While post-transplant cyclophosphamide (PTCy) is commonly used as graft-versus-host disease (GvHD) prophylaxis in haploidentical stem cell transplantation (haplo-HSCT), its dose remains a matter of debate due to side effect concerns. Standard dose of 100 mg/kg associated with tacrolimus and post-engraftment anti-thymocyte globulin (ATG) was used as the reference GvHD prophylaxis in our center and had demonstrated encouraging results. Though PTCy 80 mg/kg was shown to be feasible in patients in reduced-intensity conditioning, whether it exerts equivalent GvHD prophylactic efficacy in myeloablative conditioning (MAC) setting has not been confirmed. Here, we retrospectively analyzed the efficacy and safety of PTCy 80 mg/kg combined with tacrolimus and post-engraftment ATG as GvHD prophylaxis in patients aged more than 55 years or with cardiac antecedents or HCT-CI score >2 undergoing haplo-HSCT with MAC. The cumulative incidence of grade III-IV aGvHD at day 100 and moderate-to-severe cGvHD at 1 year was 4.8% +/- 3.4% and 19.9% +/- 7.0%, respectively. When compared with patients receiving the reference regimen, patients from the PTCy 80 mg/kg group had similar incidence of GvHDs and survival as their younger counterparts. Thus, PTCy 80 mg/kg seems to be feasible for patients treated with MAC conditioning regimens in haplo-HSCT, inviting further investigation notably in frail patients.

Abstract Peripheral T-cell lymphoma (PTCL) is a heterogeneous and aggressive disease with a poor prognosis. Histone deacetylase (HDAC) inhibitors have shown inhibitory effects on PTCL. A better understanding of the therapeutic mechanism underlying the effects of HDAC inhibitors could help improve treatment strategies. Herein, we found that high expression of HDAC3 is associated with poor prognosis in PTCL. HDAC3 inhibition suppressed lymphoma growth in immunocompetent mice but not in immunodeficient mice. HDAC3 deletion delayed the progression of lymphoma, reduced the lymphoma burden in the thymus, spleen, and lymph nodes, and prolonged the survival of mice bearing N-methyl-N-nitrosourea–induced lymphoma. Furthermore, inhibiting HDAC3 promoted the infiltration and enhanced the function of natural killer (NK) cells. Mechanistically, HDAC3 mediated ATF3 deacetylation, enhancing its transcriptional inhibitory activity. Targeting HDAC3 enhanced CXCL12 secretion through an ATF3-dependent pathway to stimulate NK-cell recruitment and activation. Finally, HDAC3 suppression improved the response of PTCL to conventional chemotherapy. Collectively, this study provides insights into the mechanism by which HDAC3 regulates ATF3 activity and CXCL12 secretion, leading to immune infiltration and lymphoma suppression. Combining HDAC3 inhibitors with chemotherapy may be a promising strategy for treating PTCL. Significance: Targeting HDAC3 suppresses progression of T‐cell lymphoma by activating ATF3 to induce secretion of CXCL12 and promote infiltration of NK cells, providing an immunostimulatory approach for treating T‐cell lymphoma patients.

Post-transplantation cyclophosphamide (PTCy) has unique advantages for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this single-center retrospective landmark analysis, we evaluated chronic GVHD (cGVHD) and clinical outcomes in patients receiving PTCy, tacrolimus, and post-engraftment low-dose anti-thymocyte globulin (PTCy-ATG) as GVHD prophylaxis after HLA-matched unrelated or haploidentical donor transplantation. Two historical patient groups receiving calcineurin inhibitor-based GVHD prophylaxis were used as control groups. A total of 71 patients with myeloid malignancies undergoing allo-HSCT with myeloablative conditioning regimens were included in the analysis. The 3-year cumulative incidences of cGVHD and moderate to severe cGVHD (M/S cGVHD) were 39.2% (95%CI 27.4%-51.0%) and 11.5% (95%CI 4.1%-18.9%), respectively, in the PTCy-ATG group, and only one instance of bronchiolitis obliterans (BO) was observed. The disease-free survival (DFS), overall survival (OS), and GVHD-free and relapse-free survival rates were 94.0% (95%CI 88.3%-99.7%), 93.0% (95%CI 87.1%-98.9%) and 83.8% (95%CI 75.0%-92.6%) respectively. Of note, the PTCy-ATG group presented with a significantly lower incidence of M/S cGVHD and BO, which translated into superior OS in multivariate analysis. In this retrospective analysis, we observed that PTCy-ATG-based GVHD prophylaxis was associated with a lower incidence of M/S cGVHD and better transplantation outcomes beyond day 100, which invites prospective evaluation.

Internal tandem duplication mutations of the FMS-like tyrosine kinase-3 (FLT3-ITDs) occur in 25%-30% of patients with acute myeloid leukemia (AML) and are associated with dismal prognosis. Although FLT3 inhibitors have demonstrated initial clinical efficacy, the overall outcome of patients with FLT3-ITD AML remains poor, highlighting the urgency to develop more effective treatment strategies. In this study, we reveal that FLT3 inhibitors reduced protein stability of the anti-cancer protein p53, resulting in drug resistance. Blocking p53 degradation with proteasome inhibitors restores intracellular p53 protein levels and, in combination with FLT3-ITD inhibitors, shows superior therapeutic effects against FLT3-ITD AML in cells, mouse models, and patients. These data suggest that this combinatorial therapeutic approach may represent a promising strategy to target FLT3-ITD AML.

PurposeChimeric antigen receptor (CAR)-T cells against CD19 have been proven to be effective in treating B-cell hematological malignancies. However, the efficacy of this promising therapy is limited by many factors.MethodsIn this study, the germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) cell line OCI-Ly1, and patient-derived xenografted (PDX) mice (CY-DLBCL) were used as the CAR-T cell-resistant model. Meanwhile, the activated B-cell-like (ABC) DLBCL cell line OCI-Ly3 and PDX mice (ZML-DLBCL) were defined as the CAR-T sensitive model. The enhancement of CAR-T cell function by lenalidomide (LEN) was examined in vitro and in vivo.ResultsLenalidomide effectively enhanced the function of third-generation CD19-CAR-T cells by polarizing CD8(+) CAR-T cells to CD8 early-differentiated stage and Th1 type, reducing CAR-T cell exhaustion and improving cell expansion. It was further demonstrated that CAR-T cells combined with LEN substantially reduce the tumor burden and prolong the survival time in various DLBCL mouse models. LEN was also found to promote the infiltration of CD19-CAR-T cells into the tumor site by modulating the tumor microenvironment.ConclusionIn summary, the results of the present study suggest that LEN can improve the function of CD19-CAR-T cells, providing a basis for clinical trials using this combination therapy against DLBCL.

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARα, which recruits corepressor complexes, including histone deacetylases (HDACs), to suppress cell differentiation and promote APL initiation. All-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) or chemotherapy highly improves the prognosis of APL patients. However, refractoriness to ATRA and ATO may occur, which leads to relapsed disease in a group of patients. Here, we report that HDAC3 was highly expressed in the APL subtype of AML, and the protein level of HDAC3 was positively associated with PML-RARα. Mechanistically, we found that HDAC3 deacetylated PML-RARα at lysine 394, which reduced PIAS1-mediated PML-RARα SUMOylation and subsequent RNF4-induced ubiquitylation. HDAC3 inhibition promoted PML-RARα ubiquitylation and degradation and reduced the expression of PML-RARα in both wild-type and ATRA- or ATO-resistant APL cells. Furthermore, genetic or pharmacological inhibition of HDAC3 induced differentiation, apoptosis, and decreased cellular self-renewal of APL cells, including primary leukemia cells from patients with resistant APL. Using both cell line- and patient-derived xenograft models, we demonstrated that treatment with an HDAC3 inhibitor or combination of ATRA/ATO reduced APL progression. In conclusion, our study identifies the role of HDAC3 as a positive regulator of the PML-RARα oncoprotein by deacetylating PML-RARα and suggests that targeting HDAC3 could be a promising strategy to treat relapsed/refractory APL.

IntroductionPost-transplantation cyclophosphamide (PT-Cy) use is a recent graft-versus-host disease (GVHD) prophylaxis strategy for patients undergoing allogeneic stem cell transplantation (allo-HSCT). PT-Cy combined with two immunosuppressants is now widely used after haplo-identical (haplo) and HLA-matched peripheral blood stem cell (PBSC) transplantations with promising GVHD and relapsefree survival (GRFS) probabilities. Although appealing, these results may benefit from improvement notably outside matched sibling donor transplantation, and should be investigated in various ethnic populations.MethodsTherefore, we report our experience of GVHD prophylaxis regimen combining PT-Cy and tacrolimus with addition of post-engraftment low-dose anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation from haplo-identical donors (Haplo). Sixtyseven patients were included in the analysis. All patients received myeloablative or intensified sequential conditioning regimen.ResultsThe median follow-up was 521 (range, 10~991) days. The cumulative incidences of 100-day grade II-IV acute GVHD was 14.9±4.4%, and no case of grade III-IV acute GVHD was documented. The cumulative incidences of 2-yearchronic GVHD and moderate-to-severe chronic GVHD were 25.4±5.4% and 11.9±4%, respectively. The non-relapse mortality at day+100 and 2year were 7.5±3.2% and 9.0±3.5%, respectively. The cumulative incidence of relapse at 2year was 16±6.4%. The 2-year probability of DFS and OS were 73.8% (95%CI, 61.5~88.4%) and 72.5% (95% CI, 57.1~92.1%), respectively. The 2-year GRFS was estimated as 63.6% (95%CI, 50.6~80%).DiscussionOur results suggested that a combination of PT-Cy, tacrolimus, and low-dose post-engraftment ATG was a promising GVHD prophylaxis with low incidence of acute GVHD in the haplo-transplantation setting.

Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with standard myeloablative conditioning regimens such as fludarabine (Flu) and busulfan (Bu) remains a major concern in patients with myeloid malignancies. A low relapse rate has been reported when thiotepa or melphalan (Mel) is added to Flu-Bu, but at a possible increased risk of nonrelapse mortality (NRM). Here we evaluated the outcomes of 100 patients (70 with acute myeloid leuke-mia, 23 with myelodysplastic syndrome, 4 with chronic myelomonocytic leukemia, and 3 with granulocytic sarcoma) who underwent their first allo-HSCT after a moderate-dose FBM conditioning regimen consisting of Flu 150 mg/m(2), Bu 6.4 mg/kg, and Mel 140 mg/m(2) (n = 69), with Mel 100 mg/m(2) for patients age 55 years and/or with a Hemato-poietic Cell Transplantation Comorbidity Index (HCT-CI) =3 (n = 31). Donors were HLA-matched siblings (n = 19), matched unrelated donors (n = 4), and haploidentical donors (n = 77). The majority of patients (88%) had an interme-diate or high Disease Risk Index. Out of 96 evaluable patients, 94 achieved neutrophil engraftment and had full donor chimerism on day +30 post-transplantation. After a median follow-up of 468 days (range, 55 to 1039 days), only 4 patients relapsed, with a 2-year cumulative incidence of relapse (CIR) of 5.3% +/- 3.6%. The 100-day and 2-year NRM were 6.8% +/- 4.4% and 12.3% +/- 3.6%, respectively. At the last follow-up, the 2-year disease-free survival (DFS) and overall survival (OS) were 82.4% +/- 4.2% and 80.3% +/- 6.0%, respectively. Comparing the transplantation outcomes between patients receiving Mel 100 mg/m(2) and those receiving Mel 140 mg/m(2), showed no significant differences in NRM and CIR between the 2 groups and similar 2-year DFS and OS in the 2 groups, although the Mel 100 group had a higher median age (58 years versus 42 years; P < .001) and a higher percentage of patients with an HCT-CI >= 3 (P = .005). In the total cohort, the sole independent factor associated with transplantation outcomes was HCT-CI >= 3, which correlated with higher NRM and inferior DFS and OS. Our study suggests that moderate-intensity FBM condi-tioning is feasible for patients with myeloid malignancies, with a low relapse rate without increased NRM. A lower Mel dose of 100 mg/m(2) maintained the low risk of relapse without excess NRM in older adults. However, the FBM regimen should be used with caution in patients with high-risk HCT-CI (>= 3).

Autologous hematopoietic stem cell transplantation (auto-HSCT) is widely used in clinical treatment of blood system diseases, but some patients still face treatment failure. The content of hematopoietic stem cells (HSC) in peripheral blood is negligible, and it must be mobilized to promote the release of HSC from bone marrow into peripheral blood. HSC mobilization is a key process of auto-HSCT, and the mobilization efficiency and collection volume have significant impacts on auto-HSCT success and post-transplant outcomes. Low peripheral blood CD34 + cell counts due to poor mobilization capacity are one of the main reasons for auto-HSCT failure. The insufficient number of reinfused HSC in auto-HSCT may affect the long-term prognosis of patients. The low count of peripheral blood CD34 + cells count due to poor mobilizers is the principal cause for auto-HSCT failure. Preemptive treatment with new HSC mobilization agent plerixafor before collection can effectively reduce the mobilization failure rate. This article intends to review application status of auto-HSCT, the status of HSC mobilization, and role of peripheral blood CD34 + count in HSC collection, in order to provide a theoretical basis for identifying patients with poor mobilization in clinical practice and guiding reasonable preemptive intervention with plerixafor.

Allogeneic stem cell transplantation from haplo-identical donors (haplo-HSCT) has become a well-established therapeutic option for hematological malignancies. The fever of unknown origin (haplo-fever) early after the infusion of T cell repleted graft, which returned to normal right after post-transplantation cyclophosphamide (PTCy), is a unique clinical feature in patients undergoing haplo-HSCT. In the current study, the characteristics of haplo-fever and cytokine profiles during haplo-fever were retrospectively analyzed in a cohort of 37 patients undergoing T cell repleted haplo-HSCT with PTCy as graft versus host disease (GvHD) prophylaxis. In total, 33 patients (89.2%) developed haplo-fever from day 0 to day +7. Patients with high peak temperatures tended to have a lower incidence of chronic GvHD (cGvHD) (p = 0.07), moderate to severe cGvHD (p = 0.08), and superior GvHD and relapse-free survival (GRFS, p = 0.04). During the haplo-fever, there were significant increases in multiple cytokines, such as interferon gamma, interleukin (IL) 6, IL2, IL2 receptor, IL8, IL10, IL17, and tumor necrosis factor (TNF). The increases in IL2 receptor (p = 0.037) and TNF (p < 0.001) on day +4 were correlated with the lower risk of cGvHD. Increased TNF > 1.8055-fold on day +4 was the best predictive threshold for cGvHD, and was correlated with a lower incidence of cGvHD (p < 0.001), moderate to severe cGvHD (p = 0.003), and superior GRFS (p < 0.001). These observations may reflect the early reactivation of donor T cells after haplo graft infusion, which would potentially be eliminated by PTCy. Further studies with larger independent cohorts of patients are warranted, to clarify the clinical significance of haplo-fever, and day +4 TNF as a potential biomarker to predict GvHD and GRFS.

Introduction: The chemoresistance mechanism of diffuse large B-cell lymphoma (DLBCL) is still poorly understood, and patient prognosis remains unsatisfactory. This study aimed to investigate drug resistance mechanisms in non-germinal center B-cell-like (non-GCB) DLBCL. Methods: Doxorubicin (DOX)-resistant OCI-Ly3 cells were generated through long-term incubation of cells in a medium with gradually increasing DOX concentrations. The expression levels of genes related to drug metabolism were determined using a functional gene grouping polymerase chain reaction (PCR) array. Drug-resistant proteins were identified using bioinformatics, and molecular association networks were subsequently generated. The association and mechanism of key genes were determined using a dual-luciferase reporter assay System and chromatin immunoprecipitation (ChIP). The expression of drug-resistant genes and target genes was then measured using Western blotting and immunohistochemistry. The correlation between gene expressions was analyzed using Spearman’s rank correlation coefficient. Results: Using the PCR array, MDR1 was identified as the key gene that regulates DOX resistance in OCI-Ly3/DOX-A100, a non-GCB DLBCL cell line. The dual-luciferase reporter assay system demonstrated that MDR1 transcription could be inhibited by PRDM1. ChIP results showed that PRDM1 had the ability to bind to the promoter region (−1,132 to −996) of MDR1. In OCI-Ly3/DOX cells, NF-κB activity and PRDM1 expression decreased with an increase in drug-resistant index, whereas MDR1 expression increased with enhanced drug resistance. Immunohistochemical analysis revealed that relative MDR1 expression was higher than that of PRDM1 in human DLBCL tissue samples. A negative correlation was observed between MDR1 and PRDM1. Conclusion: In non-GCB DLBCL cells, NF-κB downregulates PRDM1 and thereby promotes MDR1 transcription by terminating PRDM1-induced transcriptional inhibition of MDR1. Such a mechanism may explain the reason for disease recurrence in non-GCB DLBCL after R-CHOP or combined CHOP with bortezomib treatment. Our findings may provide a potential therapeutic strategy for reducing drug resistance in patients with DLBCL.

Introduction: The overall outcome of patients with refractory AML (rAML) remains poor. Though allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered as the only curative therapy, it is routinely recommended only for patients after remission with salvage chemotherapy. Objective: In this study, we evaluated the impact of salvage chemotherapy or allo-HSCT on the overall outcome in rAML. Methods: We collected the clinical data of 220 patients from 4 medical centers and performed retrospective analysis of prognosis factors, including salvage chemotherapy, intensity of chemotherapy, and allo-HSCT. Results: A total of 29 patients received allo-HSCT directly without salvage chemotherapy, 26 patients achieved complete remission (CR) or complete remission with incomplete hematological recovery (CRi) after transplantation and 4-year leukemia-free survival (LFS) and overall survival (OS) were 45.0 ± 10.7 and 51.0 ± 10.6%, respectively. Another 191 patients received salvage chemotherapy and 81 (42.2%) achieved CR or CRi. Thirty-four patients among them underwent subsequent allo-HSCT with 4-year LFS and OS of 46.0 ± 8.8 and 46.2 ± 9.0%. The 4-year LFS and OS in 26 patients who failed to obtain CR or CRi but received allo-HSCT with active disease were 32.9 ± 10.0 and 36.9 ± 10.8%, respectively. For patients who received salvage chemotherapy but not allo-HSCT, few of them became long-term survivors. In multivariate analysis, salvage chemotherapy and the intensity of chemotherapy failed to have significant impact on both OS and LFS. Allo-HSCT was the only prognostic factor for improved OS and LFS in multivariate analysis. Conclusions: These results indicate the benefit of allo-HSCT in patients with rAML and direct allo-HSCT without salvage chemotherapy could be treatment option.

Post-transplantation cyclophosphamide (PT-Cy) alone or in combination with other immunosuppressive drugs has emerged as a promising strategy in the setting of allogeneic hematopoietic stem cell transplantation. Improved survival rate was reported in lymphoid malignancies following PT-Cy strategy compared with myeloid disease in non-myeloablative bone marrow transplant setting. Thus, we aimed to evaluate the safety and efficacy of PT-Cy combined with cyclosporine as graft-versus-host disease (GVHD) prophylaxis after myeloablative conditioning and T cell-replete peripheral stem cell transplantation in lymphoid malignancies. This single-arm phase II clinical trial (NCT01435447) involving 31 adult patients was conducted from January 2013 to June 2018. The donor-type neutrophil engraftment rate was 100%, and the overall incidence of grade II to IV and grade III to IV acute GVHD was 39% and 24%, respectively. The cumulative incidence rates of chronic GVHD (35%), including moderate to severe forms (10%), were reduced compared with those of the historical group ( P = 0.03 and P = 0.04, respectively). With a median follow-up of 18 months, the estimated 2-year overall and event-free survival was 64.8% (95% confidence interval: 47.8%–86.7%) and 58.4% (95% CI: 41.9%–81.7%), respectively. The 2-year cumulative incidence rate of relapse was 19.5% (95% CI: 9.0%–35.8%), whereas the non-relapse mortality rate was 21.8% (95% CI: 11.3%–38.1%). These results demonstrated the feasibility of PT-Cy as GVHD prophylaxis in this clinical setting. This strategy could significantly reduce the incidence of chronic GVHD and its moderate to severe forms but not of acute GVHD and results in similar survival outcomes compared with the historical group. A prospective study with additional patients is warranted to confirm the role of PT-Cy in lymphoid malignancy.

The PT-Cy was considered as one of the mainstay protocol for graft verus host disease (GVHD) prophylaxis. Recent study demonstrated that PT-Cy combined with other immunosuppressants could further reduce the incidence of GVHD and improve the GVHD and relapse free survival (GRFS). In this prospective phase II study, we evaluated the effect of a new GVHD prophylaxis consist of PT-Cy combined with tacrolimus and low dose anti-thymoglobulin (ATG). A total of 23 patients were enrolled including 20 patients with acute lymphoblastic leukemia (ALL) and three patients with T cell lymphoma. The median age was 29 years (range, 16~58 years). Patients with HLA-matched related donor (MSD, n=7) received PT-Cy combined with tacrolimus, while patients with HLA matched unrelated (MUD, n = 2) or haplo-identical (Haplo, n = 14) donor received additional ATG at 2.5 mg/kg on day 15 or day 22 after engraftment of neutrophils. As to the acute GVHD (aGVHD), only three patients developed grade I (n = 1) or grade II (n = 2) aGVHD with 100-day incidence of all aGVHD and II-IV aGVHD at 13.0 ± 5.1% and 9.1 ± 6.1% respectively. Only two patients had mild and one had moderate chronic GVHD (cGVHD), with 1-year incidence of cGVHD and moderate/severe cGVHD at 15.2 ± 8.7% and 4.6 ± 4.4% respectively. A high incidence of CMV reactivation was documented (14/16 with MUD/Haplo donor and 2/7 with MSD) with only 1 CMV disease documented. There were two EBV reactivation without post-transplantation lymphoproliferative disease (PTLD) documented. With a median follow-up of 303 days (range, 75~700 days), three patients relapsed leading to 1-year cumulative incidence of relapse (CIR) at 12.8 ± 9.2%. Only one patient died of CMV pneumonia on day 91 with both 100-day and 1-year non-relapse mortality (NRM) at 4.6 ± 4.4%. The 1-year overall survival (OS), event-free survival (EFS) and GRFS were 95.5 ± 4.4%, 82.6 ± 9.5%, and 68.0 ± 11.3% respectively. Based on Simon's stage II design, our primary data showed that the PT-Cy+tacrolimus ± ATG protocol was promising in preventing aGVHD and cGVHD, which may translate into low NRM without increased CIR. Further clinical trial with large number of patients should be warranted. This trial was registered at www.clinicaltrials.gov as #NCT 04118075.

T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m 2 daily for 5 days and repeated every 6–8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3–22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.

Individualized chemotherapy, which is at the forefront of acute myeloid leukemia (AML) treatment, has moderately improved outcomes over the past decade. Monitoring the peripheral blood blast burden during induction by flow cytometry has shown significant value in the evaluation of treatment responses. Our previous study reported the day 5 peripheral blast clearance rate (D5‐PBCR) as an indicator of early treatment response, and D5‐PBCR (+) patients showed poor outcomes. We performed the present phase 2 trial of early intervention in D5‐PBCR (+) patients with homoharringtonine (HHT) introduced in the traditional induction regimen with anthracycline and cytarabine. The primary endpoint was complete remission (CR). This study enrolled 151 patients, 65 patients were D5‐PBCR (+) and 55 patients completed induction with HHT addition. The overall CR rate after one course of induction was 84.4%, with 87.5% and 80.0% for the D5‐PBCR (−) and D5‐PBCR (+) groups, respectively. The incidence of grade 3/4 adverse events was comparable between the two groups. At the median follow‐up of 53.1 months, median overall survival (OS) was not reached in the entire cohort, and median event‐free survival (EFS) was 42.2 months. Neither the OS nor EFS showed significant differences between the D5‐PBCR (−) and D5‐PBCR (+) groups. Compared to historical data, significant improvements in both OS ( p = .020) and EFS ( p = .020) were observed in the D5‐PBCR (+) group. In conclusion, optimization of induction chemotherapy with idarubicin and cytarabine according to D5‐PBCR is feasible in patients with newly diagnosed AML. The addition of HHT demonstrated a good efficacy and safety profile.

Background Arsenic trioxide [ATO, inorganic arsenite (iAs III ) in solution] plays an important role in the treatment of acute promyelocytic leukemia (APL). However, the long-term adverse effects (AEs) and the retention of arsenic among APL patients are rarely reported. In this study, we focused on arsenic methylation metabolism and its relationship with chronic hepatic toxicity, as we previously reported, among APL patients who had finished the treatment of ATO. Methods A total of 112 de novo APL patients who had completed the ATO-containing treatment were enrolled in the study. Arsenic species [iAs III , inorganic arsenate (iAs V ), and their organic metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)] in patients’ plasma, urine, hair and nails were detected by high-performance liquid chromatography combined with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Eighteen single nucleotide polymorphisms (SNPs) of the arsenic (+ 3 oxidative state) methylation transferase ( AS3MT ) gene, which was known as the main catalyzer for arsenic methylation, were tested with the polymerase chain reaction method. Results The study showed the metabolic pattern of arsenic in APL patients undergoing and after the treatment of ATO, in terms of total arsenic (TAs) and four species of arsenic. TAs decreased to normal after 6 months since cessation of ATO. But the arsenic speciation demonstrated significantly higher portion of iAs III in patient’s urine (40.08% vs. 1.94%, P < 0.001), hair (29.25% vs. 13.29%, P = 0.002) and nails (30.21% vs. 13.64%, P = 0.003) than the healthy controls’, indicating a decreased capacity of arsenic methylation metabolism after the treatment of ATO. Urine primary methylation index (PMI) was significantly lower in patients with both chronic liver dysfunction (0.14 vs. 0.28, P = 0.047) and hepatic steatosis (0.19 vs. 0.3, P = 0.027), suggesting that insufficient methylation of arsenic might be related to chronic liver disorders. Two SNPs (A9749G and A27215G) of the AS3MT gene were associated with impaired urine secondary methylation index (SMI). Conclusions The long-term follow-up of arsenic speciation indicated a decreased arsenic methylation metabolism and a probable relationship with chronic hepatic disorders among APL patients after the cessation of ATO. Urine PMI could be a monitoring index for chronic AEs of ATO, and the SNPs of AS3MT gene should be considered when determining the dosage of ATO.