Consolidation Chemotherapy Research Articles

PATH-38. INTRACRANIAL SARCOMA WITH DICER1 MUTATION IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1

Abstract A 16-year-old male with neurofibromatosis type 1 (NF1) and a history of low-grade gliomas presented for resection of a progressively enlarging, known low-grade glioma. On follow-up imaging for surgical planning of the low-grade glioma, a new area of concern was detected of a leptomeningeal-based lesion over the left frontal lobe. A biopsy of the frontal lobe lesion subsequently showed a primary intracranial sarcoma with DICER1 mutations, DICER1 p.Q1552 and p.D1709G. An important histology finding was that of prominent eosinophilic cytoplasmic globules, which are associated with intracranial sarcomas with DICER1 mutations. Additional molecular findings of this tumor included NF1 p.K1986fs and TP53 p.G279E mutations in the setting of this patient’s known history of NF1. A DICER mutation was not detected in the concurrent low-grade glioma at the time of his intracranial sarcoma diagnosis, thus thought not to be a germline-derived mutation. He went on to have a surgical resection with subsequent photon radiation therapy followed by consolidation chemotherapy. A Ewing sarcoma based regimen as per COG protocol AEWS1031 was selected for his therapy consisting of vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide (VDC-IE). This was chosen based on prior cases showing response to anthracycline-based regimens. This patient has overall shown improvement without signs of progression now 7 months out from his initial diagnosis. This case highlights the importance of recognizing the association of patients with NF1 being at an increased risk for the development of intracranial sarcomas with DICER1 mutations and correlation with histologic findings of eosinophilic cytoplasmic globules. It also points to the need for reporting these rare cases for optimization of therapy selection to provide a more standardized and evidence-based approach in the care for these patients.

Cost-Effectiveness of Total Neoadjuvant Therapy With Selective Nonoperative Management for Locally Advanced Rectal Cancer: Analysis of Data From the Organ Preservation for Rectal Adenocarcinoma Trial.

The clinical efficacy of total neoadjuvant therapy (TNT) followed by selective nonoperative management (NOM) for locally advanced rectal cancer (LARC) was examined in the Organ Preservation for Rectal Adenocarcinoma (OPRA) trial. We investigated the cost and quality-of-life implications of adopting this treatment approach. We analyzed clinical, cost, and quality-of-life outcomes for TNT with selective NOM in comparison with chemoradiotherapy (CRT)-surgery-adjuvant chemotherapy (standard of care [SOC]) using data from OPRA, prospective cohorts, and published studies. Cost-effectiveness was evaluated over varying willingness-to-pay thresholds, and sensitivity analyses evaluated cost-effectiveness for different surgical contexts and SOC variants as well as a 10-year time horizon. SOC was dominated by TNT with selective NOM in the base case analysis. TNT in which CRT was followed by consolidation chemotherapy (CNCT) was the least costly at $89,712 in Medicare proportionate US dollars (MP$), followed by TNT in which induction chemotherapy was followed by CRT (INCT) at MP$90,259 and SOC at MP$98,755. INCT was the preferred strategy, with 4.56 quality-adjusted life years, followed by CNCT at 4.42 and SOC at 4.29. TNT with selective NOM dominated SOC in all sensitivity analyses except when SOC omitted adjuvant chemotherapy without an impact on disease-free survival. CNCT was more cost effective than SOC when the proportion of patients entering NOM after TNT was ≥22% or ≥43%, for SOC with and without adjuvant therapy, both well below the rates seen in OPRA. TNT with selective NOM is cost effective. The cost-effectiveness of CNCT with NOM relative to SOC is dependent on CNCT being made available to a sufficiently large proportion of patients with LARC. Additional analyses are needed to validate these findings from a societal perspective and in the context of other emerging treatment paradigms for LARC.

Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: Insights from the Western Australian Context.

Recent studies have associated total neoadjuvant therapy (TNT) with better treatment adherence, decreased toxicity, improved complete clinical response and anal sphincter preservation rates in patients with locally advanced rectal cancer (LARC). However, real-world experience with TNT in the management of LARC remains limited. This study aimed to evaluate the efficacy and safety outcomes of TNT for LARC in Western Australia. Patients with LARC (cT2-4 and/or cN1-2) who underwent induction chemotherapy followed by neoadjuvant chemoradiotherapy or neoadjuvant chemoradiotherapy followed by consolidation chemotherapy, followed by surgery were recruited from two hospitals in Western Australia. Efficacy outcomes assessed included clinical response (complete, partial, no response), and pathologic complete response (pCR) rate, R0 resection rate, and R1 resection rate were evaluated. Those patients who achieved clinical complete response following TNT were given the option of active surveillance. The safety and tolerability of TNT were assessed. 32 patients with LARC were treated with TNT. In total, 17 patients (53%) received chemoradiotherapy followed by consolidation chemotherapy and 15 patients (47%) received induction chemotherapy followed by chemoradiotherapy. Nine (28%) of the patients with LARC treated with TNT had a complete clinical response, twenty-one (66%) patients had a partial clinical response, and two (6%) patients had no response to TNT. Of the 32 patients, 27 (84%) underwent surgery. There was a 100% R0 resection rate. The pCR rate was 15%. pCR, clinical response, and the R0 resection rate were similar between the two TNT regimens. TNT was well tolerated, with the majority of patients (88%) completing the chemotherapy course with grade 1 and 2 adverse effects. In conclusion, TNT emerges as a promising approach for the management of LARC. However, further research is warranted to refine the optimal TNT protocols, determine its long-term outcomes, and identify patient populations who would benefit the most from this innovative therapeutic strategy.

Inotuzumab Ozogamicin and Low-Intensity Chemotherapy in Older Patients With Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia.

The use of inotuzumab ozogamicin (InO), a conjugated anti-CD22 monoclonal antibody, is becoming a promising frontline treatment for older patients with ALL. EWALL-INO is an open-label prospective multicenter phase II trial (ClinicalTrials.gov identifier: NCT03249870). Patients age 55 years and older with newly diagnosed CD22+ Philadelphia chromosome-negative (Ph-) B-cell precursor (BCP) ALL were eligible. After a prephase, a first induction consisting of vincristine, dexamethasone, and three injections of InO (0.8 mg/m2 day 1, 0.5 mg/m2 day 8/day 15) was followed by a second induction combining cyclophosphamide, dexamethasone, and two injections of InO (0.5 mg/m2 day 1/day 8). Responders received up to six cycles of chemotherapy consolidation and 18-month chemotherapy maintenance. Allotransplant was allowed after three consolidations. The primary end point was 1-year overall survival (OS). Between December 2017 and March 2022, 131 patients (median age 68 years) were included. Three patients died during induction 1 (n = 130), two from multiple organ failure and one from hemorrhage, and none during induction 2 (n = 120). After induction 2, 90% of the patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 80% had measurable residual disease (MRD2) <10-4. Among responders (n = 119), 47 relapsed and 14 died in CR/CRp. One-year OS, relapse-free survival (RFS), and cumulative incidence of relapse (CIR) rates were 73.2%, 66%, and 25%, respectively. High-risk cytogenetics and lower CD22 expression (<70%) were associated with worse OS, while both high-risk cytogenetics and MRD2 ≥10-4 were associated with lower RFS and higher CIR. The 10 allotransplanted patients had very favorable outcomes (90% 2-year OS/RFS and no relapse). Only one nonfatal sinusoidal obstructive syndrome was documented during the study. Our results support InO's use in first-line regimens for older patients with CD22+ Ph- BCP-ALL.

Short-Course TNT Improves Rectal Tumor Downstaging in a Retrospective Study of the US Rectal Cancer Consortium.

The RAPIDO trial showed promising rates of pathologic complete response (pCR) after neoadjuvant short-course radiation with consolidation chemotherapy (total neoadjuvant therapy [SC TNT]) for rectal cancer. Only single-center reviews comparing tumor downstaging between SC TNT and long-course chemoradiation (LCRT) have been published in the United States. We reviewed our multi-institutional experience with both. The US Rectal Cancer Consortium database (2007-2018) including data from six high-volume rectal cancer care centers was reviewed. Patients with nonmetastatic, rectal adenocarcinoma who had neoadjuvant LCRT alone or SC TNT before excision or definitive nonoperative management were included. The primary outcome was the rate of complete response (CR), including pCR or durable (12 month) clinical complete response. Of 857 included patients, 175 (20%) received SC TNT and 682 (80%) received LCRT. The LCRT group had more low tumors (51.8% vs. 37.1%, p < 0.0001) and more clinically node-negative disease (31.8% vs. 22.3%, p < 0.0001). The CR rate was higher after SC TNT (34.1% vs. 20.3%, p = 0.0001). SC TNT was a predictor of CR (OR: 2.52, CI: 1.68-3.78). SC TNT patients completing 5-6 months of consolidation chemotherapy had a CR rate of 42.9%. There was no difference in 3-year PFS. SC TNT increases CR rate when compared to LCRT. For patients seeking nonoperative options or fewer radiation treatments, SC TRT should be preferred over LCRT alone.

Optimal Sequence for Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: An Evidence-Based Review.

Historically, multimodal therapeutic strategies involving preoperative chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (CT) have been employed to treat locally advanced rectal cancer (LARC). Total Neoadjuvant Therapy (TNT) is showing promise in improving outcomes. Despite its benefits, the optimal sequencing within TNT-whether induction chemotherapy should precede or follow chemoradiotherapy-remains a critical question. This study endeavors to explore the effects of different TNT sequencing strategies on patient outcomes, including tumor downstaging, pathological response, organ preservation, and the balance between efficacy and tolerability. Our methodology entailed a comprehensive literature review conducted on Medline, focusing on recent research, including retrospective studies, systematic reviews, and clinical trials. The review emphasized the comparison of induction chemotherapy versus consolidation chemotherapy within TNT regimens, assessing outcomes such as pathological response, organ preservation rates, and adverse effects. To ensure the selection of appropriate and high-quality studies, specific inclusion and exclusion criteria were applied. The analysis revealed that induction chemotherapy might lead to decreased adherence to subsequent chemoradiotherapy while offering an early intervention against micrometastasis and potentially improving overall chemotherapy compliance. Conversely, consolidation chemotherapy has been associated with higher pathological complete response (pCR) rates and improved tolerability, indicating its potential for patients requiring local symptom relief or those eligible for a nonoperative management approach. Comparative studies like CAO/ARO/AIO-12 and the OPRA trials have significantly contributed to our understanding, suggesting that while both strategies have distinct advantages, the choice between induction and consolidation chemotherapy should be tailored based on individual patient profiles and tumor characteristics. This narrative review underscores the importance of a nuanced approach to TNT sequencing in locally advanced rectal cancer, highlighting the need for further research to refine treatment strategies.

Total Neoadjuvant Therapy Versus Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer: A Multi-Institutional Real-World Study.

Total neoadjuvant therapy (TNT) has emerged as a promising approach for managing locally advanced rectal cancer (LARC), aiming to enhance resectability, increase pathological complete response (pCR), improve treatment compliance, survival, and sphincter preservation. This study compares the clinical outcomes of TNT, with either induction or consolidation chemotherapy, to those of the standard chemoradiotherapy (CRT). In this retrospective multi-institutional study, patients with stage II-III LARC who underwent CRT or TNT from seven oncology centers between 2021 and 2024 were retrospectively analyzed. The TNT group was categorized into induction or consolidation groups based on the sequence of chemotherapy and radiotherapy. Clinical and pathological data and treatment outcomes, including pCR, event-free survival (EFS), and overall survival (OS), were analyzed. Among the 276 patients, 105 received CRT and 171 underwent TNT. The TNT group showed significantly higher pCR (21.8% vs. 2.9%, p < 0.001) and lower lymphatic (26.3% vs. 42.6%, p = 0.009), vascular (15.8% vs. 32.7%, p = 0.002), and perineural invasion rates (20.3% vs. 37.6%, p = 0.003). Furthermore, 16.9% of TNT patients opted for non-operative management (NOM), compared to 0.9% in the CRT group (p < 0.001). The median interval between the end of radiotherapy and surgery was longer in the TNT group (17.6 weeks vs. 8.8 weeks, p < 0.001). The 3-year EFS was 58.3% for CRT and 71.1% for TNT (p = 0.06). TNT is associated with higher pCR, lower lymphatic and vascular invasion rates, and higher rates of NOM compared to CRT. This supports the use of TNT as a viable treatment strategy for LARC, offering potential benefits in quality of life.

Efficacy and safety of MR-guided adaptive simultaneous integrated boost radiotherapy to primary lesions and positive lymph nodes in the neoadjuvant treatment of locally advanced rectal cancer: a randomized controlled phase III trial

BackgroundIn locally advanced rectal cancer (LARC), optimizing neoadjuvant strategies, including the addition of concurrent chemotherapy and dose escalation of radiotherapy, is essential to improve tumor regression and subsequent implementation of anal preservation strategies. Currently, dose escalation studies in rectal cancer have focused on the primary lesions. However, a common source of recurrence in LARC is the metastasis of cancer cells to the proximal lymph nodes. In our trial, we implement simultaneous integrated boost (SIB) to both primary lesions and positive lymph nodes in the experimental group based on magnetic resonance-guided adaptive radiotherapy (MRgART), which allows for more precise (and consequently intense) targeting while sparing neighboring healthy tissue. The objective of this study is to evaluate the efficacy and safety of MRgART dose escalation to both primary lesions and positive lymph nodes, in comparison with the conventional radiotherapy of long-course concurrent chemoradiotherapy (LCCRT) group, in the neoadjuvant treatment of LARC.MethodsThis is a multi-center, randomized, controlled phase III trial (NCT06246344). 128 patients with LARC (cT3-4/N+) will be enrolled. During LCCRT, patients will be randomized to receive either MRgART with SIB (60–65 Gy in 25–28 fractions to primary lesions and positive lymph nodes; 50–50.4 Gy in 25–28 fractions to the pelvis) or intensity-modulated radiotherapy (50–50.4 Gy in 25–28 fractions). Both groups will receive concurrent chemotherapy with capecitabine and consolidation chemotherapy of either two cycles of CAPEOX or three cycles of FOLFOX between radiotherapy and surgery. The primary endpoints are pathological complete response (pCR) rate and surgical difficulty, while the secondary endpoints are clinical complete response (cCR) rate, 3-year and 5-year disease-free survival (DFS) and overall survival (OS) rates, acute and late toxicity and quality of life.DiscussionSince dose escalation of both primary lesions and positive nodes in LARC is rare, we propose conducting a phase III trial to evaluate the efficacy and safety of SIB for both primary lesions and positive nodes in LARC based on MRgART.Trial registrationThe study was registered at ClinicalTrials.gov with the Identifier: NCT06246344 (Registered 7th Feb 2024).

What Predicts Complete Response to Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer?

Total neoadjuvant therapy in treatment of stage II-III rectal cancer involves administration of either induction or consolidation chemotherapy with chemoradiation before surgery. Total neoadjuvant therapy is associated with increased complete response rate, which is defined as the proportion of patients who either had pathological complete response after surgery or sustained clinical complete response at least for a year under surveillance. To identify the predictors of complete response to total neoadjuvant therapy and compare different diagnostic tools in predicting complete response. Retrospective cohort study. A single tertiary-care center. Stage II-III rectal cancer patients who were diagnosed between January 2015 and December 2021. Total neoadjuvant therapy. Complete response rate, predictors of complete response, sensitivity and specificity of sigmoidoscopy and MRI in predicting complete response. One hundred nineteen patients (mean age 56 [±11.3] years, 47 [39.5%] female, 100 [84%] stage III rectal cancer were included. Median tumor size was 5.1 (4-6.5) cm, 63 (52.9%) were low rectal tumors. Twenty-one (17.6%) patients had extramural vascular invasion, 62 (52.1%) had elevated carcinoembryonic antigen at baseline. One hundred eight (90.8%) patients received consolidation chemotherapy. After total neoadjuvant therapy, 88 (73.9%) out of 119 patients underwent surgery, of whom 20 (22.7%) had pathological complete response. Thirty-one (26.1%) patients underwent watch-and-wait, of whom 24 (77.4%) had sustained clinical complete response. Overall complete response rate was 37%. Low rectal tumors (OR 2.6 [95% CI, 1.1-5.9], p = 0.02) and absence of EMVI [OR 5.4 (95% CI, 1.2-25.1), p = 0.01] were predictors of complete response. In predicting complete response, sigmoidoscopy was more sensitive (76.0% vs. 62.5%) and specific (72.5% vs. 69.2%) than MRI. The specificity further increased when 2 techniques were combined (82.5%). Retrospective study. Complete response rate after total neoadjuvant therapy was 37%. Low rectal tumors and absence of extramural vascular invasion were predictors of complete response. Sigmoidoscopy was better in predicting incomplete response, whereas combination (MRI and sigmoidoscopy) was better in predicting complete response.

Organ preservation after neoadjuvant long-course chemoradiotherapy versus short-course radiotherapy

Potential differences in organ preservation between total neoadjuvant therapy (TNT) regimens integrating long-course chemoradiotherapy (LCCRT) and short-course radiotherapy (SCRT) in rectal cancer remain undefined. This natural experiment arose from a policy change in response to the COVID-19 pandemic during which our institution switched from uniformly treating patients with LCCRT to mandating that all patients be treated with SCRT. Our study includes 323 locally advanced rectal adenocarcinoma patients treated with LCCRT-based or SCRT-based TNT from January 2018 to January 2021. Patients who achieved clinical complete response were offered organ preservation with watch-and-wait (WW) management. The primary outcome was 2-year organ preservation. Additional outcomes included local regrowth, distant recurrence, disease-free survival (DFS), and overall survival (OS). Patient and tumor characteristics were similar between LCCRT (n= 247) and SCRT (n= 76) cohorts. Median follow-up was 31 months. Similar clinical complete response rates were observed following LCCRT and SCRT (44.5% versus 43.4%). Two-year organ preservation was 40% [95% confidence interval (CI) 34% to 46%] and 31% (95% CI 22% to 44%) among all patients treated with LCCRT and SCRT, respectively. In patients managed with WW, LCCRT resulted in higher 2-year organ preservation (89% LCCRT, 95% CI 83% to 95% versus 70% SCRT, 95% CI 55% to 90%; P= 0.005) and lower 2-year local regrowth (19% LCCRT, 95% CI 11% to 26% versus 36% SCRT, 95% CI 16% to 52%; P= 0.072) compared with SCRT. The 2-year distant recurrence (10% versus 6%), DFS (90% versus 90%), and OS (99% versus 100%) were similar between WW patients treated with LCCRT and SCRT, respectively. While WW eligibility was similar between cohorts, WW patients treated with LCCRT had higher 2-year organ preservation and lower local regrowth than those treated with SCRT, yet similar DFS and OS. These data support induction LCCRT followed by consolidation chemotherapy as the preferred TNT regimen for patients with locally advanced rectal cancer pursuing organ preservation.

The significance of consolidation chemotherapy after concurrent chemoradiotherapy in esophageal squamous cell carcinoma: a randomized controlled phase III clinical trial.

This study explored the significance of consolidation maintenance chemotherapy after concurrent chemoradiotherapy with different regimens in patients with esophageal squamous cell carcinoma. A prospective randomized controlled phase III clinical trial was designed and registered in the China Clinical Trials Registry (Registration number: ChiCTR-TRC-12002719). Survival data were analyzed in terms of intention-to-treat (ITT) and per-protocol (PP) sets for patients undergoing cisplatin and 5-fluorouracil (PF) (group A), or cisplatin and paclitaxel (TP) (group B). The incidence risk of grade III-IV leukopenia in group B was higher than in group A (49.2% vs. 25.5%, p = 0.012). The survival rates at 1, 2, 3, and 5 years were 83.8%, 62.6%, 53.1%, and 41.3%, respectively. Consolidation chemotherapy after concurrent chemoradiation therapy had no benefit on median progression-free survival (PFS) (p = 0.95) and overall survival (OS) (p = 0.809). According to the ITT analysis, the median PFS in group A and group B was 28.6 months and 30.3 months (X2 = 0.242, p = 0.623), while the median OS was 31.0 months and 50.3 months (X2 = 1.25，p = 0.263). For the PP analysis, the median PFS in group A and group B were 28.6 months and 30.3 months (p = 0.584), while the median OS was 31.0 months and 50.3 months (p = 0.259), respectively. Patients receiving consolidation chemotherapy did not show significant OS benefits (46.9 months vs. 38.3 months; X2 = 0.059, p = 0.866). Similar PFS and OS were found between PF and TP regimens with concurrent chemoradiotherapy. Consolidation chemotherapy did not show any significant OS benefits.

Higher Relapse Rate and Resource Utilization With Ara-C Consolidation Chemotherapy Alone Compared With Hematopoietic Cell Transplantation in First Remission in a Cohort of Younger Adults With Acute Myeloid Leukemia With t(8;21) (q22;q22 .1)

Higher Relapse Rate and Resource Utilization With Ara-C Consolidation Chemotherapy Alone Compared With Hematopoietic Cell Transplantation in First Remission in a Cohort of Younger Adults With Acute Myeloid Leukemia With t(8;21) (q22;q22 .1)

AML-390 Higher Relapse Rate and Resource Utilization With Ara-C Consolidation Chemotherapy Alone Compared With Hematopoietic Cell Transplantation in First Remission in a Cohort of Younger Adults With Acute Myeloid Leukemia With t(8;21) (q22;q22.1)

AML-390 Higher Relapse Rate and Resource Utilization With Ara-C Consolidation Chemotherapy Alone Compared With Hematopoietic Cell Transplantation in First Remission in a Cohort of Younger Adults With Acute Myeloid Leukemia With t(8;21) (q22;q22.1)

Chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: Pooled analysis of the CAO/ARO/AIO-12 and the OPRA randomized phase 2 trials

Total neoadjuvant therapy (TNT) has been used for patients with locally advanced rectal cancer. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy (CT) is a matter of debate. We performed a pooled analysis of the CAO/ARO/AIO-12 and OPRA multicenter, randomized phase 2 trials to identify patient subsets that could benefit from one TNT sequence over the other regarding disease-free survival (DFS). Patients with stage II/III rectal cancer were randomized to CRT (50.4-54Gy) with either induction (INCT-CRT) or consolidation CT (CRT-CNCT) with fluorouracil, leucovorin, oxaliplatin (CAO/ARO/AIO-12 and OPRA) or capecitabine and oxaliplatin (OPRA) followed by mandatory total mesorectal excision (TME) (CAO/ARO/AIO-12) or selective watch-and-wait surveillance (OPRA). 311 and 324 patients were recruited from June 15, 2015 to January 31, 2018; and from April 12, 2014 to March 30, 2020 in the two trials, respectively. Pretreatment clinical and tumor characteristics included were age, sex, ECOG, cT-category, cN-category, clinical UICC stage, location from anal verge, and tumor grade. In total, 628 eligible patients were included in the pooled analysis (CAO/ARO/AIO-12, n=304; OPRA, n=324). Of those, 313 were randomly assigned to the INCT-CRT group, and 315 to the CRT-CNCT group. Median follow-up was 43 months (IQR, 35-49) months in the CAO/ARO/AIO-12 trial and 61,2 months (IQR, 42-68,4) in the OPRA trial. Pooled analysis of baseline clinical and tumor characteristics did not identify any subgroups of patients that would benefit by the one TNT sequence over the other with regard to DFS. To our knowledge, this is the first pooled analysis of two randomized trials after direct head-to-head comparison of both TNT sequences. Both trials reported higher rates of complete response with CRT-CNCT, and this should be considered the preferred TNT sequence if organ preservation is a priority.

Cost-effectiveness of blinatumomab for the treatment of B‑precursor acute lymphoblastic leukemia pediatric patients with high‑risk first‑relapse in Mexico

BackgroundBlinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule that engages T cells to lyse CD19-expressing B cells. Based on a multicenter, open-label, phase 3, randomized clinical trial (Clinical Trials ID: NCT02393859), we aimed to evaluate the cost-effectiveness (CE) of blinatumomab compared to standard consolidation chemotherapy (SC) for the treatment of pediatric patients with high-risk first-relapsed Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (B-ALL) from a Mexico healthcare payer perspective. MethodsA decision-analytic model, a partitioned survival model, was used to estimate the life-years (LYs) and costs over a lifetime horizon. We assumed that patients who remained alive beyond a 5-year period were cured. To account for the lingering impacts of cancer treatment, an excess mortality rate was incorporated into the model. Event-free survival (EFS) and overall survival (OS) were estimated by fitting mixture-cure and standard parametric survival distributions to the time-to-event data from the phase 3 trial. The model accounted for treatment costs, adverse event costs, follow-up costs, subsequent allogeneic hematopoietic stem cell transplantation (alloHSCT) costs, and subsequent treatment costs. ResultsBlinatumomab was associated with a lifetime gained of 5.11 years at an incremental cost of $621,111 MXN, relative to SC. The ICER for blinatumomab vs Standard of care was estimated to be $121,526 MXN/LY gained in the base case. Cost-effectiveness was sensitive to varying the time horizon. Blinatumomab had a probability of 99 % of being cost-effective, relative to SC, at the willingness to pay threshold defined in Mexico. LimitationsHealth-related quality of life values were not included in the analysis and therefore we did not estimate the quality-adjusted life-years gained. ConclusionsBlinatumomab was associated with greater benefit in terms of OS and EFS relative to SC. Probabilistic, deterministic, and scenario analyses indicate that blinatumomab represents the best value for money. Therefore, blinatumomab administered as part of consolidation therapy in B-ALL pediatric patients with high-risk first relapse is a cost-effective option.

Molecular Features and Treatment Paradigms of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a common hematologic malignancy that is considered to be a disease of aging, and traditionally has been treated with induction chemotherapy, followed by consolidation chemotherapy and/or allogenic hematopoietic stem cell transplantation. More recently, with the use of next-generation sequencing and access to molecular information, targeted molecular approaches to the treatment of AML have been adopted. Molecular targeting is gaining prominence, as AML mostly afflicts the elderly population, who often cannot tolerate traditional chemotherapy. Understanding molecular changes at the gene level is also important for accurate disease classification, risk stratification, and prognosis, allowing for more personalized medicine. Some mutations are well studied and have an established gene-specific therapy, including FLT3 and IDH1/2, while others are being investigated in clinical trials. However, data on most known mutations in AML are still minimal and therapeutic studies are in pre-clinical stages, highlighting the importance of further research and elucidation of the pathophysiology involving these genes. In this review, we aim to highlight the key molecular alterations and chromosomal changes that characterize AML, with a focus on pathophysiology, presently available treatment approaches, and future therapeutic options.

Phase II study of long-course chemoradiotherapy followed by consolidation chemotherapy as total neoadjuvant therapy in locally advanced rectal cancer in Japan: ENSEMBLE-2.

To evaluate the feasibility and safety of total neoadjuvant therapy with long-course chemoradiotherapy followed by consolidation chemotherapy in Japanese patients with locally advanced rectal cancer. This prospective, multicenter, single-arm, phase II trial was conducted at 10 centers. The eligibility criteria included age ≥20 y, locally advanced rectal cancer within 12 cm of the anal verge, and cT3-4N0M or TanyN+M0 at diagnosis, enabling curative resection. The protocol treatment was capecitabine (1650 mg/m2/day)-based long-course chemoradiotherapy (50.4 Gy/28 fractions) and consolidation chemotherapy (CAPOX, four courses) followed by total mesorectal excision. Nonoperative management was allowed if a clinical complete response was achieved. The primary endpoint was the pathologic complete response rate. Among 28 enrolled patients (19 men, 9 women; median age, 69.5 [41-79] y), the long-course chemoradiotherapy and consolidation chemotherapy completion rates were 100% and 96.4%, respectively. The clinical responses included clinical complete response, (35.7%, 10/28), near-complete response (28.6%, 8/28), and incomplete response (32.1%, 9/28). Total mesorectal excision and nonoperative management were performed in 21 and six patients, respectively. The final analysis included 21 patients. Five patients (23.8% [90% confidence interval 11.8%-41.8%]) achieved pathologic complete response, while 10 of 28 patients (35.7%) achieved a pathological complete response or a sustained clinical complete response. No treatment-related deaths occurred. Grade ≥3 adverse events included diarrhea (7.1%) and leukopenia (7.1%). ENSEMBLE-2 demonstrated comparable pathologic complete response rates and well-tolerated safety of total neoadjuvant therapy with long-course chemoradiotherapy followed by consolidation chemotherapy in Japanese patients with locally advanced rectal cancer.

Outcomes associated with total neoadjuvant therapy with non-operative intent for rectal adenocarcinoma.

To evaluate rates of clinical complete response (cCR), surgery-free survival, permanent ostomy-free survival, and factors associated with these outcomes in patients treated with total neoadjuvant therapy (TNT) with intent for non-operative management of rectal adenocarcinoma. A retrospective review was conducted of patients treated with TNT for stage II-IV rectal adenocarcinoma (n=45) at our institution between 2013 - 2022 with curative intent. All patients received radiation with concurrent capecitabine and additional chemotherapy, either prior to or following chemoradiation (CRT), with intent for non-operative management. Response rates were determined based on post-treatment MRI and endoscopy. Kaplan-Meier method was utilized to estimate the 1- and 2-year surgery- and permanent ostomy-free survivals. Cox regression was used to evaluate associations between surgery- and permanent ostomy-free survivals and various factors of interest, including patient and tumor characteristics and clinical response. Chi-squared analysis compared rates of cCR and surgery by sequence of TNT modality and cell count ratios. Of the 45 patients treated with TNT, most patients had low-lying rectal tumors with a median distance of 4.1cm from the anal verge (range, 0.0 - 12.0). Overall, 64.4% (n=29) achieved cCR after TNT. 13 patients (28.9%) underwent surgical resection following TNT, 12 of whom had incomplete response and one who elected to undergo surgery after reaching cCR. At median follow up of 32.0 months (range, 7.1 - 86.1), 22.2% (n=10) of patients had a permanent colostomy, with only 2 of these completed for tumor regrowth after cCR. At one and two years, respectively, surgery-free survival was 77.3% and 66.2%, and permanent ostomy-free survival was 90.9% and 78.2%. Rates of cCR were higher in patients who received CRT first compared to those who received chemotherapy first (72.2% vs. 33.3%, p=0.029) and rates of surgery were also lower in patients who received CRT first compared to those who received chemotherapy first (19.4% vs. 66.7%, p=0.005). On Cox regression model, cCR on 6 month post-CRT endoscopy was associated with surgery-free survival (p=0.006) and permanent ostomy-free survival (p=0.033). Clinical response at earlier follow up points did not predict surgery- nor permanent ostomy-free survival. These results support evidence that TNT may be a non-surgical option for select patients with rectal adenocarcinoma who desire organ preservation. In this investigation at a single institution, the treatment response on 6-month post-CRT endoscopy was the best predictor of surgery- and permanent ostomy-free survival, which are outcomes that are important to patient quality of life. CRT followed by consolidation chemotherapy was associated with higher rates of cCR and lower rates of surgery compared to those treated with induction chemotherapy.

Alliance A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer

BackgroundRecent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after TNT may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes.MethodsIn this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N +) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N + vs N0) and distance from anal verge (0–4; 4–8; 8–12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3–4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8–12 (± 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 evaluable patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha = 0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse event rates. Biospecimens including archival tumor tissue, plasma and buffy coat, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and had accrued 330 patients as of May 2024. Study support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org.DiscussionBuilding on data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed The Janus Rectal Cancer Trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer.Trial registrationClinicaltrials.gov ID: NCT05610163; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).

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.)