Disease Characteristics And Treatment Of Rare Lymphoma

Background and Objectives:Hairy cell leukemia-variant(HCL-v)is a sporadic Bcell lymphoma.It was first described in 1980 and was classified under "splenic B-cell lymphoma/leukemia,unclassifiable" in 2016.Some other clinical entities mimic HCL-v,especially in clinical presentation and morphology.However,HCL-v is a more aggressive disease with poor response to a number of treatments including purine nucleoside analogs(PNA)and a significantly shorter survival.Therefore,it is crucial to obtain accurate diagnosis.Due to its rarity,there is few prospective studies or large series reports on HCL-v,and features and outcomes of HCL-v remain elusive.Here,we retrospectively analyzed the clinical characteristics,biological features,response to treatments and survival of 33 patients with HCL-v from a single Chinese center.Our aims are to understand Chinese patients with HCL-v better,to exhibit the comparisons between China and western countries and to provide more evidence for recognition and management of HCL-v.Methods:We collected 33 patients diagnosed with HCL-v in our hospital from June 1990 to February 2021.Then we performed a retrospective and comprehensive analysis on patients’chief complaint,demographic information,histopathology and cytomorphology,laboratory examinations,first-line treatment options and follow-up.Results:In this study,we recruited 33 HCL-v patients(23 males and 10 females)with a median age of 59 years(range,34-79 years).The chief complaints included abdominal mass(39%)and relative signs(27%),leukocytosis(27%)and thrombocytopenia(3%).Thirteen patients(39%)exhibited B symptoms.Splenomegaly was presented in 97%cases,commonly massive.In contrast,lymphadenopathy(15%)and hepatomegaly(27%)were uncommon.The median interval between symptom onset and diagnosis was 3 months(range,0-87 months).Leukocytosis was presented in 70%patients with a median white blood cell count of 21.58×109/L(range,1.34～224.59× 109/L).Thirty-three percentage of patients exhibited anemia and 46%of cases presented with thrombocytopenia.The median percentage of tumor cells of bone marrow aspirate or peripheral blood specimens was 33%(range,6.2-96%)by multiparameter flow cytometric immunophenotypic analysis(FCM).And FCM showed that leukemic cells had a panel B-cell immunophenotype(such as CD 19,CD20,CD22 and CD79b)and were all positive for CD11c and CD81.CD 103 and CD200 were expressed in 77%and 71%cases,respectively,usually partial or dim expression.Almost all patients did not exhibit CD5,CD 10,CD23,CD25,CD43 and CD 123.BM hypoplasia was only presented in a few patients.Usually,reticulin staining showed none to mild fibrosis(MF-0 to MF-1).Immunohistochemical studies confirmed that the neoplastic cells were negative for annexin A1(n=12).Information for immunoglobulin heavy-chain variable region(IGHV)was available in 20 patients and two clone was detected in three cases.Thirty-five percentage of patients presented with unmutated IGHV.VH4-34(19%)was the most common fragment and patients with VH4-34 were all IGHV unmutated.Furthermore,the usage of IGHV genes fragment of the patient with mutated MAP2K1 was VH4-34.BRAF V600E mutation was detected in 20 patients by Sanger sequencing and target next-generation sequencing and all were negative.Seventeen percentage of patients(2/12)were positive for TP53 mutation.MAP2K1 mutation was available in four patients with a mutation frequency of 25%(1/4).Conventional karyotypes were performed in 24 cases.Fourty-two patients had abnormal karyotype,and 6 patients were classified as complex karyotypes.Interphase fluorescence in situ hybridization examination showed that the rates of IGH translocation,17p deletion,13q deletion,trisomy of chromosome 12 and 11 q deletion were 31%,20%,6%,17%and 0%,respectively.Thirty-one patients received treatment.Therapeutic options included interferon-α(IFN-α)in 11 patients,chlorambucil(CLB)in 5 patients,PNA single agent in 3 patients,PNA plus rituximab(PNA+R)in 9 patients,and others in 3 patients(traditional Chinese medicine or low-intensity chemotherapy plus splenic irradiation).Four patients who received IFN-α or CLB treatment also underwent splenectomy as a part of the initial treatment.The follow-up and survival information was available for 30 patients,and the median follow-up duration was 32 months(range,3～207 months).The median PFS and OS for the entire cohort were 30 months(95%CI 19.4～40.6)and 70 months(95%CI 51～90),respectively.Patients who received PNA+R had a higher complete response rate(88%versus 5%,P<0.001)and longer Progression-free survival[PFS,3-year PFS rate 42%(95%confidence interval 1～84)vs.16%(95%confidence interval 3～40),P=0.042]than those who received other regimens.Conclusion:HCL-v is a rare lymphoma with unique immunophenotype and molecular/cytogenetic characteristics.The PNA+R regimen is the preferred choice in the first-line treatment for HCL-v.Background and Objectives:Mantle-cell lymphoma(MCL)is a rare subtype of non-Hodgkin’s lymphoma.MCL is often of an aggressive clinical course,with a median overall survival of only 3～5 years in the era of immunochemotherapy.Although first-line intensive chemotherapy with rituximab(R)and high dose cytarabine combined with autologous transplantation(ASCT)has significantly prolonged the survival of patients with MCL,some patients still dead within few years,such as patients with high-risk Mantle cell lymphoma International Prognostic Index combined with Ki-67(MIPI-c),TP53 or MYC abnormalities,complex karyotype and aggressivehistology.Our published data show that Chinese patients with MCL are younger and have high proportion of TP53 deletion and MYC abnormality.Considering the efficacy and tolerability of the dose-enhanced immunochemotherapy R-DA-EDOCH regimen in patients with multiple high-risk aggressive B-cell lymphomas and the potential higher proliferative activity of tumor cells in Chinese patients,we proposed that alternate R-DA-EDOCH/R-DHAP induction therapy would be more effective in Chinese patients with MCL and then conducted a prospective clinical observational study of alternate R-DA-EDOCH/R-DHAP induction therapy for young patients with newly-diagnosed MCL(NCT02858804).Here,we analyzed the efficacy and safety of the initial treatment,explored the combined effect of consolidation/maintenance therapy,and further identified the risk factors in the treatment.Methods:The main inclusion criteria for young patients with newly-diagnosed MCL included age≤65 years,Ann Arbor stage Ⅱ～Ⅳ,ECOG≤1.During induction,patients received alternate R-DA-EDOCH/R-DHAP for two cycles(a total of 4 courses).Patients who achieved less than partial remission(PR)would quit the trial,while patients with at least PR would continue another one or two cycles of alternate R-DAEDOCH/R-DHAP treatment.After finishing the 6～8 cycles inductive treatment,patients would make decisions whether to continue ASCT consolidation therapy and/or R maintenance therapy according to their own willingness.The primary endpoint of this study was the progression-free survival(PFS)of patients.Key secondary endpoints were complete response rate(CRR)and objective response rate(ORR)at the end of induction(EOI),overall survival(OS),minimal residual disease(MRD)status and the incidence of adverse events(AEs).Results:In this study,we recruited 55 patients with a median age of 53 years(range,37～65 years)and a male/female ratio of 2.2:1.Fifty-three patients(94.6%)had advanced-stage disease(Ann Arbor stage Ⅲ-Ⅳ),and 38.2%patients had B symptoms.Pathologically,11.5%(6/52)cases were blastocytic type,3.8%(2/52)cases were pleomorphic type,while all other cases were classic type.Immunohistochemical studies showed that Ki-67 index≥30%was found in 43.6%(17/39)patients,and positive rate of P53≥50%was found in 50.0%(18/36)patients.Nine patients(9/46,19.6%)were identified as complex karyotypes by chromosome karyotype analysis.The proportion of 17p deletion and 9p deletion were 18.9%(10/53)and 34.1%(14/41),respectively.Mutation rates of immunoglobulin heavy chain variable region gene,TP53 gene and CDKN2A gene were 33.3%(1 1/33),26.2%(1 1/42)and 0%(0/37),respectively.And 7 patients(16.7%)were accompanied by 17p deletion and TP53 mutation.Patients of high-risk group of MIPI accounted for 21.8%of all patients,and four patients(4/39,10.3%)were of high-risk group of MIPI-c stratification.Fifty-five received at least 4 cycles of alternate R-DA-EdoCH/R-DHAP immunochemotherapy and finished the assessment of efficacy and safety,and then one patient dropped out due to the poor response.Currently,28 patients completed ASCT consolidation therapy,and 22 of them continued R maintenance therapy.Of the 25 patients without ASCT,13 chose R maintenance and 12 discontinued the whole therapy.The ORR of the alternate R-DA-EDOCH/R-DHAP inductive therapy was 98%[95%confidence interval(CI)90-100],and the CRR was 89%[95%CI 78-96].There were no significant differences in CRR and ORR among patients with different prognostic characteristics.Of the 53 patients who underwent bone marrow and radiographic evaluation,48 patients achieved CR with MRD negative.The alternate R-DA-EDOCH/R-DHAP regimen was well tolerated,and no patients were discontinued due to intolerance of treatment-related AEs.AEs were mainly hematologic,at least one hematologic AEs occurred in 85.5%of the patients.Grade 3-4 leukopenia and neutropenia were found in 49.1%and 58.2%of the patients,respectively.Peripheral blood stem cells were successfully collected in 22 of 36 patients(88.9%),with a median count of 3.15×106(range 1.96×106～24.34×106).The median follow-up of the cohort was 31 months(range 4-86).The 3-year PFS and OS rates were 66.3%and 85.4%,respectively.Sequential ASCT consolidation and/or R maintenance slightly increased CRR but significantly prolonged PFS of patients(3-year PFS rate:ASCT+R 90.4%versus R 64.6%versus without ASCT/R 33.3%,P<0.001).However,there was no significant difference in OS between the three groups(3-year OS rate:ASCT+R 94.7%versus R 82.5%versus without ASCT/R 71.4%,P=0.548).Conclusion:The alternate R-DA-EDOCH/R-DHAP induction therapy showed good efficacy and tolerability in young patients with newly diagnosed MCL with a CRR of 88%.And ASCT consolidation and R maintenance therapy could further prolong PFS after the initial treatment.The risk factors for PFS in this therapeutic pattern were age≥60 years,blastoid/pleomorphic pathologic morphology and TP53 double-allele events.