Cycles Of Consolidation Chemotherapy Research Articles

Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults

BackgroundMany older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)–negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission.MethodsIn a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point.ResultsThe data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P=0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group.ConclusionsThe addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.)

Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial.

This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs). A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.

Measurable residual disease testing by next generation sequencing is more accurate compared with multiparameter flow cytometry in adults with B-cell acute lymphoblastic leukemia

Results of measurable residual disease (MRD)-testing by next-generation sequencing (NGS) correlate with relapse risk in adults with B-cell acute lymphoblastic leukemia (ALL) receiving chemotherapy or an allotransplant from a human leukocyte antigen (HLA)-identical relative or HLA-matched unrelated donor. We studied cumulative incidence of relapse (CIR) and survival prediction accuracy using a NGS-based MRD-assay targeting immunoglobulin genes after 2 courses of consolidation chemotherapy cycles in 93 adults with B-cell ALL most receiving HLA-haplotype-matched related transplants. Prediction accuracy was compared with MRD-testing using multi-parameter flow cytometry (MPFC). NGS-based MRD-testing detected residual leukemia in 28 of 65 subjects with a negative MPFC-based MRD-test. In Cox regression multi-variable analyses subjects with a positive NGS-based MRD-test had a higher 3-year CIR (Hazard Ratio [HR] = 3.37; 95 % Confidence Interval [CI], 1.34–8.5; P = 0.01) and worse survival (HR = 4.87 [1.53–15.53]; P = 0.007). Some data suggest a lower CIR and better survival in NGS-MRD-test-positive transplant recipients but allocation to transplant was not random. Our data indicate MRD-testing by NGS is more accurate compared with testing by MPFC in adults with B-cell ALL in predicting CIR and survival. (Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR–OCH–10000940 and ChiCTROPC-14005546]).

Effect of venetoclax plus chemotherapy on treatment-naive acute myeloid leukemia patients with moderate to poor cytogenetic profiles and the combination's influence on the expression of proteins of the anti-apoptoic family

Objective: This was an open-label observational assessment aimed to evaluate whether venetoclax (VEN) plus chemotherapy could enhance the therapeutic benefits for treatment-naive acute myeloid leukemia (AML) patients with adverse cytogenetic profiles. Methods: A total of 38 adult patients (including 11 patients with moderate risk stratification and 27 patients with high risk stratification) who were treated at the Affiliated Hospital of Inner Mongolia Medical University from April 2019 to May 2022 were enrolled in this study. Patients were randomized into two cohorts according to the random number method to receive single intensive chemotherapy (18/38) alone or VEN+intensive chemotherapy (20/38), respectively. The chemotherapy cohort received 2 cycles of induction chemotherapy (idarbicin or daunorubicin plus cytarabine), followed by 6 cycles of consolidation chemotherapy (cytarabine), while the treatment for the VEN + chemotherapy cohort consisted of the same chemotherapy as above plus oral VEN. Heparinized bone marrow samples were obtained from patients at enrollment de novo and post chemotherapy. The expressions of MCL-1 and BCL-2 were detected by Western blot analysis. Results: Patients with VEN+chemotherapy showed an objective response rate (ORR) of 90.0% (18/20), compared with 55.6% (10/18, P=0.012) of the chemotherapy group. Meanwhile, the VEN + chemotherapy cohort gained more benefits in progression-free survival (PFS) and overall survival (OS) than the chemotherapy cohort (mean PFS: 27.1 months versus 17.9 months, P=0.038; mean OS: 32.2 months versus 21.3 months, P=0.004). For patients with moderate risk stratification, there were no differences in the ORR and PFS between the chemotherapy cohort and the VEN + chemotherapy cohort: the ORR was 80.0% (4/5) versus 100% (6/6, P=0.251), and the PFS was 27.9 months versus 32.0 months (P=0.582). Moreover, the ORR was 85.7% (12/14) for the VEN+chemotherapy cohort and 46.2% (6/13) for the chemotherapy cohort in the high risk profile (P=0.029). The PFS of the VEN+chemotherapy cohort was superior to the chemotherapy cohort in the high risk profile (mean PFS: 23.7 months versus 11.1 months, P=0.002). Meanwhile, in the chemotherapy cohort, there were no difference in the PFS between FAB-M5 patients and non-FAB-M5 patients; the mean PFS was 20.0 months versus 15.5 months (P=0.298) for the two groups. Nevertheless, FAB-M5 patients were inferior to non-FAB-M5 patients in PFS in the VEN + chemotherapy arm (mean PFS: 19.6 months versus 30.2 months, P=0.031). The most frequent grade 4 hematological toxicities (therapy related) were leukopenia and thrombopenia. Grade 3/4 hematological adverse events in patients treated with VEN+chemotherapy were not increased compared with those who received chemotherapy. Western blot showed VEN continuously decreased the expression of BCL-2 proteins in both FAB-M5 and non-FAB-M5 patients, but obviously increased the expression of MCL-1 proteins only in FAB-M5 patients. Conclusions: VEN combined with intensive chemotherapy have yielded high ORR and survival advantages for de novo AML patients with poor cytogenetics profiles. The high-expression of MCL-1 may drive resistance to VEN.

Role of Allogeneic Stem Cell Transplantation in Preventing Relapse in Adult BCR::ABL1-like Acute Lymphoblastic Leukemia

Background Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by the activation of several kinase pathways that promote treatment resistance leading to poor survival of patients at all ages. Despite the use of tyrosine kinase inhibitors in the Ph-like ABL-class subtype (15% Ph-like ALL), there is not a consensus approach for treatment of most patients (JAK-class especially), and the role of allogeneic stem cell transplantation (alloSCT) has scarcely been explored so far (i.e., mandatory vs. MRD-oriented). Objective To assess the outcome of Ph-like patients enrolled in the ongoing ALL19 trial from the Programa Español de Tratamientos en Hematología (PETHEMA) for adults (18-60y) with Ph-negative ALL, and to evaluate the effectiveness of alloSCT in first complete remission (CR). Methods In the ALL19 trial, patients are allocated to alloSCT according both to the end of induction (EOI) measurable residual disease (MRD) level and to high-risk genetic markers such as low-hypodiploidy, KMT2A rearrangement, TP53 biallelic alteration and concomitant deletion of IKZF1 and CDKN2A/B. Therefore, BCR::ABL1-like subtype was not a criteria for early transplantation unless meeting either poor MRD clearance at EOI or concomitant deletion of IKZF1+CDKN2A/B. Patients with MRD≥0.01% on day+35 (EOI) and/or high-risk genetics were assigned to early alloSCT (preceded by 1 cycle of consolidation chemotherapy) while those with good MRD clearance and standard risk genetics received early and delayed consolidation (3 cycles each) and maintenance therapy. Bone marrow or peripheral blood samples were analyzed by G-banding+FISH, SNP array (750K Affymetrix, Thermo Fisher) and next generation sequencing (NGS, with a custom DNA gene panel, Illumina) at diagnosis in 4 reference laboratories. MRD was centrally assessed by next generation flow cytometry with a sensitivity up to 2x10 -6. Results Twenty-four Ph-like out of 248 adult BCP ALL (10%) were detected. Baseline characteristics were similar between Ph-like and the remaining BCP-ALL. Most Ph-like ALL patients showed the JAK-class profile (20/24 [83%]: 17/24 CRLF2 rearrangement[r], 1/24 JAK2r, 1 BLNK::DNTT and 1 JAK2 R683 mutation), 3/24 belonged to the ABL-class subtype (2 ABL2r, 1 NUP214::ABL1) and 1 patient was identified by RNAseq (gene expression profiling similar to BCR::ABL1 ALL) without identifying any rearrangement. Regarding secondary genetic alterations, 17/24 (71%) patients showed the IKZF1 plus profile, 10/23 (43%) harbored JAK2 R683 mutation, 4/23 N/KRAS mutations, 2/23 CRLF2 mutation and 1/23 showed mutations in several genes such as IKZF1, NR3C1 or FLT3, among others. There were no significant differences in the probability of achieving CR between Ph-like and the remaining BCP ALL (15/20 [75%] vs. 137/162 [85%], p=0.334). However, EOI MRD level of Ph-like individuals was significantly poorer (MRD&amp;lt;0.01% Ph-like 4/15 [27%] vs. other BCP-ALL 85/136 [63%], p=0.007). By intention to treat, most Ph-like patients (17/19, 89%) were allocated to alloSCT (vs. 91/153 [59%] in the other BCP-ALL, p=0.011) due to either EOI MRD≥0.01% (9/18), IKZF1+CDKN2A/B concomitant deletions (3/18) or both (6/18). The 2-y overall survival (OS) in both groups was not significantly different (57% [95% CI, 27%-78%] vs. 67% [55%-77%, p=0.304]) (Figure 1). Interestingly, most Ph-like patients died due to treatment-related toxicity (2 transplant-related mortality, 1 CART-related, 1 during induction, 1 in CR and 1 by COVID-19 infection). The 2-y cumulative incidence of relapse (CIR) was also similar (Ph-like 27% [8%-50%] vs. other BCP-ALL 35% [25%-45%], p=0.946) (Figure 1). Conclusions Despite the short follow up of this series, our results show that Ph-like ALL patients have poorer EOI MRD clearance and higher rate of alloSCT realization than the remaining BCP ALL patients, without significant differences in outcome. This suggests that early alloSCT in first CR might overcome the poor prognosis of Ph-like ALL patients. Funding Funded in part by: PI10/01417 y FIS PI19/01183 Ministerio de Salud Carlos III, JCyL_SA118P20, FMM21/002_AP176752021, “La Caixa” Foundation, Pfizer Spain, Fundación PETHEMA. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No IMI001-07. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

Comparison of Autologous, Matched Sibling, and Alternative Donor Stem Cell Transplant Outcomes for Acute Myeloid Leukemia Patients in First Remission: A Propensity Score Matching Study

Introduction Autologous hematopoietic stem cell transplantation (auto-HSCT), matched sibling donor HSCT (MSD-HSCT), and alternative donor HSCT (AD-HSCT) are viable post-remission treatment options for acute myeloid leukemia (AML). Auto-HSCT is more commonly administered in favorable- and intermediate-risk AML with good remission, while MSD-HSCT and AD-HSCT are suggested for patients with high-risk factors. In the present study, we aim to retrospectively compared auto-HSCT with MSD-HSCT and AD-HSCT in de novo AML patients who are in first complete remission (CR1) with favorable or intermediate risk, according to 2022 ELN criteria. Methods We conducted a single-center retrospective comparative analysis, comparing auto-HSCT and allo-HSCT for favorable and intermediate-risk de novo AML in CR1. Patients with secondary AML, acute promyelocytic leukemia, poor-risk AML, those receiving syngeneic HSCT, those not in CR1 before HSCT, or those who achieved CR1 with ≥ 3 cycles of induction chemotherapy were excluded from the study. A total of 283 de novo favorable- and intermediate-risk AML patients, based on the ELN 2022 criteria, in first complete remission were initially included for propensity score matching. Persistent undetectable MRD (uMRD) was defined as uMRD after one course of chemotherapy without recurrent positive MRD before HSCT, while non-persistent uMRD was characterized by the presence of detectable MRD at least once before HSCT. The variables used for propensity score matching included induction chemotherapy cycles, consolidation chemotherapy cycles, and measurable residual disease (MRD) measurement by flow cytometer before HSCT. A caliper width of 0.2 was used. Following the matching process, 126 patients were selected for further analysis, with 42 patients in each of the auto-HSCT, MSD-HSCT, and AD-HSCT groups. Results After applying propensity score matching, a final cohort of 126 patients was available for analysis. This cohort consisted of 42 patients in each group: auto-HSCT, MSD-HSCT, and AD-HSCT. Among the AD-HSCT group, 38 of 42 (90.5%) patients received haploidentical HSCT (haplo-HSCT). All patients received myeloablative conditioning regimen. There were no significant differences observed in the 3-year overall survival (OS) and disease-free survival (DFS) among the auto-HSCT, MSD-HSCT, and AD-HSCT groups [3-year OS: 79.5% (95% CI, 67.8-93.3%), 83.0% (95% CI, 72.2-95.3%), and 65.7% (95% CI, 50.5-85.5%), respectively; P=0.21. 3-year DFS: 72.6% (95% CI, 59.9-87.9%), 83.0% (95% CI, 72.2-95.3%), and 67.5% (95% CI, 54.2-84.1%), respectively; P=0.32]. The cumulative incidence of 3-year NRM was 2.7% (95% CI, 2.0-12.5%), 7.3% (95% CI, 1.8-17.9%), and 21.9% (95% CI, 10.7-35.6%), respectively (P=0.008). The 1-year probability of OS after relapse was higher in the auto-HSCT group (44.4%; 95% CI, 21.4-92.3%) compared with MSD-HSCT (0.0%) and AD-HSCT (37.5%; 95% CI, 8.4-99.9%) (P=0.0017). The MRD status before HSCT had an impact on DFS (persistent uMRD versus non-persistent uMRD: HR=0.29; 95% CI 0.09-0.94, P=0.04) and relapse (persistent uMRD versus non-persistent uMRD: HR=0.17; 95% CI 0.05-0.66, P=0.01) following auto-HSCT. The subgroup analysis was then performed based on MRD status before HSCT. In patients with uMRD before transplant (n=83), OS was similar across the groups. However, auto-HSCT showed a trend of increased DFS compared to AD-HSCT (HR 2.85, P=0.09), resulting in a 3-year DFS and OS of 79.1% and 82.8%, respectively. In the non-persistent uMRD group (n=38), auto-HSCT exhibited a tendency to increase the risk of relapse, particularly when compared to AD-HSCT (HR 0.24, P=0.07), but this did not result in inferior OS. The monthly direct medical cost per patient within the first two years after HSCT was significantly lower in auto-HSCT compared to MSD-HSCT (P=0.015) and AD-HSCT (P&amp;lt;0.001). Conclusions Our results provide evidence for the use of auto-HSCT as a viable therapeutic option for favorable- and intermediate-risk de novo AML patients in first complete remission with persistent uMRD. Additionally, our findings demonstrated a notable cost advantage associated with auto-HSCT compared to MSD-HSCT and AD-HSCT.

Venetoclax Plus ‘2 + 5‘ Modified Intensive Chemotherapy with Daunorubicin and Cytarabine in Fit Elderly Patients with Untreated De Novo Acute Myeloid Leukaemia: A Single-Centre Retrospective Analysis

Background: The treatment options for elderly patients with acute myeloid leukemia (AML) have been limited considering the poor tolerability of intensive standard chemotherapy. Recently, we report promising clinical outcomes in 13 untreated fit elderly patients with AML who received modified intensive induction of venetoclax in combination with ‘2 + 5‘ (daunorubicin and cytarabine) chemotherapy (modified DAV regimen), followed by venetoclax plus modified intermediate-dose cytarabine consolidation. Building on this foundation, we expanded the sample size and included 11 more patients who treated with modified DAV regimen and extended follow-up time to further explore the efficacy and safety of the modified DAV regimen for induction therapy in elderly AML patients. Method: 24 elderly AML patients (aged ≥55 years) who were received induction chemotherapy that included daunorubicin (60mg/m2 days 1-2, intravenously), cytarabine (100 mg/m 2 days 1-5, intravenously), and venetoclax (100 mg day 3, 200 mg day 4, 400 mg days 5-10, orally) from March 2021 to May 2023 were retrospectively analyzed. After induction, patients received three cycles of venetoclax (400 mg days 1-14, orally) in combination with intermediate- dose cytarabine (1 g/m 2 days 1-3, intravenously) as consolidation treatment. Overall response rate, composite complete response (CRc) rate, overall survival (OS), duration of remission (DOR), and adverse events were analyzed. Results: 24 de nove elderly patients with AML were were divided into favourable- (6), intermediate- (13), and adverse-risk groups (5) according to European LeukemiaNet (ELN) risk stratification. The cohort was consisted of 9 males (37.5%) and 15 females (62.5%) and the median (range) age of which was 64 (57-71) years. The last follow-up date was 15 July 2023, with 313 days of median follow-up. After one cycle of induction, 20 patients (83.3%) achieved CR, 2 patients (8.33%) who achieved PR after one cycle of induction attained CR after receiving a second modified DAV induction. Thus, the CR rate was 91.7% after 2-cycle induction. 2 patients (8.33%) failed to achieve remission after induction therapy. In responders, 20 of the patients were measurable residual disease (MRD) negative after 2-cycle induction, detected by multi-parameter flow cytometry (MFC). Among 22 CR patients, 20 have completed the first consolidation cycle (one patient received consolidation regimen without venetoclax due to economic pressures, and another one did not receive consoliation treatment yet), 18 patients have completed the second consolidation cycle, and 16 patients have completed all cycles of consolidation chemotherapy. Of these, 3 patients relapsed during consolidation therapy and 4 patients relapsed after completion of consolidation therapy. For the total of 24 patients, the median follow-up was 313 days. The median OS was not achieved and the median EFS was 384 days. Among the 16 patients who completed three courses of consolidation therapy, the median follow-up time was 314 days, and there were no deaths to date. The median OS was not achieved and the median EFS was 398 days. The adverse events observed during the induction therapy in most patients were Grade 3-4 neutropenia (100%), anemia (100%), and thrombocytopenia (100%). For responders in the first induction cycle, the median (interquartile range [IQR]) time to blood cell count recovery (absolute neutrophil count ≥1 ×10 9/L and platelet count ≥50×10 9/L) in patients who had a response following induction therapy was 20.0 (18.75-22.0) days. The most common non-haematological grade 3-4 adverse events observed during induction included febrile neutropenia (65.2%), pneumonia (34.8%), and constipation (15.4%). Conclusions: Our study demonstrated promising response and safety of modified DAV therapy in elderly fit de novo AML patients.

Extended Nutritional Monitoring in Patients Undergoing Intensive Chemotherapy for Acute Myeloid Leukemia

Background Fit patients (pts) with acute myeloid leukemia (AML) are conventionally administered repeated cycles of intensive chemotherapy, often followed by allogeneic hematopoietic stem cell transplant. AML pts need to be long hospitalized in a protected setting, they are often prescribed a neutropenic diet and chemotherapy-induced gastro-intestinal toxicity is common. As a result, malnutrition is frequently observed, it sensibly reduces the quality of life and has the potential to undermine eligibility for intensive treatment, increase treatment-related toxicity, and ultimately reduce survival. Aims Aim of this study was to systematically assess the nutritional status of fit pts undergoing treatment for AML and to explore early predictors and associations with known nutritional risk scores and relevant clinical outcomes. Methods Nutritional Risk Screening 2002 (NRS) score was calculated for each patient at time of diagnosis (a score of 3 or more is considered high). Then, nutritional monitoring included standard anthropometric measurements (body weight, BW; body mass index, BMI) and a bioelectrical impedance analysis (BIA) performed by a registered dietitian to assess fat-free mass, body cell mass (BCM, the metabolically active component of body mass), fat mass and the phase angle. Variations in nutritional parameters between admission and day 7 (end of CHT, called “dif7”) or between admission and day 14 (called “dif14”) were calculated and tested for correlation with variations of the same parameter at discharge from the same cycle (called “dif30”) or at discharge after the first consolidation (called “dif60”). Results Up to now, 26 pts with newly diagnosed AML (median age 55y, range 21-74) were prospectively monitored during a total of 61 cycles of intensive chemotherapy (35 induction cycles, 26 consolidation cycles). Median NRS score at enrolment was 3 (range 2-6). Median follow up for surviving pts is 300 days. We observed a significant reduction in fat-free mass and body cell mass during induction cycles. Similar trends, although not significant, were observed for consolidation cycles as well. These trends were observed irrespectively of baseline NRS, disease response, or whether admission was complicated by a fever lasting more or less than 7 days. A high NRS score was only associated with a greater fat mass loss between diagnosis and discharge after first consolidation (FM dif60), but the score failed to predict any meaningful nutritional parameter variation. For fat-free mass, body cell mass and the phase angle (but not for BW or BMI), dif7 correlated with dif30 for induction and consolidation cycles. For body cell mass and the phase angle, both dif7 and dif14 also correlated with dif60. Only variations in body cell mass at day 7 (BCM dif7) correlated with cumulative weight loss at discharge after the first consolidation cycle (BW dif60). Reduction in BW, BMI and fat mass at day 7, and of phase angle at day 14, were associated with extended length of stay for consolidation chemotherapy cycles only. Conclusions In this study, pts intensively treated for AML suffered a significant reduction in the metabolically active component of body mass during admission for induction chemotherapy and, cumulatively, during the first two treatment cycles. Bioelectrical impedance analysis performed as early as seven days from admission could already reveal the first signals of nutritional deterioration: body cell mass loss between day 0 and day 7 correlated with both cumulative body cell mass loss and cumulative body weight loss after two cycles of chemotherapy. Notably, a commonly used nutritional risk screening tool failed to predict the risk of malnutrition in our cohort of patients. “NUTRIAMO” is a prospective, observational trial currently starting at our institution, where pts intensively treated for AML are monitored via known nutritional assessment tools, new biochemical markers (e.g., prealbumin and retinol-binding protein) and microbiome analysis and variations. Our aim is to find more sensitive nutritional triggers to activate earlier and more effective support measures (e.g., oral nutritional supplements, diet variations, psychological support) and ultimately improve AML patients' quality of life and survival beyond the cure of their disease.

ShorTrip Trial: A Prospective, Multicentric Phase II Single-Arm Trial of Short-Course Radiotherapy Followed by Intensified Consolidation Chemotherapy With the Triplet FOLFOXIRI as Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer

BackgroundIn patients with locally advanced rectal cancer (LARC) treated with preoperative (chemo) radiotherapy and surgery, adjuvant chemotherapy is poorly feasible and its benefit is questionable. In the last years, several total neoadjuvant treatment (TNT) strategies, moving the adjuvant chemotherapy to the neoadjuvant setting, have been investigated with the aim of improving compliance to systemic chemotherapy, treating micrometastases earlier and then reducing distant recurrence. Patients and MethodsShorTrip (NTC05253846) is a prospective, multicentre, single-arm phase II trial where 63 patients with LARC will be treated with short-course radiotherapy followed by intensified consolidation chemotherapy with FOLFOXIRI regimen and surgery. Primary endpoint is pCR. Among the first 11 patients who started consolidation chemotherapy, a preliminary safety analysis showed a high rate of grade 3 to 4 neutropenia (N = 7, 64%) during the first cycle of FOLFOXIRI. Therefore, the protocol has been emended with the recommendation to omit irinotecan during the first cycle of consolidation chemotherapy. After amendment, in a subsequent safety analysis focused on the first 9 patients treated with FOLFOX as first cycle and then with FOLFOXIRI, grade 3 to 4 neutropenia was reported in only one case during the second cycle. Aim of the studyThe aim of this study is to assess the safety and activity of a TNT strategy including SCRT, intensified consolidation treatment with FOLFOXIRI and delayed surgery. After protocol amendment, the treatment seems feasible without safety concern. Results are expected at the end of 2024.

Reduced plasma coagulation factor XIII in patients with acute leukemia in remission during consolidation chemotherapy cycles.

Acute leukemia (AL) is a malignancy from hematologic stem cells (HSC). Consolidation with intensive chemotherapy is required after induced remission and repeatedly causes treatment-related bleeding that is usually attributed to chemotherapy-induced thrombocytopenia (CIT). However, our previous study demonstrated that severe deficiency of plasma coagulation factor XIII (pFXIII) also participated in the bleeding of CIT in AL. However, the relationship between pFXIII deficiency and consolidation chemotherapy was unknown. Here, we observed the concentration of pFXIII in patients with AL before and after consolidation chemotherapy and reevaluated the correlation to bleeding in myelosuppression. Thus, we found that the concentration of pFXIII before chemotherapy in all patients was markedly lower than in the control data and was further decreased by chemotherapy, related to bleeding in myelosuppression. These findings indicated that chemotherapy-induced pFXIII deficiency should be of concern and explored in depth.

Assessing the predictive value of clinical factors to pathological complete response for locally advanced rectal cancer: An analysis of 124 patients.

To investigate the clinical factors affecting pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). Clinical data of 124 LARC patients treated with nCRT and surgery in the fourth Hospital of Hebei Medical University from 2014 to 2019 were retrospectively analyzed. In this study, univariate analysis and logistic dichotomous multivariate regression analysis were used to study the clinical factors affecting pCR, and the receiver operator characteristic curve (ROC) analysis was used to further verify the accuracy of partial indexes in predictingpCR. Of the 124 enrolled patients, 19 patients (15.32%) achieved pCR. Univariate analysis showed that the number of cycles of consolidation chemotherapy, serum carcino-embryonic antigen (CEA) level before treatment, MRI longitudinal length of tumor, and extramural vascular invasion (EMVI) were statistically correlated with pCR. ROC analysis of the longitudinal length of tumor measured by MRI showed that the area under the curve (AUC) value, sensitivity and specificity were 0.735, 89.47% and 48.57% respectively, and the optimal cut-off value was 5.5cm. The ROC analysis showed that the AUC value, sensitivity and specificity of pCR prediction using CEA were 0.741, 63.16% and 90.48%, respectively, and the optimal cut-off value was 3.1ng/ml. Multivariate results showed that the number of cycles of consolidation chemotherapy, serum CEA level before treatment, and EMVI were independent predictors of pCR. The number of cycles of consolidation chemotherapy, serum CEA level before treatment, and EMVI may be important determinants of LARC patients to reach pCR after nCRT.

Gestational trophoblastic neoplasia with primary lung cancer and mesenchymal tumor of sigmoid colon: a case report and literature review

BackgroundGestational trophoblastic neoplasia (GTN) is rare, and it is even rarer for GTN to merge with primary malignant tumors in other organs. Herein is described a rare clinical case of GTN combined with primary lung cancer and mesenchymal tumor of the sigmoid colon, followed with literature review.Case presentationThe patient was hospitalized due to diagnosis of GTN with primary lung cancer. Firstly, two cycles of chemotherapy including 5-fluorouracil (5-FU) and actinomycin-D(Act-D) was given. Laparoscopic total hysterectomy and right salpingo-oophorectomy was performed during the third chemotherapy. During the operation, a 3*2 cm nodule was removed which was protruded from the serous surface of the sigmoid colon, and the nodule was confirmed mesenchymal tumor pathologically, in accord with gastrointestinal stromal tumor. During the treatment of GTN, Icotinib tablets were taken orally to control the progression of lung cancer. After 2 cycles of consolidation chemotherapy of GTN, she received thoracoscopic lower lobe of right lung lobectomy and the mediastinum lymph nodes removal. She undertook gastroscopy and colonoscopy and the tubular adenoma of the descending colon was removed. At present, the regular follow-up is taken and she remains free of tumors.ConclusionsGTN combined with primary malignant tumors in other organs are extremely rare in clinical practice. When imaging examination reveals a mass in other organs, clinicians should be aware of the possibility of a second primary tumor. It will increase the difficulty of GTN staging and treatment. We emphasis the importance of the collaboration of multidisciplinary teams. Clinicians should choose a reasonable treatment plan according to the priorities of different tumors.

Integration of Consolidation Chemotherapy After Concurrent Chemoradiation in the Treatment of Locally Advanced Uterine Cervical Cancer.

Despite the current standard of concurrent chemoradiation (CCRT), around 30-40% are still dying from locally advanced cervical cancer. Increasing the radiation dose further was not a feasible option, but addition of chemotherapy further was tried due to the different toxicity profiles of it. So, the use of consolidation chemotherapy beyond CCRT has been studied. To evaluate the efficacy, toxicity, tumour response and loco-regional control following consolidation chemotherapy after concurrent chemoradiation in locally advanced carcinoma cervix (LACC). The patients were randomized into two arms: the conventional arm (control arm, n = 30) patients received conventional treatment with weekly injection cisplatin (35mg/m2) concurrently with pelvic external beam radiation (50Gy/25 fraction, 2Gy/fraction, 5 fraction weekly) followed by intracavitary radiotherapy of 21Gy in 3 fractions of 7Gy each by HDR brachytherapy. In the interventional arm (study arm, n = 30), patients received the standard treatment followed by 3 cycles of consolidation chemotherapy (paclitaxel + carboplatin) every three weekly. Haematological toxicity (grade 3 anaemia and grade 1 leucopenia, grade 1 and 2 thrombocytopenia) was higher in the study group. Renal, hepatic and gastrointestinal toxicity was more in the study arm. Peripheral neuropathy was mostly seen in the study arm. Median follow-up was 9months. Treatment response was better, and the rate of recurrence was less in the study arm. Addition of few cycles of consolidation chemotherapy after standard treatment is beneficial in patients with LACC with manageable toxicity and good compliance.

High-Dose Versus Standard-Dose Intensity-Modulated Radiotherapy With Concurrent Paclitaxel Plus Carboplatin for Patients With Thoracic Esophageal Squamous Cell Carcinoma: A Randomized, Multicenter, Open-Label, Phase 3 Superiority Trial

The standard dose (SD) of definitive concurrent chemoradiotherapy (dCRT) remains 50.4 Gy in patients with esophageal cancer; a higher dose, when applied with conventional radiation therapy techniques, increases toxicities without improving survival. We investigated whether a high dose of 59.4 Gy using intensity-modulated radiation therapy (IMRT) would improve survival without increasing toxicities. Patients with inoperable thoracic esophageal squamous cell carcinoma (SCC) referred for dCRT were randomly assigned (1:1) to high-dose (HD) IMRT (59.4 Gy) or SD IMRT (50.4 Gy). Chemotherapy consisted of 6 cycles of concurrent weekly paclitaxel and carboplatin and a maximum of 2 cycles of consolidation chemotherapy. Nutritional intervention was implemented for patients with malnutrition on the basis of nutritional screening. The primary endpoint was median overall survival (mOS). Analyses were by modified intention to treat. Between April 30, 2016, and April 30, 2019, 167 patients were enrolled at 9 participating centers in China. Seventy-one patients in the HD and 73 patients in the SD groups were included in the analysis; 86.8% of the patients completed radiation therapy and 70.1% received 5 or 6 cycles of concurrent chemotherapy. The median follow-up was 36.0 months. The mOS was 28.1 and 26.0 months in the HD and SD arms, respectively (P=.54). A total of 7 treatment-related deaths were observed. Grade 3 or worse treatment-related toxicities were observed in 62% and 68.5% of the patients in the HD and SD arms, respectively (P=.675). For patients with inoperable thoracic esophageal SCC, a dose of 59.4 Gy did not improve survival compared with the SD of dCRT using IMRT.

Maintenance Therapy with Combination of Azacitidine, Danazol and Thalidomide after Intensive Chemotherapy in Acute Myeloid Leukemia Patients

INTRODUCTION Despite the efficacy and outcome of AML patients increases in recent decades, the rate of relapse is still high, especially in the patients who are ineligible for allo-HSCT. How to prevent relapse is still a major therapeutic challenge. Recently, several drugs including Azacitidine (AZA), CC-486, Lenalidomide, androgen, Midostaurin, etc, used as maintenance therapy have shown a better EFS or OS, indicating that maintenance therapy is an important aspect of AML treatment. Herein, we reported the data of 11 AML patients who were administered AZA combined with Danazol (DNZ) and Thalidomide (THD) as maintenance therapy after intensive chemotherapy (IC). The purpose of this study was to observe the efficacy and safety of this maintenance therapy. METHODS Between Feb 2017 and Mar 2021, 11 patients diagnosed with AML were treated at the Baiyun Hospital. The induction therapy involved daunorubicin (DNR) 60 mg/m2/day on days 1-3, cytarabine (Ara-c) 100 mg/m2/day on days 1-7. If the patient did not achieve CR, salvage therapy was administered. Post-remission, three cycles of consolidation chemotherapy with high-dose Ara-c (3g/m2/q12h d1-3) and two cycles of reduced dose of chemotherapy (DA/HA/EA) were administered. Patient remained in CR after IC and was treated with 6-8 cycles of AZA combined with DNZ and THD maintenance therapy. AZA subcutaneous injection at 100 mg/day (approximate 50-75 mg/m2/day) d1-7, DNZ 200 mg Bid and THD 100 mg/day po followed by AZA, every four weeks. After completing the 6-8 cycles, patients continued the maintenance therapy with DNZ and THD for at least three years unless relapse or intolerance occurred. Disease evaluation included bone marrow and blood test until the duration of CR over five years. RESULTS Between Feb 2017 and Mar 2021, 11 patients who were enrolled in this study. Baseline patient and disease characteristics are summarized in Table 1. All 11 patients were treated with DA induction therapy, 10 patients achieved CR, 1 patient achieved remission after salvage therapy. 10 of 11 patients completed all consolidation therapies. 1 patient diagnosed AML with t (8;21) refused to continue chemotherapy because of renal failure after CR, and was directly switched to maintenance therapy. 9 0f 10 patients completed all IC and started on maintenance therapy. 1 AML with t (8;21) patient relapsed after stopping chemotherapy for two months and achieved CR2 by FLAG re-induction therapy refused continued chemotherapy and transplantation, and was directly switched to maintenance therapy. All patients received a median of 7 (6-12) courses of AZA combined with DNZ and THD maintenance therapy. Treatment was well tolerated and accepted by the patients. Common adverse events included mild neutropenia, thrombocytopenia, and elevated aminotransferase. No patient discontinued the maintenance therapy due to adverse events. Until June 2022, the median follow-up time was 37 (14-63) months. The RFS at 1-year and 3-years was 100% and 71.1%; the OS at 3-years was 100%, respectively (Figure 1a, 1b). All 11 patients, 3 died and 8 patients were alive with RFS. Of the 3 patients who died, 1 relapsed at 36 months and died due to disease progression at 46 months. The remaining 2 patients, one was diagnosed and died with secondary mixed phenotypic acute leukemia (NOS, T/My), the other died in a road accident. Notably, 2 cases of AML with t (8; 21) (one patient relapsed after IC, another patient developed renal failure) remained in CR by the end of follow-up. The CR duration was 24 and 13 months, respectively. The clinical outcomes of maintenance therapy after IC treatment for 11 patients are summarized in Figure 1c. Conclusion: AZA combined with DNZ and THD maintenance therapy is safe and effective in AML patients who are ineligible for allo-HSCT. Keywords: Azacitidine; Danazol; thalidomide; maintenance therapy; AML Figure 1 Response and long-term outcomes of the entire cohort Figure 1 legend, a. Relapse-free survival of the 11 patients. b. Overall survival of the 11 patients. c. Swimmer plot of the 11 patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intensified Induction Chemotherapy Results in More Rapid Early NPM1 Mutant (mut) Measurable Residual Disease (MRD) Clearance but Similar Disease Outcomes

Introduction.NPM1mut MRD assessment has been established as an independent prognostic marker in AML. The magnitude of NPM1mut MRD reduction post chemotherapy is associated with clinical outcome. At the Alfred and Austin Hospitals (Melbourne, Australia), high-dose cytarabine (HiDAC)-based induction was employed in favor of standard-dose cytarabine (SDAC) "7+3" induction until 2017. We hypothesized that HiDAC-based AML induction would result in greater reduction in NPM1mut MRD compared to SDAC-based induction and be associated with improved clinical outcome. Methods. Consecutive patients (pts) with newly diagnosed NPM1 mutated AML were retrospectively identified from 2 institutions if NPM1mut MRD results were available after achieving morphologic remission. This study was approved by the Alfred HREC (460/17). The HiDAC cohort received either high (HDAC+3, 3 g/m2 BD d1,3,5,7, from 2012 to 2014) or intermediate dose cytarabine (IDAC+3, 1.5 g/m2 BD d1,3,5,7, from 2014 to 2017), in combination with idarubicin (12 mg/m2 d1-3). The SDAC cohort received 7+3 (from 2017 to March 2020). Planned consolidation chemotherapy for the HiDAC cohort consisted of 2 cycles of IcE (idarubicin 9 mg/m2 d1-2, cytarabine 100 mg/m2 d1-5, and etoposide 75 mg/m2 d1-5), whereas in the SDAC induction cohort, either 2 cycles of IDAC+2 (cytarabine 1 g/m2 x6 doses and idarubicin 12 mg/m2 d1-2), or 4 cycles of HiDAC (cytarabine 1-3 g/m2 x6 doses) was administered. Midostaurin was available as standard of care since December 2018 in Australia. NPM1mut bone marrow copy numbers by RT-qPCR are expressed per 105ABL1 copies. Results. A total of 66 pts with NPM1mut AML were included in this study and summarized in Table. Majority had intermediate risk (95%) or normal karyotype (82%) and 38% had FLT3-ITD. The HiDAC cohort (n=28) was younger than the SDAC cohort (n=38) (median 47 vs 62 years) and more commonly underwent allogeneic HSCT in first remission (29% vs 5%). Among the HiDAC cohort, 54% completed the planned 2 cycles of consolidation chemotherapy, whereas 74% in the SDAC cohort completed at least 2 cycles of consolidation. Midostaurin was received by 9 pts, all from the SDAC cohort (24%). Baseline NPM1mut copy numbers were similar between both cohorts (Figure). Following course 1, the HiDAC cohort achieved a lower NPM1mut MRD level than the SDAC cohort: median 10 vs 82 copy numbers (p<0.001), 4.5 vs 3.4-log10 reduction (p<0.001), and 20% vs 0% with negative MRD (p=0.01). These differences narrowed after course 2: 1.9 vs 7.9 copies (p=0.05), 5.2 vs 4.4-log10 reduction (p=0.01), and 33% vs 10% with negative MRD (p=0.1). Similar findings were observed after course 3. The MRD levels at end of therapy (EOT) were similar between HiDAC and SDAC cohorts: 1.1 vs 3.8 copies (p=0.15), 5.2 vs 4.7-log10 reduction (p=0.09), and 41% (9/22) vs 22% (8/36) with negative MRD (p=0.15) (Figure). Survivors were followed up for a median of 30 months: 18 pts had relapsed AML, 12 died, and median RFS and OS were both not reached. Early death (<60 days) was observed in only 1 pt (SDAC cohort). Estimated 3-year RFS and OS were 64% and 79%, respectively, without significant differences between the HiDAC vs SDAC induction cohorts: 3-year RFS 64% vs 66% and OS 80% vs 78%. Significant prognostic factors from univariate analyses were age (for RFS only), FLT3-ITD and MRD levels. Sensitivity analysis excluding the 9 pts who received midostaurin did not affect the results. Next, we analyzed the prognostic significance of NPM1mut MRD response within each cohort of induction chemotherapy intensity. In the HiDAC cohort, NPM1mut MRD levels post course 1 (and 2), but not at EOT, were significantly associated with both risks of relapse (HR 0.31, 95% CI 0.15-0.67) and death (HR 0.31, 95% CI 0.14-0.70). Among the SDAC cohort, the log reduction at EOT, but not post course 1 and 2, was significantly associated with relapse (HR 0.47, 95% CI 0.26-0.84) and death (HR 0.45, 95% CI 0.22-0.89). Peripheral blood NPM1mut MRD levels were not available for comparison. Conclusions. Intensified induction chemotherapy resulted in more rapid early NPM1mut MRD reduction but did not have significant impact on EOT MRD levels or survival outcomes. The clinical significance of MRD reduction at various time points should be interpreted in the context of selected therapeutic regimens. Moreover, MRD thresholds should be re-validated in the context of regimens incorporating novel targeted therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Time to Count Recovery after Post-Remission Chemotherapy in AML Patients

Background Longer time to achieve complete remission (CR) and recover counts after initial induction chemotherapy in acute myeloid leukemia (AML) patients is associated with decreased overall survival (OS) and relapse-free survival. Prolonged time to count recovery is associated with increased risk of infection and bleeding, and can result in delay of planned subsequent therapies including further chemotherapy or allogeneic transplant. While CR with count recovery after induction chemotherapy typically occurs within 4-5 weeks, there is a paucity of data for count recovery after post-remission (also known as consolidation) chemotherapy. We sought to investigate the time to neutrophil and platelet recovery after the first cycle of consolidation chemotherapy and thereby to identify optimal post-remission chemotherapy regimens. Methods We retrospectively identified adults over 18 years with newly diagnosed WHO-defined AML/high grade myeloid neoplasms (>10% blasts) who received high intensity induction chemotherapy (cladribine, cytarabine, mitoxantrone, and G-CSF, also known as CLAG-M or GCLAM) between 5/1/2014 and 12/31/2019. Patients with variations to the CLAG-M backbone such as sorafenib, midostaurin, gemtuzumab ozogamicin, and decitabine were included as well. This study was approved by the local Institutional Review Board. Consolidation treatment was defined as the first cycle of therapy given once patients achieved CR in marrow by standard criteria and divided into 3 main types for analysis: CLAG-M, CLAG-M without mitoxantrone (CLAG or GCLA) and high dose cytarabine (HiDAC). Patients who did not receive post-remission therapy with these regimens (n=23) or had refractory disease/died before consolidation therapy (n=180) were excluded from analysis. Many patients were enrolled on a single-center clinical trial of CLAG-M with dose-escalated mitoxantrone (NCT02044796). The primary endpoint was evaluation of the number of days from the start of consolidation chemotherapy to the day when absolute neutrophil count (ANC) > 1,000/ml (defined as neutrophil recovery) and platelet count > 100,000/ml (defined as platelet recovery). Early death was defined as death within 28 days of receiving consolidation therapy. Results We identified 307 patients who met our inclusion criteria; of these, 207 patients (67%) received CLAG therapy, 60 patients (20%) with CLAG-M and 40 patients (13%) with HiDAC. Compared to HiDAC, the median age of patients who received CLAG or CLAG-M was lower (p=0.013). The majority of patients were treated off study in all groups. The highest proportion of patients treated on study received CLAG therapy (36%, p=0.03). Early death was a rare event overall (1% for CLAG; 2% for CLAG-M and HiDAC), and no significant differences in ELN 2017 risk, performance status, baseline WBC, platelets, creatinine, albumin, or TRM score were identified among the three groups. Median time to neutrophil recovery was 36 days for HiDAC, 37 days for CLAG, and 50.5 days for CLAG-M (Figure 1A). Median time to platelet recovery was 48 days for HiDAC, 52 days for CLAG, and 94 days for CLAG-M. In multivariable cause-specific hazard regression models controlling for age and study enrollment, no differences were noted between CLAG and HiDAC in time to neutrophil recovery (hazard ratio [HR] 1.2, 95% confidence interval [CI] 0.81-1.76), platelet recovery (HR 1.08, 95% CI 0.71-1.64), or both neutrophil and platelet recovery together (HR 1.06, 95% CI 0.69-1.61). When compared to HiDAC, CLAG-M was associated with a trend towards longer time to neutrophil recovery (HR 0.69, 95% CI 0.43-1.09), platelet recovery (HR 0.73, 95% CI 0.44-1.21), and both neutrophil and platelet recovery together (HR 0.68, 95% CI 0.41-1.13). Controlling for age and study enrollment status, CLAG-M was associated with significantly worse 8-year OS compared to HiDAC (p=0.030), but no significant difference was identified between CLAG and HiDAC (p=0.99) (Figure 1B). Conclusions Post-remission therapy with CLAG is another viable alternative to HiDAC with no significant differences in neutrophil recovery, platelet recovery, and OS. Early death was uncommon for all three groups, but a post-remission course of CLAG-M was associated with decreased OS. Future work will examine the effect of particular cytogenetic and molecular markers on count recovery after post-remission courses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hypomethylating Agent Maintenance for Favorable and Intermediate Risk Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is a heterogenous disease with variable outcomes among different risk groups. Favourable risk group AML after consolidation chemotherapy have long-term- leukemia-free survival of 60-70% [1]. Also, many patients in India in the intermediate risk group do not opt for allogenic hematopoietic stem cell transplant due to financial constraints, non-availability of fully matched donors and due to reservations regarding non relapse mortality associated with transplant. Previous studies have shown the value of azacytidine maintenance in prolonging overall survival and relapse free survival in older patients of AML [2]. We conducted this study to assess the results of hypomethylating agents as maintenance in non-adverse risk, younger AML patients who did not receive allogeneic stem cell transplant. Methods: Adults with de-novo AML (>18 years) who received treatment at our centre from January 2021 to December 2021 were included in our retrospective analysis. Induction therapies used were out of these 4 as per physician's choice- 3days x daunorubicin+7 x cytarabine; 2days x daunorubicine + 5 x cytarabine +venetoclax; azacytidine+venetoclax; Fludarabine+Cytarabine+venetoclax. Complete remission was defined as per the ELN 2017 criteria [3]. Measureable residual disease assessment was done by multiparametric flowcytometry or by PCR for patients who had NPM1 mutation or inversion 16. Consolidation chemotherapy comprised of received 3-4 cycles of intermediate dose cytarabine at a dose of 1500mg/m2 twice daily on days 1, 3 and 5. Midostaurin was administered at a dose of 50mg twice daily on day 8 through 21 in FLT3 mutated patients. Patients who were in remission after consolidation therapy received maintenance using hypomethylating agents such as Azacytidine or decitabine alone or in combination (Venetoclax 100mg x 4 days with Voriconazole 200mg twice daily). Midostaurin 50mg twice daily or Sorafenib 200mg twice daily was given if FLT3-ITD/TKD mutated in addition to the hypomethylating agents. Our aim was to asses the tolerability and results of maintenance azacytidine in a non-selected cohort. Results Fifty-three AML patients received induction therapy during the study period and out of which 23 patients went on to receive consolidation with cytarabine. Seven patients were consolidated with allogeneic bone marrow transplant, 7 had refractory AML and 3 were induction deaths, (1) relapsed post consolidation, (1) did not receive maintenance. These were excluded from the analysis. Seventeen patients were lost to follow up after induction. Nineteen patients were started on hypomethylating agent maintenance. Baseline characteristics of the cohort are shown in Table 1. The median consolidation chemotherapy cycles were 3 (range 1-4). The cumulative doses of Daunorubicin used was 261mg (range-170 to345), cytarabine 1078mg (range 840 to 1351) and venetoclax 1200mg (range 600 to 3500mg). Post induction measurable residual disease MRD was positive in 01 out of 16 patients and post consolidation MRD was positive for 03 out of 08 patients. These 3 patients who were MRD positive post consolidation received azacytidine and venetoclax as maintenance. Table 2 showing the distribution of maintenance and the grade ¾ adverse events in patients who were on maintenance. Two patients in the maintenance cohort relapsed belonging to the MRD negative group. Both these patients received salvaged chemotherapies and are awaiting allogenic transplant. Conclusion Azacytidine maintenance is feasible option for preventing relapses in patients with favourable and intermediate risk AML who do not choose bone marrow transplant as consolidative therapy, however further studies are warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hyper-CVAD and sequential blinatumomab for newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: a single-arm, single-centre, phase 2 trial

Blinatumomab is effective in relapsed or refractory B-cell acute lymphocytic leukaemia and results in high rates of minimal residual disease negativity. We aimed to establish whether the incorporation of blinatumomab into front-line therapy for acute lymphocytic leukaemia could improve outcomes. We conducted a single-arm, phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 14 years or older with confirmed, newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphocytic leukaemia were eligible, including patients who had received up to one course of chemotherapy before enrolment. Patients received four cycles of intensive chemotherapy (hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone] alternating with high-dose methotrexate and cytarabine), followed by four cycles of blinatumomab consolidation (up to 28 μg/day by continuous intravenous infusion for 28 days, given every 42 days). Maintenance consisted of 15 cycles of alternating blocks of three cycles of POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) chemotherapy and one of blinatumomab. The primary endpoint was relapse-free survival evaluated in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02877303, and is still enrolling patients. Between Nov 14, 2016, and Aug 27, 2020, 38 patients with newly diagnosed B-cell acute lymphocytic leukaemia were treated (median age 37 years [IQR 29-45]; 26 [68%] male; 21 [55%] White, non-Hispanic). With a median follow-up of 37 months (IQR 28-49), estimated 3-year relapse-free survival was 73% (95% CI 56-85). No patients relapsed more than 2 years after the start of therapy. One (3%) patient developed transient grade 3 cytokine release syndrome, and four (11%) patients had a grade 3 blinatumomab-related neurological event. The most common non-haematological grade 3-4 adverse events were infections, which occurred in 14 (37%) of 38 patients during induction and in 27 (71%) of 38 patients during consolidation chemotherapy cycles. One (3%) patient discontinued therapy because of treatment-related neurotoxicity. There were two deaths-one due to infection and one due to respiratory failure-which were not considered treatment-related. Front-line sequential chemotherapy with blinatumomab resulted in encouraging long-term survival. Future randomised studies should evaluate the routine incorporation of blinatumomab in the treatment of patients with Ph-negative B-cell acute lymphocytic leukaemia. Amgen.

Consolidation chemotherapy with capecitabine after neoadjuvant chemoradiotherapy in high-risk patients with locally advanced rectal cancer: Propensity score study.

BACKGROUNDThe effects of consolidation chemotherapy (CC) in neoadjuvant therapy in locally advanced rectal cancer (LARC) have been explored. However, the optimal neoadjuvant chemoradiotherapy (NCRT) and surgery interval, regimen, and cycles of chemotherapy remains unclear.AIMTo evaluate the effects of one to two cycles of CC with capecitabine on high-risk patients with LARC without extending NCRT and surgery interval.METHODSWe retrospectively evaluated high-risk patients with LARC, who were defined as having at least one of the following factors by magnetic resonance imaging: depth of invasion beyond the muscularis propria of more than 5 mm (cT3c-cT3d), T4, meso-rectal fascia or extramural vascular invasion positive, and treatment date between January 2015 and July 2019 in our center. Patients were divided into the CC and non-CC group according to whether they received CC (capecitabine 1000 mg/m2 twice daily from days 1 to 14 every 21 d) after NCRT. Propensity score matching (PSM) and inverse probability of treatment weight (IPTW) were used to balance the differences between the two groups. The main outcome was the complete response (CR) rate.RESULTSA total of 265 patients were enrolled: 136 patients in the CC group and 129 patients in the non-CC group. The median interval was 70 d (range, 37-168). The CR rate was 24.3% and 16.3% (P = 0.107) in the CC and non-CC groups’ original samples, respectively. After PSM and IPTW, the CR rate in the CC group was higher than that in non-CC group (27.6% vs 16.2%, P = 0.045; 25.9% vs 16.3%, P = 0.045). The median follow-up was 39.8 mo (range, 2.9-74.8), and there were no differences in 3-year non-regrowth disease-free survival nor overall survival in the original samples (73.2% vs 71.9%, P = 0.913; 92.3% vs 86.7%, P = 0.294), PSM (73.2% vs 73.5%, P = 0.865; 92.5% vs 89.3%, P = 0.612), and IPTW (73.8% vs 72.1%, P = 0.913; 92.4% vs 87.4%, P = 0.294). There was also no difference in grade 2 or higher acute toxicity during neoadjuvant therapy in the two groups (49.3% vs 53.5%, P = 0.492).CONCLUSIONOne to two cycles of CC with capecitabine after NCRT was safe and increased the CR rate in high-risk LARC but failed to improve the long-term outcomes.