Published online 5 January 2015 in Wiley Online Library (wileyonlinelibrary.com).
treatment for patients with a variety complex vascular anomalies, this agent seemed to be effective for KHE [8]. Based on this observation, sirolimus is now becoming a medication that is being utilized more routinely for patients with this disorder. In fact, the authors of this highlighted article describing their experience with vincristine [9] recently published their experience with sirolimus for a 4 month old with KHE and KMP who had failed propranolol, methylprednisolone and vincristine therapy. Hematologic improvement was seen at week 3 after initiation of sirolimus [10]. In “Steroid-resistant Kaposiform hemangioendothelioma: A restrospective study of 37 patients treated with vincristine and long-term follow-up” [9] the authors review 37 cases of KHE treated with vincristine over a 10 year period. The age of diagnosis newborn to 10 months. The majority of these infants (37/39) had not responded well to corticosteroid steroids. Most of the patients responded well to vincristine, with a wide time range for hematologic (platelet count) normalization. The average length of treatment was 31.2 þ/ 5.9 weeks. Eight patients failed to respond to vincristine. Follow-up was not truly long-term. It is known that KHE often leaves residual fibrosis and other sequelae [11]. Interestingly, the same authors published in March of this year a series of six cases of KHE refractory to “other therapies,” which responded to sirolimus. These infants were younger on average than those in the vincristine series, and time to respond to therapy was remarkably quicker with a shorter duration of therapy, which has not been replicated in other studies [12]. In many other reports, sirolimus is being used after failure of other therapies. However, it seems to be gaining favor as a first line therapy. The negatives of vincristine (necessity for a central line, potential toxicities) versus sirolimus (frequent phlebotomy and monitoring blood levels, potential long term toxicity) need to be balanced against the positives oral versus intravenous activity, suggestion of quicker response and potential shorter duration of full dose therapy. Thus, a review of steroid-resistant KHE treated with vincristine has historic interest yet it is already anachronistic, since mTor inhibitors (sirolimus or an analogue) may finally offer monotherapy for a disease that has traditionally required multiple treatments. Vascular Anomalies Program of Lenox Hill Hospital, New York, New York Conflict of interest: Nothing to declare. Correspondence to: Francine Blei, Vascular Anomalies Program of Lenox Hill Hospital, New York. E-mail: [email protected]
Received 6 October 2014; Accepted 14 October 2014
552
Blei
REFERENCES 6. 1. Sarkar M,Mulliken JB, Kozakewich HP, Robertson RL, Burrows PE. Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg 1997;100:1377–1386. 2. Enjolras O, Wassef M, Mazoyer E, Frieden IJ, Rieu PN, Drouet L, Taı¨eb A, Stalder JF, Escande JP. Infants with Kasabach-Merritt syndrome do not have “true” hemangiomas. J Pediatr 1997;130:631–640. 3. Croteau SE, Liang MG, Kozakewich HP, Alomari AI, Fishman SJ, Mulliken JB, Trenor CC III. Kaposiform hemangioendothelioma: Atypical features and risks of Kasabach–Merritt phenomenon in 107 referrals. J Pediatr 2013;162:142–147. doi:10.1016/j.jpeds.2012.06.044. Epub 2012 Aug 4. 4. Haisley-Royster C, Enjolras O, Frieden IJ, Garzon M, Lee M, Oranje A, de Laat PC, Madern GC, Gonzalez F, Frangoul H, Le Moine P, Prose NS, Adams DM. Kasabach–Merritt phenomenon: A retrospective study of treatment with vincristine. J Pediatr Hematol Oncol 2002;24:459–462. Erratum in J Pediatr Hematol Oncol 2002 Dec;24(9):794. 5. Drolet BA, Trenor CC III, Branda˜o LR, Chiu YE, Chun RH, Dasgupta R, Garzon MC, Hammill AM, Johnson CM, Tlougan B, Blei F, David M, Elluru R, Frieden IJ, Friedlander SF, Iacobas I, Jensen JN, King DM, Lee MT, Nelson S, Patel M, Pope E, Powell J, Seefeldt M, Siegel DH, Kelly M, Adams DM.
Pediatr Blood Cancer DOI 10.1002/pbc
7. 8.
9. 10. 11.
12.
Consensus-derived practice standards plan for complicated Kaposiform hemangioendothelioma. J Pediatr 2013;163:285–291. doi:10.1016/j.jpeds.2013.03.080. Shirazi F, Cohen C, Fried L, Arbiser JL. Mammalian target of rapamycin (mTOR) is activated in cutaneous vascular malformations in vivo. Lymphat Res Biol 2007;5:233–236. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011;364:1595–1606. Hammill AM, Wentzel M, Gupta A, Nelson S, Lucky A, Elluru R, Dasgupta R, Azizkhan RG, Adams DM. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 2011;57:1018–1024. doi:10.1002/pbc.23124. Epub 2011 Mar 28. Wang Z. Steroid-resistant kaposiform hemangioendothelioma: A retrospective study of 37 patients treated with vincristine and long-term follow-up. Pediatr Blood Cancer 2014;14–0208. Wang Z, Li K, Dong K, Xiao X, Zheng S. Successful treatment of Kasabach–Merritt phenomenon arising from Kaposiform hemangioendothelioma by sirolimus. J Pediatr Hematol Oncol 2013;37:72–73. Enjolras O, Mulliken JB, Wassef M, Frieden IJ, Rieu PN, Burrows PE, Salhi A, Le´aute´-Labreze C, Kozakewich HP. Residual lesions after Kasabach-Merritt phenomenon in 41 patients. J Am Acad Dermatol 2000;42:225–235. Kai L, Wang Z, Yao W, Dong K, Xiao X. Sirolimus, a promising treatment for refractory Kaposiform hemangioendothelioma. J Cancer Res Clin Oncol 2014;140:471–476.
