Resistance to venetoclax and hypomethylating agents in acute myeloid leukemia

Despite the success of the combination of venetoclax with the hypomethylating agents(HMA)decitabine or azacitidine in inducing remission in older,previously untreated patients with acute myeloid leukemia(AML),resistance-primary or secondary-still constitutes a significant roadblock in the quest to prolong the duration of response.Here we review the proposed and proven mechanisms of resistance to venetoclax monotherapy,HMA monotherapy,and the doublet of venetoclax and HMA for the treatment of AML.We approach the mechanisms of resistance to HMAs and venetoclax in the light of the agents’mechanisms of action.We briefly describe potential therapeutic strategies to circumvent resistance to this promising combination,including alternative scheduling or the addition of other agents to the HMA and venetoclax backbone.Understanding the mechanisms of action and evolving resistance in AML remains a priority in order to maximize the benefit from novel drugs and combinations,identify new therapeutic targets,define potential prognostic markers,and avoid treatment failure.

Relapsed/refractory classical Hodgkin lymphoma effectively treated with low-dose decitabine plus tislelizumab:A case report

BACKGROUND Academic studies have proved that anti-programmed death-1(PD-1)monoclonal antibodies demonstrated remarkable activity in relapsed/refractory classical Hodgkin lymphoma(cHL).However,most patients ultimately experienced failure or resistance.It is urgent and necessary to develop a novel strategy for relapsed/refractory cHL.The aim of this case report is to evaluate the combination approach of low-dose decitabine plus a PD-1 inhibitor in relapsed/refractory cHL patients with prior PD-1 inhibitor exposure.CASE SUMMARY The patient was a 27-year-old man who complained of enlarged right-sided cervical lymph nodes and progressive pain aggravation of the right shoulder over the past 3 mo before admission.Histological analysis of lymph node biopsy was suggestive of cHL.The patient experienced failure of eight lines of therapy,including multiple cycles of chemotherapy,PD-1 blockade,and anti-CD47 antibody therapy.Contrast-enhanced CT showed that the tumors of the chest and abdomen significantly shrunk or disappeared after three cycles of treatment with decitabine plus tislelizumab.The patient had been followed for 11.5 mo until March 2,2021,and no progressive enlargement of the tumor was observed.CONCLUSION The strategy of combining low-dose decitabine with tislelizumab could reverse the resistance to PD-1 inhibitors in patients with heavily pretreated relapsed/refractory cHL.The therapeutic effect of this strategy needs to be further assessed.

Pre-transplantation cytoreduction does not benefit advancedmyelodysplastic syndrome patients after myeloablative transplantation with grafts from family donors

Background:The role of pre-hematopoietic stem cell transplantation(HSCT)cytoreduction with either induction chemotherapy(IC)or hypomethylating agents(HMAs)in treating advanced myelodysplastic syndrome(MDS)remains debatable.We aimed to evaluate pre-HSCT strategies by comparing the endpoints related to disease control between advanced MDS patients with pre-HSCT cytoreduction and those with best supportive care.Methods:We described 228 consecutive advanced MDS patients who received HSCT from a haploidentical donor(HID,n=162)or matched related donor(MSD,n=66)with uniform myeloablative conditioning regimens between January 2015 and December 2018.Of these 228 patients,131(57.5%)were treated exclusively with pre-HSCT best supportive care(BSC),49(22.5%)were given HMA,and 48(21.1%)received both IC and HMA.Propensity score-matching analysis,multivariate analyses,and subgroup analyses were performed to elucidate the impact of pre-HSCT strategies on transplant outcomes.Results:The 3-year relapse-free survival(RFS)rates were 78.2% and 70.0% for the BSC and cytoreduction cohorts(P=0.189)and were 78.2%,66.7%,and 73.2% for the BSC,HMA,and HMA+IC groups,respectively(P=0.269).A propensity score-matching analysis confirmed that the 3-year RFS rates were 81.9%,87.5%,and 66.9% for BSC,cytoreduction complete remission(CR),and cytoreduction non-CRgroups,respectively(P=0.051).Multivariate analyses demonstrated that pre-HSCT cytoreduction,older patient age,monosomal karyotype,and interval between diagnosis and HSCT were poor prognostic factors for RFS.In the subgroup analyses,BSC was associated with longer RFS compared to cytoreduction among the younger patients,those with international prognostic scoring system intermediate-2/high risk at diagnosis,and those with intermediate/poor cytogenetics.Conclusions:Different pre-HSCT therapies did not yield discrepant post-HSCT outcomes.No benefit in terms of post-HSCT outcomes were correlated with pre-HSCT cytoreduction in advanced MDS even for cytoreduction CR patients.Early referral to HSCT is essential for advanced MDS patients.

Venetoclax resistance:mechanistic insights and future strategies

Acute myeloid leukemia(AML)is historically associated with poor prognosis,especially in older AML patients unfit for intensive chemotherapy.The development of Venetoclax,a potent oral BH3(BCL-2 homology domain 3)mimetic,has transformed the AML treatment.However,the short duration of response and development of resistance remain major concerns.Understanding mechanisms of resistance is pivotal to devising new strategies and designing rational drug combination regimens.In this review,we will provide a comprehensive summary of the known mechanisms of resistance to Venetoclax and discuss Venetoclax-based combination therapies.Key contributing factors to Venetoclax resistance include dependencies on alternative anti-apoptotic BCL-2 family proteins and selection of the activating kinase mutations.Mutational landscape governing response to Venetoclax and strategic approaches developed considering current knowledge of mechanisms of resistance will be addressed.