| Part one Adult hemophagocytic lymphohistiocytosisObjectiveIn adult,most of HLH are secondary.Late-onset FHLH in adult is rare.The clinical symptoms of HLH are diversity,and nonspecific,including high fever,hepato-splenomegaly,cytopenias,coagulation abnormalities,multiple organ failure,et al.Up to now,there are no specific markers for the prognosis of HLH,especially for the early mortality.To investigate the correlation between early mortality of AHLH and their clinical features and therapeutic regimen.MethodsDetailed clinical features,laboratory examination results,and follow up data of 327 HLH patients were collected.The cut-off time was 2016-03-31.In the 327 patients,only 8 patients were lost to follow up and the rate of follow-up was 97.6%.Statistical analyses were performed using SPSS software,version 22.0.Student t-test was used to compare continuous parametric variables.Chi-square and Fisher exact tests were used to determine different frequencies between groups.The primary endpoint was 8 weeks survival rate.A p-value<0.05(2-sided)was considered statistically significant.ResultsMedian age was 53 years(range,18-93 years).181 subjects were male.Most subjects presented with high fevers,hepatosplenomegaly,lymphadenopathy and hemophagocytosis in bone marrow specimens.133(42%)died within 8 weeks of diagnosis.Underlying causes were infections(N=129;39%),hematologic neoplasms(N=107;33%),unknown(N=68;21%)and autoimmune disorders(N=21;7%).Variables significantly associated with risk of early death included(1)EBV-sero-positivity(HR 3.594;[95%Cl,1.443,8.952];p=0.001);(2)hypoalbuminemia(HR 1.10[1.01,1.20];p=0.046);and(3)maximum standard uptake value(SUVmax)at diagnosis>14.9(HR 6.802;[1.233,37.519];p=0.028)in positron emission tomography(PET).ConclusionEBV-sero-positivity,hypoalbuminemia and a high SUVmax at diagnosis predict early death in adults with HLH and most likely to benefit from early therapy decisions.Part two Autologous stem cell transplantation for adult lymphoma associated hemophagocytic lymphohistiocytosisObjectiveLymphoma associated HLH(lymphoma-HLH)in secondary HLH is rare,but the heterogeneity level and mortality rate are high.The optimal treatment for lymphoma-HLH remains controversial.At present,most studies of stem cell transplantation for HLH focus on pediatric HLH rather than adult HLH.And in most studies,allogenic hematopoietic stem-cell transplantation(allo-HSCT)is used,which has the potential to cure this disease.However,its widespread use are limited because of the treatment-related mortality,donor-less and age.Autologous stem cell transplantation(ASCT)is a highly effective treatment for malignant lymphoma,but the role in lymphoma-HLH is unclear.So,it is important to investigate the effectiveness of ASCT in the treatment of lymphoma-HLH.MethodsBetween September 2009 and September 2016,a total of 8 patients with lymphoma-HLH were treated by chemotherapy followed by ASCT in our institution.Patients with lymphoma-HLH received ASCT if they responded to induction chemotherapy.Three males and 5 females were included and the median was 52.5years(range 21-64).The median follow-up was 54.5 months(range:18-59 months).The conditioning regimen of high-dose therapy(HDT)/ASCT consisted of busulfan,cytarabine,cyclophosphamide,and etoposide(7 BEAM/1 CBV).We conducted a retrospective study of 8 adult HLHs transplanted for lymphoma-associated HLH.ResultsAt the time of diagnosis,the median age was 54.5 years(range 21-64);3 males and 5 females.In these eight patients,7 patients(87.5%)presented with bone marrow involvement.Serum LDH was elevated in all the cases.According to the international prognostic index,all the cases were classified as high-intermediate risk(n=4)or high risk(n=4)patients.EBV DNA in peripheral blood mononuclear cells was detectable in two patients.Seven patients(87.5%)received EPOCH regimen and 1 received CHOP regimen.All cases with B cell lymphoma were treated by rituximab.Six patients(75%)were in complete remission and 2 patients(25%)in partial remission before HDT/ASCT.Two patients achieved complete response after HDT/ASCT.In the 8 patients,there was no transplant-related mortality.After a median follow-up of 54.5 months(range:18-59 months),8 patients all survived and there was no recurrence of HLH.ConclusionFrontline EPOCH followed by ASCT with a conditioning regimen of BEAM may be an effective and tolerable intensifying therapeutic option to improve outcomes in patients with lymphoma-associated HLH.Part three Sequencing of target genes in 103 adult patients with hemophagocytic histiocytosisObjectiveHLH is a clinical syndrome characterized by hyperinflammation and not a disease per se.It is classified as primary(genetic)or secondary(acquired).Primary HLH can be familial or genetic.Primary HLH was previously diagnosed in infants.Four genetic defects have often been identified in FHL,including SH2D1A,PFRI,MUNL3-4,STX11.Until now,it is not clear whether secondary HLH is associated with gene mutations.MethodsGene mutations was sequenced by Illumina Miseq or Nextseq in 103 adult patients with HLH.More than 18 genes were sequenced in our study at a sequencing depth of 1000 reads.For the normal Asian population,the frequency of mutations less than 1%were included.ResultsAmong the 103 selected patients,63 were males(61.2%)and 40 were females(38.8%),and the ratio of male to female was 1.5:1.The median age of onset is 48 years(range:18?85 years).The underlying causes were:infections(N=22;21.4%),hematologic neoplasms(N=61/59.2%;lymphoma N=59),autoimmune disorders(N=3;2.9%),and unknown(N=17;16.5%).HLH related gene mutations were found in 43 patients,including 1 patient with homozygous mutation(UNC13D c.G2588A[p.G863D]),2 patients with compound heterozygous mutations and 3 patients with double heterozygous mutation.A total of 7 loci were identified in this group,including UNC13D p.G863D?ITK p.R581W?AP3B1 p.T310A?STXBP2 p.T163M?UNC13D p.R411Q?LYST p.H123R and STX11 p.F281.The highest mutation rate was observed at UNC13D p.G863D locus at different alleles(3/206 to 37/8638,the odds ratio[OR]4.514,95%CI[CI]1.594-12.78;p=0.0651).The mutation rates at AP3B1 c.A928G(p.T310A),ITK p.R581W and STX11 p.F281 Clocus in HLH patients were also significantly higher than normal population(2/206 2/8648,OR 42.98,CI 95%5.938-302.5;p<0.0001),(4/206[2.0%]vs70/8652[0.8%],OR 2.428,95%CI 0.878-6.715,p=0.093)and(2/206[0.97%]vs 1/8382[0.01%],OR 160.0,p=0.0005).The mutation rates at the remaining genetic defects were no difference in our group compare to the normal Asian population.ConclusionHLH is also associated with primary HLH related genetic defect,and the use of targeted sequencing for screening of HLH related genes can be used in the diagnosis of adult HLH. |
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