| Part ⅠObjective:To explore the efficacy and safety of daratumumab(dara)plus bortezomib and dexamethasone in treatment of Mayo 2004 stage 3 primary light chain(AL)amyloidosis.Methods:Forty patients with newly diagnosed AL amyloidosis at Mayo2004 stage 3 and baseline difference between involved and uninvolved serum free light chains>50mg/L were prospectively enrolled.All patients received 6 cycles of dara plus bortezomib and dexamethasone and 6 cycles of dara.We collected treatment responses and the side effects associated with medication.Results:A total of 40 patients were enrolled,including 20 patients in Mayo 2004 stageⅢa and 20 patients in Mayo 2004 stage Ⅲb.There were 30(75%)males with a median age of 59(range 40-77),and 31(77.5%)patients with X-type amyloidosis.In terms of organ involvement,12(30%)patients had kidney involvement and 10(25%)patients had liver involvement.The median number of organs involved was 2(range 1-4).Baseline median levels of cardiac troponin I were 0.17μg/L(range 0.07-3.07),median levels of NT-proBNP were 7801ng/L(range 803-35000),and median dFLC was 274mg/L(range 72-2966).In terms of hematological response,9 patients(22.5%)achieved complete response(CR),15 patients(37.5%)achieved very good partial response(VGPR)and an overall response rate(ORR)was 85.0%at 1 month of tr eatment.At 3 months of treatment,19 patients(47.5%)achieved CR,8 patients(20.0%)achieved VGPR and ORR was 82.5%.At 12 months,21(52.5%)had achieved CR,4(10.0%)had VGPR,and 67.5%had hematological response.In terms of cardiac response,the overall response rate after 3 months of treatment was 37.5%,including complete response(CarCR)at 2.5%,very good partial response(CarVGPR)at 5.0%,and partial response(CarPR)at 30.0%.After 6 months of treatment,the overall cardiac response rate was 47.5%,including 2.5%at CarCR,25.0%at CarVGPR and 20.0%at CarPR.At 12 months,the overall cardiac response rate was 65%,with 7.5%at CarCR,32.5%at CarVGPR,and 25.0%at CarPR.In terms of survival,the median follow-up time was 18.3 months(range 12.7-22.5),a total of 11 patients died.The 1-month early mortality rate was 15%in all patients,5%in stage Ⅲa patients,and 25%in stage Ⅲb patients.Early mortality at 3 months was 17.5%overall,5%at Ⅲa,and 30%at Ⅲb.Survival rate at 18 months was 75%for all patients,79.3%for stage Ⅲa patients,and 65%for stage Ⅲb patients.In terms of treatment-related adverse events,hematologic adverse events included anemia(15 patients,37.5%),thrombocytopenia(6 patients,15%),and leukopenia(5 patients,12.5%).Other common adverse reactions were upper respiratory tract infection(14 patients,35.0%),diarrhea(10 patients,25.0%),transfusion reaction(9 patients,22.5%),nausea(8 patients,20.0%),elevated aminotransferase(8 patients,20.0%),etc.The most common grade 3-5 adverse reactions were diarrhea(5 patients,12.5%),pulmonary infection(3 patients,7.5%),nausea(2 patients,5.0%)and intestinal obstruction(2 patients,5.0%).One patient had grade 5 lung infection and died of heart failure after infection.Conclusions:Daratumumab combined with bortezomib and dexamethasone has good efficacy and safety in advanced AL amyloidosis,and can improve the prognosis of advanced patients.Part ⅡObjective:To investigate the effect of single nucleotide polymorphism(SNP)of FCγR gene on the therapeutic effect of dara in AL amyloidosis.Methods:From October 2022 to March 2023,peripheral blood samples at any time point of patients with AL amyloidosis(including relapsed and newly diagnosed)who received dara-based regimen in Peking Union Medical College Hospital were collected,and DNA was extracted for sequencing.Clinical efficacy data was collected and analyzed at the same time.Results:A total of 64 patients were enrolled in this study.Excluding patients who changed treatment regimens,lost follow-up,and died early,a total of 54 patients were included in the analysis,among which 50 patients were treated with dara as the first line and 4 patients received dara as the second line treatment.Of the 54 patients,41(75.9%)were male,the median age was 59 years(range 41-77),and 39(72.2%)were λ-type.38(70.4%)had heart involvement,15(27.8%)had kidney involvement,and 6(11.1%)had liver involvement.In the aspect of SNP detection of FcγR gene,49 people(90.7%)had FCGR2A-131HR and 5 people(9.3%)had FCGR2A-131RR.Thirty-one patients(57.4%)had FCGR2B-232Ⅱtype and 23 patients(42.6%)had FCGR2B-232IT.One patient did not have FCGR3A gene successfully sequenced.Six(11.3%)patients have FCGR3A-158VV,46(85.2%)had FCGR3A-158VF and 1(1.9%)had FCGR3A-158FF.In terms of the relationship between SNPs of FcγR gene and the best hematological efficacy,only the FCGR2B-232IT group had a significantly higher rate of≥VGPR than the FCGR2B-232Ⅱ group(91.3%vs.67.7%,RR 0.74,95%CI 0.56-0.98,P=0.039,P=0.039),and there was no significant difference in the rate of≥VGPR among other SNPs.Conclusions:Among SNPs of FcγR gene,FCGR2A-131 and FCGR3A-158 are not associated with the hematological efficacy of dara in treating AL amyloidosis,and FCGR2B-232IT is associated with a higher≥VGPR rate of best hematological response than FCGR2B-232Ⅱ.Part ⅢObjective:To investigate immunoscenescence and immune cell exhaustion in peripheral blood and bone marrow between patients with AL amyloidosis and healthy control.Methods:We enrolled newly diagnosed AL patients in Peking Union Medical College Hospital from December 2022 to April 2023,and collected 2 ml of peripheral blood and/or 2 ml of bone marrow.Peripheral blood from healthy controls was collected during the same period.The percentage of T cell subsets and the expression of exhaustion markers on T cells were analyzed by flow cytometry.Results:A total of 17 newly diagnosed AL patients and 9 healthy controls were included in the study.All AL patients donated peripheral blood samples,and 13 of them had matched bone marrow samples.Flow cytometry analysis showed that CD4+ T cell subsets in peripheral blood and bone marrow of AL patients were not significantly different from healthy controls.The level of CD8+ naive T cells in peripheral blood of AL patients was lower than that of healthy controls(15.30%vs 25.31%,P=0.038).The level of CD8+terminal differentiation effect memory T cells in peripheral blood of AL patients was significantly higher than that of healthy controls(26.90%vs 24.49%,P=0.041).In terms of T cell exhaustion,the percentage of CD4+LAG3+T cells in peripheral blood of AL patients was significantly higher than that of healthy controls(5.66%vs 1.84%,P=0.020).The percentage of CD4+PD-1+T cells in peripheral blood of AL patients was significantly higher than that of healthy controls(4.82%vs 1.83%,P=0.001).The percentage of CD8+CD28+ T cells in peripheral blood of AL patients was significantly lower than that of healthy controls(16.09%vs 25.13%,P=0.014).Comparing the exhaustion of T cells in peripheral blood and bone marrow of AL patients,the percentage of CD4+LAG3+T cells in bone marrow was significantly lower than that in peripheral blood(P=0.013).The percentage of CD8+PD-1+T cells in bone marrow was significantly higher than that in peripheral blood(P=0.005),and the percentage of CD8+TIGIT+T cells in bone marrow was significantly higher than that in peripheral blood(P=0.013).Conclusion:T cells in AL patients showed a trend of immunoscenescence,and CD4+T cells in peripheral blood showed a state of exhaustion.There were differences in T cell exhaustion in bone marrow and peripheral blood of AL patients. |
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