Page 1140 - Williams Hematology ( PDFDrive )

1114 Part VIII: Monocytes and Macrophages Chapter 71: Inflammatory and Malignant Histiocytosis 1115

LABORATORY FEATURES on the HLH-94 protocol was 55 percent. In a study of patients with
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Ferritin Epstein-Barr virus–associated HLH, early administration of intrave-
nous etoposide was associated with improved outcomes. Etoposide
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Although no one diagnostic criterion is sufficient to make the diag- was recently demonstrated to have specific cytotoxicity to activated T
nosis of HLH, a highly elevated serum ferritin along with four other cells, which may explain why it is effective in HLH. 245
criteria is strongly indicative. A ferritin concentration of greater than A second protocol, HLH-2004, containing minor modifications
500 mcg/L was included in the HLH-2004 diagnostic criteria because from the first included starting oral cyclosporine at the onset of induc-
a survey found that most children with infectious diseases had levels tion therapy, adding glucocorticoids to intrathecal therapy in patients
less than that level and those with rheumatologic diagnoses only rarely with CNS disease, adding etoposide to conditioning in patients who
had higher levels. Ferritin concentrations greater than 500 mcg/L were undergo AHSCT, and considering depletion of T cells in patients who
100 percent sensitive for HLH in a retrospective review over a 2-year receive stem cells from unrelated donors. At this time, we consider
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period. However, at this level there is considerable overlap with other HLH-94 the standard of care. Data are not yet available to evaluate the
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disorders. Ferritin concentrations more than 10,000 mcg/L were 90 per- benefits of early cyclosporine, and it has known risks including increas-
cent sensitive and 96 percent specific for HLH with very minimal over- ing susceptibility to posterior reversible encephalopathy syndrome
lap with sepsis, infections, and liver failure. Analysis of ferritin values in (PRES). 246
an extended cohort suggests that 2000 mcg/L may be a more appropri- Intravenous antithymocyte globulin (ATG) has been used as a pri-
ate measure for diagnosis of HLH than 500 mcg/L. 238 mary treatment of 38 cases of familial HLH. It was intended that all of
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The following tests should be done on a previously healthy patient these patients undergo AHSCT, which ultimately cured 16 of 19 cases.
who presents with persistent fevers, hepatosplenomegaly, and cytope- ATG was ineffective for patients who had been previously treated with
nia of at least two cell lines: serum ferritin, aspartate aminotransferase/ etoposide, dexamethasone, and cyclosporine and who had relapsed
alanine aminotransferase, lactate dehydrogenase, bilirubin, coagula- while on therapy.
tion studies, fibrinogen, triglycerides. A marrow biopsy and aspirate is A study that is open as of this writing, hybrid immunotherapy for
needed, as well as a lumbar puncture for spinal fluid examination. NK HLH (HIT-HLH; clinicaltrials.gov: NCT01104025) combines strategies
cell function, perforin expression of T cells and NK cells, and sCD25 of early immune suppression with ATG and prolonged immune sup-
concentrations should be evaluated, usually requiring access to spe- pression with etoposide.
cialty laboratories, if there is clinical suspicion for HLH. Following daily A significant number of patients with HLH will fail to respond to
serum ferritin levels is useful because rapidly rising ferritin is a strong initial therapy or will develop recurrent episodes of inflammation while
indicator of HLH, and inferior outcomes are associated with slow nor- awaiting AHSCT. Treatment failures and recurrences are associated with
malization. It may be necessary to repeat the marrow biopsy or biopsy very high rates of mortality. Escalation of dexamethasone and etoposide
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an enlarged liver or lymph nodes, if the first marrow biopsy fails to show is a typical first step for patients with recurrence. Additional salvage
hemophagocytosis and clinical suspicion of HLH is high.
strategies that have been reported include infliximab, dalizubumab,
anakinra, and other agents. A retrospective multiinstitutional study
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DIFFERENTIAL DIAGNOSIS reported that 77 percent of patients who received alemtuzumab therapy
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Patients with fever of unknown origin, moderate infections, sepsis, for refractory or recurrent HLH survived to AHSCT. A clinical trial
is currently open to test the efficacy and safety of inhibition of IFN-
multiorgan dysfunction, hepatitis, anemia and thrombocytopenia, and γ in patients with HLH with recurrent inflammation (clinicaltrial.gov:
autoimmune phenomena such as Kawasaki disease, lupus erythema- NCT01818492).
tosus, or rheumatoid arthritis may present with features that overlap AHSCT may be indicated for patients with familial HLH or with
the diagnostic criteria for HLH. These may represent alternative or gene defects, CNS disease, or who relapse either on or off HLH therapy.
concurrent diagnoses. One must consider HLH if no clear diagnosis is Long-term survival was 50 to 65 percent with myeloablative condition-
established of the above mentioned entities is evident and the patient is ing, but patients experience significant treatment-related morbidity and
deteriorating. Identification of an underlying immune deficiency such mortality. 214,249 Institutional series have demonstrated improved survival
as X-linked lymphoproliferative disease (Chap. 80), Griscelli syndrome and decreased treatment-associated complications with reduced inten-
(Chap. 80), or Chédiak-Higashi syndrome (Chap. 80) should increase sity conditioning (RIC) strategies that include alemtuzumab. RIC strat-
the suspicion of HLH. Epstein-Barr virus, cytomegalovirus, and other egies are associated with improved survival. 248,250 A multicenter clinical
herpes virus infections are the most frequent viral infections associated trial (Reduced Intensity Conditioning for Children and Adults with
with HLH. A wide variety of bacterial fungal and protozoal infections Hemophagocytic Syndromes or Selected Primary Immune Deficiencies
may also lead to HLH.
[RICHI]) is currently testing the safety and efficacy of RIC with “inter-
mediate” timed alemtuzumab. (clinicaltrials.gov:NCT01998633)
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THERAPY Patients with HLH are generally acutely ill, and therapies for HLH
Before treatment with immune-modulating therapy fewer than 10 per- may exacerbate cytopenias and susceptibility to opportunistic infec-
cent of patients with HLH survived. After case reports and case series tions. Patients may require multiple transfusions of red cells, plate-
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described patients successfully treated with strategies that included lets, and fresh frozen plasma. Prophylaxis against Pneumocystis carinii
aggressive immune suppression, podophyllotoxin derivatives, or a com- infection with sulfamethoxazole and against fungi with fluconazole is
bination of immune suppression with etoposide, a prospective treat- necessary. Newly diagnosed HLH patients should have human leuko-
ment protocol was developed that included induction therapy with oral cyte antigen typing done and a donor search initiated in case AHSCT is
or intravenous dexamethasone and intravenous etoposide, followed by required for therapy.
continuous treatment with oral cyclosporine and pulses of dexametha-
sone and intravenous etoposide. 241–243 Patients with CNS symptoms or Macrophage Activation Syndrome
cerebrospinal fluid lymphocytosis or pleocytosis also received intrath- This nomenclature describes patients with symptoms and signs of
ecal methotrexate. Patients with resistant disease, recurrent disease, or HLH in the setting of juvenile rheumatoid arthritis or systemic lupus
familial HLH underwent AHSCT. The overall estimated 3-year survival erythematosus. Similar to classic HLH, macrophage activation is
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