Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Emory University on 08/23/15 For personal use only.
Review
Risk for complications in patients with hemophagocytic lymphohistiocytosis who undergo hematopoietic stem cell transplantation: myeloablative versus reducedintensity conditioning regimens Expert Rev. Clin. Immunol. 10(8), 1101–1106 (2014)
Tal Schechter*, Ahmed Naqvi and Sheila Weitzman Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Canada *Author for correspondence: Tel.: +1 416 813 6906 tal.schechter-finkelstein @sickkids.ca
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with primary hemophagocytic lymphohistiocytosis (HLH) and for patients with secondary HLH who fail to respond to therapy. Advances in HSCT and supportive care measures have resulted in improved patient outcomes and decreased treatment-related mortality. Despite the overall improvement in outcome, HLH patients who undergo HSCT using myeloablative conditioning regimens are still at significant risk for complications. The HLH-94 study conducted by the Histiocyte Society reported a 30% TRM with increased pulmonary and hepatic complications. Recently, the use of reduced-intensity conditioning (RIC) regimens has shown favorable outcomes when compared to conventional HSCT and lower rate of acute complications. In this review we compare the potential complications of myeloablative and RIC regimens for HSCT in HLH patients. KEYWORDS: BMT • children • complications • hemophagocytic lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) is a rare immunoregulatory disorder characterized by selective deficiency of cellular cytotoxicity and activation of T cells and macrophages [1]. HLH may be inherited (primary) or may be secondary to any severe infection, malignancy or rheumatologic condition. The majority of cases of primary (familial) HLH are due to inherited disorders involving the cytolytic secretory pathway, whereby cytotoxic T cells and NK cells destroy their target [1]. The clinical presentation of HLH includes prolonged fever, hepatosplenomegaly, lymphadenopathy, cytopenias, a consumptive coagulopathy and other characteristic laboratory abnormalities [1]. The approach to diagnosis and front-line therapy has been summarized in several recent reviews [2,3] and will not be repeated here. informahealthcare.com
10.1586/1744666X.2014.920234
Despite improvement in survival with the use of chemotherapy and immunosuppressive agents, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with primary HLH as well as patients with secondary HLH who fail to respond to therapy [4–9]. Since not all the underlying genetic abnormalities have been identified even in obligate familial cases, HSCT should also be strongly considered in cases of recurrent or refractory HLH when no underlying recurrent malignancy or uncontrolled rheumatic disease is present. Two large international studies, the HLH-94 and HLH-2004 protocols, were developed for HLH therapy by the Histiocyte Society. To date, only the results of the HLH-94 protocol have been reported. This and
Ó 2014 Informa UK Ltd
ISSN 1744-666X
1101
Review
Schechter, Naqvi & Weitzman
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Emory University on 08/23/15 For personal use only.
Table 1. Complications and outcome after hematopoietic stem cell transplantation. Myeloablative conditioning regimen (%)
Reduced-intensity conditioning regimen (%)
Day 100 – TRM
25–35
0–16
Infections
15–72
10–50
VOD
18–41
0–5
Pulmonary complications
9–41
0–12
Acute GVHD
14–40
4–33
Graft failure
9–22
0–23
GVHD: Graft-versus-host disease; TRM: Treatment-related mortality; VOD: Veno-occlusive disease.
other studies supported the use of a myeloablative conditioning regimen utilizing busulfan, cyclophosphamide and etoposide with or without antithymocyte globulin [4,10]. This approach resulted in overall survival (OS) ranging from 54 to 66% [5,8,10–12]. The OS was similar for matched related donor and matched unrelated donor transplants, but decreased survival was reported when mismatched unrelated or haploidentical donor transplants were utilized [12]. In general, matched related donors are the most suitable donors, particularly as primary and even secondary graft failures and the need for donor lymphocyte infusions (DLIs) are relatively common. The selection of a sibling as a donor source is complicated, in cases where the underlying genetic defect is unknown. The chance of using an affected sibling as a donor is increased by the fact that the age of presentation may vary among siblings [13] The relatively low survival rate in myeloablative HSCTs is likely multifactorial. The high treatment-related mortality (TRM) and morbidity rates were observed mainly in the first 100 days after transplant [10–12,14]. The patients are significantly immunosuppressed and may have pretransplant morbidity due to clinical or subclinical organ dysfunction prior to HSCT or because of active disease on admission to HSCT. Because of the high TRM, several transplant centers have used reducedintensity conditioning (RIC) regimens for HLH HSCT. Most RIC regimens utilize fludarabine and melphalan. Anti-CD52 antibody (alemtuzumab) has become an integral part of the regimen too [15]. The use of RIC regimens resulted in improved survival. Cooper et al. were the first to report the use of RIC in the setting of HLH. The reported survival rate in 12 children was 75% [16]. In a follow-up report with additional children, the OS increased to 84% [17]. Marsh et al. reported that an RIC regimen eliminated the early mortality (
Review
Risk for complications in patients with hemophagocytic lymphohistiocytosis who undergo hematopoietic stem cell transplantation: myeloablative versus reducedintensity conditioning regimens Expert Rev. Clin. Immunol. 10(8), 1101–1106 (2014)
Tal Schechter*, Ahmed Naqvi and Sheila Weitzman Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Canada *Author for correspondence: Tel.: +1 416 813 6906 tal.schechter-finkelstein @sickkids.ca
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with primary hemophagocytic lymphohistiocytosis (HLH) and for patients with secondary HLH who fail to respond to therapy. Advances in HSCT and supportive care measures have resulted in improved patient outcomes and decreased treatment-related mortality. Despite the overall improvement in outcome, HLH patients who undergo HSCT using myeloablative conditioning regimens are still at significant risk for complications. The HLH-94 study conducted by the Histiocyte Society reported a 30% TRM with increased pulmonary and hepatic complications. Recently, the use of reduced-intensity conditioning (RIC) regimens has shown favorable outcomes when compared to conventional HSCT and lower rate of acute complications. In this review we compare the potential complications of myeloablative and RIC regimens for HSCT in HLH patients. KEYWORDS: BMT • children • complications • hemophagocytic lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) is a rare immunoregulatory disorder characterized by selective deficiency of cellular cytotoxicity and activation of T cells and macrophages [1]. HLH may be inherited (primary) or may be secondary to any severe infection, malignancy or rheumatologic condition. The majority of cases of primary (familial) HLH are due to inherited disorders involving the cytolytic secretory pathway, whereby cytotoxic T cells and NK cells destroy their target [1]. The clinical presentation of HLH includes prolonged fever, hepatosplenomegaly, lymphadenopathy, cytopenias, a consumptive coagulopathy and other characteristic laboratory abnormalities [1]. The approach to diagnosis and front-line therapy has been summarized in several recent reviews [2,3] and will not be repeated here. informahealthcare.com
10.1586/1744666X.2014.920234
Despite improvement in survival with the use of chemotherapy and immunosuppressive agents, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with primary HLH as well as patients with secondary HLH who fail to respond to therapy [4–9]. Since not all the underlying genetic abnormalities have been identified even in obligate familial cases, HSCT should also be strongly considered in cases of recurrent or refractory HLH when no underlying recurrent malignancy or uncontrolled rheumatic disease is present. Two large international studies, the HLH-94 and HLH-2004 protocols, were developed for HLH therapy by the Histiocyte Society. To date, only the results of the HLH-94 protocol have been reported. This and
Ó 2014 Informa UK Ltd
ISSN 1744-666X
1101
Review
Schechter, Naqvi & Weitzman
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Emory University on 08/23/15 For personal use only.
Table 1. Complications and outcome after hematopoietic stem cell transplantation. Myeloablative conditioning regimen (%)
Reduced-intensity conditioning regimen (%)
Day 100 – TRM
25–35
0–16
Infections
15–72
10–50
VOD
18–41
0–5
Pulmonary complications
9–41
0–12
Acute GVHD
14–40
4–33
Graft failure
9–22
0–23
GVHD: Graft-versus-host disease; TRM: Treatment-related mortality; VOD: Veno-occlusive disease.
other studies supported the use of a myeloablative conditioning regimen utilizing busulfan, cyclophosphamide and etoposide with or without antithymocyte globulin [4,10]. This approach resulted in overall survival (OS) ranging from 54 to 66% [5,8,10–12]. The OS was similar for matched related donor and matched unrelated donor transplants, but decreased survival was reported when mismatched unrelated or haploidentical donor transplants were utilized [12]. In general, matched related donors are the most suitable donors, particularly as primary and even secondary graft failures and the need for donor lymphocyte infusions (DLIs) are relatively common. The selection of a sibling as a donor source is complicated, in cases where the underlying genetic defect is unknown. The chance of using an affected sibling as a donor is increased by the fact that the age of presentation may vary among siblings [13] The relatively low survival rate in myeloablative HSCTs is likely multifactorial. The high treatment-related mortality (TRM) and morbidity rates were observed mainly in the first 100 days after transplant [10–12,14]. The patients are significantly immunosuppressed and may have pretransplant morbidity due to clinical or subclinical organ dysfunction prior to HSCT or because of active disease on admission to HSCT. Because of the high TRM, several transplant centers have used reducedintensity conditioning (RIC) regimens for HLH HSCT. Most RIC regimens utilize fludarabine and melphalan. Anti-CD52 antibody (alemtuzumab) has become an integral part of the regimen too [15]. The use of RIC regimens resulted in improved survival. Cooper et al. were the first to report the use of RIC in the setting of HLH. The reported survival rate in 12 children was 75% [16]. In a follow-up report with additional children, the OS increased to 84% [17]. Marsh et al. reported that an RIC regimen eliminated the early mortality (
