A complete oral regimen for induction therapy of patients with high-risk APL: An oral etoposide instead of intravenous infusion for cytoreductive chemotherapy.

There is an urgent need for an oral, efficient and safe regimen for high-risk APL under the pandemic of COVID-19. We retrospectively analysed 60 high-risk APL patients. For induction therapy (IT), in addition to all-trans retinoic acid (ATRA) and oral arsenic (RIF), 22 patients received oral etoposide (VP16) as cytotoxic chemotherapy (CC), and 38 patients received intravenous CC as historical control group. The median dose of oral VP16 was 1000 mg [interquartile rage (IQR), 650-1250]. One patient died during IT in the control group, 59 evaluable patients (100%) achieved complete haematological remission (CHR) after IT and complete molecular remission (CMR) after consolidation therapy. The median time to CHR and CMR was 36 days (33.8-44) versus 35 days (32-42; p = 0.75) and 3 months (0.8-3.5) versus 3.3 months (2.4-3.7; p = 0.58) in the oral VP16 group and in the control group. Two (9.1%) and 3 (7.9%) patients experienced molecular relapse in different group respectively. The 2-year estimated overall survival and event-free survival were 100% versus 94.7% (p = 0.37) and 90.9% versus 89.5% (p = 0.97) respectively. A completely oral, efficient and safe induction regimen including oral VP16 as cytoreductive chemotherapy combined with ATRA and RIF is more convenient to administer for patients with high-risk APL.

Allogeneic stem cell transplantation is still a highly curative therapy in adults with philadelphia chromosome-positive acute lymphoblastic leukaemia.

The application of tyrosine kinase inhibitors (TKIs) and novel immunotherapies has improved outcomes in patients with Ph + acute lymphoblastic leukaemia (ALL), and the issue of whether there is still a need for stem cell transplantation has become controversial. We performed a retrospective study to explore whether stem cell transplantation still held a place in patients with Ph + ALL if only imatinib and 2nd generation TKIs are available and affordable. A total of 292 patients were included. The median age was 38 years [range 14-64, IQR 28-48]. Patients receiving transplants (n = 216) had better rates of 4-year disease-free survival (DFS, 68% vs. 24%, P < .0001) and overall survival (OS, 72% vs. 47%, P < .0001) than those receiving continuous TKIs plus chemotherapy (TKI-chemo) (n = 76). In the multivariate analysis, male sex, WBC count ≥ 95 × 109/L and PLT count ≤ 154 × 109/L at diagnosis were significantly associated with poorer outcomes, and transplantation was significantly associated with favourable DFS and OS. In addition, the transplant outcomes were superior in any subgroup according to the number of risk variables. Furthermore, propensity score matching (PSM) analyses showed similar findings in the whole cohort and in age- and BCR-ABL1 level-based subgroups after the first or second consolidation. In conclusion, transplantation as a one-time procedure for adults with Ph + ALL patients remains important in countries lacking accessibility to third-generation TKIs or immunotherapies, regardless of the depth of the molecular response.

Comparison of efficacy between homoharringtonine, aclarubicin, cytarabine (HAA) and idarubicin, cytarabine (IA) regimens as induction therapy in patients with de novo core binding factor acute myeloid leukemia.

To compare efficacy between homoharringtonine combined with cytarabine and aclarubicin (HAA) and idarubicin and cytarabine (IA) regimens as first induction chemotherapy in patients with core binding factor acute myeloid leukemia (CBF-AML). Cox regression model and propensity score matching (PSM) were used to identify the regimen associated with a better remission rate and outcomes. In total, 374 patients with CBF-AML (243 with RUNX1::RUXN1T1 and 131 with CBFB::MYH11) were included in this study. The patients received the HAA or IA regimen (187 each) as the first induction therapy. For patients with RUNX1::RUXN1T1, multivariate analyses showed that the HAA regimen was significantly associated with a higher CR/CRi rate after the first induction (hazard ratio [HR] = 5.3 [95% CI 2.3, 12.2]; p < 0.001) and more favorable relapse-free survival (RFS) (HR = 0.5 [0.3, 0.8], p = 0.01). In PSM analysis, the HAA regimen also had a higher CR/CRi rate (96% vs. 77%, p < 0.001), especially for those harboring wild-type KIT (KITWT) (96% vs. 83%, p = 0.02) or non-D816 KIT mutation (100% vs. 63%, p = 0.002), as well as more favorable RFS (p = 0.01), compared with the IA regimen. However, there was no difference in the remission rate or outcomes between the two regimens for patients with CBFB::MYH11. The HAA regimen as first induction chemotherapy resulted in a higher CR/CRi rate in AML patients with RUNX1::RUNX1T1, especially those harboring KITWT and non-D816 KIT mutation, and a more favorable RFS compared with the IA regimen. The efficacy between the two regimens did not differ in those with CBFB::MYH11.

Patients with AML-MRC benefit from decitabine in combination with low-dose G-CSF, cytarabine and aclarubicin: A single center cohort study.

Patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) are insensitive to conventional chemotherapy and, therefore, have a poor prognosis. To evaluate the clinical efficacy and safety of low-dose decitabine in combination with small-dose CAG regimen (D-CAG regimen) in treating AML-MRC, a total of 80 patients with newly diagnosed AML-MRC from September 2015 to January 2020 in our center were included in the study. Amongst these patients, 43 and 37 patients received two courses of the D-CAG and CAG regimens, respectively. The complete remission (CR) and complete remission with incomplete blood count recovery (CRi) rate in the D-CAG group was higher than that of the CAG group (62.2% vs. 48.8%, P = 0.013). Among patients with less than 9 months of myelodysplastic syndrome (MDS) history and poor karyotypes, the (CR+CRi) rate of the D-CAG group was statistically higher than that of the CAG group. Except for patients receiving hematopoietic cell transplantation, among patients with less than 9 months of MDS history, the D-CAG group showed a better probability of overall survival than the CAG group did. In conclusion, patients with AML-MRC may benefit from the D-CAG regimen as an induction therapy, especially patients with less than 9 months of MDS history or with poor karyotypes.

Oral etoposide combined with oral arsenic plus retinoic acid for two cases with newly diagnosed high-risk acute promyelocytic leukemia during COVID19 pandemic.

Acute promyelocytic leukemia (APL) is a highly curable hematology malignancy. The major factor influence prognosis of APL is early deaths (ED) during the course of induction therapy, especially in high-risk APL. Therefore, effective reduction of white blood cells and correction of coagulation abnormalities are the key points of treatment for high-risk APL. Due to COVID19 pandemic in China since Jan 2020, some patients with hematologic malignancies suspected of COVID-19 infection had been isolated and traditional intravenous chemotherapy drugs is not available in isolated wards. We had explored a regimen of an oral etoposide to reduce the tumor burden for high-risk APL and dual induction with retinoic acid (ATRA) and oral arsenic realgar-Indigo nautralis formula (RIF), and finally two cases of high-risk APL patients received complete remission in one month. It is indicated that pure oral induction regimen: oral etoposide, ATRA and RIF provides a novel therapy in outpatient clinics.

PML-RARA transcript levels at the end of induction therapy are associated with prognosis in non-high-risk acute promyelocytic leukaemia with all-trans retinoic acid plus arsenic in front-line therapy: long-term follow-up of a single-centre cohort study.

Despite the high cure probability for acute promyelocytic leukaemia (APL), a minority of patients will relapse and the risk factors for relapse are unclear. We retrospectively analysed 212 patients who were diagnosed with non-high-risk APL and received all-trans retinoic acid (ATRA) plus arsenic as front-line therapy at Peking University Institute of Hematology from February 2014 to December 2018. A total of 176 patients (83%) received oral arsenic (realgar-indigo naturalis formula) plus ATRA, 36 patients (17%) received arsenic trioxide plus ATRA and 203 patients were evaluable for relapse. After a median (range) follow-up of 53·6 (24·3-85·4) months, two patients had molecular relapse and eight had haematological relapse. A promyelocytic leukaemia/retinoic acid receptor alpha (PML-RARA) transcript level of ≥6·5% at the end of induction therapy was associated with relapse (P = 0·031). The 5-year cumulative incidence of relapse, event-free survival and overall survival were 5·5%, 92·3% and 96·3% respectively. In conclusion, the present long-term follow-up study further confirmed the high cure probability of ATRA plus oral arsenic as front-line therapy for non-high-risk APL and showed that the PML-RARA transcript level at the end of induction therapy was associated with relapse.

Interferon-α as maintenance therapy can significantly reduce relapse in patients with favorable-risk acute myeloid leukemia.

To evaluate the efficacy of interferon-α (IFN-α) as maintenance therapy in patients with favorable-risk acute myeloid leukemia (AML), this retrospective study enrolled 84 patients with favorable-risk AML: 42 patients who received IFN-α maintenance therapy and 42 patients who did not (control). The median follow-up time and duration of IFN-α treatment was 26 (6-54) months and 18 (2-24) months, respectively. The 4-year estimated relapse-free survival (RFS) after the last consolidation chemotherapy was 86.8% (95% confidence interval (CI), 75.8-97.8%) in the IFN-α group and 55.7% (95% CI, 37.2-74.3%) in the control group (p=.007). The 4-year estimated overall survival was 94.4% (95% CI, 86.8-102%) and 76.4% (95% CI, 61.9-90.9%) in IFN-α and control groups, respectively (p=.040). The Cox regression analysis showed that IFN-α treatment was the only independent factor affecting RFS (p=.004). Maintenance therapy with IFN-α may prevent relapse in favorable-risk AML after consolidation chemotherapy.

Detection of measurable residual disease may better predict outcomes than mutations based on next-generation sequencing in acute myeloid leukaemia with biallelic mutations of CEBPA.

Acute myeloid leukaemia (AML) patients with biallelic mutations of CEBPA (bi CEBPA) have a 30-50% relapse rate. This study established the value of mutations based on next-generation sequencing (NGS) and multiparameter flow cytometric measurable residual disease (MFC-MRD) detection and compared the outcomes. From 2014 to 2018, 124 newly diagnosed bi CEBPA AML patients were treated. The median age was 37·5 (16-69) years. The 3-year cumulative incidence of relapse (CIR), relapse-free survival (RFS) and overall survival (OS) were 33·0%, 64·7% and 84·3%, respectively. Patients without additional mutations and with GATA2 mutations were defined as 'NGS low risk', which was the only favourable independent factor for CIR and RFS of pretreatment parameters. Patients with sustained positive MRD after two consolidation cycles and MRD negative losses at any time were defined as 'MRD high risk', which was the only poor independent factor for CIR, RFS and OS, including pretreatment and post-treatment parameters. In CR2 and non-remission patients who underwent allo-HSCT, superior OS was achieved. We conclude that NGS low risk was a favourable factor in the analysis of pretreatment parameters. MRD risk stratification was an independent prognostic factor in pretreatment and post-treatment parameters. Relapsed patients still have a favourable outcome followed by allo-HSCT.

Improved survival after offspring donor transplant compared with older aged-matched siblings for older leukaemia patients.

Donor selection for older leukaemia patients undergoing haematopoietic cell transplant (HCT) is not well defined: outcomes might be improved with a younger offspring donor rather than an older human leukocyte antigen (HLA)-matched sibling donor (MSD). We extended our multicentre dataset. A total of 185 acute leukaemia patients (≥ 50 years) transplanted in first complete remission who received HCT from offspring (n = 62) or MSD (n = 123) were included. A 1:1 ratio matched-pair analysis was performed. We were able to match 54 offspring with 54 MSD patients. Outcomes were compared between the two matched-pair groups. The cumulative incidence of grade II/IV acute graft-versus-host disease (GVHD) (26% vs. 35%; P = 0·23) and chronic GVHD (37% vs. 24%; P = 0·19) was comparable between groups (MSD vs. offspring). The lower three-year transplant-related mortality (9% vs. 26%; P = 0·023) and relapse incidence (6% vs. 17%; P = 0·066) resulted in higher overall survival (85% vs. 58%; P = 0·003) and leukaemia-free survival (LFS) (85% vs. 56%; P = 0·001) in offspring HCT compared with that in MSD HCT. These data might favour a young offspring over an older MSD in patients >50 years. The current analyses confirm that non-HLA donor characteristics, such as kinship and donor age, rather than HLA disparity, predominantly influence survival in older acute leukaemia patients.

High frequency of CD4+ CD25- CD69+ T cells is correlated with a low risk of acute graft-versus-host disease in allotransplants.

Regulatory T cells (Tregs) maintain transplantation tolerance and suppress graft-versus-host disease (GvHD) in humans. We monitored 17 subjects with acute GvHD to determine whether Treg frequency correlates with acute GvHD. We found the percent of CD4(+) CD25(-) CD69(+) Tregs decreases when acute GvHD develops and increases after acute GvHD is controlled. We next sequentially studied 50 subjects receiving conventional allotransplants. We show a high frequency and increased numbers of CD4(+) CD25(-) CD69(+) Tregs are associated with a reduced risk of acute GvHD. We also show that CD4(+) CD25(-) CD69(+) Treg numbers increase substantially early after allografts and that a low percent of CD4(+) CD25(-) CD69(+) Tregs is associated with an increased risk of acute GvHD. Reconstitution of Tregs early post-transplant is associated with less acute GvHD. These data imply that CD4(+) CD25(-) CD69(+) Tregs are a novel subset of regulatory T cells that may protect against acute GvHD after allotransplants.

IL-17-producing T cells contribute to acute graft-versus-host disease in patients undergoing unmanipulated blood and marrow transplantation.

The aim of this study was to investigate the effects of IL-17-producing T cells, including Th17 and Tc17 cells, on acute graft-versus-host disease (aGVHD) in patients who had undergone granulocyte colony-stimulating factor (G-CSF)-mobilised peripheral blood progenitor cell (PBPC) and G-CSF-primed bone marrow (G-BM) transplantation. Allografts from forty-one patients were analysed for IL-17-producing T cells with respect to aGVHD. Furthermore, ten patients with aGVHD onset were monitored for the presence of Th17 cells in the peripheral blood by flow cytometry. Patients who received a higher dose of Th17 cells in the G-BM (>8.5 × 10(4) /kg, p=0.005) or a higher dose of Tc17 cells in PBPC (>16.8 × 10(4) /kg, p=0.001) exhibited a higher incidence of aGVHD. An increased Th17 population (up to 4.99% CD4(+) T lymphocytes) was observed in patients with aGVHD onset. In contrast, the percentage of Th17 population decreased drastically in aGVHD patients following treatment to achieve partial and complete remission (p=0.013 and p=0.008, respectively). All percentages of Th17 and Tc17 cells were significantly reduced after in vivo G-CSF application. Our results suggested that IL-17-producing T cells contributed to aGVHD. The application of G-CSF in vivo aided in reducing the occurrence of aGVHD through a decrease in IL-17 secretion by T cells.