Minimal Residual Disease Negativity Research Articles

Philadelphia chromosome-positive or Philadelphia chromosome-like B-cell precursor acute lymphoblastic leukemia with multilineage involvement in pediatric patients: a report of two cases and literature review.

Based on driver mutations and gene expression profiles, the International Consensus Classification currently divided the entity 'Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL)' into two subtypes: lymphoid-only and multilineage involvement (Ph+ ALL-L and -M, respectively). The similar biological characteristics of Ph-like ALL and Ph+ ALL drove us to assume that Ph-like ALL-M subtypes exist. This report presents two pediatric ALL cases (one Ph+ and one Ph-like) with minimal residual disease negativity established by multicolor flow cytometry but persistent transcript detection by quantitative PCR (qPCR) even after second-line treatment with tyrosine kinase inhibitors combined with blinatumomab immunotherapy. Using droplet digital PCR, BCR::ABL1 or TPM3::PDGFRB transcripts were identified in CD19+ cells as well as in non-CD19+ cells, suggesting the presence of a Ph+ or Ph-like ALL-M subtype originating from hematopoietic stem cells. This report provides information for better characterization, diagnosis, and treatment of these ALL subtypes.

Long-term real-world evidence of CPX-351 of high-risk AML patients identified high rate of negative MRD and prolonged OS

CPX-351 has been approved for patients with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). No extensive data are available on MRD and long-term clinical outcome using CPX-351 in AML in real-life. We retrospectively collected data from 168 patients in 36 centers in France and Italy who had received one or two cycles of induction with CPX-351. All patients were older than 18 years and had newly diagnosed, untreated t-AML or MRC-AML. With a median follow-up of 3 years, median OS was 13.3 months. Median OS was 20.4 months vs. 12.9 months for patients with MRD below or above 10-3, respectively (p=0.006). In a multivariate analysis, only MRD >10-3 was associated with a poorer OS (hazard ratio [HR]=2.6, 95% CI 1.2-5.5, p=0.013). We also observed a trend towards a better median OS in patients who underwent HSCT with MRD <10-3 (not reached vs. 26.0 months, p=0.06). Achievement of MRD negativity contributed to the improvement of OS in the overall population and, maybe, in transplanted patients. These data provide the rationale for the two ongoing studies evaluating CPX-351 vs. 7+3 in non-MRC-AML and non-t-AML using MRD as the primary endpoint for ALFA-2101 phase II clinical trial and event-free survival for AMLSG 30-18 phase III clinical trial. Funding: Any

Development of an 18-color flow cytometry panel for B-lymphoblastic leukemia minimal residual disease detection

Abstract B-cell acute lymphoblastic leukemia (B-ALL) is characterized by a neoplastic proliferation of precursor B cells that have blast cytomorphology and immature immunophenotype. Following treatment of B-ALL, flow cytometry is utilized to detect minimal residual disease (MRD), which aids in monitoring therapeutic response and informing prognosis. In our institution, the BD FACSCanto cytometer is used in conjunction with two standardized 8-antibody EuroFlow panels to detect MRD in B-ALL patients. The objective of this study was to validate a new 18-color B-ALL MRD panel for bone marrow aspirate specimens to be run on a BD LSRFortessa cytometer, with the intention of improving sensitivity and consolidating the testing into one antibody panel. The proposed panel consisted of 22 antibodies, some of which were stacked within the same fluorescence channel, in addition to a viability stain. Twelve bone marrow aspirate specimens collected in 2023 (five positive and seven negative B-ALL MRD specimens) were stained with the new antibody panel and analyzed on the Fortessa cytometer. CD45 dim, CD19-positive blasts were analyzed using BD FACSDiva Software. For the five specimens previously reported as B-ALL MRD-positive using the EuroFlow panels, we were able to detect phenotypically identical B-ALL cells with the 18-color panel. A paired t-test done on the five MRD-positive specimens showed no significant difference in the percentage of residual B-ALL cells (out of total viable cells) measured by the 18-color panel when compared to the EuroFlow panels (EuroFlow/18-color: 0.0096%/0.0097%, 0.024%/0.012%, 0.94%/0.99%, 0.85%/0.85%, 0.022%/0.017%; p=0.58). All seven specimens that were previously reported as B-ALL MRD-negative using the EuroFlow panels were also negative for residual B-ALL cells when stained with the 18-color panel and analyzed on the Fortessa cytometer. The antibody cost per test of the EuroFlow panels ($20-$25, ~$44 for both panels) and new 18-color panel ($63) were calculated based on the unit cost of each antibody aliquot and the required volume of reagent per test. In summary, the new 18-color B-ALL MRD panel run on the BD LSRFortessa cytometer appears to provide similar results as the EuroFlow panels run on the BD FACSCanto cytometer. Although compared to the two EuroFlow panels, the single 18-color panel is more expensive per test in terms of antibodies, it may be preferable when there is scant tissue (such as cerebrospinal fluid) as there may not be enough material to run both EuroFlow panels.

Real-World Evidence on Prognostic Value of MRD in Multiple Myeloma Using Flow Cytometry.

Minimal residual disease (MRD) is one of the most important prognostic factors in multiple myeloma (MM) and a valid surrogate for progression-free survival (PFS) and overall survival (OS). Recently, MRD negativity was approved as an early clinical endpoint for accelerated drug approval in MM. Nevertheless, there is limited evidence of MRD utility in real-world setting. In this retrospective multicenter study, we report outcomes of 331 newly diagnosed MM patients with MRD evaluation at Day+100 after autologous stem cell transplantation using flow cytometry with a median limit of detection of 0.001%. MRD negativity was reached in 47% of patients and was associated with significantly prolonged median PFS (49.2 months vs. 18.4 months; hazard ratios (HR) = 0.37; p < 0.001) and OS (not reached vs. 74.9 months; HR = 0.50; p = 0.007). Achieving MRD negativity was associated with PFS improvements regardless of age, International Staging System (ISS) stage, lactate dedydrogenase (LDH) level, or cytogenetic risk. Importantly, MRD positive patients benefited from lenalidomide maintenance versus no maintenance (18-months PFS: 81% vs. 46%; HR = 0.24; p = 0.002) while in MRD negative patients such benefit was not observed (p = 0.747). The outcomes of our real-world study recapitulate results from clinical trials including meta-analyses and support the idea that MRD positive patients profit more from lenalidomide maintenance than MRD negative ones.

Measurable residual disease monitoring in AML with FLT3-ITD treated with intensive chemotherapy plus midostaurin

AbstractMeasurable residual disease (MRD) monitoring in acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITDpos]) has been hampered by the broad heterogeneity of ITD mutations. Using our recently developed FLT3-ITD paired-end next-generation sequencing (NGS)–based MRD assay with a limit of detection of 10−4 to 10−5, we evaluated the prognostic impact of MRD at different time points in 157 patients with FLT3-ITDpos AML who were enrolled in the AMLSG16-10 trial and who were treated with a combination of intensive chemotherapy and midostaurin, followed by midostaurin maintenance. Achievement of MRD negativity (MRDneg) after 2 cycles of chemotherapy (Cy2), which was observed in 111 of 142 (78%) patients, was predictive of superior 4-year rates of cumulative incidence of relapse (CIR) (4y-CIR; 26% vs 46%; P = .001) and overall survival (OS) (4y-OS; 70% vs 44%; P = .012). This survival advantage was also seen among patients who underwent allogeneic hematopoietic-cell transplantation during first complete remission (4y-CIR, 14% vs 39%; P = .001; 4y-OS, 71% vs 49%; P = .029). Multivariate models for CIR and OS after Cy2 revealed FLT3-ITD MRDneg as the only consistent favorable variable for CIR (hazard ratio [HR], 0.29; P = .006) and OS (HR, 0.39; P = .018). An NPM1 co-mutation correlated with a deeper molecular response as reflected by stronger MRD reduction and a higher rate of FLT3-ITD MRDneg after Cy2. During follow-up, conversion from MRDneg to MRDpos was a strong, independent factor for inferior CIR (HR, 16.64; P < .001) and OS (HR, 4.05; P < .001). NGS-based FLT3-ITD MRD monitoring allows for the identification of patients at high risk for relapse and death following treatment with intensive chemotherapy and midostaurin. Using NGS-based technology, FLT3-ITD emerges as a novel, highly clinically relevant target for MRD monitoring. This trial was registered at www.ClinicalTrials.gov as #NCT01477606.

B-227 Customized molecular tests for minimal residual disease: a tool for therapeutic decisions in follicular lymphoma patients

Abstract Background Monitoring of minimal residual disease (MRD) is based on accurate laboratory tests which can recognize a small fraction of malignant cells that survived the course of treatment. Several studies of the B-non-Hodgkin lymphoma group have been presented that MRD positivity at the end of treatment is a negative prognostic index. Follicular lymphoma (FL) is a chronic indolent malignancy, which response highly to immuno-chemotherapy followed by prolonged remissions but with inevitable relapse in most patients. The GALLIUM study showed that immuno-chemotherapy combinations, 6 cycles of bendamustine-obinutuzumab (BO), is the most efficacious treatment, but with severe side effects .In addition, 90% of patients achieved negative MRD from peripheral blood (PB) or bone marrow (BM) after only 3 BO cycles. These findings raise the possibility for MRD based treatment approach, where the duration of chemotherapy could be decided according to MRD status at mid-induction (MI). Identification of a marker in the PB and/or BM of each FL patient which will be use to the design of a sensitive RQ-PCR test for MRD detection for follow-up. Methods Qualitative PCR for translocation 14:18 and for the VDJ rearrangement sequence of the immunoglobulin heavy chain was used for marker identification. MRD monitoring was done by RQ-PCR. MRD monitoring for VDJ was designed specifically to each patients based on his VDJ sequence. MRD was assessed on PB and BM at MI. Results Marker for monitoring was identified at 11/21 patients in this study. After 3 combined therapy cycles, 7 patients were found to have MRD negativity by RQ-PCR therefore continue with immuno-therapy only. MRD positivity was assessed in BM of 3 patients (0.11%, 0.022%, and 0.133%). These 3 patients continued with the combined therapy. RQ-PCR sensitivity was 10-4-10-5. Conclusions This study will reveal the ability to use sensitive and specific MRD that has to be designed for each patient according to his marker and enable the establishment of a treatment with a high safety profile for FL patients. Correlation between MRD status and clinical and safety parameters will be assessed at the end of the study, 30 months after the first treatment, taking into account MRD status from different time point of the follow-up period.

T(11;14) with multiple myeloma: Standard risk survival but slow and poor response.

We described 790 patients with newly diagnosed multiple myeloma, including 224 (28.4%) standard risk (SR) patients without t(11;14), 99 (12.5%) patients with t(11;14)alone, 58 (7.3%) with t(11;14) + HR, and 409 (51.8%) in the high-risk cytogenetic abnormality (HRCA) group including t(4;14), t(14;16), t(14;20), C1A1 and/or del(17p) but without t(11;14), to evaluate the impact of t(11;14) in NDMM patients on response rate, response kinetics and survival. Our study showed that NDMM patients in the t(11;14)alone group had similar PFS (49.3 vs. 50.7months; P = 0.392) and OS (112.4 vs. NR months; P = 0.982) as those in the SR group. However, the t(11;14)alone group exhibited a significantly poorer depth of response compared to the SR group, particularly with a lower MRD negativity rate (60.0% vs. 76.0%, P = 0.009). In the t(11;14)alone group, MRD status did not significantly impact PFS or OS, which was in contrast to the other groups. Response kinetics analyses showed that the t(11;14)alone group had a slower response rate than the other subgroups (t(11;14)alone vs. SR vs. HRCA: median time to MRD negativity = 9.19 vs. 4.25 vs. 4.27 months; P < 0.001). Our study showed that t(11;14)alone was characterized by survival comparable to standard risk cytogenetics despite exhibiting the slowest timing of response onset and lowest plateau of remission, which suggested a relatively indolent clinical course.

Clinical Outcome of Induction Treatment in the Era of Novel Agents and the Impact of the Number of High-Risk Cytogenetic Abnormalities (HRA) on Prognosis of Patients With Newly Diagnosed Multiple Myeloma (NDMM): Insights From a Multicenter Study.

In the era of novel agents, the clinical outcomes of induction treatment and the impact of the number of high-risk cytogenetic abnormalities (HRA) in newly diagnosed multiple myeloma (NDMM) need to be explored. Through this study, we aim to analyze the effectiveness of different induction treatments and explore the survival outcomes of patients with varying numbers of HRA. A total of 734 patients from seven medical centers were included in our study. Patients in the CD38 monoclonal antibody or IMiDs plus proteasome inhibitors (PI) groups had significantly superior overall survival (OS) and progression-free survival (PFS) compared to those receiving IMiDs or PI alone. Additionally, the CD38 monoclonal antibody conferred a PFS advantage over IMiDs plus PI. Patients with ≥ 2 high-risk cytogenetic abnormalities (HRA) exhibited an extremely poor prognosis and should be considered ultra-high-risk individuals in multiple myeloma (MM). The CD38 monoclonal antibody, transplantation, and achieving minimal residual disease (MRD) negativity only partly mitigated the poor prognosis in patients with HRA. Furthermore, patients with 1q21 gain/amplification (1q21+) only had a significantly worse prognosis compared to patients without HRA, and those with 1q21+ plus del17p or t(4;14) exhibited an inferior prognosis compared to those with 1q21+ alone. Our results suggested that double-hit multiple myeloma was associated with extremely poor survival outcomes, and more effective treatments needed to be explored for this particular subtype of MM.

Insights from Clinical Trials: Evidence-Based Recommendations for Induction Treatment of Newly Diagnosed Transplant-Eligible Multiple Myeloma.

Multiple myeloma (MM) is a hematological malignancy and poses significant therapeutic challenges. This review synthesizes evidence from pivotal clinical trials to guide induction treatment for transplant-eligible (TE), newly diagnosed MM (NDMM) patients. Emphasizing the evolution from three-drug to four-drug induction therapies, we highlight the integration of monoclonal antibodies, particularly CD38 recombinant monoclonal antibody agents, into treatment regimens. This analysis includes a comprehensive literature review of research from major databases and conferences conducted between 2010 and 2023, culminating in the detailed evaluation of 47 studies. The findings underscore the superiority of quadruple regimens in TE NDMM, notably those incorporating daratumumab, in achieving superior responses including progression-free survival (PFS), minimal residual disease (MRD) negativity, objective response rate (ORR), and overall survival (OS) when compared to triple-drug regimens. As treatment regimens evolve with additional agents, the improved outcomes with treatment-related adverse events should be carefully balanced. This review advocates for a paradigm shift towards quadruple induction therapies for TE NDMM, offers a detailed insight into the current landscape of MM treatment, and reinforces a new standard of care.

Mega-dose decitabine conditioning and prophylactic donor lymphocyte infusion for patients with relapsed/refractory AML with active disease at the time of allogeneic haematopoietic cell transplantation: A multicenter prospective phase II study.

Patients with relapsed/refractory acute myeloid leukaemia (R/R AML), especially those who failed in novel target agents are related to dismal survival. We developed a multi-institutional, single-arm, prospective phase II trial, to investigate intensified conditioning with 'Mega-Dose' decitabine (MegaDAC) following allogeneic haematopoietic cell transplantation (allo-HCT) for R/R AML. From 2019 to 2023, 70 heavily treated R/R AML patients in active disease were consecutively enrolled. Significantly, every patient (n = 18) harbouring specific mutations exhibited no response to their best available target agents (BATs). Moreover, 74.3% of the enrolled patients did not reach remission following venetoclax-based regimens. All patients underwent intravenous decitabine (400 mg/m2) along with busulfan and cyclophosphamide. Median follow-up was 26 months (8-65) after HCT. All engrafted patients achieved MRD negativity post-HCT, with a median 3.3-log reduction in recurrent genetic abnormalities. The regimen was well tolerated, without irreversible grades III-IV toxicity peri-engraftment. The estimated 2-year CIR was 29.6% (18.4%-41.7%) and the est-2-year NRM was 15.5% (7.8%-25.5%). The est-2-year LFS, OS, and GRFS were 55.0% (43.5%-69.4%), 58.6% (47.0%-73.0%), and 42.9% (31.9%-57.6%), respectively. Multivariate analysis showed that pre-HCT drug exposures had no significant impact on primary outcomes. MegaDAC is highlighted as an effective and safe option for R/R AML in the new era of targeted therapies.

Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial.

Primary results (median follow-up, 10.7 months) from the pivotal EPCORE® NHL-1 study in relapsed or refractory (R/R) large B-cell lymphoma (LBCL) demonstrated deep, durable responses with epcoritamab, a CD3xCD20 bispecific antibody, when used as monotherapy. We report long-term efficacy and safety results in patients with LBCL (N = 157; 25.1-month median follow-up). As of April 21, 2023, overall response rate was 63.1% and complete response (CR) rate was 40.1%. Estimated 24-month progression-free survival (PFS) and overall survival (OS) rates were 27.8% and 44.6%, respectively. An estimated 64.2% of complete responders remained in CR at 24 months. Estimated 24-month PFS and OS rates among complete responders were 65.1% and 78.2%, respectively. Of 119 minimal residual disease (MRD)-evaluable patients, 45.4% had MRD negativity, which correlated with longer PFS and OS. CR rates were generally consistent across predefined subgroups: 36% prior chimeric antigen receptor (CAR) T-cell therapy, 32% primary refractory disease, and 37% International Prognostic Index ≥3. The most common treatment-emergent adverse events were cytokine release syndrome (51.0%), pyrexia (24.8%), fatigue (24.2%), and neutropenia (23.6%). These results underscore the long-term benefit of epcoritamab for treating R/R LBCL with deep responses across subgroups, including patients with hard-to-treat disease and expected poor prognosis (ClinicalTrials.gov Registration: NCT03625037).

Philadelphia-like B-cell acute lymphoblastic Leukaemia: Disease features and outcomes in the era of immunotherapy.

Philadelphia chromosome (Ph)-like acute lymphoblastic leukaemia (ALL) is a high-risk subtype with a gene expression profile similar to Ph-positive ALL, due to activation of tyrosine kinase signalling. To understand the clinical implications of Ph-like ALL, this single-centre retrospective study evaluates outcomes in 268 adults, largely Hispanic ALL patients treated between 2013 and 2024, with a subgroup analysis of 139 haematopoietic stem cell transplantation (HSCT) patients. ALL subtypes included 68 (25.4%) Ph-like, 89 (33.2%) Ph-positive, and 111 (41.4%) Ph-negative. Ph-like patients were the youngest age at diagnosis (p = 0.007), most likely to have refractory disease (p < 0.001), and least likely to achieve minimal residual disease (MRD) negativity after induction (p = 0.031). Relative to Ph-negative ALL, Ph-like achieved worse event-free survival (EFS) (HR = 1.66; 95% CI 1.12-2.46; p = 0.012), whereas Ph-positive had improved EFS (HR = 0.60; 95% CI 0.38-0.93; p = 0.024) and cumulative incidence of relapse (CIR) (HR = 0.59; 95% CI 0.35-0.99; p = 0.046). Within the transplant subgroup, Ph status did not impact disease-free survival (DFS), CIR, or overall survival (OS). However, patients who received blinatumomab within 1-year pre-HSCT had improved DFS (HR = 0.43; 95% CI 0.20-0.94; p = 0.034) and CIR (HR = 0.26; 95% CI 0.09-0.75; p = 0.13). In conclusion, our data suggest that Ph-like is less likely to respond to standard induction therapy and HSCT may result in similar survival outcomes to Ph-negative ALL.

Ruxolitinib combined with venetoclax and azacitidine in the treatment of refractory T-ALL patients with JAK1, JAK3, and STAT5B gene mutations: a case report and literature review

Refractory acute T-lymphoblastic leukemia (T-ALL), which is characterized by a low sensitivity to conventional induction therapy and poor prognosis, poses significant challenges during treatment. This study reported a case of refractory T-ALL patient with mutations in the JAK1, JAK3, and STAT5B genes from Nanjing University's Gulou Hospital. Following an unsuccessful course of standard VDLP regimen chemotherapy, the treatment was modified to include ruxolitinib in combination with venetoclax and azacitidine. Subsequent to this therapy, the patient achieved bone marrow minimal residual disease (MRD) negativity. Notably, pleural effusion and mediastinal mass significantly improved the post-chest cavity infusion of dexamethasone combined with etoposide at the same stage. The patient also underwent allogeneic hematopoietic stem cell transplantation upon achieving bone marrow remission and was followed up until January 2024. Ruxolitinib combined with venetoclax and azacytidine has shown promising efficacy and safety in treating refractory T-ALL harboring the JAK1, JAK3, and STAT5B mutations, providing a novel therapeutic approach for such patients.

Efficacy and safety of venetoclax combined with decitabine, modified HA regimen and DLI in the treatment of relapsed pediatric AML/MDS after allogeneic hematopoietic stem cell transplantation

Objective: To investigate the efficacy and safety of venetoclax combined with the decitabine, cytarabine, and homoharringtonine (HHT) regimen and donor lymphocyte infusion (DLI) for the preventive and salvage therapy of pediatric acute myeloid leukemia (AML) /myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (HSCT) . Methods: A total of 29 relapsed pediatric/minimal residual disease-positive AML after HSCT were recruited at the Peking University Institute of Hematology from January 1, 2021, to June 1, 2023. They were treated with the above combination regimen and administered with DLI after 24-48 hours at the end of chemotherapy, and the treatment response and adverse reactions were regularly assessed. Results: The overall response rate (ORR) was 75.8%, CR rate was 88.9% (8/9) in the hematologic relapse group, and MRD negativity rate was 61.1% (11/18) in the MRD-positive group. The incidence of agranulocytosis, anemia, and thrombocytopenia with a classification above grade 3 were 100%, 82.7%, and 100%, respectively. The median time of the granulocyte deficiency period was 15 days. Acute graft-versus-host diseases (aGVHD) with a classification of grades Ⅲ-Ⅳ occurred in 11.1% of the patients after DLI, while moderate or severe cGVHD occurred in 7.4% of the patients. The single risk factor for ORR was MNC counts of less than 10×10(8)/kg, and the relapse occurred within 100 days. At a median follow-up of 406 days, the 1-year OS was 65%, and the 1-year OS was 57% in the group with no reaction (P=0.164) compared with 71% in the group who had an overall reaction. Conclusion: The combined regimen based on the DAC, VEN, and modified HA regimen showed a high response rate in the salvage therapy for pediatric AML after the relapse of HSCT. However, bridging to transplantation should be performed immediately after remission to result in a long survival rate.

Daratumumab, bortezomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone alone in transplant-ineligible Asian patients with newly diagnosed multiple myeloma: final analysis of the phase 3 OCTANS Study.

The superiority and tolerability of daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) was previously described in the global phase 3 ALCYONE study. The primary analysis of the phase 3 OCTANS study further demonstrated the superiority and tolerability of D-VMP (n = 144) versus VMP (n = 71) in transplant-ineligible Asian patients with NDMM. The current analysis describes the final efficacy and safety outcomes for D-VMP versus VMP in OCTANS, with a follow-up of > 3 years. D-VMP demonstrated a benefit versus VMP with regard to the rate of very good partial response or better (80.1% vs. 47.3%), median progression-free survival (38.7 vs. 19.2 months), median time to next treatment (46.8 vs. 20.6 months), rate of complete response or better (46.6% vs. 18.9%), median duration of response (41.3 vs. 18.5 months), achievement of minimal residual disease (MRD) negativity (40.4% vs. 10.8%), and sustained MRD negativity for ≥ 12 months (24.7% vs. 1.4%) and ≥ 18 months (15.1% vs. 1.4%). Median progression-free survival was longer among patients who achieved MRD negativity and sustained MRD negativity. The progression-free survival benefit observed with D-VMP was preserved across most clinically relevant subgroups, including patients with high-risk cytogenetics. No new safety concerns were identified with extended follow-up. This final analysis of OCTANS continues to demonstrate a clinical benefit for D-VMP versus VMP in transplant-ineligible Asian patients with NDMM, consistent with the global ALCYONE study, and supports the use of daratumumab combinations in this population. Trial registration: ClinicalTrials.gov Identifier NCT03217812 submitted July 13, 2017.

Diagnostic genomic analysis is prognostic in AYA patients with ALL treated on an MRD-stratified pediatric protocol

AbstractOver the last decade, next-generation sequencing has enabled classification of multiple new recurrent genomic drivers of acute lymphoblastic leukemia (ALL). The aim of this study was to describe the genomic drivers of ALL in an adolescent and young adult (AYA) cohort (ALL06; target age, 15-39 years; recruited age, 16.6-39 years), treated uniformly on a pediatric-inspired protocol (the Australasian Leukaemia and Lymphoma Group ALL06 study). ALL06 assessed the safety and efficacy of adapting a pediatric chemotherapy protocol in older patients. Genomic risk classification of patients with B-cell ALL (B-ALL) and T-cell ALL (T-ALL) enrolled to the study was based on the use of multiple assays: messenger RNA sequencing, multiplex ligation-dependent probe amplification, immunophenotyping, and cytogenetics. Using this approach, 36 of 40 (90%) patients with B-ALL and 13 of 17 (76.5%) patients with T-ALL were classified according to genomic risk. A strong correlation existed between adverse genomic risk and minimal residual disease (MRD) at the end of consolidation, translating to inferior overall and relapse free survival. Patients with adverse risk genomics who achieved negative MRD status had improved responses compared with those with persistent MRD. Patients with standard-risk genomics had excellent responses regardless of MRD status. This is, to our knowledge, the first report of the impact of genomics in an individual cohort of AYA patients treated on a single protocol. These data argue strongly for incorporation of a genomic risk classification into future ALL treatment paradigms at the time of diagnosis, and also for the rigorous assessment of risk assignments in a group of patients who are not children and not older adults. This trial was registered at https://anzctr.org.au/ as #ACTRN12611000814976.

Clinical Efficacy and Safety of CD7-Targeted CAR T Cell Therapy for T-cell Malignancies: A Systematic Review and Meta-analysis.

Although T-cell malignancies are relatively less prevalent compared to B-cell malignancies, they are highly malignant, and patients usually have poor prognoses. Employing CD7-targeted chimeric antigen receptor (CAR) T cell therapy as a novel immunotherapy to treat malignant T cells faces numerous challenges and is in its early phase. To evaluate this possibility, we aimed to review and meta-analyze the related clinical trials systematically. On October 9, 2023, the online databases of PubMed, Scopus, Embase, and Web of Science were systematically searched for pertinent studies. After completing a two-step title/abstract and full-text screening process, the eligible studies were included. We observed a pooled overall response rate (ORR) of 100%. Partial response (PR), stringent and/or complete response (sCR/CR), and relapse rate were 6%, 85%, and 18%, respectively. Additionally, the pooled rate of minimal residual disease (MRD) negativity was 85%. The most common grade ≥3 adverse events were related to hematological toxicities, including neutropenia (100%), thrombocytopenia (79%), and anemia (57%). Cytokine release syndrome (CRS) was also a frequent complication with a 100% rate; however, 81% of CRS events were low grades. No grade ≥3 GVHD was reported, and the immune effector cell-associated neurotoxicity syndrome (ICANS grade ≥3) was rare (4%). CD7 is an active and safe target that shows promising results in the treatment of relapsed and/or refractory (r/r) T-cell malignancies.

AML-002 Impact of Delayed Hematological Recovery on Outcome in Acute Myeloid Leukemia With Negative Minimal Residual Disease Post Induction I in Children

AML-002 Impact of Delayed Hematological Recovery on Outcome in Acute Myeloid Leukemia With Negative Minimal Residual Disease Post Induction I in Children

Impact of Delayed Hematological Recovery on Outcome in Acute Myeloid Leukemia With Negative Minimal Residual Disease Post Induction I in Children

Impact of Delayed Hematological Recovery on Outcome in Acute Myeloid Leukemia With Negative Minimal Residual Disease Post Induction I in Children

Safety and efficacy of belantamab mafodotin with pembrolizumab in patients with relapsed or refractory multiple myeloma.

Belantamab mafodotin (belamaf) has shown promising antimyeloma activity in relapsed or refractory multiple myeloma (RRMM) as a single agent. It was hypothesized that its multimodal activity may be enhanced by programmed cell death protein 1 pathway inhibition and activation of T cell-mediated antitumor responses. This study investigated the efficacy and safety of belamaf with pembrolizumab in patients with RRMM. DREAMM-4 (NCT03848845) was an open-label, single-arm, phase 1/2 study divided into dose-escalation (part 1) and dose-expansion (part 2) phases. Patients were ≥18 years old with ≥3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 agent. Patients received belamaf (2.5 or 3.4 mg/kg, part 1; 2.5 mg/kg, part 2) and 200 mg pembrolizumab for ≤35 cycles. Of 41 enrolled patients, 34 (n=6 part 1, n=28 part 2) who received 2.5 mg/kg belamaf plus pembrolizumab were included in this final analysis. Sixteen patients (47%) achieved an overall response. Minimal residual disease negativity was achieved in three of 10 patients who had very good partial response or better. Five of eight patients who had prior anti-B-cell maturation antigen therapy achieved partial response or better, including two who had B-cell maturation antigen-refractory disease. Common grade ≥3 adverse events were keratopathy (38%) and thrombocytopenia (29%). Despite belamaf-related ocular events, quality-of-life measures remained stable over time. No new safety signals were observed. The results of DREAMM-4 demonstrated clinical activity and a favorable safety profile of belamaf plus pembrolizumab in patients with RRMM. This trial is registered at www. gov as NCT03848845.