Phase Ⅱ open-label study of recombinant circularly permuted TRAIL as a single-agent treatment for relapsed or refractory multiple myeloma

Background: Despite the recent development of new therapies, multiple myeloma(MM) remains an incurable disease. Thus, new, efective treatments are urgently needed, particularly for relapsed or refractory MM(RRMM). In an earlier phase I study, a novel form of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) that is currently in clinical development for the treatment of hematologic malignancies, i.e., circularly permuted TRAIL(CPT), was well tolerated at a dose of 2.5 mg/kg per day and showed promising preliminary activity in patients with RRMM. This phase II, open-label, multicenter study further investigated the eicacy and safety of 2.5-mg/kg per day CPT as single-agent therapy for patients with RRMM.Methods: Patients with RRMM were treated once daily with CPT(2.5 mg/kg, intravenously) for 14 consecutive days for each 21-day cycle. Clinical response and toxicity were assessed after each treatment cycle.Results: Twenty-seven patients received CPT. Using the European Group for Blood and Marrow Transplantation criteria, we calculated the overall response rate of 33.3% with 1 near-complete response(n CR) and 8 partial responses(PRs). The clinical beneit rate(48.1%) included 1 nCR, 8 PRs, and 4 minimal responses. The most common treatmentrelated adverse events(TRAEs) were fever, aspartate aminotransferase elevation, alanine aminotransferase elevation, leucopenia, rash, neutropenia, and thrombocytopenia. We graded toxicity using the Common Toxicity Criteria for Adverse Events, version 3.0, and determined that 37.0% of patients had at least 1 grade 3–4 TRAE.Conclusions: CPT as a single agent can elicit a response in patients with RRMM and is well tolerated. Further clinical investigation is warranted.

Anti-BCMA CAR-T Cell Therapy in Relapsed or Refractory Multiple Myeloma Patients with Impaired Renal Function

Anti-B cell maturation antigen(BCMA)chimeric antigen receptor(CAR)T-cell therapyis effective and well-tolerated for refractory or relapsed multiple myeloma(RRMM).The purposcof the present study was to analyze efficacy in RRMM patients with renal impairment treated byanti-BCMA CAR-T cell therapy.A total of 59 RRMM patients were selected,and divided intoimpaired renal function(lRF)group[basclinc cstimated giomerular filtration rate(eSFR)<90 m/min/1.73 m^2(n=18)]and normal renal function(NRF)group(baseline eGFR≥90 mL/min/1.73 m,n=41).For patients with IRF,eGFR at the 6th month post-CAR-T cells infusion was significantlyhigher than the baseline(P<0.05).The multivariate analysis showed that light chain type and beta-2 micro-globulin(bcta-2M)were associated factors with the decrease of serum creatinine.Medianprogression-free survival(PFS)in the NRF group and IRF group was 266 days and 181 daysrespectively.Overall survival(OS)in the NRF group and lRF group was 877 days and 238 daysrespectively.There was no significant difference in the objective response rate(ORR)between thelRF group and the NRF group.It is suggested that CAR-T cells therapy could improve the renalfunction during the treatment of RRMM.The renal function could be more significantly improvedin RRMM patients with light chain type than with other types.

Venetoclax in combination with chidamide and dexamethasone in relapsed/refractory primary plasma cell leukemia without t(11;14):A case report

BACKGROUND Conventional therapies for primary plasma cell leukemia(pPCL)are usually ineffective,with a short remission time with the use of multiple myeloma medications,showing aggressiveness of pPCL.B-cell lymphoma-2 inhibitor venetoclax is usually used for relapsed/refractory multiple myeloma(RRMM)with t(11;14).There are very few studies published on the use of venetoclax in pPCL without t(11;14).Similarly,histone deacetylase inhibitors are considered effective for the treatment of RRMM,but there are no reports on their use in pPCL.CASE SUMMARY A 57-year-old woman with severe anemia,thrombocytopenia,multiple bone destruction,impaired renal function,and 42.7%of peripheral plasma cells is reported.After multiple chemotherapy regimens and chimeric antigen receptor Tcell treatment,the disease progressed again.The patient had very good partial response and was maintained for a long time on venetoclax in combination with chidamide and dexamethasone therapy.CONCLUSION The success of venetoclax-chidamide-dexamethasone combination therapy in achieving a very good partial response suggested that it can be used for refractory/relapsed pPCL patients who have been exhausted with the use of various drug combinations and had poor survival outcomes.

Treatment of refractory/relapsed extranodal NK/T cell lymphoma with decitabine plus anti-PD-1:A case report

BACKGROUND Extranodal natural killer/T cell lymphoma,nasal type(ENKL) is a highly aggressive malignancy characterized by its association with Epstein-Barr virus(EBV) and extranodal involvement,which shows a poor clinical outcome.Although L-asparaginase-based chemotherapy has improved the response rates of relapsed/refractory(R/R) ENKL,relapse occurs in up to 50% of patients with disseminated disease.CASE SUMMARY Immune evasion has emerged as a critical pathway for survival in ENKL and may be effectuated via STAT3-driven upregulation of programmed cell death ligand 1(PD-L1) or other molecular pathways.Anti-PD-1 is effective for R/R ENKL with EBV-driven upregulation of PD-L1 expression.Anti-PD-1 combined with decitabine showed positive preliminary results in a patient with R/R ENKL and resistance to anti-PD-1.CONCLUSION The treatment experience,in this case,demonstrated the potential ability of decitabine combined with PD-1 inhibitor to treat R/R ENKL,thus providing a new treatment strategy for this tumor.

Chidamide,Decitabine,Cytarabine,Aclarubicin,and Granulocyte Colony-stimulating Factor Therapy for Patients with Relapsed/Refractory Acute Myeloid Leukemia:A Retrospective Study from a Single-Center

Objective Preclinical evidence and clinical trials have suggested synergistic effects of epigenetic modifiers in combination with cytotoxic agents for the treatment of leukemia.However,their efficacy in patients with relapsed/refractory acute myeloid leukemia(R/R AML)remains unclear.Methods Clinical data of R/R AML patients who received a CDCAG regimen(chidamide,decitabine,cytarabine,aclarubicin,and granulocyte colony-stimulating factor)from July 1,2018 to October 31,2021 at our center were retrospectively assessed,and the safety and efficacy of the CDCAG regimen were evaluated.Patients were followed up until November 30,2021,with a median follow-up of 21.6 months(95%CI:10.0–33.2 months).Results A total of 67 patients were enrolled.Two patients died within 3 weeks after the initiation,and therefore only 65 patients underwent the assement for clinical response and survival.It was found that 56.9%patients achieved complete remission with a median overall survival(OS)of 9.6 months.The median OS of responders was 25.9 months,while that of non-responders was 5.0 months(P<0.0001).Patients with gene mutations had a superior overall response rate(ORR)(80.4%vs.45.5%,P=0.043)compared to those without gene mutations.The presence of DNA methyltransferase 3 A(DNMT3A),ten-eleven translocation-2(TET2),and isocitrate dehydrogenase 1/2(IDH1/2)mutations did not affect the response rate(88.2%vs.68.9%,P=0.220)and reflected a better OS(not attained vs.9.0 months,P=0.05).The most common non-hematologic adverse events were pulmonary infection(73.1%),followed by febrile neutropenia(23.9%)and sepsis(19.4%).Conclusions The CDCAG regimen was effective and well-tolerated in R/R AML patients,increasing the potential for allogeneic hematopoietic stem cell transplantation.Moreover,patients with DNMT3A,TET2,and IDH1/2 mutations might benefit from this regimen.

Pomolidomide for relapsed/refractory light chain amyloidosis after resistance to both bortezomib and daratumumab:A case report

BACKGROUND Immunoglobulin light chain(AL)amyloidosis is a rare disease characterized by deposition of ALs essentially in any organ or tissue,with cardiac involvement being very frequent(61%).Early diagnosis is of high importance because early initiation of treatment in AL amyloidosis may improve outcomes.Despite the administration of immunotherapeutic agents,in particular bortezomib and daratumumab,which have improved the outcomes of AL amyloidosis,antiplasma cell therapy remains suboptimal for some patients.CASE SUMMARY We report the case of a 55-year-old man presenting with heart failure who was diagnosed with cardiac AL amyloidosis by an endomyocardial biopsy.He experienced a short-term hematological remission with no organ response after being administered a bortezomib-daratumumab containing regimen.The treatment was switched to pomolidomide due to pulmonary involvement and progressive pleural effusion,in which flow cytometry analysis showed abnormal plasma cells.After two cycles of this regimen,the pleural effusion was controlled effectively with no recurrence.CONCLUSION This case emphasizes the crucial role of endomyocardial biopsy in early diagnosis of cardiac amyloidosis and suggests that pomolidomide may be an effective treatment for patients with AL amyloidosis that is relapsed/refractory to both bortezomib and daratumumab.

Programmed cell death protein-1 inhibitor combined with chimeric antigen receptor T cells in the treatment of relapsed refractory non- Hodgkin lymphoma: A case report

BACKGROUND Chimeric antigen receptor T cell(CART)therapy has benefited many refractory lymphoma patients,but some patients experience poor effects.Previous studies have shown that programmed cell death protein-1(PD-1)inhibitors can improve and prolong the therapeutic effect of CAR-T cell treatment.CASE SUMMARY A 61-year-old male presented with 15-d history of diarrhea and lower-limb edema.A large mass was detected in the pelvis,and pathology indicated non-Hodgkin diffuse large B-cell lymphoma.After three cycles of the R-CHOP chemotherapeutic regimen,the patient showed three subcutaneous nodules under the left armpit and both sides of the cervical spine.Pathological examination of the nodules indicated DLBCL again.The patient was diagnosed with relapsed and refractory diffuse large B-cell lymphoma.We recommended CAR-T cell treatment.Before treatment,the patient’s T cell function and expression of immune detection points were tested.Expression of PD-1 was obviously increased(52.7%)on cluster of differentiation(CD)3+T cells.The PD-1 inhibitor(3 mg/kg)was infused prior to lymphodepleting chemotherapy with fludarabine and cyclophosphamide.CAR-CD19 T cells of 3×10^(6)/kg and CAR-CD22 T cells 1×10^(6)/kg were infused,respectively.The therapeutic effect was significant,and the deoxyribonucleic acid copy numbers of CAR-CD19 T cells and CAR-CD22 T cells were stable.Presently,the patient has been disease-free for more than 12 mo.CONCLUSION This case suggests that the combination of PD-1 inhibitors and CAR-T cellsimproved therapeutic efficacy in B-cell lymphoma.

An Evaluation of the Clinical Efficacy and Safety of Ixazomib for Relapsed/Refractory Multiple Myeloma

Objective:To investigate the clinical efficacy and safety of ixazomib in the treatment of relapsed/refractory multiple myeloma(RRMM).Methods:The clinical data of 20 patients with RRMM admitted to the hospital from January 2020 to January 2022 were analyzed retrospectively.All patients were treated with ixazomib-based chemotherapy regimen(IRD regimen 13 cases;ID regimen 7 cases).The objective response rate(ORR)and adverse events(AEs)were observed.Results:All 20 patients received two to seven courses of treatment,in which the median was three courses.One patient had CR,four patients had VGPR,seven patients had PR,two patients had SD,and six patients had PD.The ORR was 60.00%(12/20),and 25.00%(5/20)of them had VGPR or more.The ORR of patients with previous treatment lines≥3,ISS stage III,and high-risk cytogenetic was lower than that of patients with previous treatment lines<3,ISS stage I/II,and low-risk cytogenetics.The main AEs include anemia,thrombocytopenia,neutropenia,nausea and vomiting,diarrhea,constipation,and respiratory tract infection,most of which are grade I/II.Conclusion:Ixazomib is effective in the treatment of RRMM in some patients,and the AEs are controllable.Patients who had received less than 3 lines of treatment in the past,with ISS stage I to II and low-risk cytogenetics had better treatment effect.

Subcutaneous daratumumab in Chinese patients with relapsed or refractory multiple myeloma:an open-label,multicenter,phase 1 study(MMY1010)

Despite recent progress in multiple myeloma(MM)treatments,most patients will relapse and require additional treatment.Intravenous daratumumab,a human IgGκmonoclonal antibody targeting CD38,has shown good efficacy in the treatment of MM.A subcutaneous version of daratumumab was formulated to reduce the burden of intravenous infusions.We aimed to investigate the efficacy and safety of subcutaneous daratumumab in Chinese patients with relapsed/refractory MM based on the demonstrated noninferiority of subcutaneous daratumumab to intravenous daratumumab,with a shorter administration time and reduced infusion-related reaction rate in global studies.This phase 1,multicenter study(MMY1010;ClinicalTrials.gov Identifier:NCT04121260)evaluated subcutaneous daratumumab in Chinese patients with relapsed/refractory MM after 1 prior line(n=1)or≥2 prior lines(n=20)of therapy,including a proteasome inhibitor and an immunomodulatory drug.Primary endpoints were pharmacokinetics and safety.Mean(standard deviation)maximum trough concentration of daratumumab was 826(335)μg/mL,which was consistent with prior studies of subcutaneous daratumumab and intravenous daratumumab.Safety was consistent with safety profiles observed in other daratumumab studies,with no new safety concerns identified.Incidences of infusion-related reactions and injection-site reactions were low and consistent with other subcutaneous daratumumab studies.At a median follow-up of 7.5 months,the overall response rate was 57.1%,with a very good partial response or better rate of 38.1%and complete response or better rate of 19.0%.Our results demonstrate a favorable benefit/risk profile of subcutaneous daratumumab in Chinese patients with relapsed/refractory MM,potentially impacting clinical administration of daratumumab in this population.

Ivosidenib in Chinese patients with relapsed or refractory isocitrate dehydrogenase 1 mutated acute myeloid leukemia:a registry study

Ivosidenib,an isocitrate dehydrogenase 1(IDH1)inhibitor,has demonstrated clinical benefits in a pivotal study(AG120-C-001)in patients with IDH1-mutated(mIDH1)acute myeloid leukemia(AML).A registry study(CS3010-101:NCT04176393)was conducted to assess the pharmacokinetic(PK)characteristics,safety,and efficacy of ivosidenib in Chinese patients with relapsed or refractory(R/R)mIDH1 AML.Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression.Ten subjects underwent intensive PK/progressive disease(PD)assessments.All subjects had the clinical response assessed at screening,every 28 days through month 12,and then every 56 days.Between November 12,2019,and April 2,2021,30 patients were enrolled;26(86.7%)had de novo AML and 18(60.0%)were transfusion-dependent at baseline.Following single and repeated doses of ivosidenib,median time to maximum plasma concentration(T_(max))was 4.0 and 2.0 hours,respectively.The inter-individual variability of pharmacokinetic exposure was moderate to high(coefficient of variation[CV],25%–53%).No obvious accumulation was observed after repeated doses at cycle 2 day 1.Regarding the clinical response,the CR+CRh rate was 36.7%(95%confidence interval[CI]:19.9%–56.1%),the median duration of CR+CRh was 19.7 months(95%CI:2.9 months–not reached[NR]),and median duration of response(DoR)was 14.3 months(95%CI:6.4 months–NR).Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months,as compared with primary data cutoff,and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.

A novel drug of elotuzumab for treatment of refractory/relapsed multiple myeloma: a meta-analysis of eight trials

Elotuzumab was approved by the US FDA in 2015 as a new drug for the treatment of multiple myeloma（MM）, and it became a new choice for MM patients. The drug is the first immunostimulatory drug to treat MM and used to treat recurrent/refractory multiple myeloma（R/RMM） in combination with lenalidomide and dexamethasone. Therefore, we collected the reports from existing clinical trials to analyze the efficacy of the drug in clinical applications to better evaluate the effects of the drug on R/RMM. The search strategy used ＂elotuzumab＂ and ＂multiple myeloma＂ as keywords to search from the database of Cochrane, Embase, Pub Med and Medline. The heterogeneity among the studies was assessed using the Cochrane χ~2 test, and its extent was evaluated using I^2 statistics. A P value of less than 0.05 was considered as statistically significant. All meta-analyses were conducted with R Software 3.3.2. We identified eight prospective studies consisting of 608 MM patients. The meta-analysis showed that the overall response rate（ORR） was 63%, 162 patients（26.6%） achieved a very good partial response rate（VGPR）, and 34 patients（5.59%） achieved complete response rate（CR）. The most common adverse effects of the drug included anemia, lymphopenia, thrombocytopenia, neutropenia and fatigue. Therefore, elotuzumab combination regimens offered clinical benefits to R/RMM patients, and such a combination therapy was a suitable option for continuous treatment for R/RMM patients.

Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer

The successes achieved by chimeric antigen receptor-modified T （CAR-T） cells in hematological malignancies raised the pos- sibility of their use in non-small lung cancer （NSCLC）. In this phase I clinical study （NCT01869166）, patients with epidermal growth factor receptor （EGFR）-positive （〉50% expression）, relapsed/refractory NSCLC received escalating doses of EGFR-targeted CAR-T cell infusions. The EGFR-targeted CAR-T cells were generated from peripheral blood after a 10 to 13-day in vitro expansion. Serum cytokines in peripheral blood and copy numbers of CAR-EGFR transgene in peripheral blood and in tissue biopsy were monitored periodically. Clinical responses were evaluated with RECISTI.1 and im- mune-related response criteria, and adverse events were graded with CTCAE 4.0. The EGFR-targeted CAR-T cell infusions were well-tolerated without severe toxicity. Of 11 evaluable patients, two patients obtained partial response and five had stable disease for two to eight months. The median dose of transfused CAR＋ T cells was 0.97x 10^7 cells kg J （interquar- tile range （IQR）, 0.45 to 1.09x 10^7 cells kg 1）. Pathological eradication of EGFR positive tumor cells after EGFR-targeted CAR-T cell treatment can be observed in tumor biopsies, along with the CAR-EGFR gene detected in tumor-infiltrating T cells in all four biopsied patients. The EGFR-targeted CAR-T cell therapy is safe and feasible for EGFR-positive advanced re- lapsed/refractory NSCLC.

Different dose combinations of bortezomib and dexamethasone in the treatment of relapsed or refractory myeloma： an open-label,observational, multi-center study in China

Background Although previous clinical study revealed that bortezomib combined with dexamethasone had improved the outcomes of relapsed or refractory multiple myeloma （RRMM）, the optimal dose combinations of bortezomib and dexamethasone remain unknown. This trial aimed to observe the efficacy and safety of different dose combinations of bortezomib and dexamethasone in the treatment of RRMM patients in China.Methods A total of 168 patients with relapsed multiple myeloma （MM） who were refractory to at lest two prior treatments were enrolled in this multicenter, open-label, non-randomized, prospective clinical trial. Twenty patients received 1.3 mg/m2 of bortezomib twice weekly for 2 weeks of a 3-week cycle for up to 8 cycles and oral or intravenous dexamethasone 20 mg on the day of and after each bortezomib dose （group 1）; 66 patients received less than 1.3 mg/m2（0.7-1.0 mg/m2） of bortezomib and dexamethasone 20 mg on the same schedule （group 2）; 37 patients received 1.3 mg/m2 of bortezomib and dexamethasone 40 mg （group 3） and 45 patients received less than 1.3 mg/m2 （0.7-1.0 mg/m2）of bortezomib and dexamethasone 40 mg （group 4）. The response was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation and confirmed by an independent review committee. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0. Results The median age of groups 1 to 4 was 61,62, 56, and 60 years, respectively. Most patients were in stages Ⅱ/Ⅲ of MM and the most common subtype was IgG The rate of overall response to bortezomib and dexamethasone of group 1 to 4 was 72.2% （13/18）, 73.8% （48/65）, 78.8% （26/33） and 78.0% （32/41） （P=0.91）, including a complete response rate of 22.2% （4/18）, 20.0% （13/65）, 33.3% （11/33） and 29.3% （12/41） （P=0.67）, respectively. There was no statistical significance in time to progression and overall survival among these 4 groups （P 〉0.05）. The most commonly adverse events of any grade in the entire 4 groups were fatigue, gastrointestinal effects, peripheral neuropathy and thrombocytopenia, and there was no significance in the number of adverse events among the 4 groups （P 〉0.05） except that peripheral neuropathy was reported more frequently in group 3 （36.3%） than in group 2 （13.8%, P 〈0.05） and group 4 （14.6%, P〈O.05）.Conclusions The combination of bortezomib and dexamethasone was associated with high responses in Chinese RRMM patients. No significant differences of efficacy were detected in different dose combinations of bortezomib and dexamethasone. Moreover, low dose of bortezomib reduced the incidence of peripheral neuropathy without affecting outcome in the treatment of patients with RRMM in China.

Impact of prophylactic/preemptive donor lymphocyte infusion and intensified conditioning for relapsed/refractory leukemia:a real-world study

Prophylactic/preemptive donor lymphocyte infusion(p/pDLI)and intensified conditioning have shown promising results in experimental studies of refractory/relapsed acute leukemia(RRAL),but real-world data remain scarce.We conducted a multicenter,population-based analysis of 932 consecutive patients.The three-year leukemia-free survival(LFS)rates were 56%for patients receiving both p/pDLI and intensified myeloablative conditioning(MAC)(intenseMAC)and 30%for those who received neither therapy per landmark analysis.Multivariable analyses were run separately for acute myeloid leukemia(AML)and acute lymphoblastic leukemia(ALL),and p/pDLI treatment was linked to significantly higher LFS than non-DLI for both AML and ALL patients without increasing the nonrelapse mortality.IntenseMAC was associated with significantly lower relapse and higher LFS than nonintensified MAC despite higher nonrelapse mortality rates in ALL,while there was no impact of intenseMAC observed in AML.p/pDLI achieved superior outcomes in both matched-sibling donor(MSD)and haploidentical donor transplantation,while intenseMAC only influenced MSD outcomes.Data suggest that RRAL patients receiving“total therapy”by way of p/pDLI and intensified conditioning treatment have an improved chance for LFS,with p/pDLI being safer with a more extensive impact relative to intenseMAC.Patients with RRAL can tolerate both interventions and achieve a reasonable outcome.

Chimeric antigen receptor T-cell therapy: a promising treatment modality for relapsed/refractory mantle cell lymphoma

Mantle cell lymphoma(MCL)is a distinct histological type of B-cell lymphoma with a poor prognosis.Several agents,such as proteasome inhibitors,immunomodulatory drugs,and inhibitors of B cell lymphoma-2 and Bruton’s tyrosine kinase have shown efficacy for relapsed or refractory(r/r)MCL but often have short-term responses.Chimeric antigen receptor(CAR)T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin’s lymphoma.However,long-term safety and tolerability associated with CAR T-cell therapy are not defined well,especially in MCL.In this report,we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy.CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient.This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL,who are generally elderly and have comorbid conditions.

Different sites of extranodal involvement may affect the survival of patients with relapsed or refractory non-Hodgkin lymphoma after chimeric antigen receptor T cell therapy

Factors associated with complete and durable remissions after anti-CD19 chimeric antigen receptor T(CAR-T)cell immunotherapy for relapsed or refractory non-Hodgkin lymphoma(r/r NHL)have not been well characterized.In this study,we found that the different sites of extranodal involvement may affect response,overall survival(OS),and progression-free survival(PFS)in patients with r/r NHL treated with anti-CD19 CAR-T cells.In a cohort of 32 treated patients,12(37.5%)and 8(25%)patients exhibited soft tissue lymphoma and bone marrow(BM)infiltrations,respectively,and 13(41%)patients exhibited infiltration at other sites.The factors that may affect prognosis were identified through multivariable analysis.As an independent risk factor,soft tissue infiltration was the only factor significantly correlated with adverse prognosis(P<0.05),whereas other factors did not reach statistical significance.Furthermore,the site of extranodal tumor infiltration significantly and negatively affected OS and PFS in patients with r/r NHL treated with anti-CD19 CAR-T cell therapy.PFS and OS in patients with BM involvement were not significantly different from those of patients with lymph node involvement alone.Thus,anti-CD19 CAR-T cell therapy may improve the prognosis of patients with BM infiltration.

Prognostic factors and efficacy of GDP-R therapy in refractory/relapsed diffuse large B-cell lymphomas not eligible for high-dose therapy

Aim:The main aim of the present study was to evaluate the overall survival(OS)and time to treatment failure(TTF)in a cohort of relapsed/refractory diffuse large B-cell lymphomas(DLBCLs)not eligible for high-dose therapy(HDT)treated with gemcitabine in association with dexamethasone,cisplatin and rituximab(GDP-R)protocol.The secondary aim was to identify the prognostic factors impacting OS and TTF.Methods:The authors retrospectively analyzed 45 patients with refractory/relapsed DLBCLs treated with GDP-R.Results:Overall response rate(ORR)was 48.8%;complete response 15/45(33.3%),partial response 7/45(15.5%).Response was influenced by the number of previous therapies administered and International Prognostic Index(IPI)value.Although no significant impact occurred with regard to OS,patients pre-treated with 2 or<2 chemotherapeutic regimens had better ORR(P=0.014)and a longer TTF(P=0.029 in multivariate Cox model).IPI value also influenced TTF.Patients with<2 IPI value had significantly more prolonged TTF than the other ones(P=0.048 in multivariate Cox model).Treatment was well-tolerated,with the majority of patients treated on out-patient modality.GDP-R regimen represents a valid treatment for aggressive relapsed/refractory B-cell lymphoma not eligible for HDT thanks to its efficacy and good toxic profile.Conclusion:The number of previous chemotherapeutic regimens and IPI value select those who benefit more from this treatment.

Overall Survival and Health Care Costs of Medicare Patients with Previously Treated Chronic Lymphocytic Leukemia

Background: Bendamustine-based regimens are often used in the management of patients with chronic lymphocytic leukemia (CLL) but few studies have analyzed the comorbidity- and/or adverse event (CAE)-related healthcare costs in patients receiving these regimens in a real-world setting. Aims: To describe all-cause and CAE-related healthcare costs in relapse/refractory (R/R) elderly patients with CLL treated with bendamustine-based regimens in a real-world setting. Methods: Adult patients with R/R CLL who received bendamustine-based regimens on/after January 2010 were selected from the Medicare Limited Data Set (LDS) 5% Standard Analytic Files. Selected patients were classified into cohorts based on the two most prevalent bendamustine-based regimens observed (index treatment): 1) bendamustine + rituximab (BR cohort) and 2) bendamustine monotherapy (B-mono cohort). For each cohort, all-cause and CAE-related healthcare costs, while on treatment, were reported per-patient-per-month (PPPM). Overall survival (OS) rates following initiation of the index treatment were described using age- and gender-adjusted Kaplan-Meier curves. Results: A total of 275 patients were included in the BR cohort and 100 patients in the B-mono cohort. Most patients were male and the mean age was approximately 75 years old. During treatment, total all-cause healthcare costs were $14,520 PPPM for the BR cohort and $13,125 PPPM for the B-mono cohort—outpatient costs (mainly driven by CLL-drug costs) represented 86.1% of the total all-cause healthcare costs for the BR cohort and 69.8% for the B-mono cohort. CAE costs accounted for 58.3% of the total all-cause healthcare costs for the BR cohort and 66.9% for the B-mono cohort. Median OS was 35 months in the BR cohort and 21 months in the B-mono cohort. Conclusion: In this population of elderly patients with R/R CLL treated with bendamustine-based regimens, CAEs were common and translated into important medical costs. Median OS was also relatively short suggesting an unmet medical need.

Efficacy and safety analysis of the combination of cladribine,cytarabine,granulocyte colony stimulating factor( CLAG ) regime in patients with refractory or relapsed acute myeloid leukemia

Objective To analyze efficacy and safety of CLAG regimen in patients with refractory or relapsed acute myeloid leukemia(AML).Methods Efficacy and adverse events of patients with refractory or relapsed AML who were treated with one course of CLAG from April 1st,2014 through December 9th,2015 in our hospital were retrospectively reviewed.Results Thirty-three

Targeting HMGCS1 restores chemotherapy sensitivity in acute myeloid leukemia

Acute myeloid leukemia(AML)is a common hematological malignancy with overall poor prognosis.Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory(RR)AML patients.Through clinical specimens,animal models and cell-level studies,we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1(HMGCS1)in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation,increase chemotherapy sensitivity and improve the occurrence and development of AML.Here,we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival(OS).Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity,while stable overexpression of HMGCS1 had the opposite effects.Mechanistically,we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase(MAPK)pathway activity,while overexpression of HMGCS1 could remarkably enhance the pathway.U0126,a MEK1 inhibitor,offset the effects of HMGCS1 overexpression,indicating that HMGCS1 promotes RR AML through the MAPK pathway.Further,we verified that hymeglusin,a specific inhibitor of HMGCS1,decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients.Furthermore,combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin(ADR)had synergistic toxic effects on AML cells.Our study demonstrates the important role of HMGCS1 in AML,and targeting this protein is promising for the treatment of RR AML.