Management of ALL in adults: 2024 ELN recommendations from a European expert panel.

ABSTRACT: Experts from the European Leukemia Net (ELN) working group for adult acute lymphoblastic leukemia have identified an unmet need for guidance regarding management of adult acute lymphoblastic leukemia (ALL) from diagnosis to aftercare. The group has previously summarized their recommendations regarding diagnostic approaches, prognostic factors, and assessment of ALL. The current recommendation summarizes clinical management. It covers treatment approaches, including the use of new immunotherapies, application of minimal residual disease for treatment decisions, management of specific subgroups, and challenging treatment situations as well as late effects and supportive care. The recommendation provides guidance for physicians caring for adult patients with ALL which has to be complemented by regional expertise preferably provided by national academic study groups.

A prognostic score system in adult T-cell acute lymphoblastic leukemia after hematopoietic stem cell transplantation.

Adult T-cell acute lymphoblastic leukemia (T-ALL) is highly aggressive with poor prognoses, while hematopoietic stem cell transplantation (HSCT) is a curable option. However, no transplant-specific prognostic model for adult T-ALL is available. We identified 301 adult T-ALL patients who received HSCT at our hospital between 2010 and 2022. These patients were randomly assigned at a 7:3 ratio to a derivation group of 210 patients and a validation group of 91 patients. Next, we developed a prognostic risk score system for adult T-ALL with HSCT, which we named COMM, including 4 predictors (central nervous system involvement, Non-CR1 (CR2+ or NR) at HSCT, minimal residual disease (MRD) ≥ 0.01% after first induction therapy, and MRD ≥ 0.01% before HSCT). Patients were categorized into three risk groups, low-risk (0), intermediate-risk (1-4), and high-risk (5-12), and their 3-year overall survival (OS) were 87.5% (95%CI, 78-93%), 65.7% (95%CI, 53-76%) and 20% (95%CI, 10-20%; P < 0.001), respectively. The area under the subject operating characteristic curve for 2-, 3- or 5-year OS in the derivation cohort and in the validation cohort were all greater than 0.75. Based on internal validation, COMM score system proved to be a reliable prognostic model that could discriminate and calibrate well. We expect that the first prognostic model in adults T-ALL after HSCT can provide a reference of prognostic consultation for patients and families, and also contribute to future research to develop risk adapted interventions for high-risk populations.

Concordance of Next-Generation Sequencing and Multiparametric Flow Cytometry Methods for Detecting Measurable Residual Disease in Adult Acute Lymphoblastic Leukemia: Optimizing Prediction of Clinical Outcomes From a Single-Center Study.

INTRODUCTION: Detection of measurable residual disease (MRD) in adults with acute lymphoblastic leukemia (ALL) is a vital biomarker in risk prediction and treatment selection. Next-generation sequencing (NGS) offers greater sensitivity relative to multiparametric flow cytometry (MFC) and may be a better predictive tool for identifying ALL patients at risk of relapse. PATIENTS AND METHODS: This single-center retrospective study compares MRD detection by NGS versus MFC in 52 adult B- and T-ALL patients treated at our institution between 2018 and 2023. Pretreatment bone marrow samples were used for assay calibration, while post-treatment MRD assessment was completed up to 4.5 months after the first complete remission (CR1) using an MRD cutoff of 10-6 for distinguishing relapse risk. RESULTS: The 2-year cumulative incidence of relapse (CIR) among patients who were MRD positive using MFC and NGS was 39.5% and 46.2%, respectively. Unlike MFC, post-CR1 MRD positivity with NGS significantly predicted CIR (HR = 9.47, P = .028). In patients who were MRD negative by MFC, low levels of MRD detected by NGS distinguished patients at high risk of relapse (HR 10.3, P = .026, 2-year CIR 51.6%). CONCLUSION: Our data suggests that assessment of post-CR1 MRD using a highly sensitive NGS assay can identify ALL patients undergoing frontline therapy at increased risk of relapse and guide the use of adjuvant therapy.

Impact of pretransplant minimal residual disease in patients with multiple myeloma and a very good partial response or better receiving autologous hematopoietic stem cell transplantation.

BACKGROUND: The prognostic significance of minimal residual disease (MRD) status before autologous hematopoietic stem cell transplantation (autoHCT) in patients with multiple myeloma (MM) has not been clearly elucidated. METHODS: Retrospective single-center study of adult MM patients who achieved ≥very good partial response (VGPR) after induction therapy from 2015 to 2021 received upfront autoHCT and had available pretransplant MRD status by next-generation flow cytometry. The cohort was divided into pretransplant MRD-negative (MRDneg) and MRD-positive (MRDpos) groups. RESULTS: A total of 733 patients were included in our analysis; 425 were MRDneg and 308 MRDpos at autoHCT. In the MRDpos group, more patients had high-risk cytogenetic abnormalities (48% vs. 38%, respectively; p = .025), whereas fewer patients achieved ≥CR before autoHCT (14% vs. 40%; p < .001). At day 100 after autoHCT, 37% of the MRDpos versus 71% of the MRDneg achieved ≥CR, and at best posttransplant response 65% versus 88% achieved ≥CR, respectively. After a median follow-up of 27.6 months (range, 0.7-82.3), the median PFS was significantly shorter for patients in the MRDpos group compared to the MRDneg group: 48.2 months (95% confidence interval [CI], 0.3-80.5) versus 80.1 months (95% CI, 0.5-80.1), respectively (p < .001). There was no significant difference in overall survival between the two groups (p = .41). Pretransplant MRDpos status was predictive of shorter PFS in multivariate analysis (hazard ratio, 1.80; 95% CI, 1.31-2.46; p < .001). The impact of pretransplant MRD status was retained in most of the examined subgroups. CONCLUSIONS: In patients achieving ≥VGPR to induction, pretransplant MRDpos status was associated with a lower CR rate after autoHCT and a shorter PFS.

Multifunctional bioactive glasses with spontaneous degradation for simultaneous osteosarcoma therapy and bone regeneration.

For the treatment of tumor-related bone defects resulting from surgical resection, simultaneous eradication of residual tumor cells and repair of bone defects represent a challenge. To date, photothermal therapy based on photothermal materials is used to remove residual tumor cells under near infrared light. However, most of photothermal materials have no function for bone repair, and even if combined with bioactive materials to enhance osteogenesis, they still cause potential harm to the body due to inability to degrade or poor degradability. Herein, multifunctional bioactive glasses (PGFe5-1100, PGCu5-1100) based on phosphate glass doped with transition metal elements were prepared for photothermal ablation, bone regeneration, and controllable degradation. The glasses exhibited excellent photothermal effect, which was derived from the electron in-band transition after light absorption due to energy level splitting of doped transition metal element and the subsequent electron nonradiative relaxation. The photothermal performance can be controlled by laser power density, element doping content and glass melting temperature. Moreover, the hyperthermia induced by the glasses can effectively kill tumor cells in vitro. In addition, the glasses degraded over time, and the released P, Ca, Na, Fe could promote bone cell proliferation and osteogenic differentiation. Therefore, these results successfully demonstrated that transition metal element-doped phosphate glasses have multifunctional abilities of tumor elimination, bone regeneration, and spontaneous degradation simultaneously with better biosecurity and bioactivity, which is believed to pave the way for the design of novel biomaterials for osteosarcoma treatment.

Quantitative analysis with multiphase contrast-enhanced computed tomography to evaluate residual tumor activity of hepatocellular carcinoma after DEB-TACE.

Most hepatocellular carcinomas (HCC) treated by transcatheter arterial chemoembolization with drug-eluting beads (DEB-TACE) are characterized by coagulation necrosis; therefore, it is often difficult to distinguish enhancement in the arterial phase that would lead to false negative evaluation. This study aimed to evaluate the specificity and sensitivity of the difference value of multiphase contrast-enhanced computed tomography (CECT) in predicting residual tumor activity in HCC lesions after DEB-TACE. This retrospective diagnostic study analyzed CECT images of 73 HCC lesions in 57 patients 20 to 40 days (average 28 days) after DEB-TACE treatment at our Hospital from January to December 2019. Postoperative pathology or digital subtraction angiography images were used as references. Residual tumor activity after the first intervention was determined based on the presence of tumor staining in digital subtraction angiography or the postoperative pathological discovery of HCC tumor cells. A significant difference was observed between the active and inactive residual groups in ∆ HU difference between CT values of arterial phase and non-contrast scans (AN, P = .000), difference between CT values of venous phase and non-contrast scans (VN, P = .000), difference between CT values of delay phase and non-contrast scans (DN, P = .000), (difference between CT values of venous and arterial phase scans, P = .001), and (difference between CT values of delay and arterial phase scans, P = .005). No statistically significant difference was observed between the delayed and venous phases (difference between CT values of delay and venous phase scans, P = .361). The area under the curve (AUC) of the ROC curve showed that the diagnostic efficacies in difference in CT value of AN (AUC = 0.976), VN (AUC = 0.927), and DN (AUC = 0.924) were higher, and their cutoff values were 4.86, 12.065, 20.19 HU with their sensitivities of 93.3%, 84.4%, 77.8% and specificities of 100%, 96.4%, and 100%, respectively. difference in CT value values of AN, VN, DN, difference between CT values of venous and arterial phase scans and difference between CT values of delay and arterial phase scans can sensitively detect residual tumor activity 20-40 days after DEB-TACE. Thus, more sensitive active residual foci were detected using all 3 enhanced phases rather than only the arterial phase. Quantitative analysis of multiphase CECT can detect residual tumor activity in an early and noninvasive manner, which can provide time for patients to receive early follow-up treatment.

Measurable residual disease in patients undergoing allogeneic transplant for acute myeloid leukemia.

The most common indication for allogeneic hematopoietic cell transplant (alloHCT) is maintenance of remission after initial treatment for patients with acute myeloid leukemia (AML). Loss of remission, relapse, remains however the most frequent cause of alloHCT failure. There is strong evidence that detectable persistent disease burden ("measurable residual disease", MRD) in patients with AML in remission prior to alloHCT is associated with increased risk of post-transplant relapse. MRD status as a summative assessment of response to pre-transplant therapy may allow superior patient-personalized risk stratification compared with models solely incorporating pre-treatment variables. An optimal methodology for AML MRD detection has not yet been established, but molecular methods such as DNA-sequencing may have additional prognostic utility compared to current approaches. There is growing evidence that intervention on AML MRD positivity may improve post-transplant outcomes. New initiatives will generate actionable data on the clinical utility of AML MRD testing for patients undergoing alloHCT.

Novel Tools for Diagnosis and Monitoring of AML.

In recent years, major advances in the understanding of acute myeloid leukemia (AML) pathogenesis, together with technological progress, have led us into a new era in the diagnosis and follow-up of patients with AML. A combination of immunophenotyping, cytogenetic and molecular studies are required for AML diagnosis, including the use of next-generation sequencing (NGS) gene panels to screen all genetic alterations with diagnostic, prognostic and/or therapeutic value. Regarding AML monitoring, multiparametric flow cytometry and quantitative PCR/RT-PCR are currently the most implemented methodologies for measurable residual disease (MRD) evaluation. Given the limitations of these techniques, there is an urgent need to incorporate new tools for MRD monitoring, such as NGS and digital PCR. This review aims to provide an overview of the different technologies used for AML diagnosis and MRD monitoring and to highlight the limitations and challenges of current versus emerging tools.

Natural Chlorogenic Acid Planted Nanohybrids with Steerable Hyperthermia for Osteosarcoma Suppression and Bone Regeneration.

Surgical resection is the most common approach for the treatment of osteosarcoma. However, two major complications, including residual tumor cells and large bone defects, often arise from the surgical resection of osteosarcoma. Discovering new strategies for programmatically solving the two above-mentioned puzzles has become a worldwide challenge. Herein, a novel one-step strategy is reported for natural phenolic acid planted nanohybrids with desired physicochemical properties and steerable photothermal effects for efficacious osteosarcoma suppression and bone healing. Nanohybrids are prepared based on the self-assembly of chlorogenic acid and gold nanorods through robust Au-catechol interface actions, featuring precise nanostructures, great water solubility, good stability, and adjustable hyperthermia generating capacity. As expected, on the one hand, these integrated nanohybrids can severely trigger apoptosis and suppress tumor growth with strong hyperthermia. On the other hand, with controllable mild NIR irradiation, the nanohybrids promote the expression of heat shock proteins and induce prominent osteogenic differentiation. This work initiates a brand-new strategy for assisting osteosarcoma surgical excision to resolve the blockage of residual tumor cells elimination and bone regeneration.

Measurable residual disease in acute lymphoblastic leukemia: How low is low enough?

Quantification of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) is a well-established clinical tool used to risk stratify patients during the course of chemotherapy, immunotherapy, and/or transplant therapy. As technologies evolve, the sensitivity for quantifying exceptionally low disease burden using either next generation sequencing (NGS) or next generation flow cytometry (NGF) has improved. It is now possible to detect MRD and quantify it precisely in patients who would previously have been deemed MRD negative by older, lower sensitivity methods. Persistence or recurrence of ALL disease burden above 10-4 (0.01%) is accepted as the minimum threshold for making clinical decisions, but with NGS and NGF, clinicians now confront decision-making with disease burdens sometimes quantified to as low as 10-6 (0.0001%, or one leukemia cell in a million leukocytes). Emerging data suggest these higher sensitivity methods are superior for identifying patients at lowest risk for relapse, but it remains controversial whether to institute therapies such as blinatumomab or chimeric antigen receptor (CAR)-T cells or move patients to allogeneic hematopoietic cell transplant (alloHCT) when they have quantifiable disease burden less than 10-4. With additional evidence to facilitate integration of highly sensitive MRD quantification into clinical care and to contextualize MRD within the genotype of individual patients, it will likely be increasingly possible to identify patients able to avoid alloHCT and potentially even de-escalate therapy.

Overcoming minimal residual disease using intensified conditioning with medium-dose etoposide, cyclophosphamide and total body irradiation in allogeneic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia in adults.

BACKGROUND AIMS: An intensified conditioning regimen incorporating medium-dose etoposide (VP16) is an option for patients with acute lymphoblastic leukemia (ALL). However, the prognostic impacts of the addition of VP16 to cyclophosphamide (CY) and total body irradiation (TBI) in patients with Philadelphia chromosome-positive (Ph+) ALL with regard to minimal residual disease (MRD) status have not been elucidated. METHODS: The authors retrospectively compared the outcomes of patients with Ph+ ALL who underwent allogeneic transplantation following VP16/CY/TBI (n = 101) and CY/TBI (n = 563). RESULTS: At 4 years, the VP16/CY/TBI group exhibited significantly better disease-free survival (DFS) (72.6% versus 61.7%, P = 0.027) and relapse rate (11.5% versus 21.1%, P = 0.020) and similar non-relapse mortality (16.0% versus 17.2%, P = 0.70). In subgroup analyses, the beneficial effects of the addition of VP16 on DFS were more evident in patients with positive MRD status (71.2% versus 48.4% at 4 years, P = 0.022) than those with negative MRD status (72.8% versus 66.7% at 4 years, P = 0.24). Although MRD positivity was significantly associated with worse DFS in patients who received CY/TBI (48.4% versus 66.7%, P < 0.001), this was not the case in those who received VP16/CY/TBI (71.2% versus 72.8%, P = 0.86). CONCLUSIONS: This study demonstrated the benefits of the addition of VP16 in Ph+ ALL patients, especially those with positive MRD status. VP16/CY/TBI could be a potential strategy to overcome the survival risk of MRD positivity.

Increasing Role of Targeted Immunotherapies in the Treatment of AML.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. The standard of care in medically and physically fit patients is intensive induction therapy. The majority of these intensively treated patients achieve a complete remission. However, a high number of these patients will experience relapse. In patients older than 60 years, the results are even worse. Therefore, new therapeutic approaches are desperately needed. One promising approach in high-risk leukemia to prevent relapse is the induction of the immune system simultaneously or after reduction of the initial tumor burden. Different immunotherapeutic approaches such as allogenic stem cell transplantation or donor lymphocyte infusions are already standard therapies, but other options for AML treatment are in the pipeline. Moreover, the therapeutic landscape in AML is rapidly changing, and in the last years, a number of immunogenic targets structures eligible for specific therapy, risk assessment or evaluation of disease course were determined. For example, leukemia-associated antigens (LAA) showed to be critical as biomarkers of disease state and survival, as well as markers of minimal residual disease (MRD). Yet many mechanisms and properties are still insufficiently understood, which also represents a great potential for this form of therapy. Therefore, targeted therapy as immunotherapy could turn into an efficient tool to clear residual disease, improve the outcome of AML patients and reduce the relapse risk. In this review, established but also emerging immunotherapeutic approaches for AML patients will be discussed.

Deeper sections reveal residual tumor cells in rectal cancer specimens diagnosed with pathological complete response following neoadjuvant treatment.

Guidelines and requirements for diagnosing pathological complete response (pCR) in rectal adenocarcinoma following neoadjuvant treatment vary, and there is currently no consensus on the appropriate number of sections to examine per formalin-fixed, paraffin-embedded (FFPE) tissue block. The consequences of systematic use of deeper sections on the diagnostic accuracy and prognosis for patients classified as ypT0 rectal cancer were investigated. In this retrospective study, 23 out of 155 patients who underwent neoadjuvant therapy and surgical resection between 2015 and 2020 were diagnosed with ypT0 rectal cancer. Three additional deeper sections were cut from each FFPE block from the primary tumor site and reviewed for presence of residual tumor cells. Additional sections revealed residual viable tumor cells in seven patients (30.4%), reducing the rate of pCR in the cohort from 14.8 to 10.3%. Of the seven patients, three patients later had local recurrence or distant metastasis during the follow-up period, compared with one patient with no residual tumor cells in deeper sections (p = 0.07). A nonsignificant reduction in disease-free survival (p = 0.08) was observed in the patients with residual tumor. Systematic use of deeper sections in evaluation of tumor regression in rectal cancer reveals the presence of residual tumor cells in a subset of patients originally diagnosed with pCR based on a single section per FFPE block. Although the results are not statistically significant, it cannot be excluded that accurately distinguishing complete from near-complete response may be clinically relevant for prognostic prediction.

Minimal residual disease in advanced or metastatic solid cancers: The G0-G1 state and immunotherapy are key to unwinding cancer complexity.

In the last decade, a large amount of research has focused on elucidating the mechanisms that account for homing disseminated cancer cells (DCCs) from solid tumours to distant organs, which successively progress to overt metastatic disease; this is currently incurable. A better understanding of DCC behaviour is expected to allow detectable metastasis prevention by more effectively targeting 'metastatic seeds before they sprout'. As DCC biology co-evolved with that of the primary tumour, and due to the many similarities between them, the term 'niche' has been borrowed from normal adult stem cells (ASCs) to define the site of DCC metastatic colonisation. Moreover, heterogeneity, survival, protection, stemness and plasticity as well as the prolonged G0-G1 dormant state in the metastatic niche have been the main aspects of intense investigation. Consistent with these findings, in solid cancers with minimal residual disease (MRD), it has been proposed to prolong adjuvant therapy by targeting specific molecular pathway(s) involving DCC dormancy. However, so far, few disappointing clinical data have been reported. As an alternative strategy, because immune-surveillance contributes to the steady state of the DCC population and likely to the G0-G1 state of cancer cells, we have used prolonged immune-modulatory cytostatic chemotherapy, active immune stimulation with an INF-ß/IL-2 sequence or drugs inhibiting myeloid-derived suppressor cell (MDSC)/Treg-mediated immune suppression. This strategy, mainly aimed at boosting the immune response, is based on recent findings suggesting the downregulation of immune escape mechanisms as well as other principal hallmarks during the G0-G1 state and/or in MRD. Preliminary clinical and/or laboratory data suggest the efficacy of this strategy in gastrointestinal and some endocrine-dependent cancers. Following this, we propose therapeutic schedules to prevent DCC activation and proliferation in solid cancers at a high risk of relapse or as maintenance therapy in metastatic patients after complete response (CR) to conventional treatment.

Long-term remissions in patients with early relapse of diffuse large B-cell lymphoma following high-dose chemotherapy, autologous stem cell transplantation, and radiotherapy of residual disease.

PURPOSE: The prognosis of an early relapse of diffuse large B-cell lymphoma (DLBCL) appears to be poor following autologous stem cell transplantation (ASCT). The aim of this study is to contribute data to the open question on whether additional radiotherapy can improve the outcome. PATIENTS AND METHODS: Forty-eight patients with an early relapse (median 4 months after the end of initial immunochemotherapy, range 1-11) of DLBCL have been treated in our institution with high-dose therapy (usually the BEAM protocol) and ASCT since 2008 (median age 61 years, range 28-73). Twenty-three patients received ASCT in a second treatment line, 25 in a third line (19 refractory to second-line salvage therapy, 5 after second relapse). Fifteen of these 48 patients received radiotherapy (36-50 Gy, median 40) of residual masses after ASCT. RESULTS: Three-year overall survival (OS) and progression-free survival (PFS) after second-line ASCT were 61 and 57%, after third-line ASCT 47 and 44%, respectively, without significant differences. A prognostic factor was the International Prognostic Index (IPI) at the start of salvage therapy. Three-year OS and PFS in low-risk patients were 69 and 69%, in low-intermediate-risk 63 and 53%, and in high-intermediate-risk 23 and 23%, respectively (p = 0.033). Twenty-three patients achieved a sustained complete remission (13-146 months, median 62). CONCLUSION: Sustained long-term remissions can be achieved in patients with early relapse of DLBCL following ASCT in a second or third treatment line, particularly in patients with low- and low-intermediate-risk IPI, following radiotherapy of residual disease after ASCT. Further investigations are required to clarify which patients need an alternative therapy (potentially CAR T­cells or allogeneic transplantation).

Prognostic heterogeneity of adult B-cell precursor acute lymphoblastic leukaemia patients with t(1;19)(q23;p13)/TCF3-PBX1 treated with measurable residual disease-oriented protocols.

The prognosis of t(1;19)(q23;p13)/transcription factor 3-pre-B-cell leukaemia homeobox 1 (TCF3-PBX1) in adolescent and adult patients with acute lymphoblastic leukaemia (ALL) treated with measurable residual disease (MRD)-oriented trials remains controversial. In the present study, we analysed the outcome of adolescent and adult patients with t(1;19)(q23;p13) enrolled in paediatric-inspired trials. The patients with TCF3-PBX1 showed similar MRD clearance and did not have different survival compared with other B-cell precursor ALL patients. However, patients with TCF3-PBX1 had a significantly higher cumulative incidence of relapse, especially among patients aged ≥35 years carrying additional cytogenetic alterations. These patients might benefit from additional/intensified therapy (e.g. immunotherapy in first complete remission with or without subsequent haematopoietic stem cell transplantation).