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Refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) patients' failure of salvage chemotherapy had extremely worse prognoses. Herein, 14 R/R DLBCL patients failed to salvage chemotherapy were exposed to dual epigenetic agents (Chidamide 30 mg biw*2w and Decitabine 10 mg/m

Dysregulation of EZH2 has a crucial role in lymphomagenesis. We did a first-in-human study to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of SHR2554, an oral EZH2 inhibitor, in patients with relapsed or refractory mature lymphoid neoplasms, including B-cell lymphomas, T-cell lymphomas, and classical Hodgkin lymphoma.This was a multicentre, dose-escalation, dose-expansion, and clinical expansion phase 1 study done at 13 hospitals in China. Eligible patients had histologically or cytologically confirmed mature lymphoid neoplasms that had relapsed or were refractory to standard systemic therapies or had no standard-of-care. The study included a dose-escalation phase, at doses of SHR2554 from 50 mg to 800 mg twice daily; a dose-expansion phase, at two selected doses; and a subsequent clinical expansion phase at the recommended phase 2 dose in selected tumours. Primary endpoints were the safety, maximum tolerated dose, and recommended phase 2 dose. Objective response rate was a secondary endpoint. Safety and activity were assessed in all patients who received at least one dose of SHR2554 and had at least one post-baseline evaluation. This study is registered with ClinicalTrials.gov, NCT03603951, and follow-up is ongoing.Between Aug 14, 2018, and July 13, 2021, 113 patients received SHR2554. At data cutoff (Sept 10, 2021), the median follow-up duration was 7·0 months (IQR 3·7-12·0). 71 (63%) patients were men and 42 (37%) were women, 110 (97%) were of Han ethnicity and 3 (3%) of other ethnicities, and 53 (47%) had received three or more lines of previous anticancer therapies. Dose-limiting toxicities occurred in two (67%) of three patients who received 400 mg SHR2554 twice daily and one (17%) of six patients who received 350 mg SHR2554 twice daily. The maximum tolerated dose and recommended phase 2 dose was determined to be 350 mg twice daily. The most common grade 3 or 4 treatment-related adverse events in all 113 patients were decreased platelet count (20 [18%]), decreased neutrophil count (ten [9%]), decreased white blood cell count (nine [8%]), and anaemia (seven [6%]). 18 (16%) patients had serious treatment-related adverse events. Two patients (2%) died due to treatment-related adverse events: one (1%) due to skin infection and toxic epidermal necrolysis and one (1%) due to respiratory failure. 107 (95%) of the 113 enrolled patients had post-baseline assessments for tumour response and were included in the activity analysis. 46 (43%; 95% CI 33-53) of these 107 patients had an overall response.SHR2554 showed an acceptable safety profile and promising antitumour activity in patients with relapsed or refractory lymphomas, providing evidence for future investigations.Jiangsu Hengrui Pharmaceuticals.For the Chinese translation of the abstract see Supplementary Materials section.

Epstein–Barr virus (EBV) and cytomegalovirus (CMV) reactivations are common complications after allogeneic hematopoietic cell transplantation (allo-HCT), but data focusing on non–Hodgkin lymphoma (NHL) are limited. We retrospectively analyzed the prevalence of EBV and CMV reactivation post-allo-HCT and the impacts on transplant outcomes in 160 NHL patients. The 1-year incidences of EBV and CMV reactivation were 22.58% and 25.55%, respectively. Independent impactors for EBV reactivation were more than 6 lines of chemotherapy (P = 0.030), use of rituximab (P = 0.004), and neutrophil recovery within 30 days post-HCT (P = 0.022). For T-cell lymphoblastic lymphoma patients, the International Prognostic Index (IPI) (P = 0.015) and chronic GVHD (P = 0.001) increased the risk of CMV reactivation. CMV reactivation was independently related to a lower risk of relapse (P = 0.027) but higher transplant-related mortality (TRM) (P = 0.038). Although viral reactivation had no significant impact on overall survival (OS) in the whole cohort, it led to an inferior 2-year OS (67.6% versus 92.5%, P = 0.005) and TRM (20.1% versus 4.7%, P = 0.020) in recipients surviving for more than 180 days. We concluded that EBV and CMV reactivation post-allotransplant still deserved concern particularly in NHL patients with high-risk factors, since it is generally related to a deteriorated prognosis. Large-scale studies are warranted to validate our findings.

BACKGROUND The main aim of this study was to determine some simple but meaningful parameters that indicate immunochemotherapy-related interstitial lung disease (ILD) early in B-cell lymphoma and provide direction to hematologists. METHODS The clinical and laboratory characteristics, the treatments and outcomes of 21 B-cell lymphoma patients with ILD who underwent rituximab (RTX) -based immunochemotherapy were collected and retrospectively analyzed. RESULTS More cycles of immunochemotherapy and higher cumulative doses of RTX and doxorubicin hydrochloride liposome conferred a high risk of ILD. Compared to the baseline, patients had a significantly lower white blood cell count (WBC), absolute lymphocyte count (ALC), and albumin level (4.95×109 vs. 6.32×109, 0.71×109 vs. 1.61×109, 34.1 vs. 40.4 g/L; P

Hepatosplenic γ δ T-cell lymphoma (HSTCL) is a rare subtype of peripheral T-cell lymphoma (PTCL) with aggressive clinical behavior. To date, no standard therapy for HSTCL has been established. This study analyzed the clinical features, treatment, and prognosis for patients with HSTCL to determine the best therapeutic approach. We reviewed the clinical characteristics, treatments, and responses to treatment of patients in our center between January 2001 and June 2021, and also reviewed related literature. Median patient age was 38 years (range 16–60 years) and the patients included eight males and six females. HSTCL in these patients typically presented with B symptoms (71.4%), splenomegaly (100%), and hepatomegaly (50.0%), but lymphadenopathy was extremely rare. In these patients, routine laboratory testing showed elevated lactate dehydrogenase (71.4%), liver dysfunction (42.9%), and decreased fibrinogen (35.7%). In the induction phase, five of the 14 patients received chemotherapy regimens containing anthracycline (CHOP, or CHOP plus bortezomib or Chidamide), and six were treated with non-CHOP chemotherapy. Seven patients responded to induction treatment, four of whom received allogeneic hematopoietic cell transplantation and then achieved a complete response in the consolidation phase. survival time of patients who received alloHCT range from 10 to 27 months. Hepatosplenic γ δ T-cell lacks a standard therapy and is often refractory to conventional chemotherapy regimens. Intensive induction chemotherapy followed by hematopoietic cell transplantation may improve the prognosis of HSTCL.

Background: R/R B-NHL patients with disease progression after CAR-T therapy have poor prognosis and no standard chemotherapy regimen has been defined. We aimed to explore whether receiving allo-HSCT could improve the outcomes of R/R B-NHL patients who have disease progression after CAR-T therapy.Methods: From October 2017 to June 2021, we retrospectively report outcomes of R/R B-NHL patients with disease progression after CAR-T cell treatment, then receiving allo-HSCT. Results: Among 9 patients, 4 were males and 5 females, with a median age of 44 (27-52) years. 5 patients were diagnosed refractory/relapsed diffuse large B cell lymphoma, 1 patient was Burkitt lymphoma, 1 was B lymphoblastic lymphoma, 1 was transformed DLBCL and 1 was gray zone lymphoma. 8/9 donors were haploidentical family member, 1/9 donor was identical sibling. The median time from CAR-T treatment to transplantation was 2.3 (1.0-12.3) months. 9/9 patients obtained complete engraftment. The median time of neutrophil implantation was 12 (11- 19) days, and 13 (9-20) days of platelet implantation. The median follow-up was 7.9 (3.4-48.6) months. 4/9 patients received CR and 1/9 patient received PR during the follow up. The objective response rate (ORR) was 55.6%. The six-months overall survivaln (OS) and progression-free survival (PFS) were 66.7% and 33.3%, respectively. 1 case experienced acute graft-versus-host disease（aGVHD）grade Ⅱ, 1 case with aGVHD grade Ⅲ. Among 5 survivals, localized chronic GVHD occurred in 1 patient. During the follow up, four patients have died and the causes were disease relapses and progressions (2 patients), acute renal failure (1 patient), severe pulmonary infection (1 patient). No-relapse mortality was 22.2%.Conclusion: The present study demonstrated that allo- HSCT is a feasible and safe choice with favorable outcome for R/R B-NHL patients with disease progression after CAR-T therapy.

Epstein–Barr virus (EBV) reactivation after allogeneic hematopoietic cell transplantation (allo-HCT) is one of the major concerns that may lead to fatal EBV diseases. However, updated data are needed because of the remarkable evolution of the HCT protocol and donor selection. We conducted a retrospective study that enrolled 890 allo-HCT recipients. Independent risk factors for EBV reactivation were use of antithymocyte globulin, haploidentical donor, and the presence of chronic graft-versus-host disease. The cumulative incidence of EBV reactivation was 2.9%, 11.7%, 27.3%, and 41.9% for patients with 0, 1, 2, and 3 risk factors, respectively (P

Chimeric antigen receptor T-cell (CAR-T) therapy demonstrates impressive efficacy in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, CAR-T therapy-related severe cytokine release syndrome and neurological toxicity limit its clinical application in R/R DLBCL patients with high tumor burden. Here, we conducted a phase II clinical trial testing the efficacy and toxicities of CAR-T therapy in R/R non-Hodgkin lymphoma patients (NCT03196830). Among the enrolled patients, 10 R/R DLBCL patients with high tumor burden were analyzed. Before CAR-T therapy, 4 were treated with intensive combined chemotherapy (C-CAR-cohort), and 6 were exposed to radiotherapy (R-CAR-cohort). Patients in the R-CAR-T-cohort showed a higher overall response rate (100% vs. 25%, P=0.033) and less severe cytokine release syndrome (0% vs. 100%, P=0.0048) and neurotoxicity (0% vs. 75%, P=0.033) incidences than patients in the C-CAR-T-cohort. Furthermore, one case who responded to CAR-T therapy initially and who suffered a relapse shortly was exposed to radiation and achieved complete remission, with an increase in the number of CAR-T copies detected. This study demonstrates that radiotherapy is an optimal debulking regimen to managing R/R DLBCL patients before CAR-T therapy and a promising alternative salvage therapy for patients who suffer a relapse after CAR-T therapy by fuelling CAR-T copies.

BACKGROUND: Chimeric antigen receptor T cell (CAR-T) therapy has achieved remarkable effects in refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL). However, many patients receiving CAR-T therapy still eventually die of disease recurrence or progression due to target antigen loss or exhaustion of CAR-T cells. Therefore, maintaining the efficacy of CAR-T has become a particular research focus. As lenalidomide can regulate T cell function, we conducted a study to evaluate the efficacy of lenalidomide maintenance after CAR-T therapy in R/R DLBCL patients. METHODS: Seven R/R DLBCL patients who received lenalidomide maintenance after CAR-T therapy and nine DLBCL patients that underwent CAR-T treatment alone were included. The clinical data of all subjects were collected to evaluate the efficacy of lenalidomide maintenance. In order to understand the possible mechanisms of lenalidomide in CAR-T therapy, CAR-T copies of peripheral blood were regularly detected by quantitative real-time polymerase chain reaction, and an in vitro test was also conducted. RESULTS: Overall survival (OS) was significantly prolonged in the lenalidomide maintenance group. Furthermore, one case responding to CAR-T therapy initially but suffering a relapse shortly achieved complete remission again after lenalidomide exposure, with an increase in the number of CAR-T copies detected. The in vitro test showed that lenalidomide could delay the exhaustion of CAR-T cells. CONCLUSIONS: Lenalidomide maintenance after CAR-T therapy is a safe and effective choice for R/R DLBCL patients. We confirmed that lenalidomide maintenance can improve patients’ OS, and the delayed exhaustion of CAR-T cells may contribute to this OS benefit.

To compare the outcomes of antihuman T lymphocyte globulin (ATG-F) and porcine antihuman lymphocyte globulin (p-ALG) as part of a conditioning regimen in hematopoietic stem cell transplantation (HSCT) for severe aplastic anemia (SAA).we performed a retrospective analysis, evaluating the outcome of patients with SAA who received ATG-F based conditioning (The median time to neutrophil engraftment was 11 days (range, 8 - 38) and 11 days (range, 9 - 24) in the p-ALG and ATG-F groups (Patients in the ATG-F group functioned significantly better on role-physical (As part of the conditioning regimen, p-ALG achieved a similar efficacy as ATG-F without increasing the incidence of transplantation complications in SAA patients.

We analyzed the outcomes of 44 patients with paroxysmal nocturnal hemoglobinuria (PNH) who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) (haploidentical [haplo]-donors, 25; matched sibling donors [MSDs], 15; and matched unrelated donors, 4) between July 2007 and May 2018. All patients achieved successful donor engraftment. The median time was 12 days (range, 7 to 26) for myeloid engraftment and 13 days (range, 11 to 75) for platelets. The cumulative incidences were 15.91% and 2.27% for grades II to IV and grades III to IV acute graft-versus-host disease (GVHD), respectively, with a median follow-up time of 36 months (range, 4 to 132). The cumulative incidences were 26.73% for chronic GVHD and 9.70% for moderate to severe chronic GVHD. No patients relapsed. The probabilities of 3-year overall survival (OS) and GVHD-free, failure-free survival (GFFS) were 90.4% ± 4.6% and 85.6% ± 5.4%, respectively. The 3-year OS rates of the haplo-donor and MSD groups were 86.5% ± 7.3% versus 93.3% ± 6.4% (P = .520). The 3-year GFFS rates of the haplo-donor and MSD groups were 78.3% ± 8.6% versus 92.9% ± 6.9% (P = .250). The preliminary results indicated that allo-HSCT is a feasible option for patients with PNH; however, this should not be considered as a first-choice therapy, because the results seemed to only suggest rather than confirm that haplo-HSCT and MSD-HSCT exerted similar therapeutic efficacies.

The aim of this study is to determine whether the modified BuCy (semustine, cytarabine, busulfan, and cyclophosphamide, mBuCy) conditioning regimen can be safely used as an alternative to the SEAM (semustine, etoposide, cytarabine, and melphalan) regimen by comparing the efficacy and toxicity of the mBuCy and SEAM regimens. We matched 34 pairs of patients with regard to disease status at the time of autologous stem cell transplantation (auto-SCT). We found no significant difference in the time of platelet engraftment between the two groups. Furthermore, neutrophil engraftment was somewhat faster in the mBuCy group than in the SEAM group (median: 9 days vs 10 days, p = 0.015). With regard to toxicity, the incidence of nausea/vomiting, hepatic impairment, renal impairment, pulmonary infection, and treatment-related mortality (TRM) was similar between the two groups. In addition, compared to patients conditioned with SEAM, patients conditioned with mBuCy were less likely to develop mucositis and diarrhea (p = 0.027; p = 0.050). The 2-year progression-free survival (PFS) rates in the mBuCy and SEAM groups were 79% and 70% (p = 0.378), respectively, and the 2-year overall survival (OS) rates were 81% and 78.0%, respectively (p = 0.789). These analyses showed that the mBuCy conditioning regimen was well tolerated and can be used as an alternative to the SEAM regimen for lymphoma.

7525 Background: Dysregulation of histone methyltransferase EZH2 plays critical roles in lymphomagenesis. Emerging evidence shows that EZH2 also contributes to tumor immune evasion. SHR2554 is an oral, small-molecule inhibitor exhibiting potent selectivity for EZH2. We initiated a first-in-human study to assess SHR2554 across a broad spectrum of lymphoid neoplasms that had relapsed or was refractory to standard systemic therapies, including B-cell lymphomas, T-cell lymphomas, and classical Hodgkin lymphoma (cHL). Methods: This multicenter, phase 1 study was composed of 3 parts: dose escalation phase according to mTPI-2 design, dose expansion phase, and clinical expansion phase in selected tumor subtypes. Dose was escalated at 50, 100, 200, and 400 mg BID, and then de-escalated at 300 and 350 mg based on the observed toxicities. Two dose levels (300 and 350 mg) were expanded. Subsequently, follicular lymphoma (FL), peripheral T-cell lymphoma (PTCL), and cHL were selected for clinical expansion at RP2D. Primary endpoints were to assess the safety and determine the MTD and RP2D. Key secondary endpoint included clinical activity at RP2D in different subtypes. Results: As of Sep 10, 2021, 113 heavily pretreated pts were enrolled, with 53 (46.9%) having received ≥3 lines of prior systemic therapies. In dose escalation phase, DLTs occurred in 2 of 3 pts at 400 mg and 1 of 6 pts at 350 mg; thus, 350 mg BID was the MTD. Combined with the safety, tolerability, PK/PD, and preliminary efficacy findings observed in dose escalation and expansion phases, RP2D was determined to be 350 mg BID. As of cutoff date, 41 FL, 22 PTCL, and 21 cHL pts who received SHR2445 at 350 mg BID completed at least one post-baseline efficacy assessment. ORR in FL was 58.5% (95% CI 42.1-73.7); majority of responses (66.7%) were still ongoing, and the estimated median DoR was 9.3 mos (95% CI 5.6-NR). EZH2mut FL pts showed a slightly higher ORR than EZH2WT FL pts (62.5% vs 55.2%). EZH2 mutations were not detected in pts with PTCL or cHL. ORR in PTCL was 63.6% (95% CI 40.7-82.8); majority of responses (71.4%) were still ongoing, and the estimated median DoR was 7.4 mos (95% CI 2.9-NR). All cHL pts had received prior chemotherapy and anti-PD-1/PD-L1 antibodies. Shrinkage in target lesions was shown in 76.2% of cHL pts; ORR was 19.0% (95% CI 5.4-41.9); majority of responses (75.0%) were still ongoing, and the median DoR had not been reached yet. Grade ≥3 treatment-related AEs occurred in 38 of the 113 pts (33.6%), with the most common being decreased platelet count (17.7%), decreased neutrophil count (8.8%), decreased white blood cell count (8.0%), and anemia (6.2%). Conclusions: SHR2554 showed a manageable safety profile and promising anti-tumor activity in pts with r/r lymphomas, supporting further explorations in FL, PTCL, and cHL. Clinical trial information: NCT03603951.

7547 Background: Despite impressive clinical response of covalent Bruton’s tyrosine kinase (BTK) inhibitors in multiple B cell malignancies, treatment failure often occurs through drug resistance most commonly due to BTK cysteine-481 (C481) mutation or intolerance due to off-target toxicities. We evaluated the safety, pharmacokinetics (PK) and preliminary antitumor efficacy of MH048, an orally bioavailable, potent, and reversible inhibitor of both wild type and C481S-mutant BTK, in selected patients with relapsed or refractory (R/R) B-cell malignancies. Methods: Eligible patients with R/R B-cell malignancies were enrolled in a Phase 1, multicenter, open-label, dose escalation study. The primary objectives were to assess the safety and tolerability of MH048, and to determine the maximal tolerated dose (MTD) and the recommended dose for expansion. The secondary objectives were to assess the PK profile and preliminary evidence of anti-tumor activity. Results: Twelve patients were treated with MH048 across six dose levels (5 mg, 15 mg, 45 mg, 90 mg, 135 mg, 200 mg QD) in fast state. No dose-limiting toxicities were observed and the MTD was not reached. The most common drug-related TEAEs (Any grade) that occurred in > 2 patients were platelet count decrease (n=5), anemia (n=4), neutrophil count decrease (n=4), lipase increase (n=3), and white blood cell count decrease (n=3). Drug-related grade 3 TEAEs included platelet count decrease, neutrophil count decrease, lipase increase, and hypertension (one patient for each). Plasma exposure of MH048 and its active metabolite (M3) increased in a dose-proportional manner from 5 to 200 mg dose levels. Sign of efficacy was observed starting from 15 mg. Among eleven efficacy-evaluable patients (one patient in 200 mg cohort is yet to be evaluated), one complete response (CR) and four partial responses (PRs) were achieved in ≥90 mg cohorts, including patients with MZL (n=1, CR), MCL (n=2), SLL (n=1) and DLBCL (n=1). Of the two MCL patients with PRs, one was heavily pretreated including ibrutinib prior to the enrollment. The recommended doses for expansion were selected as 135 and 200 mg. Conclusions: MH048 was well-tolerated and efficacy in heavily pre-treated patients with B-cell malignancies was observed. Pharmacokinetics studies suggest once-daily dosing. The dose expansion study is ongoing at 135 and 200 mg QD for CLL and MCL patients. Clinical trial information: NCT04689308.

We retrospectively compared the outcomes and health-related quality of life (HRQoL) of severe aplastic anemia (SAA) patients who received haploidentical hematopoietic stem cell transplantation with a single unrelated cord blood unit (Haplo-cord HSCT) (n = 180) or matched related donor (MRD)-HSCT (n = 128). After propensity score matching, we were able to match 88 patients in each group and to compare the outcomes between the two matched-pair groups. Haplo-cord recipients exhibited a longer median days for neutrophil engraftment (12 vs 11, P = 0.001) and for platelet engraftment (15 vs 13, P = 0.003). Haplo-cord recipients a high cumulative incidence of grades II–IV acute graft-versus-host disease (GVHD) (29.8 vs 14.0%, P = 0.006), while similar III–IV acute GVHD, total chronic GVHD, and moderate to severe chronic GVHD at four-year (all P < 0.05). Among the Haplo-cord HSCT and MRD-HSCT groups, the four-year GVHD-free/failure-free survival rates were 73.5% and 66.9% (P = 0.388) respectively, and the overall survival rates were 81.5% and 77.2% (P = 0.484), respectively. Similar comparable results also were observed between the corresponding first-line, older or younger than 40 years old subgroups. The Haplo-cord HSCT group exhibited higher scores in the physical component summary, physical functioning, general health and social functioning than the MRD-HSCT group (all P < 0.05). In the multivariate analysis, young age and Haplo-cord HSCT were favorable factors for HRQoL, while moderate to severe cGVHD was associated with lower HRQoL. These results suggest that for SAA patients, Haplo-cord HSCT could achieve at least comparable efficacy and HRQoL to MRD-HSCT.

We analyzed the outcomes of 14 patients with severe aplastic anemia (SAA) who received first-line double-unit cord blood transplantation (dUCBT). Patients’ median age was 24.5 years (range, 10-44 years). The median numbers of infused nucleated and CD34+ cells were 5.48 × 107/kg (range, 3.33-7.96 × 107/kg) and 2.30 × 105/kg (range, 0.86-3.97 × 105/kg), respectively. One patient died 5 days after transplantation. Three of the 13 patients acquired autologous myeloid recovery. Neutrophil engraftment was observed in 10 patients (76.29%), and the median time of neutrophil recovery was 19 days (range, 15-40 days). Platelet engraftment was observed in 7 cases (53.8%), and 3 patients experienced platelet graft failure. The median time of platelet recovery was 32 days (range, 22-80 days). The cumulative incidence of grade II-IV acute graft-vs-host disease (GVHD) was 38.5%. One patient demonstrated mild chronic GVHD. After a median follow-up of 61 months (range, 18-102 months), 6 patients were alive. The predicted 5-year overall survival and GVHD-free, failure-free survival rates were 42.9% ± 13.2% and 14.3% ± 9.4%, respectively. The first-line dUCBT for SAA is still primarily evaluated through multicenter prospective clinical trials by an optimal conditioning regimen, cell dose, and other graft and transplantation-related factors.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) and T-lymphoid/myeloid mixed phenotype acute leukemia (T/M-MPAL) are closely related entities and remain a therapeutic challenge. In this study, we characterized the clinical features of 43 ETP-ALL and 41 T/M-MPAL patients and compared clinical outcomes and safety between cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CAG)-like regimens in 34 patients and conventional ALL regimens in 50 patients. In our series, ETP-ALL and T/M-MPAL showed similar biological characteristics, immunophenotypes, genomic alterations, and outcomes. The complete remission (CR) rate and minimal residual disease (MRD)-negative CR rate of CAG-like regimens were significantly higher compared with conventional ALL regimens (CAG-like: 80.0% and 59.7%, respectively; P = .039; ALL: 51.4% and 31.3%, respectively; P = .048). Overall, 90.0% of cases (18/20) achieved CR using combined decitabine and CAG-like regimens. Additionally, CAG-like regimens had lower rates of grade 3 or 4 infection (18.8% vs. 38.2%; P = .059) and grade 1 or 2 hepatotoxicity (37.5% vs. 60.0%; P = .043) than conventional ALL regimens. The 38 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the first CR (CR1) had better overall survival (OS) and leukemia-free survival (LFS) than the 11 patients who underwent allo-HSCT in the second CR (CR2) or in no remission (median OS not reached vs. 7.6 months, P = .0004; median LFS not reached vs. 11.6 months, P = .0008). There was a significant difference in 3-year OS (95.7% vs. 52.5%; P = .0039) and LFS (95.8% vs. 43.5%; P = .0003) after allo-HSCT between pre-transplant MRD-negative and MRD-positive patients. The median OS for patients without allo-HSCT was 32.1 months in the CAG-like group compared with 12.1 months in the non-CAG-like group (P = .019). These findings suggest that ETP-ALL and T/M-MPAL possess overlapping characteristics and CAG-like regimens improve their clinical outcomes.

We retrospectively analyzed the outcomes of 214 patients with severe aplastic anemia (SAA) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with rabbit anti-thymocyte globulin (r-ATG) or ATG-Fresenius (ATG-F). Using propensity score matching, we performed a case-control study comparing 44 and 23 patients in the r-ATG and ATG-F groups, respectively. The median time was 11 versus 11 days (P = .368) for myeloid engraftment and 11 versus 13 days (P = .030) for platelet engraftment in the r-ATG and ATG-F groups, respectively. The r-ATG group showed a lower incidence of grade III to IV acute graft-versus-host disease (GVHD) than the ATG-F group (2.27% versus 17.39%, P = .026). Similar outcomes were observed between the r-ATG and ATG-F groups for infection rate (59.09% versus 56.52%, P = .840), grade II to IV acute GVHD (20.45% versus 21.74%, P = .948), overall incidence of chronic GVHD (26.83% versus 22.73%, P = .704), moderate to severe chronic GVHD (9.76% versus 13.64%, P = .648), and transplantation-related mortality (11.36% versus 4.35%, P = .614). There was no statistical difference in 5-year overall survival (86.40% versus 95.7%, P = .245); GVHD-free, failure-free survival (77.30% versus 78.30%, P = .986); or health-related quality of life (P > .05) between r-ATG and ATG-F.

Rituximab in combination with chemotherapy has shown efficacy in patients with diffuse large B-cell lymphoma (DLBCL) for more than 15 years. HLX01 was developed as the rituximab biosimilar following a stepwise approach to demonstrate biosimilarity in analytical, pre-clinical, and clinical investigations to reference rituximab. With demonstrated pharmacokinetic similarity, a phase 3 multi-center, randomized, parallel, double-blind study (HLX01-NHL03) was subsequently conducted to compare efficacy and safety between HLX01 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (H-CHOP) and reference rituximab plus CHOP (R-CHOP) in a total of 407 treatment-naïve, CD20-positive DLBCL patients aged 18–80 years. The primary efficacy endpoint was best overall response rate (ORR) within six cycles of treatment in the per-protocol set (PPS). Secondary endpoints included 1-year efficacy outcomes, safety, and immunogenicity profile. The results showed difference in ORRs [H-CHOP 94.1%; R-CHOP 92.8%] between two treatment groups was 1.4% (95% confidence interval [CI], − 3.59 to 6.32, p = 0.608) which falls within the pre-defined equivalence margin of ± 12%. The safety profile was comparable between the treatment groups, with a similar overall incidence of treatment-emergent adverse events (H-CHOP 99.5%, R-CHOP 99.0%, p = 1.000) and serious adverse events (H-CHOP 34.0%, R-CHOP 32.5%, p = 0.752). This study established bioequivalence in efficacy and safety between HLX01 and reference rituximab. The trial was registered at http://www.chinadrugtrials.org.cn on 26 August 2015 [#CTR20150583].

Background: Blood-based biomarker such as circulating tumor DNA (ctDNA) has emerged as a promising tool for assessment of response to immunotherapy in solid tumors; But in hematological malignances, evidences are still lacking to support its clinical utility. In current study the feasibility of ctDNA for prediction and monitoring of response to anti-PD-1 therapy in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r cHL) was assessed. Methods: A total of 192 plasma samples from 75 patients with r/r cHL were collected at baseline and upon therapeutic evaluation. ctDNA were sequenced by targeting panels capturing frequently mutated genes in cHL and other hematological malignancies and then quantified. Analysis on: 1) Gene mutation profile and association of the gene mutations with progression-free survival; 2) Association of pre- and post-treatment ctDNA variant allelic frequencies with clinical outcome; (3) Correlation of the mutated genes with treatment resistance; were performed. Findings: Somatic mutations were detected in 50 out of 61 patients by ctDNA genotyping. The mutations of CHD8 was significantly higher in patients with PFS ≥ 12 months. Baseline ctDNA was significantly higher in responders and a decrease of ctDNA ≥ 40% from baseline indicated superior clinical outcome. Strong agreement between ctDNA dynamic and radiographic response change during therapy was observed in majority of the patients. Furthermore, the mutations of B2M, TNFRSF14 and KDM2B were found to be associated with acquired resistance. Interpretation: ctDNA could be an informative biomarker for anti-PD-1 immunotherapy in r/r cHL. Funding: This work was supported by Innovent Biologics, Eli Lilly and Companyhttps://doi.org/10.13039/501100002852, China National New Drug Innovation Program (2014ZX09201041-001 and 2017ZX09304015), Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001) and National Key Scientific Program Precision Medicine Research Fund of China (2017YFC0909801). The funders had no role in study design, data collection, data analysis, interpretation or writing. Keywords: Circulating tumor DNA, Immunotherapy, anti-PD-1, Biomarker, Classical hodgkin lymphoma, Sintilimab

Primary testicular lymphoma (PTL) is quite rare. Immunohistochemical analyses show that the majority of cases are diffuse large B-cell lymphoma accounting for about 1–7% of all testicular malignanc...

Background: CD19 chimeric antigen receptor T (CAR-T) cells therapy has shown great success in B-cell acute lymphoblastic leukemia (B-ALL). To reduce the possibility of relapse due to CD19 antigen loss, sequential CD19/CD22 and tandem CD19/CD22 dual targets CAR-T cells have been developed. However, the optimal combination strategy of target antigens for CAR-T cells is still uncertain. This study was designed to compare the efficacy and safety of single CD19, tandem CD19/CD22 and sequential CD19/CD22 CAR-T cells therapies in relapsed/refractory(R/R) B-ALL patients. Methods: Between March 2016 and August 2020, a total of 200 patients with R/R B-ALL successfully received 230 CAR-T treatments (30 patients received the second CAR-T therapy and 8 patients received the third CAR-T therapy) were screened in this study. Among them, 168 patients received single CD19 CAR-T therapy, 49 patients received tandem CD19/CD22 CAR-T therapy, and 13 patients received sequential CD19/CD22 CAR-T therapy. ALL patients enrolled in the CD19 CAR-T clinical trials (NCT03919240) or CD19/CD22 CAR-T clinical trials (NCT03614858). Results: The baseline characteristics of patients were similar among the three groups. The complete remission (CR) rates were 82.7% (139/168) in patients who received CD19 CAR-T therapy, 95.9% (47/49) in patients who received tandem CD19/CD22 CAR-T therapy, and 69.2% (9/13) in patients who received sequential CD19/CD22 CAR-T therapy (P=0.012). Tandem CD19/CD22 CAR-T therapy remained one of the significant favorable factors in multivariate logistic regression analysis of CR rate in all patients (hazard ratio, 0.081; 95% CI, 0.010-0.671). Furthermore, minimal residual disease (MRD)-negative CR rates were 66.7%, 81.6% and 61.5%, respectively (P=0.092). There was no significant difference in the incidence of adverse events among the three groups. Severe cytokine release syndrome (CRS, Grade ≥ 3) occurred in 25.0% of patients in CD19 group, 18.4% of patients in tandem CD19/CD22 group, and 23.1% in sequential CD19/CD22 group (P=0.641). There was no significant difference in overall survival (OS) and leukemia-free survival (LFS) among three groups (6-month OS: 83.1%, 90.0% and 88.9%, respectively, P=0.1620; 6-month LFS: 76.2%, 76.2% and 88.9%, respectively, P=0.8179). Univariate and multivariate Cox regression analyses showed that a better LFS related to less frequencies of relapse, lower tumor burden, MRD-negative CR and bridging allogeneic hematopoietic stem cell transplantation (allo-HSCT). Conclusions: Tandem CD19/CD22 dual targets CAR-T cells therapy obtains superior CR rate than single CD19 and sequential CD19/CD22 CAR-T cells therapy. This provides an effective treatment option for R/R B-ALL patients with chemotherapy resistance. Disclosures No relevant conflicts of interest to declare.

To investigate the effect of haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the outcome of 58 patients with Ph+ ALL who received Haplo-HCT (n=42) or matched unrelated donor transplantation (MUD-HCT) (n=16) during the same period were analyzed retrospectively. All patients received a tyrosine kinase inhibitor (TKI)-based regimen before transplantation, and TKI was resumed primarily after transplantation. At the 3-year follow-up, the overall survival (OS), leukemia-free survival (LFS), the cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) rates in Haplo-HCT group were 69.1, 64.3, 19.0, and 14.3%, respectively, without significant differences from that of MUD-HCT. Haplo-HCT was not related to higher incidences of severe acute graft-versus-host disease (GvHD) (17.6±5.2% vs. 20.0±10.0%, P=0.603) or chronic GvHD (19.5±7.1% vs. 13.3±8.6%, P=0.637) as compared to MUD-HCT. Multivariate analysis showed that chronic GvHD was associated with lower relapse rate in Haplo-HCT group. Haplo-HCT is a promising choice for improving the long-term survival in Ph+ ALL patients.

Peripheral T cell lymphomas (PTCLs) often carry poor outcomes with conventional chemotherapy, and hematopoietic cell transplantation (HCT) can benefit patients with PTCL. We conducted a retrospective review of 67 patients with PTCL who underwent autologous HCT (autoHCT, n = 43; median age, 40 years) or allogeneic HCT (alloHCT, n = 24; median age, 36.5 years) from 2004 to 2016. With a median follow-up of 27 months, 5-year progression-free survival (PFS) and overall survival (OS) of autoHCT patients were 49% and 57%, respectively. Among alloHCT recipients, the 5-year PFS and OS were 54% and 55%, respectively. When considering incidence of disease relapse or progression (CIR) and nonrelapse mortality (NRM), the 5-year CIR and 1-year NRM of alloHCT recipients were 38% and 18%, respectively, and 58% and 7% for autoHCT patients, respectively. There were no differences between autoHCT and alloHCT in 5-year PFS (P = .499), OS (P = .566), CIR (P = .555), and NRM (P = .202). When specifically examining recipients in primary refractory disease, 3-year PFS rates of autoHCT and alloHCT were 20% and 49% (P = .054); 3-year OS rates were 20% and 53% (P = .042), respectively. Based on these results, we favor proceeding to alloHCT in patients with PTCL in primary refractory disease.

BACKGROUND: Autologous stem cell transplantation (ASCT) is the standard treatment for refractory/relapsed B cell non-Hodgkin’s lymphoma (R/R B-NHL), whereas chimeric antigen receptor T (CAR-T) therapy targeting CD19 is emerging as an alternative strategy. Here, we report a comparative analysis of the 2 strategies in a single center. METHODS: We performed a prospective, single-arm study of CAR-T therapy in 29 patients with R/R B-NHL and compared the outcomes with 27 contemporaneous patients who received ASCT. NHL was diagnosed by histopathologic assessments, and the safety and efficacy of treatments were compared. RESULTS: The CAR-T group exhibited better rates of complete response (CR) (48.0% vs. 20.8%, P = 0.046) and 1-year overall survival (OS) (74.4% vs. 44.5%, P = 0.044) compared with the ASCT group. Subpopulation analysis showed that patients with International Prognostic Index scores of at least 3 achieved a significantly higher objective response rate and CR rate in the CAR-T group than in the ASCT group (ORR 72.0% vs. 10.0%, P = 0.002, and CR 38.9% vs. 0%, P = 0.030, respectively). The most common severe adverse events in the CAR-T group were cytokine release syndrome, neurotoxicity, and infection compared with cytopenia, gastrointestinal toxicity, and infection in the ASCT group. Additionally, the incidence of nonhematologic severe adverse events was markedly lower in the CAR-T group than in the ASCT group (20.7% vs. 48.1%, P = 0.030). CONCLUSION: CAR-T therapy exhibited superior clinical outcomes in safety and efficacy over ASCT in patients with R/R B-NHL, suggesting that CAR-T may be a recommended alternative to ASCT. TRIAL REGISTRATION: ClinicalTrials.gov NCT03196830. FUNDING: Funding was supplied by UniCar Therapy, National Natural Science Foundation of China (81730003), National Science and Technology Major Project (2017ZX09304021), and Science Planning Project of Suzhou (sys2018049).

We analyzed the outcomes of 146 severe aplastic anemia (SAA) patients who received a combination of haploidentical haematopoietic stem cell transplantation (haplo-HSCT) and an unrelated cord-blood (UCB) unit between September 2011 and December 2017. One hundred and seventeen patients underwent transplantation as first-line therapy. Seven patients experienced early mortality, and among the evaluable 139 patients, one patient experienced primary graft failure (GF), while the other 138 patients achieved successful haploidentical donor engraftment; additionally, three patients experienced secondary GF. Six patients demonstrated delayed platelet recovery, and three patients demonstrated platelet GF. The median time for myeloid and platelet engraftment was 11 (range: 9–28) days and 15 (range: 9–330) days, respectively. With a median follow-up of 40 (range: 18–93) months, the cumulative incidences were 31.43% and 10.00% for grades II–IV and grades III–IV acute graft-versus-host disease (GVHD), respectively. The cumulative incidences of chronic GVHD (cGVHD) and moderate–severe cGVHD were 36.23% and 11.71%, respectively. There was no patient relapse. The probabilities of 4-year overall survival and GVHD-free, failure-free survival were 81.4 ± 3.3% and 69.2 ± 3.9%, respectively. These encouraging preliminary results indicated that haplo-HSCT combined with the infusion of UCB is a feasible choice for SAA patients without matched donors.