Leukemia Relapse Research Articles

Pretransplantation risk factors for positive MRD after allogeneic stem cell transplantation in AML patients: a prospective study.

We aimed to prospectively explore the risk factors for measurable residual disease (MRD) positivity after allogeneic stem cell transplantation (allo-SCT) in AML patients (n = 478). The cumulative incidences (CIs) of post-SCT MRD positivity at 100 days, 360 days and 3 years were 4.6%, 12.1% and 18.3%, respectively. Positive pre-SCT MRD and pre-SCT active disease were risk factors for post-SCT MRD positivity at both 360 days and 3 years (P < 0.001). European LeukemiaNet (ELN) 2017 risk stratification was a risk factor for positive post-SCT MRD at 360 days (P = 0.044). A scoring system for predicting post-SCT MRD positivity at 360 days was established by using pre-SCT MRD, pre-SCT active disease and ELN 2017 risk stratification. The CI of positive post-SCT MRD at 3 years was 13.2%, 23.7%, and 43.9% for patients with scores of 0, 1, and 2, respectively (P < 0.001). Multivariate analysis demonstrated that the scoring system was associated with a higher CI of post-SCT MRD positivity, leukemia relapse and inferior survival. Our data indicate that positive pre-SCT MRD status, pre-SCT active disease, and ELN 2017 risk stratification are risk factors for positive post-SCT MRD status in AML patients.

Short-course subcutaneous alemtuzumab induces clinical responses in relapsed T-cell large granular leukemia.

Not available.

The mechanisms of B-cell acute lymphoblastic leukemia relapsing following chimeric antigen receptor-T cell therapy; the plausible future strategies.

Research has demonstrated the high mortality and morbidity associated with B-Acute lymphoblastic lymphoma (B-ALL). Researchers have developed several therapeutic approaches to combat the disorder. Recently, researchers developed chimeric antigen receptors (CARs)-T cells, which recognize antigens independently of major histocompatibility complexes (MHCs) and activate at a higher level with additional persistence. However, relapsing B-ALL has been reported in several cases. This review article was aimed to collecting recent information regarding the mechanisms used by B-ALL-related lymphocytes to escape from CAR-T cells and the plausible resolution projects.

Relapsed AML in a Patient Presenting to a College Health Center: A Case Report

Acute myelogenous leukemia (AML) represents nearly 40% of all cancers affecting the adolescent and young adult (AYA) population. Although overall survival has improved, cure rates for AYAs lag behind younger leukemia patients. The primary care provider (PCP), including the college health provider, is a crucial member of the medical team for children and AYA cancer survivors. In the college setting, the PCP plays a key role in close monitoring for relapse and late effects. This case highlights the presentation of a college student to their university's health center for complaints later found to be due to relapsed leukemia. The PCP must distinguish the unique needs of AYA cancer survivors to provide early recognition and referral to treatment for concerns.

Gallic acid enhances GVL effects of T cells without exacerbating GVHD after haematopoietic stem cell transplantation.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for acute myeloid leukaemia (AML), predominantly due to its potent graft-versus-leukaemia (GVL) effect. However, leukaemia relapse remains a major obstacle to the success of allo-HSCT. In this study, we demonstrated that gallic acid (GA), a natural dietary compound, can enhance T-cell-mediated GVL effects both invitro and invivo. GA-treated T cells exhibited increased activation and elevated secretion of cytotoxic cytokines, leading to the apoptosis of AML cells in co-culture systems invitro. In a non-irradiated leukaemia mouse model, we showed that GA treatment prolonged the survival of leukaemic mice and reduced leukaemia cell infiltration. Further analysis revealed that GA treatment increased T-cell activation and tumour necrosis factor-α secretion. Moreover, integrated transcriptomic and proteomic analyses indicated that GA augments T-cell-mediated GVL effects through the activation of the MAPK and NF-κB pathways. Blocking these pathways individually diminished the protective effect of GA in AML model mice. Importantly, GA administration did not accelerate graft-versus-host disease (GVHD) progression in a mouse model. In conclusion, our study revealed that GA can enhance the GVL effects of T cells without exacerbating GVHD, offering insights into its potential to improve outcomes for patients after HSCT.

Precision medicine results from equitable representation.

In this special issue of Bone Marrow Transplantation, investigators report the impact of IDH1 [1], IDH2 [2], and FLT3-TKD [3] measurable residual disease (MRD) pre-hematopoietic cell transplantation (HCT) in predicting relapse of acute myeloid leukemia (AML) in adults receiving allogeneic HCT. The patient population for these retrospective cohorts, reflecting clinical transplant practice patterns and research biobank participation, was 84-86% non-Hispanic White (NHW) in each study. In this commentary, we explore the implications of racial and ethnic disparities in access to both HCT and HCT-related research and propose strategies to promote representation in precision medicine, given the emerging impact of the field on HCT outcomes.

Severe acute cutaneous only graft-versus-host disease after late relapse of chronic myeloid leukemia and ultraviolet B phototherapy.

Not available.

Myeloid sarcoma mimicking as recurrent squamous cell carcinoma: What is the etiology?

Abstract Introduction/Objective Myeloid sarcoma is an extramedullary malignancy of primitive myeloid cells and can occur during, preceding, or as a relapse of acute myeloid leukemia that occurs mostly in the soft tissue and skin. Methods/Case Report A 77-year-old white male with a history of oral squamous cell carcinoma status post resection (18 months ago) followed by radiation and chemotherapy (15 months prior), presented to the ear nose and throat clinic with increasing weakness and dizziness. He received two doses of Cisplatin and was currently on Pembrolizumab. On examination, there were two lesions in the oral cavity, one on the right gingivobuccal sulcus and a second on the left posterior mandibular ridge, suspicious for squamous cell carcinoma recurrence. Interestingly, the biopsy did not show evidence of recurrent squamous cell carcinoma but showed sheets of blasts that were positive for MPO, CD117, CD43, and CD68, consistent with myeloid sarcoma. Subsequent peripheral blood and bone marrow examinations showed acute myeloid leukemia. Results (if a Case Study enter NA) NA Conclusion Myeloid neoplasms post-cytotoxic therapy (MN-pCT) occur after radiation, alkylating agents, DNA topoisomerase II inhibitors, antimetabolites, and PARP1 inhibitors for a non-myeloid malignancy. Topoisomerase inhibitors are associated with MN-pCT after a latency period of 1 to 3 years; alkylating agents and radiation are associated with MN-pCT after a latency period of 5 to 7 years. Interestingly, this patient developed myeloid sarcoma in a previously irradiated area within 2 years. Cisplatin was discontinued after 2 doses due to side effect complications and is unlikely to be the culprit. Pembrolizumab is not considered to be a cytotoxic therapy and has not been reported to be associated with MN-pCT, however, the latency period for radiation-induced MN-pCT is unusually short in this patient and this raises the possibility of a Pembrolizumab-induced secondary myeloid neoplasm; additional investigation with other patients on this medication with second subsequent malignancies is required.

Isolated intracranial myeloid sarcoma as an acute myeloid leukemia relapse: A case report

Abstract Introduction/Objective Adequate assessment during intraoperative consultation on a patient with a brain mass is imperative to provide critical information that will direct the therapeutic approach during surgery. Methods/Case Report The patient is a 67-year-old female with acute myeloid leukemia (AML) on maintenance therapy and in remission for the past 2 years that developed altered mental status and seizures. Imaging revealed a diffuse intra-axial mass within the corpus callosum and right hypothalamic region. A brain stereotactic biopsy was performed. Blood work showed mild leukopenia (3.63x109/L), thrombocytopenia (platelet count of 82x109/L), and an essential normal hemoglobin level of 11.9 g/dL. A frozen section assessment during intraoperative consultation revealed an infiltration of small blue cells, suggesting a hematolymphoid process. Further histological assessment showed small to intermediate-sized monomorphic cells in sheets and around the vessels with open fine chromatin, prominent nuclei, and scant cytoplasm admixed with tingible body macrophages. Differential diagnoses included high- grade B-cell lymphoma, Burkitt lymphoma, mantle cell lymphoma blastoid variant, lymphoblastic lymphoma, and myeloid sarcoma (MS). The tumor cells were positive for CD34, CD43, and MPO (subset) and negative for CD20, PAX5, TdT, CD3, and AE1/AE3 by immunohistochemical staining, consistent with MS. Concurrent bone marrow biopsy with flow cytometric evaluation showed progressive trilineage hematopoiesis without evidence of residual leukemia. Results (if a Case Study enter NA) NA Conclusion Intracranial MS is extremely rare, and literature reviews are limited to primarily case reports. MS can occur before, during, or after the initial presentation of AML. Interestingly, this patient had an isolated intracranial myeloid sarcoma as an AML relapse without bone marrow involvement. We aim to increase the awareness of isolated recurrence of AML in the form of an intracranial MS; this disease warrants consideration in patients with a history of a myeloid neoplasm who present with neurological symptoms despite the absence of peripheral disease.

Isolated Unilateral Optic Nerve Involvement as the Presenting Feature of Early Relapse in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Central Mervous System involvement (CNS) in Acute Lymphoblastic Leukemia (ALL) can be present at initial diagnosis or at disease relapse and early detection is crucial for prompt intervention. Optic nerve infiltration by leukemic cells is an oncologic emergency that requires urgent therapy to spare vision along with systemic therapy, with limited data about the optimal therapeutic strategy. Isolated optic nerve Involvement at relapse is rare; described in Philadelphia chromosome negative (Ph-) ALL in 2.2% of relapses in children and exceeding rare in Philadelphia chromosome positive (Ph+) cases, particularly in the absence of systemic disease. Here we report isolated unilateral optic nerve involvement as the sole feature of early disease relapse in Ph+ ALL in the absence of systemic disease, leading to early detection of molecular relapse.

Isolated Unilateral Optic Nerve Involvement as the Presenting Feature of Early Relapse in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Central Mervous System involvement (CNS) in Acute Lymphoblastic Leukemia (ALL) can be present at initial diagnosis or at disease relapse and early detection is crucial for prompt intervention. Optic nerve infiltration by leukemic cells is an oncologic emergency that requires urgent therapy to spare vision along with systemic therapy, with limited data about the optimal therapeutic strategy. Isolated optic nerve Involvement at relapse is rare; described in Philadelphia chromosome negative (Ph-) ALL in 2.2% of relapses in children and exceeding rare in Philadelphia chromosome positive (Ph+) cases, particularly in the absence of systemic disease. Here we report isolated unilateral optic nerve involvement as the sole feature of early disease relapse in Ph+ ALL in the absence of systemic disease, leading to early detection of molecular relapse.

Survival and prognostic factors for relapsed childhood acute lymphoblastic leukemia after treatment with the Chinese children's cancer group ALL-2015 protocol: a single center results.

This retrospective study was conducted to assess the survival rates and prognostic factors in children with relapsed acute lymphoblastic leukemia (ALL) who were treated according to the Chinese Children's Cancer Group ALL-2015 protocol at the Children's Hospital of Chongqing Medical University. The study cohort involving 852 evaluable children with ALL reported a total of 146 relapses during a median follow-up period of 53 months. The primary outcomes measured were the second complete remission (CR2) rates, and 5-year event-free survival (EFS) and overall survival (OS) for patients who received re-treatment post-relapse. Patient data were stratified by ALL subtype (B-ALL vs. T-ALL), age at relapse, site of relapse, and timing of relapse. Univariate and multivariate analyses were performed to identify factors significantly associated with EFS and OS. As of March 31, 2023, 146 relapses were observed, including 128 B-ALL and 18 T-ALL cases. The 8-year CIR was (19.8 ± 1.6)%, with no significant difference between B-ALL and T-ALL (P=0.271). Among the 105 patients who underwent re-treatment, 70 achieved CR2, resulting in a CR2 rate of 67.6%. The 5-year EFS and OS rates for re-treated patients were (45.0 ± 5.4)% and (56.9 ± 5.2)%, respectively. Significant differences in 5-year OS and EFS were found between B-ALL and T-ALL relapses (P < 0.001). The 5-year EFS and OS varied significantly with relapse timing and site of relapse. Factors significantly affecting EFS after relapse included the site of relapse, immunophenotyping, CR2 achievement, and hematopoietic stem cell transplantation (HSCT). Immunophenotyping, CR2 achievement, and HSCT were also identified as significant factors affecting OS after relapse. Despite treatment with the CCCG-ALL-2015 protocol, a significant relapse rate was observed, with 72% of children opting for re-treatment post-relapse. The study highlights the importance of considering specific prognostic factors to inform tailored treatment strategies for relapsed childhood ALL. The findings emphasize the need for further research into improving therapeutic approaches for this patient population. This retrospective study was conducted to assess the survival rates and prognostic factors in children with relapsed acute lymphoblastic leukemia (ALL) who were treated according to the Chinese Children's Cancer Group ALL-2015 protocol at the Children's Hospital of Chongqing Medical University.

18F-FDG PET/CT Finding of Bilateral Breast Relapse in a Male Acute Lymphoblastic Leukemia Patient

Abstract Extramedullary relapse with involvement of the breasts by acute lymphoblastic leukemia is rare. Herein, we report a case of bilateral breast relapse of acute B-cell lymphoblastic leukemia in a man detected by 18F-FDG PET/CT. After systematic therapy, follow-up PET/CT showed a complete response of the bilateral breasts and the axillary lymph nodes.

Measurable residual disease as predictor of post–day +100 relapses after allografting in adult AML

AbstractMeasurable residual disease (MRD) by multiparametric flow cytometry (MFC) before allogeneic hematopoietic cell transplantation (HCT) identifies patients at high risk of acute myeloid leukemia (AML) relapse, often occurring early after allografting. To examine the role of MFC MRD testing to predict later relapses, we examined 935 adults with AML or myelodysplastic neoplasm/AML transplanted in first or second morphologic remission who underwent bone marrow restaging studies between day 70 and 100 after HCT and were alive and without relapse by day +100. Of 935 adults, 136 (15%) had MRD before HCT, whereas only 11 (1%) had MRD at day +70 to +100. In day +100 landmark analyses, pre-HCT and day +70 to +100 MFC MRD were both associated with relapse (both P < .001), relapse-free survival (RFS; both P < .001) overall survival (OS; both P < .001), and, for post-HCT MRD, nonrelapse mortality (P = .001) after multivariable adjustment. Importantly, although 126/136 patients (92%) with MRD before HCT tested negative for MRD at day +70 to +100, their outcomes were inferior to those without MRD before HCT and at day +70 to +100, with 3-year relapse risk of 40% vs 15% (P < .001), 3-year RFS of 50% vs 72% (P < .001), and 3-year OS of 56% vs 76% (P < .001), whereas 3-year nonrelapse mortality estimates were similar (P = .53). Thus, despite high MRD conversion rates, outcomes MRD positive/MRD negative (MRDneg) patients are inferior to those of MRDneg/MRDneg patients, suggesting all patients with pre-HCT MRD should be considered for preemptive therapies after allografting.

Leukemic occult infiltrative optic neuropathy presenting as optic neuritis: a case report

Isolated ocular relapses of leukemia are rare and typically present as infiltrative lesions of the optic nerve. This report presents a case of an isolated ocular relapse of leukemia in a female patient, characterized by occult infiltrative optic neuropathy. Despite the absence of leukemic cell infiltration on MRI, a 33-year-old female patient presented with optic neuritis, which resolved after intrathecal administration of chemotherapeutic agents. However, due to her non-compliance with the treatment regimen, leukemia progressed to infiltrative optic neuropathy. She refused radiation therapy, and while intrathecal injections provided temporary stabilization, they were insufficient for sustained disease control. This case uniquely documents the extended progression of an isolated ocular relapse of leukemia, evolving from an occult infiltrative lesion initially presenting as optic neuritis to a more pronounced infiltrative lesion. It suggests that leukemic optic nerve infiltration can occur in patients with leukemia even in the absence of MRI-detectable abnormalities. Radiation therapy emerges as a critical modality in the management of infiltrative lesions of the optic nerve.

Single-cell dissection reveals promotive role of ENO1 in leukemia stem cell self-renewal and chemoresistance in acute myeloid leukemia.

Quiescent self-renewal of leukemia stem cells (LSCs) and resistance to conventional chemotherapy are the main factors leading to relapse of acute myeloid leukemia (AML). Alpha-enolase (ENO1), a key glycolytic enzyme, has been shown to regulate embryonic stem cell differentiation and promote self-renewal and malignant phenotypes in various cancer stem cells. Here, we sought to test whether and how ENO1 influences LSCs renewal and chemoresistance within the context of AML. We analyzed single-cell RNA sequencing data from bone marrow samples of 8 relapsed/refractory AML patients and 4 healthy controls using bioinformatics and machine learning algorithms. In addition, we compared ENO1 expression levels in the AML cohort with those in 37 control subjects and conducted survival analyses to correlate ENO1 expression with clinical outcomes. Furthermore, we performed functional studies involving ENO1 knockdown and inhibition in AML cell line. We used machine learning to model and infer malignant cells in AML, finding more primitive malignant cells in the non-response (NR) group. The differentiation capacity of LSCs and progenitor malignant cells exhibited an inverse correlation with glycolysis levels. Trajectory analysis indicated delayed myeloid cell differentiation in NR group, with high ENO1-expressing LSCs at the initial stages of differentiation being preserved post-treatment. Simultaneously, ENO1 and stemness-related genes were upregulated and co-expressed in malignant cells during early differentiation. ENO1 level in our AML cohort was significantly higher than the controls, with higher levels in NR compared to those in complete remission. Knockdown of ENO1 in AML cell line resulted in the activation of LSCs, promoting cell differentiation and apoptosis, and inhibited proliferation. ENO1 inhibitor can impede the proliferation of AML cells. Furthermore, survival analyses associated higher ENO1 expression with poorer outcome in AML patients. Our findings underscore the critical role of ENO1 as a plausible driver of LSC self-renewal, a potential target for AML target therapy and a biomarker for AML prognosis.

High-dimensional Immune Profiles and Machine Learning May Predict Acute Myeloid Leukemia Relapse Early following Transplant.

Identification of early immune signatures associated with acute myeloid leukemia (AML) relapse following hematopoietic stem cell transplant (HSCT) is critical for patient outcomes. We analyzed PBMCs from 58 patients with AML undergoing HSCT, focusing on T cell subsets and functional profiles. High-dimensional flow cytometry coupled with Uniform Manifold Approximation and Projection dimensionality reduction and PhenoGraph clustering revealed distinct changes in CD4+ and CD8+ T cell populations in 16 patients who relapsed within 1 y of HSCT. We observed increased IL-2, IL-10, and IL-17-producing CD4+ T cells, alongside decreased CD8+ T cell function early in relapsing patients. Notably, relapsing patients exhibited increased TCF-1intermediate cells, which lacked granzyme B or IFN-γ production in the CD4+ T cell compartment. We then developed a supervised machine learning algorithm that predicted AML relapse with 90% accuracy within 30 d after HSCT using high-throughput assays. The algorithm leverages condensed immune phenotypic data, alongside the ADASYN algorithm, for data balancing and 100 rounds of XGBoost supervised learning. This approach holds potential for detecting relapse-associated immune signatures months before clinical manifestation. Our findings demonstrate a distinct immunological signature potentially capable of predicting AML relapse as early as 30 d after HSCT.

Safe and potent anti-CD19 CAR T-cells with shRNA-IL-6 gene silencing element in patients with refractory or relapsed B-cell acute lymphoblastic leukemia.

Severe cytokine release syndrome (sCRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have limited the widespread use of chimeric antigen receptor T (CAR T)-cell therapy. We designed a novel anti-CD19 CAR (ssCART-19) with a small hairpin RNA (shRNA) element to silence the interleukin-6 (IL-6) gene, hypothesizing it could reduce sCRS and ICANS by alleviating monocyte activation and proinflammatory cytokine release. In a post hoc analysis of two clinical trials, we compared ssCART-19 with common CAR T-cells (cCART-19) in relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Among 87 patients, 47 received ssCART-19 and 40 received cCART-19. Grade ≥3 CRS occurred in 14.89% (7/47) of the ssCART-19 group versus 37.5% (15/40) in the cCART-19 group (p = 0.036). ICANS occurred in 4.26% (2/47) of the ssCART-19 group (all grade 1) compared to 15% (2/40) of the cCART-19 group. Patients in the ssCART-19 group showed comparable rates of treatment response (calculated with rates of complete remission and incomplete hematological recovery) were 91.49% (43/47) for ssCART-19 and 85% (34/40) for cCART-19 (p = 0.999). With a median follow-up of 21.9 months, cumulative nonrelapse mortality was 10.4% for ssCART-19 and 13.6% for cCART-19 (p = 0.33). Median overall survival was 37.17 months for ssCART-19 and 32.93 months for cCART-19 (p = 0.40). Median progression-free survival was 24.17 months for ssCART-19 and 9.33 months for cCART-19 (p = 0.23). These data support the safety and efficacy of ssCART-19 for r/r B-ALL, suggesting its potential as a promising therapy.

Association of CD34 Expression with Future Relapse in Pediatric T-cell Acute Lymphoblastic Leukemia

Background: Developing novel prognostic markers is crucial for childhood T-cell acute lymphoblastic leukemia (T-ALL). Objectives: This study aimed to investigate whether the prognostic impact of CD34, a progenitor marker, is associated with outcomes. Methods: This retrospective cohort study included 82 risk-adapted pediatric patients with T-ALL who were treated under the National Protocol of Childhood ALL in China (NPCLC)-ALL2008 from March 2008 to December 2016. Results: CD34 expression was observed in 37.8% of all T-ALL patients, with a median expression level of 62.7%. Patients with CD34 expression had a favorable event-free survival (EFS, 74.2% [66.3% - 82.1%]) with a hazard ratio of 0.69 (P = 0.33) and a reduced cumulative incidence of relapse (CIR, 22.6% [15.0% - 30.2%]; P = 0.86) at five years. Even after adjusting for potential factors and competing events in multivariable regression models, there was no connection between the CD34 immunophenotype and the risk of recurrence. Conclusions: CD34 expression did not serve as a predictive factor for relapse in this limited series. Larger multicenter studies are recommended to determine whether this biomarker at initial diagnosis can predict outcomes.

Sorafenib maintenance after allogeneic stem cell transplantation in patients with FLT3+ AML receiving midostaurin during induction and consolidation: a retrospective analysis.

Acute myeloid leukemia (AML) relapse is the main cause of death after allogeneic stem cell transplant (allo-SCT). In AML FLT3+, it was shown that Sorafenib used as maintenance therapy after allo-SCT, significantly reduces the risk of relapse and death. We analyzed 29 adult patients with FLT3m AML and underwent allogeneic stem cell transplant from 2019 to 2023. All patients received midostaurin plus conventional CT during induction and consolidation. After transplantation, Sorafenib maintenance was administered in all patients independently from MRD status at transplantation. Sorafenib maintenance was applied in 18 patients out 29 patients (62%). Median time to start sorafenib was 100 days (range 37-225) and median duration of treatment was 775 days (range 140-1064). For the whole population (n=29), 2-year OS, LFS, and CIR was 76%, 68% and 28%, respectively. The median time to relapse was 137 days (range 49-246). For patients treated with sorafenib (n=18), the 2-year OS, LFS, and CIR were 94%, 84% and 11%, respectively. For the whole population, the 100-day NRM was 0% and 1-year NRM was 3%. Death was caused by transplant-associated thrombotic microangiopathy in 1 patient. For patients who were administered with Sorafenib, the 1-y NRM was 5%. Death was caused by transplant associated transplant-associated thrombotic microangiopathy. This retrospective study suggests that sorafenib maintenance seem to be effective even in patients pre-treated with midostaurin.