Cycles Of Induction Chemotherapy Research Articles

Incorporation of PD-1 blockade into induction chemotherapy improved tumor response in patients with locoregionally advanced nasopharyngeal carcinoma in a retrospective patient cohort

ObjectiveTo investigate the short-term efficacy and safety of induction chemotherapy (IC) combined with anti-PD-1 immunotherapy in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). MethodsA total of 217 patients diagnosed with LA-NPC at the First Affiliated Hospital of Nanchang University, including 67 who received IC combined with anti-PD-1 and 150 who received IC, were retrospectively enrolled. Efficacy was evaluated at the end of the IC cycles and one month after radiotherapy based on RECIST v1.1 criteria. Acute toxicities were graded based on the CTCAE v5.0 criteria. Quantitative variables were compared by unpaired t-tests, and categorical variables were evaluated by Fisher Freeman-Halton test or Pearson Chi-square test. ResultsAt the end of all induction therapy cycles, the objective response rate (ORR) of the IC + anti-PD-1 group was 88.1 % (59/67) as opposed to 70.0 % (105/150) in the IC group. Subgroup analysis showed that patients in both stage Ⅲ and ⅣA achieved a significant improvement in ORR with the inclusion of anti-PD-1 therapy. Patients with T3-4 or N2-3 category appeared to benefit more from anti-PD-1 compared to patients with T1-2 or N0-1 category. However, neither ORR nor the complete response (CR) rate was significantly different between the two treatment groups one month after the end of radiotherapy. In addition, the frequency of Grade 3–4 adverse events were also similar in both groups. ConclusionsIC combined with anti-PD-1 immunotherapy significantly improved the ORR of LA-NPC patients after induction therapy compared to IC alone.

Abstract PO2-03-05: Neoadjuvant anthracycline followed by Toripalimab combined with nab-paclitaxel in patients with stage IIA-IIIC triple negative breast cancer (NeoTENNIS): efficacy and safety results of a phase II study

Abstract Background: Immune checkpoint inhibitors(ICIs)have shown promising antitumor activity in triple negative breast cancer (TNBC) patients. Toripalimab, a novel PD-1 antibody, has been approved for the treatment in multiple solid tumors. However, the neoadjuvant use of toripalimab with chemotherapy has not been evaluated in TNBC patients. In addition, whether chemotherapy could sensitize the ICI treatment has not drawn conclusion yet. In this phase II trial, a sequential use of chemotherapy and anti-PD1 therapy was given in a neoadjuvant setting. The efficacy and safety of toripalimab were evaluated. Patients and methods: Female patients with histologically confirmed stage IIA to IIIC TNBC were included. Eligible patients received neoadjuvant therapy with four cycles of epirubicin-cyclophosphamide every 2 weeks followed by toripalimab (240 mg) every 3 weeks plus nab-paclitaxel weekly for 12 weeks. The primary endpoint was pathologic complete response (tpCR; ypT0/is ypN0) rate. Key secondary endpoints were breast pCR (bpCR; ypT0/is) rate, biomarker analysis, and safety. Results: Among 70 enrolled patients (median age, 51 years; 62.9% stage III), 66 patients completed study treatment without progression and received surgery after study treatment. Overall, the percentages of patients with a tpCR and bpCR were 55.7% (39 of 70 patients) and 58.6 % (41 of 70 patients), respectively. For women with CD8–positive and negative tumors, the tpCR rates were 66.0% and 30.0% (P = 0.006), respectively. Significant upregulation of CD8 positive cells after 4 cycles of epirubicin-cyclophosphamide induction chemotherapy (P = 0.011) were shown in sequential biopsy samples. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 30 patients (42.9%), the most common of which were neutropenia (15.7%), leukopenia (14.3%) and alanine aminotransferase increase (4.3%). Most common immune-related AEs were hepatobiliary disorders (Grade 3, 7.2%), creatinine increase (all Grade 1-2, 2.8%) and hypothyroidism (all Grade 1-2, 2.8%). Conclusions: The addition of toripalimab to neoadjuvant chemotherapy is efficacious and safe in patients with locally advanced TNBC. Anthracycline-based chemotherapy could sensitize the ICI treatment with upregulated tumor immune response. The event-free survival results are expected with further follow up. Mechanisms of chemotherapy sensitization are still under investigation (ClinicalTrials.gov number: NCT04418154). Citation Format: Min He, Linxiaoxi Ma, Shuang Hao, Benlong Yang, Bingqiu Xiu, Ya-Yun Chi, Ruo-Hong Shui, Zhong-Hua Wang, Zhi-Ming Shao, Jiong Wu. Neoadjuvant anthracycline followed by Toripalimab combined with nab-paclitaxel in patients with stage IIA-IIIC triple negative breast cancer (NeoTENNIS): efficacy and safety results of a phase II study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-03-05.

Long-term survival, toxicities, and the role of chrono-chemotherapy with different infusion rates in locally advanced nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy: a retrospective study with a 5-year follow-up.

This study aimed to evaluate 5-year outcomes and the late toxicity profile of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma (NPC). Our retrospective analysis included 70 patients with locally advanced NPC stages III and IVB (according to the 2010 American Joint Committee on Cancer staging system). Patients were treated with two cycles of induction chemotherapy (IC) before concurrent chemoradiotherapy (CCRT) at Guizhou Cancer Hospital. The IC with docetaxel, cisplatin (DDP) and fluorouracil regimen. Patients were divided into two groups during CCRT. Using a "MELODIE" multi-channel programmed pump, DDP (100 mg/m2) was administered for 12 hours from 10:00 am to 10:00 pm and repeated every 3 weeks for 2-3 cycles. DDP was administered at the peak period of 4:00 pm in the sinusoidal chrono-modulated infusion group (Arm A, n=35). The patients in Arm B received a constant rate of infusion. Both arms received radiotherapy through the same technique and dose fraction. The long-term survival and disease progression were observed. After a median follow-up of 82.8 months, the 5-year progression-free survival rate was 81.3% in Arm A and 79.6% in Arm B (P = 0.85). The 5-year overall survival rate was not significantly different between Arm A and Arm B (79.6% vs 85.3%, P = 0.79). The 5-year distant metastasis-free survival rate was 83.6% in Arm A and 84.6% in Arm B (P = 0.75). The 5-year local recurrence-free survival rate was 88.2% in Arm A and 85.3% in Arm B (P = 0.16). There were no late toxicities of grade 3-4 in either group. Both groups had grade 1-2 late toxicities. Dry mouth was the most common late toxic side effect, followed by hearing loss and difficulty in swallowing. There was no statistically significant difference between Arm A and Arm B in terms of side effects. Long-term analysis confirmed that in CCRT, cisplatin administration with sinusoidal chrono-modulated infusion was not superior to the constant infusion rate in terms of long-term toxicity and prognosis.

Assessment of the safety and feasibility of neoadjuvant chemotherapy (2 cycles of FLOT chemotherapy + chemoradiotherapy) followed by surgery in the treatment of locally advanced gastric cancer

The aim of the study was to analyze of the safety and feasibility of neoadjuvant chemotherapy (2 cycles of FLOT chemotherapy + chemoradiotherapy) followed by surgery in the treatment of locally advanced gastric cancer. Material and Methods. The phase II clinical trial included 47 patients with histologically verified locally advanced gastric cancer (cT3/T4a-b: 26/21 and cN0/N1–3: 20/27) treated at the A.F. Tsyba MRRC from 2018 to 2021. Lesion location was: upper third in 19 patients (esophageal invasion in 9 patients), middle third in 13 patients, lower third in 14 patients, and entire stomach in 1 patient. The tumor grade was G3 in 23 patients, G2 in 13 patients and G1 in 7 patients. Signet ring cell carcinoma was revealed in 4 patients. The patients received 2 cycles of induction chemotherapy with FLOT regimen (85 mg/m2 oxaliplatin + 200 mg/m2 calcium folinate + 50 mg/m2 docetaxel on day 1 + 2600 mg/m2 fluorouracil as 24-hour infusion from day 1; every 2 weeks) followed by 3d-conformal external beam radiotherapy (46 Gy in daily fractions of 2 Gy) combined with chemotherapy with capecitabine and oxaliplatin). The patients then underwent follow-up examination to exclude disease progression and to plan surgery. Postoperative complications were analyzed using the Clavien-dindo classification. Results. Induction chemotherapy followed by concurrent chemoradiotherapy was well tolerated. Forty-five (95.7 %) patients underwent surgery, 97.7 % of them underwent radical surgery. Postoperative complications were observed in 11 (23.4 %) patients. Grade III and more severe complications were observed in 3 (6.4 %) patients. It should be noted that postoperative mortality rate was low, amounting to 2.2 % (1 patient). Conclusion. Induction FLOT polychemotherapy followed by concurrent chemoradiotherapy was shown to be safe, feasible, and tolerable. Moreover, this treatment regimen did not reduce the frequency of R0 surgeries and did not increase incidence and severity of postoperative complications.

The optimal number of induction chemotherapy cycles in clinically lymph node-positive bladder cancer.

To investigate the optimal number of induction chemotherapy cycles needed to achieve a pathological response in patients with clinically lymph node-positive (cN+) bladder cancer (BCa) who received three or four cycles of induction chemotherapy followed by consolidative radical cystectomy (RC) with pelvic lymph node dissection. We included 388 patients who received three or four cycles of cisplatin/gemcitabine or (dose-dense) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), followed by consolidative RC for cTanyN1-3M0 BCa. We compared pathological complete (pCR = ypT0N0) and objective response (pOR = yp ≤T1N0) between treatment groups. Predictors of pCR and/or pOR were assessed using uni- and multivariable logistic regression analysis. The secondary endpoints were overall (OS) and cancer-specific survival (CSS). We evaluated the association between the number of induction chemotherapy cycles administered and survival outcomes on multivariable Cox regression. Overall, 101 and 287 patients received three or four cycles of induction chemotherapy, respectively. Of these, 72 (19%) and 128 (33%) achieved pCR and pOR response, respectively. The pCR (20%, 18%) and pOR (40%, 31%) rates did not differ significantly between patients receiving three or four cycles (P > 0.05). The number of cycles was not associated with pCR or pOR on multivariable logistic regression analyses. The 2-year OS estimates were 63% (95% confidence interval [CI] 0.53-0.74) and 63% (95% CI 0.58-0.7) for patients receiving three or four cycles, respectively. Receiving three vs four cycles was not associated with OS and CSS on uni- or multivariable Cox regression analyses. Pathological response and survival outcomes did not differ between administering three or four induction chemotherapy cycles in patients with cN+ BCa. A fewer cycles (minimum three) may be oncologically sufficient in patients with cN+ BCa, while decreasing the wait for definitive local therapy in those patients who end up without a response to chemotherapy. This warrants further validation.

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.

Induction Chemotherapy Followed by Radiotherapy vs Chemoradiotherapy in Nasopharyngeal Carcinoma

Induction chemotherapy plus concurrent chemoradiotherapy is recommended for locoregionally advanced nasopharyngeal carcinoma but is associated with higher rates of acute toxic effects and low compliance. Evidence on de-escalating treatment intensity after induction chemotherapy is limited. To assess if radiotherapy was noninferior to chemoradiotherapy after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma. From April 2015 to March 2018, a multicenter, open-label, randomized, noninferiority, phase 3 trial was conducted at 5 Chinese hospitals. A total of 383 patients aged 18 to 70 years with an untreated histologically confirmed nonkeratinizing tumor, Karnofsky performance status score not worse than 70, proper organ function, and stage III to IVB nasopharyngeal cancer were enrolled. Data were analyzed from April 2023 to June 2023. Patients were assigned randomly. Both groups received 3 cycles of induction chemotherapy consisting of intravenous administration (on day 1) of cisplatin at 60 mg/m2 and docetaxel at 60 mg/m2 and continuous intravenous infusion (from day 1 to day 5) of daily fluorouracil (600 mg/m2), repeated every 21 days. Subsequently, the patients received radiotherapy alone (induction chemotherapy in combination with radiotherapy [IC-RT] group) or concomitant cisplatin (30 mg/m2/week) with radiotherapy for 6 to 7 weeks (induction chemotherapy combined with chemoradiotherapy [IC-CCRT] group). The primary end point was 3-year progression-free survival (time from the initiation of therapy until the first indication of disease progression or death), with a noninferiority margin of 10%. The secondary end points included overall survival, locoregional failure-free survival, distant metastasis-free survival, response rate, and toxic effects. A total of 383 patients (median [range] age, 48 [19-70] years; 100 women [26%]). Median follow-up time was 76 months (IQR, 70-89 months). The 3-year progression-free survival was 76.2% and 76.8% in the IC-RT (n = 193) and IC-CCRT groups (n = 190), respectively, in the intention-to-treat population, showing a difference of 0.6% (95% CI, -7.9% to 9.1%; P = .01 for noninferiority). Identical outcomes were reported in the per-protocol population. The incidence of grade 3 to 4 short-term toxic effects in the IC-RT group was less than the IC-CCRT group. No differences were observed in late toxic effects. The results of this randomized clinical trial suggest that after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma, radiotherapy alone was noninferior to chemoradiotherapy in terms of 3-year progression-free survival. ClinicalTrials.gov Identifier: NCT02434614.

Evaluation of Total Parenteral Nutrition in the Autologous Transplantation Setting in Patients with AML: A Retrospective Exploratory Analysis

Malnutrition remains a clinical challenge in AML patients undergoing autologous hematopoietic stem cell transplantation (ASCT), leading to physical deconditioning and prolonged hospitalization. Prospective data are mainly lacking to identify those patients who may particularly benefit from parenteral nutrition in this setting. This observational, non-randomized, retrospective, exploratory cohort study assessed the nutritional development in patients following high-dose chemotherapy (HDCT) with ASCT and explored their survival outcomes. The study included all consecutive AML patients who underwent HDCT with ASCT at a single academic center between January 2000 and January 2019. Patients were divided into two primary cohorts: those who received TPN following high-dose chemotherapy and ASCT and those who did not. We identified 126 patients with AML in first complete remission undergoing ASCT consolidation, including 75 patients receiving TPN after HDCT and ASCT and 51 patients without TPN. Neither group differed in gender, age, or subgroups of AML. The nutritional condition at first diagnosis and after induction chemotherapy was equal in both groups, as were median weight changes throughout the induction chemotherapy cycles. Finally, progression-free and overall survival rates were comparable in both groups. Our data suggest that the need to provide TPN for an average of 11 days following HDCT with ASCT for consolidation of first remission in AML patients does not affect the clinical outcome of these patients.

Camrelizumab and apatinib plus induction chemotherapy and concurrent chemoradiotherapy in stage N3 nasopharyngeal carcinoma: a phase 2 clinical trial

The antiangiogenic agent apatinib has been shown to clinically improve responses to immune checkpoint inhibitors in several cancer types. Patients with N3 nasopharyngeal carcinoma have a high risk of distant metastasis, however, if the addition of immunotherapy to standard treatment could improve efficacy is unclear. In this phase II clinical trial (ChiCTR2000032317), 49 patients with stage TanyN3M0 nasopharyngeal carcinoma were enrolled and received the combination of three cycles of induction chemotherapy, camrelizumab and apatinib followed by chemoradiotherapy. Here we report on the primary outcome of distant metastasis-free survival and secondary end points of objective response rate, failure-free survival, locoregional recurrence-free survival, overall survival and toxicity profile. After induction therapy, all patients had objective response, including 13 patients (26.5%) with complete response. After a median follow-up of 28.7 months, the primary endpoint of 1-year distant metastasis-free survival was met for the cohort (1-year DMFS rate: 98%). Grade≥3 toxicity appeared in 32 (65.3%) patients, with the most common being mucositis (14[28.6%]) and nausea/vomiting (9[18.4%]). In this work, camrelizumab and apatinib in combination with induction chemotherapy show promising distant metastasis control with acceptable safety profile in patients with stage TanyN3M0 nasopharyngeal carcinoma.

Quantification of midostaurin in plasma and serum by stable isotope dilution liquid chromatography-tandem mass spectrometry: Application to a cohort of patients with acute myeloid leukemia.

Midostaurin is an oral multitargeted tyrosine kinase inhibitor for the treatment of acute myeloid leukemia (AML). Therapeutic drug monitoring of midostaurin may support its safe use when suspecting toxicity or combined with strong CYP3A4 inhibitors. A stable isotope dilution liquid chromatography-tandem mass spectrometry method was developed and validated for the determination and quantification of midostaurin in human plasma and serum. Midostaurin serum concentrations were analyzed in 12 patients with FMS-like tyrosine kinase 3 (FLT3)-mutated AML during induction chemotherapy with cytarabine, daunorubicin, and midostaurin. Posaconazole was used as prophylaxis of invasive fungal infections. Linear quantification of midostaurin was demonstrated across a concentration range of 0.01-8.00 mg/L. Inter- and intraday imprecisions of the proposed method were well within ±10%. Venous blood samples were taken in nine and three patients in the first and second cycle of induction chemotherapy. Median (range) midostaurin serum concentration was 7.9 mg/L (1.5-26.1 mg/L) as determined in 37 independent serum specimens. In a real-life cohort of AML patients, interindividual variability in midostaurin serum concentrations was high, highlighting issues concerning optimal drug dosing in AML patients. A personalized dosage approach may maximize the safety of midostaurin. Prospective studies and standardization of analytical methods to support such an approach are needed.

Stereotactic radiotherapy plus anti PD-1 therapy in patients with locally advanced unresectable pancreatic cancer: Results from a phase 1/2 clinical trial (CA209-9KH).

649 Background: The outcomes after the treatment for pancreatic ductal adenocarcinoma (PDAC) are generally disappointing. Except for MSI high tumors, PDAC is considered to be resistant to immune checkpoint inhibitors (ICI). Radiotherapy is thought to be a potential option to foster the effect of ICI. This investigator-initiated trial evaluated safety and efficacy of combining stereotactic radiotherapy (SRT) and ICI. Methods: In this open-label, multicenter phase 1/2 study, patients (pts) aged ≥ 18 years with histologically confirmed locally advanced unresectable PDAC with no distant metastases were enrolled after initial four cycles of induction chemotherapy with FOLFIRINOX. The experimental treatment consisted of SRT (32 Gy in 4 fractions/4 weeks) and sequential nivolumab (N) therapy (3mg/kg every two weeks) administered until disease progression or unacceptable toxicity. After N discontinuation pts could continue treatment with standard chemotherapy regimens. The primary end point was safety (events graded according to NCI CTCAE 4.03 criteria). The secondary objectives were progression free survival (PFS), overall survival (OS), evaluation of selected biomarkers, and quality of life (QoL; EORTC QLQ-C30 questionnaire). The PFS and OS were defined as the time from enrollment to event (i.e., did not include 3-month of ICT and screening). Results: A total of 22 pts. were screened, and 15 pts. were enrolled. Median age was 58 (range 38-74) years, and 53 % were males. All tumors were microsatellite (MS) stable or had unknown MS status. All patients underwent SRT according to the study protocol and all started N. The median number of N cycles was 11 (range 2-17). The toxicity of SRT was low and non-significant. The toxicity of N therapy was expectable. No Grade 4-5 toxicity was observed. Three pts. discontinued therapy because of toxicity (liver test elevation in two cases and unmanageable arthralgia). Median PFS and OS were 8.1 and 13.0 months, resp.; 12-month PFS and OS were 0 % and 66.7%, resp.; and 24-month OS was 8.9 %. The level of selected biomarkers correlated with clinical or radiological disease control. The QoL assessed by pts during the therapy was acceptable, deterioration of QoL in most cases occurred with tumor progression. Conclusions: The toxicity of SRT and N therapy was low and acceptable. There was no unexpected toxicity of combination of SRT of PDAC primary tumor and N, but this regimen did not lead to any long-term treatment responses. Trial registration: EudraCT: 2017-003404-52; ClinicalTrials.gov: NCT04098432. The study was financially supported by Bristol-Meyer-Squibb. Clinical trial information: NCT04098432 .

Combination of nivolumab with standard induction chemotherapy in children and adults with EBV-positive nasopharyngeal carcinoma : Protocol of aprospective multicenter phase2trial.

Treatment of Epstein-Barr virus(EBV)-positive nasopharyngeal carcinoma (NPC) with cisplatin/5-fluorouracil (5-FU) induction chemotherapy, followed by radiochemotherapy and subsequent interferon‑β, has yielded high survival rates in children, adolescents, and young adults. Aprevious study has shown that reduction of radiation dose from 59.4 to 54.0 Gy appears to be safe in patients with complete response (CR) to induction chemotherapy. As immune checkpoint-inhibitors have shown activity in NPC, we hypothesize that the addition of nivolumab to standard induction chemotherapy would increase the rate of complete tumor responses, thus allowing for areduced radiation dose in agreater proportion of patients. This is aprospective multicenter phase2 clinical trial including pediatric and adult patients with their first diagnosis of EBV-positive NPC, scheduled to receive nivolumab in addition to standard induction chemotherapy. In cases of non-response to induction therapy (stable or progressive disease), and in patients with initial distant metastasis, treatment with nivolumab will be continued during radiochemotherapy. Primary endpoint is tumor response on magnetic resonance imaging (MRI) and positron emission tomography (PET) after three cycles of induction chemotherapy. Secondary endpoints are event-free (EFS) and overall survival (OS), safety, and correlation of tumor response with programmed cell death ligand 1 (PD-L1) expression. As cure rates in localized EBV-positive NPC today are high with standard multimodal treatment, the focus increasingly shifts toward prevention of late effects, the burden of which is exceptionally high, mainly due to intense radiotherapy. Furthermore, survival in patients with metastatic disease and resistant to conventional chemotherapy remains poor. Primary objective of this study is to investigate whether the addition of nivolumab to standard induction chemotherapy in children and adults with EBV-positive NPC is able to increase the rate of complete responses, thus enabling a reduction in radiation dose in more patients, but also offer patients with high risk of treatment failure the chance to benefit from the addition of nivolumab. EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) No. 2021-006477-32.

Impact of Hemodilution on Measurable Residual Disease Measured Via Flow-Cytometry in Acute Myeloid Leukemia Analyzed Using Subsequent Pulls

Background: Measurable residual disease (MRD) detection plays a crucial role in assessing remission status and prognosis for acute myeloid leukemia (AML) patients. Multiparameter flow cytometry (MFC) and NPM1 gene mutations reverse transcriptase polymerase chain reaction (RT-PCR) are validated and recommended used methods for MRD measurement after two cycles of high-dose induction chemotherapy. However, the accuracy of MRD assessment can be compromised by hemodilution, a phenomenon that occurs during bone marrow (BM) aspiration when peripheral blood (PB) mixes with the BM sample. Due to the lower presence of MRD in PB, this may lead to false-negative results. Although formulas to quantify hemodilution exist, their validation and adoption remain limited, and the exact impact of hemodilution remains unclear. Aim: This prospective study aimed to investigate the impact of hemodilution on MFC-MRD assessment by aspirating three sequential pulls of 2 ml each, instead of the standard 6 ml BM sample, and comparing them with a PB sample collected on the same day. Additionally, we evaluated the performance of different hemodilution formulas and analyzed changes in ratios/percentages of cell populations across the BM pulls and PB samples. Methods: We included 30 AML patients in complete remission, resulting in 40 samples measured after one or two cycles of induction chemotherapy with 46 leukemia-associated immunophenotypes (LAIPs). The first 2 ml of BM were collected as the “first pull”, followed by a second aspirate of another 2 ml to form the “second pull”. This process was repeated to obtain the “third pull”. Precautions were taken during BM aspiration to prevent aspirate loss between pulls, and the aspiration needle remained stationary throughout the procedure. All samples from one time point were analyzed on the same machine by the same operator. The formulas proposed for hemodilution assessment were evaluated using a newly developed tube containing additional markers (CD10, CD16, CD38, and CD138) not present in the standard MFC-MRD assay. Differences in outcomes from the formulas and cell populations across the specimens were analyzed using the non-parametric Friedman's ANOVA test. Moreover, the ability of individual populations or formulas to differentiate between BM and PB samples was assessed using the area under the receiver operating characteristic curve (ROC-AUC) in a binary classification task. Results: Significant decreases in blasts and median MRD% were observed between different pulls and PB samples. The median MRD% in pull 1 (0.06%) was significantly higher than in pull 2 (0.05%), pull 3 (0.04%), and PB (0.01%) ( P<0.001). Pairwise comparisons, adjusted for multiple testing, revealed significant differences between pull 1 and pull 2 ( P=0.025), and between pull 2 to pull 3 ( P=0.025), indicating the effect of hemodilution ( Figure 1A). In the first pull 18/46 LAIPs were above the 0.1% cut-off, compared to 14/46 in the third pull. This resulted in 9 patients being MRD-positive in the first/second pull, compared to 8 patients in the third pull. The evaluated formulas demonstrated progressively higher quantities of diluted samples from pull 1 to PB. Five parameters exhibited an AUC above 0.9, indicating their ability to differentiate between BM and PB samples. These parameters are CD10 (AUC: 0.956), plasma cells (AUC: 0.949), CD16 dim cells (AUC: 0.940), mast cells (AUC: 0.924), and the PB contamination index formula (AUC: 0.905) ( Figure 1B). Conclusion: Hemodilution occurs even after aspirating the initial milliliters of BM, emphasizing the need to consider hemodilution when assessing MRD in AML to avoid false-negative results. We recommend incorporating a hemodilution detection formula into routine practice for AML patients to further evaluate the effect on clinical choices. The results of this study support the examination of the CD16 dim population or mast cell population (CD117hi) for this purpose. Furthermore, we suggest implementing a practical approach that involves numbering each pull of BM during aspiration and taking this into account when giving the final MRD result, thus providing clarity regarding the specific pull being measured. In cases of doubt (e.g., MFC-MRD between 0.07% and 0.09% in a later pull), repeating the BM aspiration is recommended to ensure reliability.

Venetoclax and Azacitidine for Molecular Relapse during First Line Intensive Chemotherapy in Patients with NPM1 Mutated or Core Binding Factor (CBF) AML. a Study from the Dataml Registry

Introduction: Molecular follow-up (FU) for AML patients (pts) with NPM1 mutation, RUNX1::RUNX1T1 or CBFB::MYH11 fusion transcripts has been established over the last ten years. Real-time quantitative PCR (qPCR) is the gold standard for the evaluation of measurable residual disease (MRD) in pts undergoing intensive chemotherapy (IC). Failure to achieve a deep molecular response is a strong predictive factor of relapse and survival and may guide post remission therapy (Ivey A, NEJM 2016). Moreover, the ELN MRD working party recommended a schedule for molecular FU and recently established a definition of molecular relapse (Heuser M, Blood 2021). However, there is no therapeutic consensus for pts with molecular relapse before overt clinical relapse. Frontline allogeneic hematopoietic cell transplantation (alloHCT), salvage IC or even waiting for morphological relapse in order to screen molecular characteristics of the relapsing disease or propose a clinical trial, may be discussed with pts. Venetoclax with azacitidine (VEN/AZA) was recently approved in unfit AML pts and demonstrated a particular efficacy in NPM1-mutated AML. In this study, we thought to describe the safety and efficacy of VEN/AZA in pts with NPM1 mutated or CBF AML in molecular relapse after first line IC. Methods: Pts of the DATAML registry with the following criteria were included in this study : AML with NPM1 mutation, RUNX1::RUNX1T1 or CBFB::MYH11 transcripts, first line IC, morphological complete remission (CR), no alloHCT in first line, regular monitoring of MRD by qPCR in bone marrow (BM) and/or blood, molecular relapse defined according to ELN2021 guidelines on two successive samples, at least one cycle of VEN/AZA. Pts with molecular relapse followed by morphological relapse before VEN/AZA or those who relapsed after alloHCT were not included. Treatment: First line IC was cytarabine 200 mg/m² d1-7 with idarubicin 9mg/m²/d1-5 or daunorubicin 90mg/m²/d1-3 in pts 18-60y or cytarabine 100 mg/m² d1-7 with idarubicin 8mg/m²/d1-5 and lomustine 200 mg/m²/d1 in pts > 60y. Post remission therapy was intermediate or high dose cytarabine or mini-consolidations according to age and performance status. Midostaurin was added in FLT3-mutated pts. At time of molecular relapse, pts received off label venetoclax 400 mg/d (d1-14, d1-21 or d1-28 according to centers) with no ramp-up and azacitidine 75 mg/m²/d subcutaneously (d1-5, d8-9). Antifungal/antibiotic prophylaxis and G-CSF use were not systematically recommended. Results: Twenty-two pts treated with VEN/AZAfrom 21/09/2020 to30/03/2023 were included. Their characteristics at diagnosis were: female (n= 14), median age 55y (range 27-71), de novo AML (n=21), median WBC (68 giga/L, range 2.32-339.7), NPM1 mutation (n=20), CBFB::MYH11 (n=2), FLT3 mutation (n=13). All pts achieved first CR after one cycle of induction chemotherapy. Pts received a median of three consolidation cycles. All but three pts had negative MRD or low level MRD (LL-MRD) in blood and/or BM at the end of consolidation. The median time between CR1 and molecular relapse was 9.5 months (range, 1-50). The median time between molecular relapse and first VEN/AZA cycle was 51 days. During first cycle of VEN/AZA, 12, 5 and 5 pts received 14, 21 or 28 days venetoclax, respectively; 19 were treated as out-pts, 4 received posaconazole and GCSF was used in 11 pts. 12 and 3 pts had grade 3-4 neutropenia or febrile neutropenia (FN), respectively. Only 3 pts (14%) were hospitalized for FN. The median number of VEN/AZA cycles was 2 (range 1-12). After C1+/-C2, 10 (45%) and 11 pts (55%) had undetectable or LL MRD in blood, respectively (Fig1). 20 pts were bridged to alloHCT in morphological CR after a median of 2 cycles (range, 1-4). Only one pt had a molecular progression before transplantation after 2 cycles. Two pts died, one had a molecular relapse after 7 cycles and progress rapidly to frank relapse, the other one died of post-transplant complication while in CR with undetectable MRD. All other pts remained in CR at date of last news. With a median FU from D1C1 of 13.5 months, median OS wat not reached and 1y-OS was 86% (Fig2). Conclusion: In the setting of molecular relapse, VEN/AZA is safe, prevent overt relapse, and induce a high rate of molecular response before alloHCT. Molecular relapse becomes a major therapeutic challenge. Clinical trial endpoints should include the treatment of molecular relapse as an event for RFS and EFS estimation.

Comparison of Safety and Efficacy between Venetoclax Combined with CAG (cytarabine, aclarubicin, G-CSF) Regimen and CAG Regimen Alone in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background: Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) have dismal outcomes, representing an urgent unmet need. The BCL2 inhibitor venetoclax has exhibit encouraging anti-tumor activity in AML. The clinical efficacy of the CAG regimen in patients with R/R AML has been confirmed in previous studies. The aim of this study was to retrospectively compare the safety and efficacy of the combination of venetoclax with CAG regimen and CAG alone in patients with R/R AML. Patients and methods: We retrospectively reviewed and compared the efficacy and safety of venetoclax combined with the CAG regimen (Ven-CAG group, n=37) and CAG regimen alone (CAG group, n=37) for 74 patients with R/R AML treated at our institution between August, 2016 and March 2023. The patients included those who were refractory to at least one cycle of induction chemotherapy, and patients with relapsed leukemia. According to the duration from complete remission (CR) to relapse, the relapsed patients were further divided into two subgroups, the favorable-risk relapsed group (the duration≥12 months) and the poor-risk relapsed group (the duration<12 months). The incidence of composite complete remission (CCR), minimal residual disease (MRD) status, one-year overall survival (OS), and adverse events (AEs) were analyzed and compared in two groups. Results: Patient age, sex, ELN risk stratification, disease status, risk stratification according to the duration from CR to relapse were comparable between two groups (Table 1). The CCR of Ven-CAG group was 78.4% (29/37)，which was superior to 56.8% (21/37) of CAG group (P=0.047) . Furthermore, the rate of MRD elimination in patients who achieved CCR in Ven-CAG group was significantly higher than that in CAG group [44.8% (13/29) vs. 9.5% (2/21), P= 0.007] (Table 2). The rate of MRD elimination in favorable-risk relapsed group (CR to hematological relapse ≥12 months) was higher in Ven-CAG group [100% (5/5) vs. 25% (1/4), P= 0.048]. The one-year OS were 78.4% (95% CI, 62.3%-94.5%) and 66.7% (95% CI, 51.2%-82.2%) in Ven-CAG and CAG group (P=0.225), respectively. The incidences of grade 3-4 hematologic AEs in Ven-CAG group and CAG group were 100% (37/37) and 97.3% (36/37), respectively (P=1.000). The incidences of febrile neutropenia were 67.6% (25/37) and 62.2% (23/37), respectively (P=0.626). Among patients who achieved CCR, the median time for neutrophil recovery in the Ven-CAG group and CAG group were 8 (3-30) days and 9.5 (3-31) days (P=0.781), while the median time for platelet recovery was 9 (3-28) days and 8 (3-19) days (P=0.708). The incidences of grade 3-4 non-hematologic AEs were comparable in Ven-CAG and CAG group (32.4% vs. 35.1%, P=0.806). The most common nonhematologic AEs were infections, with the incidences of 18.9% and 27%, respectively (P=0.407). No patients died within 4 weeks after initiating the induction course in Ven-CAG group. There was one case of early death during induction in CAG group due to cerebral hemorrhage. Conclusions: Venetoclax added to CAG regimen was safe and active in patients with R/R AML, producing higher CCR and MRD-negative remissions than CAG regimen alone. These results highlight the incremental benefit of venetoclax added to CAG regimen. This requires further verification through prospective, larger size clinical trials.

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<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.

A Phase 2 Study of Lenalidomide in Combination with Mitoxantrone, Etoposide, and Cytarabine (Len plus MEC) in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background: Outcomes for patients with relapsed or refractory acute myeloid leukemia (R/R AML) remain extremely poor. Response rates with salvage chemotherapy regimens, such as mitoxantrone, etoposide, and Cytarabine (MEC), have been associated with a complete remission rate of around 20-30%. We previously reported a phase I study combining Lenalidomide (Len) with MEC salvage chemotherapy, with encouraging response rates in R/R AML compared to other historical standards (DeAngelo et al. AJH 2018). This led to the current phase 2 study (NCT03118466) of Len combined with MEC in R/R AML to evaluate for the efficacy of this combination. Methods: We conducted a phase 2 study of Len plus MEC in adult patients (≥ 18 yrs) with R/R AML after 1 or more cycles of induction chemotherapy. Patients received Len dosed at 50mg/day on days 1-10, and Mitoxantrone 8mg/m2/d, Etoposide 100mg/m2/d and Cytarabine 1000mg/m2/d on days 4 through 8 of induction (Kohrt et al AJH 2010). Patients who achieved a complete remission (CR), complete remission with incomplete blood count recovery (CRi) or incomplete platelet recovery (CRp) could proceed with consolidation chemotherapy or hematopoietic stem cell transplantation at the discretion of the treating physician. The study followed a Simon two-stage design powered to detect improvement to a 45% response rate. The primary objective was to determine the response rate. Secondary objectives included time to neutrophil and platelet count recovery, treatment related mortality, rates of relapse, and overall survival. Results: A total of 40 patients were enrolled and received study treatment. The median age was 56 years (range, 19-70); 58% of the patients were male. 73% of patients had relapsed after initial therapy (29/40) while 27% had primary refractory AML (11/40) after their initial induction chemotherapy. The median number of prior therapies was 2 (range, 1-4). The majority of patients had adverse ELN 2023 risk (n=22; 55%). Recurrent gene mutations in 5 or more patients included DNMT3A (n=8), TET2 (n=7), NRAS (n=6), IDH2 (n=5), and ASXL1 (n=5); 2 patients harbored TP53 mutations. The most frequent grade 3-4 treatment-related toxicities were febrile neutropenia (n = 30; 75%), platelet count decrease (n = 40; 100%), anemia (n = 18; 45%), neutrophil count decrease (n = 14; 34%), blood bilirubin increase (n=6, 14%), and anorexia (n = 5; 12%). Three patients (8%) died during the study treatment period, all secondary to hepatic failure; no other early deaths occurred. Two of these patients had baseline grade 1 bilirubin elevation (no other patients in the study reported baseline bilirubin elevations). Median follow-up was 21 months. The overall response rate was 50% (20/40) where 19 achieved CR while 1 achieved CRi. Of 20 responders, the median time to neutrophil count recovery was 28 days and to platelet recovery was 34 days. The median time to relapse was 22.6 months. The median overall survival (OS) of the entire cohort was 16 months (Figure 1). Conclusions: Len plus MEC was associated with a high response rate and improved OS in patients with R/R AML as compared to historical controls. The overall safety profile was similar to prior MEC chemotherapy trials but several patients did experience early hepatic toxicity. Overall these data support evaluating high-dose Len combined with MEC for patients with R/R AML in a randomized study.

Frontline Venetoclax Therapy for 18-Year-Old Male with Ataxia Telangiectasia and Early T-Cell Precursor Acute Lymphoblastic Leukemia

Ataxia Telangiectasia (AT) is an autosomal recessive disorder which is associated with progressive neurodegeneration, immunodeficiency, and predisposition to cancer. Specifically, around 40% of patients with AT will develop malignancy during their lifetime, most commonly lymphoid malignancies. Patients with AT have increased toxicity to chemotherapy and radiation, which necessitates modified and individualized therapy approaches. Early T-cell precursor ALL (ETP-ALL) is considered high risk and venetoclax has emerged as potential therapy combined with other chemotherapy to help achieve remission but there have been no reports of venetoclax use in patients with AT. Here, we present a case of an 18-year-old male with Ataxia Telangiectasia diagnosed with ETP-ALL, who achieved remission after therapy was augmented with venetoclax during consolidation phase of chemotherapy. The patient initially presented with lower limb swelling, fatigue and nose bleeds and found to have a white cell count (WBC) of 107 K/uL with 72% peripheral blasts. He was treated with steroid monotherapy for 38 days prior to presentation to our institution. On arrival to our institution he had a WBC count of 42 K/uL with 75 % blasts in peripheral blood. His bone marrow evaluation had 83% blasts. Flow cytometry was positive for CD3, CD5 (partial), CD7, CD38, CD45, CD54, CD56, CD 117 (partial), negative for MPO, TdT, HLA-DR. This confirmed the diagnosis of ETP-ALL. An 81 gene panel testing was positive for NOTCH 1, SRSF2, EZH2, CREBBP. No abnormal fusions or translocations were present, and cytogenetics did not reveal a clonal abnormality. Induction chemotherapy was given as per COG AALL1231 protocol with dose modifications including 50% decrease in vincristine and cyclophosphamide. His end of induction (EOI) bone marrow evaluation was positive for 32% MRD. Molecular diagnosis positive for NOTCH1, SRSF2 and EZH2. As it is not uncommon for patients with ETP-ALL to have persistent disease after induction chemotherapy cycle, we proceeded with consolidation per AALL0434 protocol with Nelarabine. Unfortunately, even with dose reduced vincristine he developed vocal cord paralysis, lower extremity neuropathy and urinary retention, hence vincristine was omitted. Bone marrow evaluation was repeated mid consolidation and was still positive for 20% MRD. Due to significant modifications in therapy as well as persistent disease midway through consolidation, venetoclax was added to augment therapy during the consolidation phase. He was given 150 mg/m2 for 7 days directly followed by nelarabine. End of consolidation marrow was negative for MRD, and molecular testing (81 gene panel) was also negative. He tolerated venetoclax well without any significant toxicities and remains in remission 4 months post therapy with venetoclax. This report indicates that venetoclax can be used safely in patients with AT. This patient showed persistent MRD positive mid-way through consolidation with negativity after augmentation with venetoclax. Patients with AT have increased risk of toxicity from chemotherapy agents which requires dose modifications in their chemotherapy regimen. Venetoclax augmentation may be a viable approach for patients with AT or DNA repair disorders.

Delaying Pegaspargase Administration during Induction in Adults with Acute Lymphoblastic Leukemia

Background Pegaspargase (PEG-asparaginase) is a key drug in pediatric-inspired regimens that is utilized frequently in young adults with acute lymphoblastic leukemia (ALL). Pegaspargase has unique toxicities including hypersensitivity, hepatotoxicity, pancreatitis, thrombosis and hypertriglyceridemia. Hepatotoxicity occurs frequently during the induction cycle in newly diagnosed (ND) adults with ALL, and although it is usually reversible, its prolonged persistence may cause interruptions in the treatment. We analyzed two approaches for pegaspargase administration in ND adults with ALL; early administration on day 4 and delayed administration on day 15 that were utilized in our treatment protocols.We hypothesized that later administration of pegaspargase is associated with lower risk of toxicity while maintaining similar response rate. Methods This is a retrospective analysis of adult patients (age:19-71) with ND ALL that received pegaspargase during their first induction chemotherapy cycle. Patients were stratified into two groups, the early (day 4) and delayed (day 15) pegaspargase group. The primary objective was to assess differences in toxicities, including hepatotoxicity, hypertriglyceridemia, thrombosis, and pancreatitis. Adverse events were graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Key secondary outcomes included differences in minimal residual disease (MRD), complete remission (CR) rates, and induction related mortality. Statistical analysis was done with descriptive statistics, Mann Whitney U test, Pearson chi-squared test, and multivariate analysis (p-value < 0.05). Results Of 117 patients analyzed, there were 72 (62%) patients who received early pegaspargase (EP) while 45 (38%) patients received delayed pegaspargase (DP). The median age of patients was younger in the EP cohort (31.5 vs. 38, p=0.03) and there was no significant difference in gender (p=0.36), BMI (p=0.42), or median pegaspargase dose (p=0.12). CALGB10403 was the most common chemotherapy regimen in the EP cohort and in 20% of DP cohort, while modified BFM was the most common chemotherapy regimen in DP cohort (80%). Grade 3/4 transaminitis occurred more frequently in EP compared to DP cohort (15% vs 2%; p=0.02), however, other grade 3/4 toxicities were not statistically different: hyperbilirubinemia (21% vs 11%; p=0.17), hypertriglyceridemia (3% vs 9%; p=0.14), and pancreatitis (4% vs 2%; p=0.57), respectively. The CR rate (88% vs 80%; p= 0.18) and end of induction MRD negative rate (60% vs 61%; p=0.86) were similar for EP and DP cohorts, respectively. There was no significant difference in the rates of documented infections during induction (10% vs 9%; p=0.88) and 90-day mortality (2% vs 0%; p=0.42) between EP and DP cohorts, respectively. Post-pegaspargase dose modifications to induction chemotherapy were only observed in the EP cohort (18% vs 0%; p=0.002), with modifications including reduction (5%), delays (6%), and discontinuation (5%) of other chemotherapy agents. In multivariable logistic regression analysis, only older age (OR 1.05; p=0.025) and EP administration (OR 4.58; p=0.007) predicted increased risk of grade 3/4 hepatotoxicity (transaminitis and/or hyperbilirubinemia). Conclusions Delaying pegaspargase administration from day 4 to day 15 during induction cycle in adults with ALL was associated with lower rate of high-grade hepatotoxicity and subsequent treatment dose modifications. Delaying pegaspargase had no negative impact on CR or MRD-negativity rates at the end of induction.

Efficacy and Safety of Clifutinib, a Novel, Highly Selective, Oral FLT3 Inhibitor, in Patients with FLT3-Mutated Relapsed or Refractory Acute Myeloid Leukemia：Updated Results from a Phase I Study

Background: Patients with relapsed/ refractory (R/R) FLT3-internal tandem duplication positive (FLT3-ITD+) acute myeloid leukemia (AML) have limited treatment options and poor prognosis. Clifutinib is a novel, highly selective, oral FLT-3 inhibitor with potent activity against FLT3-ITD(+) leukemic models both in vitro and in vivo. This study is a first-in-human study of clifutinib, with the purpose of evaluating the safety, tolerability, efficacy, and pharmacokinetic (PK) profile in Chinese patients with R/R FLT3-mutated AML (NCT04827069). Methods: Patients aged ≥18 years with AML who were refractory to ≥ 2 cycles of standard induction chemotherapy or relapsed after achieving remission from previous treatments were enrolled. Previous use of FLT3 inhibitors were allowed. The study included two parts, a dose-escalation part (10 to 100 mg/day cohorts) and a dose-expansion part (40 and 70 mg/day cohorts). The primary endpoints were safety and tolerability, and the secondary endpoints were efficacy [CR(complete remission)/CRh (complete remission with partial hematologic recovery) rate, composite complete remission (CRc: CR+CRh+CRi, CRi defined as complete remission with incomplete hematological recovery) rate, TTR (time to remission), duration of remission (DOR), and overall survival (OS)] and pharmacokinetics (PK). Results: As of May 2023, 75 patients (pts) were enrolled (Figure 1), with a median age of 55 years (range:18-80), and 96.0% pts were FLT3-ITD(+) or TKD(+) [80.0% with ITD(+)/TKD(-), 9.3% with ITD(+)/TKD(UK), 5.3% with ITD(+)/TKD(+), 1.3% with ITD(-)/TKD(+)], 58.7% pts had received ≥2 lines of previous treatment, and 32.0% pts exposed to FLT3 inhibitors. 3 pts experienced dose-limiting toxicities (DLT): one out of 6 pts in the 55 mg/day cohort (Grade 3 QTcF prolongation with ΔQTcF =71 ms) and 2 out of 6 pts in the 100 mg/day cohort (Grade 3 nausea and Grade 3 atrial fibrillation). Therefore, the maximum tolerated dose of clifutinib was 70 mg/day. The most common (rate ≥20%) treatment-related adverse events (TRAEs) included leukopenia (70.7%), thrombocytopenia (68%), neutropenia (64%), anemia (48%), lymphopenia (26.7%), pneumonia (26.7%), hypokalemia (26.7%), aspartate aminotransferase increased (22.7%), alkaline phosphatase increased (21.3%) and alanine aminotransferase increased (20.0%). Grade ≥3 TRAEs occurring in ≥20% pts were leukopenia, thrombocytopenia, neutropenia, anemia, lymphopenia, and pneumonia. Approximately dose-proportional PK parameters were observed across 40-100 mg/day dose range for both single and repeat dosing (the parent drug might approach saturation at 100 mg/day), and median t max ranged from 2 to 6 hours. For efficacy, responses occurred in 28 (40.6%) of 69 FLT3-ITD(+) or TKD(+) efficacy evaluable pts, including 5 (7.2%) CR, 5(7.2%) CRh, 17 (24.6%) CRi, 1 (1.4%) MLFS, and the median TTR was 32 days (range: 26-149 days). The efficacy was better in the 40 mg/day group compared to 70 mg/day and 40-100 mg/day groups, with CR/CRh rate of 21.2% (7/33) vs 8.3% (2/24) vs 14.5% (10/69), CRc rate of 48.5% (16/33) vs 33.3% (8/24) vs 39.1% (27/69), and median DOR of CR/CRh was 3.2 months (95% CI:1.9, NA) vs 0.9 months (95% CI: NA, NA ) vs 3.2 months (95% CI: 0.9, 7.4 ), the median OS was 6.5 months vs 5.4 months vs 6.3 months, respectively. Among FLT3-ITD(+)/TKD(-) subjects administered with clifutinib 40 mg/day, the CR/CRh rate was 23.1% (6/26) with 3 patients achieved CR, median DOR of CR/CRh was 3.7 months, the CRc rate was 53.8% (14/26), and median OS was 7.4 months. Compared to FLT3-ITD(+) or TKD(+) pts, 40 mg dose group exhibited better efficacy in FLT3-ITD(+)/TKD(-) pts. In addition, clifutinib exhibited more potent anti-leukaemic activity in patients received only one line of previous treatment. Among patients experienced only one line treatment of 40 mg dose group, the CR/CRh rate was 30.8% (4/13), the CRc rate was 53.8% (7/13), and the median OS was 7.9 months (Table 1) . Conclusion: This phase 1 study has demonstrated an acceptable safety profile and a significant anti-leukaemic activity of clifutinib in FLT3 mutant R/R AML, with the best response at the dose of 40 mg/day in FLT3-ITD(+)/TKD(-) AML. A confirmatory phase 3 study is currently ongoing to further evaluate the efficacy and safety of clifutinib dosed at 40 mg/day in R/R AML pts after first-line therapy with FLT3-ITD(+)/TKD(-) (NCT05586074). Keywords: Acute myeloid leukemia, FLT3 inhibitor, Clifutinib