Page 854 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 52 Histiocytic Disorders 737

intensive therapy, and CNS involvement. Long-term disease-free unrecognized. Recent evidence suggests that mild subclinical MAS
survival after HCT was approximately 50% to 65% before the year occurs in as many as one-third of patients with active soJIA and may
2000, regardless of whether a matched sibling or closely matched be the first manifestation of soJIA. Infections or change in medica-
unrelated donor was used. Most patients transplanted during that era tions may precede the diagnosis of MAS; in most patients, MAS
succumbed to “transplant-related” complications during the first 100 is triggered by a flare-up of the underlying rheumatologic disease.
days after infusion. A significant proportion of fatal complications Published observations suggest that as in HLH, MAS patients have
involved inflammatory conditions termed acute respiratory distress profoundly depressed NK cell function, sometimes associated with
syndrome, veno-occlusive disease, and multisystem organ failure, unspeci- abnormal perforin expression, and these abnormalities are associated
fied. In rare cases, residual HLH was identified at autopsy despite the with specific perforin and Munc13-4 polymorphisms.
use of myeloablative conditioning therapy.
During the past decade, the use of reduced-intensity conditioning
(RIC) regimens before HCT has been investigated after encouraging Diagnosis and Treatment
results from an institutional series. Most cases of RIC pretreatment
have included alemtuzumab and demonstrated superior early post- There are no validated diagnostic criteria for MAS, and early diag-
transplant survival. In a single-center analysis directly comparing nosis is often difficult. A recent consensus conference has developed
HCT outcomes after myeloablative conditioning versus RIC, a sta- expert-based classification criteria for MAS, although these have
tistically significant improvement was observed after RIC condition- not been validated as diagnostic criteria in clinical trials. Thus, in a
ing, with all patients surviving at 6 months after transplant. At patient with persistently active underlying rheumatologic disease, a
present, published data regarding outcome of RIC transplants using fall in the erythrocyte sedimentation rate (ESR) and platelet count,
umbilical cord blood is not sufficient to draw conclusions regarding particularly in combination with persistently high C-reactive protein
safety or efficacy. Donor choice should also take into account the and increasing levels of ferritin, should raise a suspicion of impending
possibility of an occult predisposition to HLH in siblings of patients MAS. The diagnosis of MAS is usually confirmed by the demonstra-
without identified gene defects. Much remains to be learned and tion of hemophagocytosis in the BM. Assessment of the levels of
refined regarding the optimal application of alemtuzumab as well as sCD25 and sCD163 in serum may help with the timely diagnosis of
other agents used before HCT. The timing of pretransplant alemtu- MAS. Although mild elevation of sCD25 has been reported in many
zumab impacts the probability of graft-versus-host disease, mixed rheumatic diseases, including JIA and SLE, a several-fold increase in
chimerism, and, in rare cases, rejection. Other factors, such as donor the levels of sIL2Rα in these diseases is highly suggestive of MAS. The
source, human leukocyte antigen match, cell dose, and patient condi- application of the HLH diagnostic criteria to systemic JIA patients
tion with regard to HLH disease activity at time of conditioning, may with suspected MAS is problematic. Some of the HLH markers,
all play roles in determining the likelihood of success after RIC HCT. such as lymphadenopathy, splenomegaly, and hyperferritinemia, are
Patients with CNS HLH need close posttransplant follow-up. The common features of active systemic JIA itself and therefore do not
authors recommend examination of CSF within 100 days of HCT distinguish MAS from a conventional systemic JIA flare. Patients
even in asymptomatic patients. Follow-up MRIs are recommended if with systemic JIA often have increased white blood cell and platelet
pretransplant abnormalities were present. In some patients with counts, as well as serum levels of fibrinogen as a part of the inflam-
mixed or full hematopoietic donor chimerism, HLH disease activity matory response seen in this disease. Therefore, when they develop
in the CSF can be effectively treated with intrathecal therapy during MAS, they reach the degree of cytopenias and hypofibrinogenemia
the early posttransplant months. CNS disease is subsequently con- seen in HLH only at the late stages of the syndrome when medical
trolled as donor immune reconstitution progresses. management becomes challenging. This is even more problematic for
the diagnosis of MAS in patients with SLE in whom autoimmune
cytopenias are common and difficult to distinguish from those caused
Prognosis by MAS.
Early recognition of this syndrome and immediate therapeutic
Significant strides have been made in the treatment of HLH, with intervention to produce a rapid response are critical. Prompt admin-
survival now generally ranging from 50% to 70%. In children with istration of more aggressive treatment in these patients may, in fact,
nonfamilial HLH, overall survival has been reported at 72%, but only prevent development of the full-blown syndrome. To achieve rapid
20% of the patients did not require HCT. Survival is increased in reversal of coagulation abnormalities and cytopenias, most clinicians
children, irrespective of genetic status, who receive HSCT from start with intravenous methylprednisolone pulse therapy (30 mg/kg
matched rather than unmatched donors. RIC pretransplant regimens for 3 consecutive days) followed by 2–3 mg/kg/day divided in four
appear to further decrease mortality. The best outcomes in HSCT are doses. After normalization of hematologic abnormalities and resolu-
seen in children who have a rapid and complete response to pretrans- tion of coagulopathy, steroids are tapered slowly to avoid relapses of
plant therapies and who do not exhibit significant neurologic involve- MAS. Commonly, however, MAS appears to be corticosteroid resis-
ment. Prompt initiation of HSCT in familial patients after disease tant, with deaths being reported even among patients treated with
remission is obtained is also likely to increase survival. Patients with massive doses of steroids. Parenteral administration of cyclosporine
significant neurologic involvement may experience severe and perma- A has been shown to be highly effective in patients with corticosteroid-
nent sequelae even if they survive. resistant MAS. The utility of biologic drugs in MAS treatment
remains unclear. Although tumor necrosis factor-inhibiting agents,
biologics that neutralize IL-1 and IL-6, have been reported to be
MACROPHAGE ACTIVATION SYNDROME effective in occasional MAS patients, other reports describe patients
in whom MAS occurred while they were receiving these agents. Based
MAS is the name commonly given to a severe, potentially fatal inflam- on some success with IVIG administration in virus-associated HLH,
matory condition seen in the context of rheumatologic disorders such this treatment might be effective in MAS triggered by viral infection.
as soJIA or systemic lupus erythematosus (SLE). The syndrome of If MAS, however, is driven by EBV infection, rituximab, a monoclo-
MAS shares many similarities with classic HLH, and many investiga- nal antibody that depletes B lymphocytes (the main type of cells
tors view it as a special form of HLH, suggesting that the name may harboring the EBV virus) may be considered.
be changed to rheumatologic HLH (or R-HLH). The main manifesta-
tions of MAS include fever, hepatosplenomegaly, lymphadenopathy,
severe cytopenias, serious liver disease, and coagulopathy consistent Future Directions
with DIC. Hemophagocytosis is often (although not always) seen in
the BM of patients with MAS. The true incidence of MAS may be As an alternative approach to etoposide-based approaches for the
underestimated because relatively mild cases of MAS often remained treatment of HLH, ATG–prednisone has been used for a number of