Consolidation Therapy Research Articles

Correlation of mid-chemoradiation ctDNA results and clinical complete response to total neoadjuvant therapy (TNT) for locally advanced rectal adenocarcinoma.

263 Background: The total neoadjuvant therapy (TNT) paradigm for locally advanced rectal cancer (LARC) is evolving with intensification and de-escalation neoadjuvant therapies. Chemoradiation (CRT) followed by consolidation chemotherapy offers the highest rate of organ preservation. Circulating tumor DNA (ctDNA) response during TNT may serve as a biomarker that allows for therapy personalization to better select candidates for rectal organ preservation (Watch-and-Wait, WW). Methods: We enrolled patients with mismatch repair proficient LARC eligible for TNT on a prospective protocol (NCT05108428). Patients underwent CRT to 50.4 Gy with a mid-treatment evaluation (27 Gy) on a MRI-linac followed by 8 cycles of consolidation FOLFOX. A sequential MRI-guided adaptive radiotherapy boost to 59.4 Gy was delivered if rectal tumor volume reduced > 30% at 27 Gy. Standard restaging with diagnostic MRI and endoscopy occurred after TNT to evaluate organ preservation candidacy. ctDNA was obtained at diagnosis, mid-CRT (27 Gy), completion of TNT, and regular intervals in surveillance. ctDNA analysis was performed using a clinically validated, personalized, tumor-informed assay (Signatera, Natera, Inc.). Descriptive statistics for clinical response for mid-treatment assessment are reported. Additional clinical outcomes will be reported as follow up matures. Results: A total of 20 patients were enrolled (70% male, 70% cN+) with average age of 58 (range: 30-86) and 40% with threatened or involved radial margin. Average follow up is 12 months (range: 4-24 months) from date of completion of TNT. Average initial tumor volume was 26cc (range: 8.6cc- 66.8cc) with an average tumor reduction of 68.5% at 27 Gy. Volumetric change based on mid treatment MRI >30% did not predict WW eligibility (2 patients with <30% volumetric change maintains clinical complete responses). All patients demonstrated positive ctDNA at diagnosis (average 7.08 MTM/mL, range: 0.08 MTM/mL -77.96 MTM/mL). 25% of patients had elevated CEA at diagnosis. Conversion to negative ctDNA at mid-CRT occurred in 53% of patients. 57% of patients with a positive ctDNA at this timepoint underwent formal oncologic mesorectal excision with adenocarcinoma confirmed in the specimens. 25% of patients with negative ctDNA at this timepoint underwent a local excision, with no histologic invasive cancer in both specimens. We observed a 100% rectal organ preservation rate when early conversion to negative ctDNA at the 27 Gy of CRT timepoint. Conclusions: ctDNA clearance during CRT may be a good early predictor for patients that may be a candidate for a WW protocol. This biomarker may also guide consolidation therapy escalation (FOLFIRINOX) or de-escalation (chemotherapy omission) for select patients. Longer follow up is needed to correlate with clinical outcomes and future studies with more patients is needed. Clinical trial information: NCT05108428 .

ALLG APML5: Bioavailability and safety of oral arsenic trioxide assessed during consolidation therapy for APL.

The prognosis for patients with acute promyelocytic leukemia (APL) has improved dramatically since the introduction of all-trans retinoic acid (ATRA) and intravenous arsenic trioxide (ATO). However, ATO administration requires daily infusions over several months, representing an onerous burden for hospitals and patients. We evaluated the bioavailability of a novel encapsulated oral ATO formulation in APL patients in first complete remission during standard-of-care consolidation. After a pilot study exploring the likely oral dose requirement, total arsenic pharmacokinetics were evaluated in 20 patients after both intravenous and oral ATO 0.15 mg/kg/d, with exposure to oral ATO restricted to the first week in 2 of the 4 ATO cycles. The primary endpoint was bioequivalence of area under the curve from 0-24 hours (AUC0-24), with bioequivalence of maximum concentration achieved (Cmax) as the key secondary endpoint. The 90% confidence intervals (CI) around point estimates of the geometric means of the oral/intravenous ratios for AUC0-24 and Cmax were compared with bioequivalence limits specified by the European Medicines Agency (0.80-1.25). The estimated oral/intravenous ratios and 90% CI for AUC0-24 in whole blood and plasma were 0.993 (0.954-1.034) and 1.030 (0.977-1.087) respectively; data for Cmax also satisfied bioequivalence requirements. Exploratory studies of arsenic species in plasma showed bioequivalence for AUC0-24 with As(III) (oral/intravenous ratio 0.966 (0.879-1.063)). The adverse event profiles of oral and intravenous ATO were comparable for cycles commencing with the IV and oral formulations. In conclusion, this novel oral ATO formulation is bioequivalent with intravenous ATO and offers a convenient alternative for patients with APL. Accession Number: ACTRN12616001022459.

Radiotherapy(R) Integration(I) Strategy for Small(S)-Cell Lung Cancer in Extensive(E) Stage (RISE) with up to 10 metastases- a study protocol of a randomized phase II trial

Background The current standard of care (SoC) for patients with extensive-disease small-cell lung cancer (ED-SCLC) is chemo-immunotherapy. The efficacy of radiotherapy (RT) for chest consolidation has been established for patients with ED-SCLC who have responded to chemotherapy. There is a lack of data on incorporating RT as chest consolidation and metastasis-directed therapy for ED-SCLC. The RISE (Radiotherapy for Extensive-Stage Small-Cell Lung Cancer) study aims to evaluate the effectiveness of different RT strategies for residual lesions for patients with ED-SCLC who receive chemo-immunotherapy.MethodsA total of 165 patients with ED-SCLC will be recruited, with 55 patients assigned to each of the three study arms. Patients with stabilization or partial regression, according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, during chemo-immunotherapy will be included.• Arm I will serve as the control group, comprising patients who continue SoC of programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) immunotherapy (durvalumab or atezolizumab) following platinum-based chemo-immunotherapy.• Arm II will receive the SoC with consolidative RT to the chest area and potentially, according to palliative indications to metastatic lesions, delivered in 30 Gy in 3-Gy fractions.• Arm III will receive SoC with RT of 45 Gy in 3-Gy fractions to the chest area and stereotactic body radiotherapy (SBRT) with 24 Gy in 8-Gy fractions to the metastatic lesions.Blood samples for circulating tumor DNA (ctDNA) will be collected before RT, during each week of treatment, and at the time of disease progression.The primary endpoint is progression-free survival (PFS) based on RECIST 1.1 or patient death. 1. Secondary endpoints are OS, treatment toxicity (frequency of G3 toxicity according to CTCAE v.5.0), area of progression (primary tumor localization/new lesions), Overall response rate (ORR), and the response rate in non-irradiated lesions.DiscussionThe study population of patients with ED-SCLC has a poor prognosis. Dose-escalated chest RT and SBRT (for up to 10 metastases) administered with modern techniques offer the possibility to improve OS and PFS.Trial registrationClinicaltrials.gov NCT06529081 (Registered 26th Jul 2024).

XPO1/Exportin-1 in Acute Myelogenous Leukemia; Biology and Therapeutic Targeting

Exportin 1 is responsible for the export of hundreds of proteins, several RNA species and ribosomal components from the nucleus to the cytoplasm. Several transported proteins are important for regulation of cell proliferation and survival both in normal and malignant cells. We review the biological importance and the possibility of therapeutic targeting of Exportin 1 in acute myeloid leukemia (AML). Exportin 1 levels can be increased in human primary AML cells, and even exportin inhibition as monotherapy seems to have an antileukemic effect. The results from Phase I/II studies also suggest that exportin inhibition can be combined with conventional chemotherapy, including intensive induction and consolidation therapy possibly followed by allogeneic stem cell transplantation as well as AML-stabilizing therapy in elderly/unfit patients with hypomethylating agents. However, the risk of severe toxicity needs to be further evaluated; hematological toxicity is common together with constitutional side effects, electrolyte disturbances, and gastrointestinal toxicity. A recent randomized study of intensive chemotherapy with and without the Exportin inhibitor selinexor in elderly patients showed reduced survival in the selinexor arm; this was due to a high frequency of relapse and severe infections during neutropenia. Experimental studies suggest that Exportin 1 inhibition can be combined with other forms of targeted therapy. Thus, Exportin 1 inhibition should still be regarded as a promising strategy for AML treatment, but future studies should focus on the risk of toxicity when combined with conventional chemotherapy, especially in elderly/unfit patients, combinations with targeted therapies, identification of patient subsets (AML is a heterogeneous disease) with high susceptibility, and the possible use of less toxic next-generation Exportin 1 inhibitors.

Practical Considerations for Early Relapsed/Refractory Multiple Myeloma in the Canadian Landscape in 2024

Multiple-class drug combinations have long been integral to the management of multiple myeloma (MM). This has led to significant advances in myeloma survival with agents such as lenalidomide and daratumumab moving to frontline therapy. Therefore, relapse therapy requires rational sequencing strategies to prioritize effective regimens with each treatment line without compromising access to subsequent lines. At first relapse, most transplant-eligible patients would have undergone RVd (lenalidomide, bortezomib, dexamethasone) induction with subsequent consolidative high-dose therapy with autologous stem cell rescue and Len (lenalidomide) maintenance. For transplant-ineligible patients, frontline therapy with DRd (daratumumab, lenalidomide, dexamethasone) has become the standard of care until myeloma progression or drug intolerance. With the increasing adoption of quadruple therapy in frontline treatment, a significant proportion of patients will soon be multi-class exposed or refractory at early relapse, including exposure to daratumumab, lenalidomide, and bortezomib. This shift necessitates careful consideration of treatment sequences based on available regimens, which include previous treatment responses, cytogenetic and molecular risk profiles (e.g., high-risk versus standard-risk disease), disease kinetics at relapse, and the potential benefit of therapies with novel mechanisms of action. Achieving and maintaining sustained minimal residual disease (MRD) negativity is also critical, as patients in this category consistently experience better outcomes, regardless of cytogenetic risk or line of therapy.

Surgery versus concurrent chemoradiotherapy for stage III non-small cell lung cancer: a retrospective study with propensity score matching

BackgroundNo study has directly compared the outcomes of surgery and concurrent chemoradiotherapy (cCRT) in patients with stage III non-small cell lung cancer (NSCLC) to date. This study aimed to compare the treatment efficacy of complete resection and definitive cCRT.MethodsPatients were recruited in this retrospective study from Yokohama Municipal Citizens’ Hospital between January 2013 and December 2022. We analyzed patients with pathological stage III NSCLC who underwent complete surgical resection and those with clinical stage III NSCLC who underwent definitive cCRT. Propensity score matching was performed to balance baseline clinicopathological factors, and the prognoses of patients in each treatment group were examined using Cox proportional hazards regression.ResultsOf the 923 patients with NSCLC who underwent surgery, 97 with pathologic stage III NSCLC underwent complete resection (surgery group) and 125 with clinical stage III NSCLC underwent cCRT (cCRT group), of whom 54 (43.2%) received consolidation therapy with durvalumab. Overall survival (OS) was significantly higher in the surgery group than in the cCRT group (5-year OS: 60.5% versus 43.0%), hazard ratio [HR] = 0.585, 95% confidence interval [CI]: 0.390–0.877, p = 0.010). However, no significant difference in OS was found between the two groups after propensity score matching (5-year OS: 59.8% versus 48.1%, HR = 0.728, 95% CI: 0.416–1.277, p = 0.268).ConclusionsThe outcomes of the surgery and cCRT groups did not significantly differ in the treatment of stage III NSCLC. Appropriate evaluation of the treatment required should be reviewed on a case-by-case basis.

A case report of acute promyelocytic leukemia with myeloid sarcoma of the lumbar spine and literature review

Acute promyelocytic leukemia (APL) presenting solely as myeloid sarcoma (MS) is extremely rare. This report describes a 53-year-old male who presented with low back pain and a movement disorder in his lower limbs. MRI and PET/CT scans of the lumbar spine revealed an intraspinal mass. Pathological analysis of the surgically resected mass identified it as myeloid in origin. Routine blood tests were unremarkable, and bone marrow smears and immunophenotyping showed no evidence of abnormal myeloblasts or promyelocytes. However, bone marrow aspirates testing for acute leukemia fusion genes by qPCR revealed the presence of the PML::RARA fusion. Further investigation via FISH confirmed the fusion in both the bone marrow and the extramedullary mass. The patient was ultimately diagnosed with isolated promyelocytic extramedullary sarcoma (MS/APL). Treatment with all-trans retinoic acid and arsenic trioxide alleviated the back pain and restored the patient’s mobility. After 1 year of consolidation therapy, bone marrow smears confirmed sustained remission, and the PML::RARA fusion gene was undetectable. In addition to this case, we review 41 other APL patients with extramedullary sarcoma as their first symptom (MS/APL) at the time of diagnosis and provide an analysis of these cases.

The Society of Thoracic Surgeons (STS) Clinical Practice Guideline on Surgical Management of Oligometastatic Non-small Cell Lung Cancer.

The use of local consolidative therapy (LCT) in patients with oligometastatic non-small cell lung cancer (NSCLC) is rapidly evolving, with a preponderance of data supporting the benefits of such therapeutic approaches incorporating pulmonary resection for appropriately selected candidates. However, practices vary widely institutionally and regionally, and evidence-based guidelines are lacking. The Society of Thoracic Surgeons assembled a panel of thoracic surgical oncologists to evaluate and synthesize the available evidence regarding the role of pulmonary resection as LCT. Clinical and research questions of interest were identified, and a complete literature review was conducted. Best practice guidelines were developed accordingly. The panel identified 7 areas of controversy, and data were assimilated to support the best recommended practices related to these clinical issues. Ultimately, a number of issues in this realm were found to have a high level of evidence to support the role for surgical therapy in patients with stage IV lung cancer. However, the nuances of how these operations are conducted remain in equipoise, without ample evidence to support the extent of resection or nodal dissection. Clear data exist to support the use of surgical resection of the primary lung tumor as LCT in stage IV lung cancer. Evidence-based recommendations have been provided to guide multidisciplinary teams on the implementation of treatment plans as well as to guide researchers on areas of ongoing need for further investigation.

Local consolidative therapy in oligometastatic non-small-cell lung cancer after effective systemic treatment: who will benefit?

Local consolidative therapy in oligometastatic non-small-cell lung cancer after effective systemic treatment: who will benefit?

High-dose MTX-based polychemotherapy for primary CNS lymphoma in younger patients: Long-term efficacy of the modified Bonn protocol.

Polychemotherapy based on high-dose methotrexate (HD-MTX) is the standard therapy for newly diagnosed younger patients (<65 years) with primary CNS lymphoma (PCNSL). In the modified Bonn protocol, consolidation therapy consists of intraventricular chemotherapy that is added to the continuation of HD-MTX-based chemotherapy. This study investigates the efficacy and toxicity of the modified Bonn protocol in first-line therapy of young patients with PCNSL. All consecutive immunocompetent patients aged <65 years who were newly diagnosed with PCNSL from 2012 to 2021 and started first-line therapy with the modified Bonn protocol at the Neurooncology Center Bonn were included in this retrospective analysis. Treatment comprised 3 courses of rituximab/HD-MTX/IFO followed by consolidation therapy with 2 courses of HD-AraC and 2 courses of HD-MTX/IFO, including intrathecal MTX and intrathecal AraC. Progression-free and overall survival were evaluated. Forty-three patients were included. Thirty-seven patients (86%) reached intrathecal consolidation therapy. Grade 3/4 toxicity was observed in 58.1%. The median PFS was 102.8 months; 5-year OS rate was 76% (median not reached). Eighteen patients developing refractory/relapsed PCNSL received second-line therapy using the modified Freiburg protocol (AraC/TT +/- HD-MTX/rituximab followed by BCNU/TT-based HD-ASCT). A second relapse was observed in 11/18 patients (median follow-up of 17 months (IQR 5-43.7 months)). First-line treatment of PCNSL with the modified Bonn protocol is highly effective. The outcome compares well with other seemingly more toxic PCNSL protocols for younger patients. In patients with disease recurrence, second-line therapy according to the modified Freiburg protocol appears to be effective.

How I Treat AML relapse after allogeneic HCT

Allogeneic hematopoietic stem-cell transplantation (HCT) is one of the principal curative approaches in the treatment of acute myeloid leukemia (AML); however, relapse post-transplantation remains a catastrophic event with poor prognosis. The incidence of relapse has remained unchanged over the last three decades despite an evolving understanding of the immunobiology of the graft-versus leukemia effect and the immune escape mechanisms that lead to post-HCT relapse. The approach to post-transplant relapse is highly individualized and is dictated both by disease biology and genomics as well as the patient's clinical status at the time of relapse and the interval between relapse and transplantation. With the help of three illustrative cases, we discuss our approach to early, late, and incipient relapse. Current therapeutic strategies incorporate immunosuppression taper when feasible, a variety of targeted and non-targeted chemotherapeutic agents and consolidative cellular therapies including donor lymphocyte infusions or a second allogeneic transplant. We then summarize evolving frontiers in the treatment and prognostication of relapse including the critical role of measurable residual disease. Finally, we emphasize enrollment on clinical trials and thoughtful discussions regarding goals of care and supporting frail patients as universal principles that should be incorporated in approaches to treatment of AML relapse post-transplantation.

A phase 2 pilot study of umbilical cord blood infusion as an adjuvant consolidation therapy in elderly patients with acute myeloid leukemia

Acute myeloid leukemia (AML) is an aging-related malignancy, with patients aged ≥60 years old facing significantly poorer prognosis. Umbilical cord blood (UCB) has emerged as a promising source with effective anti-aging roles. Here, we conducted a prospective, phase 2, single-arm trial of UCB infusion as an adjuvant consolidation therapy in elderly AML patients (ChiCTR-OPC-15006492). A total of 51 patients were enrolled (median age 66 years; range, 60–75) and received two cycles of consolidation chemotherapy combined with UCB infusion. At a median follow-up of 27.3 months (range, 9.3–100), the median overall survival (OS) was not yet reached and the median event-free survival (EFS) was 72.2 months (range, 5.4–100). The 2-year OS and EFS rates were 76.9% and 62.8%, respectively. No acute graft-versus-host disease (aGVHD) or toxicity-related death occurred in any patient. The median times to platelet and neutrophil recovery were 11.5 days (range, 6–17) and 12.2 days (range, 0–21), respectively. Single-cell RNA sequencing (scRNA-seq) identified enhanced anti-tumor and anti-aging properties of UCB, manifested through activation of immune responses and telomere synthesis/maintenance. These findings suggest that UCB infusion is an effective and safe post-remission adjuvant therapy for elderly AML patients. This study provides evidence that anti-aging therapy may serve as a new and promising dimension in combined cancer treatment.

Computational assessment of measurable residual disease in acute myeloid leukemia using mixture models

BackgroundThe proportion of residual leukemic blasts after chemotherapy assessed by multiparameter flow cytometry, is an important prognostic factor for the risk of relapse and overall survival in acute myeloid leukemia (AML). This measurable residual disease (MRD) is used in clinical trials to stratify patients for more or less intensive consolidation therapy. However, an objective and reproducible analysis method to assess MRD status from flow cytometry data is lacking, yet is highly anticipated for broader implementation of MRD testing.MethodsWe propose a computational pipeline based on Gaussian mixture modeling that allows a fully automated assessment of MRD status while remaining completely interpretable for clinical diagnostic experts. Our pipeline requires limited training data, which makes it easily transferable to other medical centers and cytometry platforms.ResultsWe identify all healthy and leukemic immature myeloid cells in with high concordance (Spearman’s Rho = 0.974) and classification performance (median F-score = 0.861) compared to manual analysis. Using control samples (n = 18), we calculate a computational MRD percentage with high concordance to expert gating (Spearman’s rho = 0.823) and predict MRD status in a cohort of 35 AML follow-up measurements with high accuracy (97%).ConclusionsWe demonstrate that our pipeline provides a powerful tool for fast (~3 s) and objective automated MRD assessment in AML.

Clinicopathological risk factors for prognosis and therapeutic response of primary central nervous system lymphoma in China: a single-center retrospective analysis of 118 cases.

To investigate the prognostic significance of clinicopathological factors in patients with primary central nervous system lymphoma (PCNSL) in a single center. Patients newly diagnosed with PCNSL at our center were recruited between January 2019 and March 2023. Baseline demographic and clinicopathological data were collected retrospectively. The Kaplan-Meier method and Cox regression analysis were performed for survival analyses. A total of 118 patients were enrolled. The median age was 64 (IQR, 54-68). The median progression-free survival (PFS) and overall survival (OS) were 12.70 (95%CI, 9.73-23.30) months and 36.87 (95%CI, 25.57-NR) months, respectively. KPS < 70 and ECOG ≥ 3 were significantly associated with worse PFS and OS. High International Extranodal Lymphoma Study Group (IELSG) score (IELSG 4-5) and high-risk Memorial Sloan-Kettering Cancer Center (MSKCC) score were also adverse factors for PFS and OS. BTK inhibitors (BTKi) therapy (HR 0.39, 95% CI, 0.18-0.86, p = 0.020) and consolidation therapy (HR 0.19, 95% CI, 0.06-0.64, p = 0.007) were confirmed as independent favorable factors for OS. A high NK lymphocyte proportion was associated with worse OS (p = 0.008). Patients in the high NK lymphocyte group experienced a higher rate of primary tumor resistance (57.14%) than the low NK lymphocyte group (33.33%). KPS < 70, ECOG ≥ 3, IELSG 4-5, and high-risk MSKCC score are adverse factors for PFS and OS. Importantly, BTKi therapy and consolidation therapy are independent favorable factors for OS. Peripheral lymphocyte immunophenotyping could be a potential predictive indicator for prognosis and therapeutic response in PCNSL.

The Role of Stereotactic Body Radiotherapy in Oligometastatic Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is a major cause of mortality in Canada, with many patients presenting with metastatic disease. The oligometastatic state (OM-NSCLC) may be amenable to cure using aggressive local consolidative therapies. Stereotactic body radiotherapy (SBRT), which entails the utilization of a high dose of radiation in one or few fractions, has many benefits in this setting, including its applicability in varied patient populations to ablate lesions in varied anatomical locations. It has also been demonstrated to prolong the time to next-line systemic therapy, to reduce financial burden, to improve quality-adjusted life years, and reduce adverse events caused by these lesions. This review outlines the published phase II and III trials that have already demonstrated the utility of SBRT in OM-NSCLC, as well as the many ongoing trials aiming to further define its role, including the largest phase II/III trial to date, NRG-LU002. Overall, SBRT appears to improve outcomes when combined with a broad range of standard-of-care therapies and is generally well tolerated; however, careful patient selection is necessary to maximize benefits while minimizing harm. Ongoing trials will help define the optimal patients for SBRT and the best timing for this intervention.

Durvalumab as consolidation therapy in patients who received chemoradiotherapy for unresectable stage III NSCLC: Real-world data from an expanded access program in Brazil (LACOG 0120).

The PACIFIC trial established standard therapy for patients with unresectable stage III NSCLC who did not progress after platinum-based concurrent chemoradiation therapy. However, real-world data, particularly from Latin America, remain limited. The LACOG 0120 study aimed to evaluate the efficacy and safety of consolidation therapy with durvalumab in a real-world setting in Brazil. Patients with unresectable stage III NSCLC who received chemoradiotherapy followed by durvalumab consolidation therapy through an expanded access program were evaluated. The primary objective was to assess progression-free survival (PFS). Secondary endpoints included overall survival (OS), treatment compliance, and safety, with a focus on the incidence and severity of immune-mediated adverse events (NCT04948411). Thirty-one patients from seven centers were evaluated. Median follow-up was 50.3 months (95% CI: 48.6-54.4). Median PFS was 9.9 months (95% CI: 7.3-52.4), with a 36 month-PFS of 34.5% (95% CI: 17.7-52.1). Median OS was 34.9 months (95% CI: 26.0-NR), and the 36 month-OS was 46.3% (95% CI: 25.7-64.6). Durvalumab was administered for a median of 17 cycles (10 to 24), with 45.2% of patients completing the planned therapy. The main reason for discontinuation was disease progression. Treatment-related adverse events of any grade occurred in 12 patients (38.7%), with grade 3 events reported in two (6.5%). Pneumonitis was observed in 4 patients (12.9%) - grade 3 in 1 patient. PFS was lower in this analysis compared to the PACIFIC trial; however, OS was similar, indicating comparable efficacy in a real-world setting among Brazilian patients with unresectable stage III NSCLC. No new safety concerns were identified.

Optimizing the Treatment of Acute Promyelocytic Leukemia: A Maintenance-Free Strategy for Complete Remission

Background: Acute promyelocytic leukaemia (APL) is a distinct variant of acute myeloid leukaemia (AML), comprising 5-10% of all AML cases. Characterized by the t(15; 17) chromosomal translocation, APL presents a unique challenge due to its associated bleeding manifestations and coagulopathy, emphasizing the need for urgent and specialized management. Methods: This prospective open-label pilot study enrolled ten newly diagnosed APL patients, stratified based on the Sanz risk score. Low and intermediate-risk patients underwent ATRA+ATO induction therapy without chemo, followed by consolidation therapy. High-risk patients received additional single dose chemo Daunorubicin or Mitoxantrone alongside ATRA+ATO induction. The study evaluated patient characteristics, clinical findings, laboratory results, and treatment outcomes, focusing on complete remission (CR) after induction therapy and disease-free survival (DFS) at 3 years. Results: The study observed a 100% CR rate after induction therapy, with favourable 3-year DFS and event-free survival (EFS). No treatment failures, mortality, or relapses were reported. Laboratory findings and clinical outcomes were consistent with the characteristics of APL, including the hematological parameters. The absence of maintenance therapy minimized associated toxicities, supporting the safety and efficacy of the chemotherapy-free ATRA+ATO approach. Conclusion: This pilot study underscores the potential paradigm shift in APL management by demonstrating the safety and efficacy of a chemotherapy-free ATRA+ATO strategy. The results align with the 2023 National Comprehensive Cancer Network (NCCN) update, endorsing the ATRA+ATO regimen for APL. The on-going nature of the research emphasizes its contribution to evolving APL management practices, encouraging further comprehensive evaluations on a broader scale.

Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma: Final Part 1 Analysis of the GMMG-HD7 Trial.

Previously, addition of isatuximab (Isa) to standard-of-care lenalidomide-bortezomib-dexamethasone (RVd) in transplant-eligible patients with newly diagnosed multiple myeloma in the GMMG-HD7 trial (ClinicalTrials.gov identifier: NCT03617731) resulted in a significant increase of minimal residual disease negativity (MRD-) rates after induction therapy. A total of 662 patients were randomly assigned to receive induction therapy with Isa-RVd (n = 331) or RVd (n = 329), followed by single or tandem autologous stem-cell transplant and second random assignment to maintenance with lenalidomide alone or Isa-lenalidomide. We report updated results for part 1 from first random assignment to post-transplant. As of January 31, 2024, MRD- rates continued to deepen after transplant (66% Isa-RVd v 48% RVd). Isa-RVd induction therapy significantly prolonged progression-free survival (PFS) compared with RVd regardless of maintenance therapy (hazard ratio, 0.70 [95% CI, 0.52 to 0.95]; P = .0184). Weighted risk set estimator analysis accounting for second random assignment followed by maintenance with only lenalidomide confirmed a statistically significant benefit for Isa-RVd followed by lenalidomide maintenance versus RVd followed by lenalidomide maintenance (stratified weighted log-rank test P = .016). In conclusion, after 18-week induction therapy followed by transplant without consolidation therapy, adding Isa to RVd resulted in a significant PFS benefit, regardless of maintenance strategy.

Mutation- and MRD-informed treatment decisions for the transplant-eligible AML patient.

Acute myeloid leukemia (AML) is classified by risk groups according to a number of genetic mutations, which may occur alone or in combination with other mutations and chromosomal abnormalities. Prognosis and appropriate therapy can vary significantly based on a patient's genetic risk group, making mutation-informed decisions crucial to successful management. However, the presence of measurable residual disease (MRD) after induction and consolidation therapy, before hematopoietic cell transplant, and during posttransplant monitoring can be even more significant to patient prognosis than their genetic subtype. Clinicians must select MRD-monitoring methods most appropriate for a patient's genetic profile and a treatment regimen that considers both a patient's primary genetic subgroup and other risk factors, including MRD information. Recent clinical trial data and drug approvals, together with advances in the validation of MRD using next-generation sequencing, require a deeper understanding of the complex AML mutation and MRD matrix, enabling more insightful monitoring and treatment decisions for intensively treated AML patients. Here, we provide an overview on methods and clinical consequences of MRD monitoring in genetic subgroups of patients with AML. As treatment options become more personalized, on-treatment MRD monitoring will become even more important to effective AML care.

Evolving strategies in the management of transplant-eligible patients with newly diagnosed multiple myeloma.

Multiple myeloma treatment has evolved significantly with the introduction of triplet and quadruplet regimens, notably incorporating anti-CD38 antibodies. While autologous stem cell transplantation remains a cornerstone of therapy, its role in the context of increasingly effective upfront treatments is debated. Current guidelines still recommend transplant for all eligible patients, especially those with high-risk features at diagnosis, despite concerns regarding the lack of overall survival benefits and the potential long-term toxicities associated with high-dose melphalan. Delaying transplantation until first relapse has been proposed, but this approach carries the risk of patients becoming ineligible for transplantation due to worsening health or disease progression. Consolidation therapy after transplant is not strongly endorsed in recent guidelines, and studies show mixed results regarding its efficacy. Some data suggests a progression-free survival advantage with post-ASCT consolidation; others found no significant differences in outcomes among various strategies. Nonetheless, tandem transplant may be beneficial for high-risk patients. Maintenance therapy, particularly with lenalidomide, has proven effective, offering substantial progression-free and overall survival benefits. While lenalidomide remains the standard, emerging data indicate that combinations with proteasome inhibitors or anti-CD38 antibodies could enhance outcomes, particularly in high-risk populations. As our understanding of myeloma biology deepens, tailoring treatment approaches based on risk profiles and response depth will be crucial for optimizing patient outcomes.