Recurrent Acute Lymphoblastic Leukemia Research Articles

A Late Testicular Relapse in an Adult with Acute Lymphoblastic Leukemia, 5 Years after the Diagnosis and 4 Years after Allotransplant-A Rare Case.

Acute lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells that affects both pediatric and adult populations. Although isolated testicular or any other organ recurrence can occur in the pediatric population, it is rare in adults. We present images for an atypical case of the late testicular recurrence of acute lymphoblastic leukemia in a 56-year-old man previously diagnosed with ALL pro-T who was in remission following polychemotherapy (GMALL 2013 protocol) and the allotransplantation of peripheral blood stem cells from a related donor. Five years later (2022), the unilateral testicular relapse of ALL was suspected by imaging and diagnosed by immunophenotyping from sperm fluid infiltrated with atypical cells with an immunophenotype concordant with that of the underlying disease (ALL T). Bone marrow aspiration and biopsy showed no evidence of systemic leukemia relapse. Testicular ablation or chemotherapy and irradiation were considered. Given the strictly testicular relapse, orchiectomy would have been useful, but given the abdominal adenopathy, a chemotherapy course with HyperCVAD Block A was first required. Testicular relapse can occur at any age, and the recognition of this is important as it may be the first manifestation of systemic relapse.

Abstract 5845: Cytarabine resistance leads to a unique mutational signature

Abstract The prognosis of recurrent T-cell acute lymphoblastic leukemia (T-ALL) is poor, mainly due to chemotherapy resistance. The mechanism(s) leading to chemoresistance at relapse are incompletely understood. We previously characterized a mouse strain that is hypomorphic for the DNA replication factor Mcm2. Mcm2hypo mice develop T-ALL due to acquired DNA copy number variations (CNV) involving tumor suppressor or oncogenes. We hypothesize that treatment of Mcm2hypo cells with specific chemotherapy agents may reveal CNV that lead to chemoresistance. We treated two Mcm2hypo T-ALL cell lines (designated 2883 and 2869) and an Mcm2 WT T-ALL cell line (designated 7298) with cytarabine (ARAC), an active agent often incorporated in T-ALL treatment regimens. After one year of treatment with gradually increasing ARAC concentrations, we obtained ARAC resistant cell lines (designated with the suffix CR) that tolerate drug concentrations up to 10,000X that of parental cell lines. These samples were characterized by sparse WGS (for CNV assessment), RNA-Seq and WES. Both the 2883CR and 2869CR cell lines had bi-allelic mutations involving Dck, which is the rate-limiting enzyme in the cytidine salvage pathway, and is thought to be required for metabolism of ARAC. In both cases, one allele was deleted while the second allele had a splice site/region mutation leading to partial intron retention and resultant frameshift. The 7298CR cell line had homozygous deletion of Dck. Western blotting showed absence of WT Dck protein in all three cell lines. Further analysis of WES data revealed thousands of acquired single nucleotide variants (SNV) in both Dck mutant Mcm2hypo cell lines. These mutations occurred in a specific trinucleotide context (C>T in a GCG context, T>C in a GTC context, T>G mutations in GTC and GTT context, and C>G in a GCC context) generating a mutational signature that is not present in the COSMIC database. In addition, the parental 2883 and 2869 cell lines showed fewer mutations (ie, hundreds vs thousands) in a similar context (C>T in a GCG context, T>C in a GTC context, T>G mutations in GTC and GTT context, but not the C>G in GCC context). A GEMINI (Genotoxic Mutational Signature Identified After Clonal Expansion In Vitro) assay of untreated 2883CR and 2869CR cells demonstrated that ongoing ARAC exposure was not required for the mutational signature. We hypothesize that the basic signature (C>T in a GCG context, T>C in a GTC context, T>G mutations in GTC and GTT context) can be produced by Mcm2 deficiency, and this signature is amplified and modified (to include a C>G in GCC context) by Dck inactivation. In summary, we identified three mechanisms responsible for Dck inactivation associated with ARAC resistance: copy number loss, splice site mutations, and splice region mutations. Moreover, Dck inactivation leads to a specific mutation signature. These findings add to emerging data that exposure to specific chemotherapy agents can lead to specific mutational signatures. Citation Format: Dengchao Cao, Mianmian Yin, Zhenhua Zhang, Taimour Baslan, Jack Zhu, Ryan Bertoli, Paul Meltzer, Peter Aplan. Cytarabine resistance leads to a unique mutational signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5845.

Evaluation of Central Nervous System Relapse in Adults with Acute Lymphoblastic Leukemia (ALL) Receiving Hyper-CVAD Treatment in Seyyed Al-Shohada Hospital: Isfahan, 2014-2019.

Background: Recurrence of ALL in the central nervous system, CNS Relapse, is known as a poor prognostic factor. Few studies have been performed on the CNS Relapse in adults with ALL. This study aimed to evaluate the recurrence of acute lymphoblastic leukemia in the central nervous system, CNS relapse, in adults with ALL. Materials and Methods: Seventy newly diagnosed patients with acute lymphoblastic leukemia aged 15 years and older referred to Seyyed Al-Shohada Hospital in Isfahan between 2014 and 2019 were included in this study. All patients treated with the Hyper-CVAD regimen underwent prophylaxis for the central nervous system based on the risk of CNS relapse. All study participants with CNS relapse underwent intrathecal chemotherapy. Results: The median age of patients was 34 years. Four patients (5.7%) had primary central nervous system involvement. Out of 70 patients receiving the Hyper-CVAD regimen, 59 (84.2%) achieved complete remission. Of the 59 patients achieving CR, ten (16.94%) developed CNS relapse. The median duration of CR before CNS relapse was 21 weeks. Out of 10 patients with CNS relapse, seven (70%) achieved complete remission. Of seven patients achieving CR in the central nervous system, one had a second recurrence in the central nervous system, but finally achieved CNS complete remission. The median survival of patients after CNS relapse was four months. The results also showed that out of 10 patients with CNS relapse, four (40%) survived one year. Conclusion: This study shows that the prognosis of CNS relapse in adults with ALL has not improved much. Limited studies have been conducted on the recurrence of the central nervous system in adults with acute lymphoblastic leukemia. Therefore, further studies on CNS relapse after complete remission of ALL are required to clarify more details.

Olverembatinib Based Therapy in Recurrent Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with BCR/ABL Mutation

Acute lymphoblastic leukemia (ALL) accounts for approximately 20% of adult leukemias, 25% of which are Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). In the past decade, tyrosine kinase inhibitors (TKIs) based regimens greatly improved the prognosis for newly diagnosed and recurrent Ph+ ALL patients, but facing challenges of kinase mutations. In the current study, five relapsed/refractory (R/R) Ph+ ALL patients harboring BCR/ABL kinase mutations were treated with olverembatinib, a third-generation TKI based therapy. Before the treatment, all patients had bone marrow relapses, of whom one presented with central nervous system leukemia (CNSL) and one with both CNSL and extramedullary disease (pleura involvement). The patients received olverembatinib in combination with glucocorticoids or chemotherapy, and intrathecal prophylaxis was used regardless of CNS involvement. At the last follow-up, all patients responded to olverembatinib based treatment with three complete molecular remission (CMR), one complete remission (CR) and one partial remission (PR). Our results suggest that olverembatinib is effective with R/R Ph+ ALL with BCR/ABL kinase mutations and warrants broader clinical evaluation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characteristics and prognosis of children with recurrent T-cell acute lymphoblastic leukemia: a long-term follow-up report in China

This study assessed the relapse characteristics and prognosis of 145 children newly diagnosed with T-cell acute lymphoblastic leukemia (T-ALL). The overall complete response (CR) rate was 91.7% (133/145), and the overall recurrence rate was 31.6% (42/133). The recurrence rate in the intermediate-risk (IR) group and high-risk (HR) group was 15.4% and 47.1%, respectively (p < 0.001). Patients with young age, early T-cell precursor ALL, central nervous system (CNS) involvement, TCRγ gene rearrangement, karyotypic abnormalities, or absence of TCRβ gene rearrangement (p < 0.05) tended to relapse. All recurrences occurred within 36 months after diagnosis. The HR group recurred earlier than the IR group (p= 0.026). The 3-year overall survival (OS) rate was significantly lower in the HR group than in the IR group (p < 0.001). All relapsed children died within 12 months after recurrence. Early intervention may benefit children with a high risk of recurrence.

Contribution of Model Organisms to Investigating the Far-Reaching Consequences of PRPP Metabolism on Human Health and Well-Being.

Phosphoribosyl pyrophosphate synthetase (PRS EC 2.7.6.1) is a rate-limiting enzyme that irreversibly catalyzes the formation of phosphoribosyl pyrophosphate (PRPP) from ribose-5-phosphate and adenosine triphosphate (ATP). This key metabolite is required for the synthesis of purine and pyrimidine nucleotides, the two aromatic amino acids histidine and tryptophan, the cofactors nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+), all of which are essential for various life processes. Despite its ubiquity and essential nature across the plant and animal kingdoms, PRPP synthetase displays species-specific characteristics regarding the number of gene copies and architecture permitting interaction with other areas of cellular metabolism. The impact of mutated PRS genes in the model eukaryote Saccharomyces cerevisiae on cell signalling and metabolism may be relevant to the human neuropathies associated with PRPS mutations. Human PRPS1 and PRPS2 gene products are implicated in drug resistance associated with recurrent acute lymphoblastic leukaemia and progression of colorectal cancer and hepatocellular carcinoma. The investigation of PRPP metabolism in accepted model organisms, e.g., yeast and zebrafish, has the potential to reveal novel drug targets for treating at least some of the diseases, often characterized by overlapping symptoms, such as Arts syndrome and respiratory infections, and uncover the significance and relevance of human PRPS in disease diagnosis, management, and treatment.

In vitro and in vivo effects of AVA4746, a novel competitive antagonist of the ligand binding of VLA-4, in B-cell acute lymphoblastic leukemia.

Treatment of resistant or recurrent acute lymphoblastic leukemia (ALL) remains a challenge. It was previously demonstrated that the adhesion molecule integrin α4, referred to hereafter as α4, mediates the cell adhesion-mediated drug resistance (CAM-DR) of B-cell ALL by binding to vascular cell adhesion molecule-1 (VCAM-1) on bone marrow stroma. In addition, it was previously observed that the blockade of α4 with natalizumab or inhibition using the small molecule antagonist TBC3486 sensitized relapsed ALL cells to chemotherapy. However, α4-targeted therapy is not clinically available for the treatment of leukemia to date. In the present study, the use of a novel non-peptidic small molecule integrin α4 antagonist, AVA4746, as a potential new approach to combat drug-resistant B-ALL was explored. An in vitro co-culture = model of primary B-ALL cells and an in vivo xenograft model of patient-derived B-ALL cells were utilized for evaluation of AVA4746. VLA-4 conformation activation, cell adhesion/de-adhesion, endothelial tube formation, in vivo leukemia cell mobilization and survival assays were performed. AVA4746 exhibited high affinity for binding to B-ALL cells, where it also efficiently blocked ligand-binding to VCAM-1. In addition, AVA4746 caused the functional de-adhesion of primary B-ALL cells from VCAM-1. Inhibition of α4 using AVA4746 also prevented angiogenesis in vitro and when applied in combination with chemotherapy consisting of Vincristine, Dexamethasone and L-asparaginase, it prolonged the survival of ~33% of the mice in an in vivo xenograft model of B-ALL. These data implicate the potential of targeting the α4-VCAM-1 interaction using AVA4746 for the treatment of drug-resistant B-lineage ALL.

A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia.

Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients’ experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T-cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells, and CAR T-cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T-cells, and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T-cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load, and leukemia burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model.

Gene Modified CAR-T Cellular Therapy for Hematologic Malignancies

With advances in the understanding of characteristics of molecules, specific antigens on the surface of hematological malignant cells were identified and multiple therapies targeting these antigens as neoplasm treatments were developed. Among them, chimeric antigen receptor (CAR) T-cell therapy, which got United States Food and Drug Administration (FDA) approval for relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) as well as for recurrent acute lymphoblastic leukemia (ALL) within the past five years, and for r/r mantle cell lymphoma (MCL) this year, represents one of the most rapidly evolving immunotherapies. Nevertheless, its applicability to other hematological malignancies, as well as its efficacy and persistence are fraught with clinical challenges. Currently, more than one thousand clinical trials in CAR T-cell therapy are ongoing and its development is changing rapidly. This review introduces the current status of CAR T-cell therapy in terms of the basic molecular aspects of CAR T-cell therapy, its application in hematological malignancies, adverse reactions during clinical use, remaining challenges, and future utilization.

Analysis of Adct-602 Pre-Clinical Activity in B-Cell Lymphoma Models and Identification of Potential Biomarkers for Its Activity

Analysis of Adct-602 Pre-Clinical Activity in B-Cell Lymphoma Models and Identification of Potential Biomarkers for Its Activity

Случай развития переднего увеита на фоне острого лимфобластного лейкоза

A clinical case of the development of a rare form of ocular manifestation of acute lymphoblastic leukemia, one of the most common oncological diseases in childhood, is described. A seven-year-old child initially had weakness, decreased appetite, and a single episode of subfebrile condition for two days without catarrhal symptoms. Further, an increase in the cervical lymph nodes was noticed. Then a hemorrhagic rash appeared all over the body. In the complete blood count (CBC) test: erythrocytes (RBC) – 3.8 * 1012 / l, hemoglobin (HGB) – 115 g/L, leukocytes (WBC) – 121*109/L, platelets (PLT) – 22*109/L. The child was admitted to the regional children’s clinical hospital. On examination, 90% of blast cells were detected in the myelogram. Against the background of a confirmed remission of the oncological disease, iridocyclitis of the left eye was diagnosed. It could not be stopped by standard antibacterial and antiinflammatory therapy. After a while, the right eye was also involved in the pathological process. Hematologists confirmed the recurrence of acute lymphoblastic leukemia after bone marrow puncture. The presented clinical case demonstrates the fact that the treatment of ocular manifestations of acute lymphoblastic leukemia can be effective only in the treatment of the underlying disease.

Disseminated Corynebacterium striatum Infection in a Patient With Recurrent Acute Lymphoblastic Leukemia

Disseminated Corynebacterium striatum Infection in a Patient With Recurrent Acute Lymphoblastic Leukemia

Management of Recurrent Acute Lymphoblastic Leukemia With T-Cell Engagement: CAR T, BiTEs, and Beyond.

Immunotherapies targeting CD19 (blinatumomab) and CD22 (inotuzumab ozogamicin) have demonstrated higher complete response rates and improved survival compared with chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL), and are now standard of care in the relapsed setting. However, most adult patients still die of ALL despite these therapies, with or without hematopoietic stem cell transplant. At the NCCN 2019 Annual Congress: Hematologic Malignancies, Dr. Jae Park summarized clinical data from key trials of novel immunotherapies in ALL and reviewed evidence-based treatment approaches for adults with relapsed/refractory B-cell ALL.

Inotuzumab Ozogamicin and Chemotherapy in Treating Patients With Recurrent or Refractory B-cell Acute Lymphoblastic Leukemia

Inotuzumab Ozogamicin and Chemotherapy in Treating Patients With Recurrent or Refractory B-cell Acute Lymphoblastic Leukemia

Nursing management for adult recipients of CAR T-19 therapy

With limited cancer treatment options available for patients with certain types of advanced or recurrent acute lymphoblastic leukemia and certain types of non-Hodgkin lymphoma, the recent FDA approvals of tisagenlecleucel (Kymriah, formerly known as CTL019), and axicabtagene ciloleucel (Yescarta), CAR T-cell therapy provides a new opportunity to achieve cancer remission for many patients.1,2 These genetically enhanced T cells can destroy cancer cells. This article explores the science behind CAR T-cell therapy and ways critical care nurses can recognize and intervene in potentially life-threatening adverse reactions associated with this new therapy: cytokine release syndrome and CAR T-cell-related encephalopathy syndrome.3

A case of isolated intraocular recurrence of acute lymphoblastic leukemia

The development of diagnostic and therapeutic capabilities in hematology contributed to a growth in survival rate in patients with acute leukemia and to the increase in number of different ocular conditions as rare signs of hemoblastosis recurrence and treatments side effects. We observed a female patient with extramedullar leukemic ocular damage in acute lymphoblastic leukemia. It is noteworthy that the process of ocular involvement into the underlying disease occurred on the background of complete confirmed hematologic remission.

Central Hyperventilation in a Patient with Recurrent Acute Lymphoblastic Leukemia.

Central Hyperventilation in a Patient with Recurrent Acute Lymphoblastic Leukemia.

Massive Parallel Sequencing and Mutations Analysis of Mismatch Repair Genes in Recurrent Childhood Acute Lymphoblastic Leukemia Cases-Identification of Possible Molecular Signature of Poor Clinical Outcome

[Introduction] Mechanism of recurrence is fully characterized and is significant to improve prognosis in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and T lymphoblastic leukemia (T-ALL).. We have analyzed recurrent cases of childhood BCP-ALL and T-ALL. [Procedure] We analyzed clinical samples of 18 cases with BCP-ALL and 3 cases with T-ALL, who had been treated in our institution. We have investigated gene status of IKZF1, CRLF2, CDKN2A/2B, JAKs, IL7RA, and TP53 using RT-PCR and MLPA methods and IGH/TCR on genomic PCR. Whole exome analysis was done using Ion AmpliSeq Exome in seven cases. [Result] We analyzed clinical samples of 21 cases with ALL, who had been treated in our institution. The cases were 18 cases with BCP-ALL and 3 cases with T-ALL. We have investigated gene status of IKZF1, CRLF2, CDKN2A/2B,JAKs,IL7RA, NOTCH (for T-ALL), and TP53. Whole exome analysis was done in two cases, particularly for a case from which we have established cell line. < Result > Eight BCP-ALL cases with P2RY8-CRLF2 chimeric transcript: four cases of which had P2RY8-CRLF2 chimeric transcript only at initial diagnosis; two cases obtained transcript at recurrence. This was confirmed employing LD-PCR genomic analysis. Ten BCP-ALL cases had deletion of IKZF1; two showed deletion at relapse and a case demonstrated deletion at diagnosis only. Two BCP-ALL cases showed mutation of IL7RA. One of T-ALL cases from which we have established cell line showed mutation of MSH2 and more than 200 non-synonymous mutations on whole exome analysis. One T-ALL cases showed mutation of JAK3 at diagnosis. One BCP-ALL case had MLH1 mutation < Discussion > The present study has suggested acquisition of complex genetic change at different point of evolution may work in recurrence of ALL. The present study has indicated P2RY8-CRLF2 works not as simple growth advantage but rather as manifestation of genomic instability. This may be also illustrated by recurrent cases with T-ALL having mutation of MSH2 and BCP-ALL having mutation of MLH1.Mutation of mismatch repair gene may be driver of gene mutation acquisition and consequently alterations of CREBBP and RAS or IKZF1, TP53, mismatch repair genes, or emergence of P2RY-CRLF2 chimeric transcript may be prognostically relevant in childhood acute lymphoblastic leukemia. DisclosuresNo relevant conflicts of interest to declare.

Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients

20% of children suffering from high hyperdiploid acute lymphoblastic leukemia develop recurrent disease. The molecular mechanisms are largely unknown. Here, we analyzed the genetic landscape of five patients at relapse, who developed recurrent disease without prior high-risk indication using whole-exome- and whole-genome-sequencing. Oncogenic mutations of RAS pathway genes (NRAS, KRAS, FLT3, n=4) and deactivating mutations of major epigenetic regulators (CREBBP, EP300, each n=2 and ARID4B, EZH2, MACROD2, MLL2, each n=1) were prominent in these cases and virtually absent in non-recurrent cases (n=6) or other pediatric acute lymphoblastic leukemia cases (n=18).In relapse nucleotide variations were detected in cell fate determining transcription factors (GLIS1, AKNA). Structural genomic alterations affected genes regulating B-cell development (IKZF1, PBX1, RUNX1). Eleven novel translocations involved the genes ART4, C12orf60, MACROD2, TBL1XR1, LRRN4, KIAA1467, and ELMO1/MIR1200. Typically, patients harbored only single structural variations, except for one patient who displayed massive rearrangements in the context of a germline tumor suppressor TP53 mutation and a Li-Fraumeni syndrome-like family history. Another patient harbored a germline mutation in the DNA repair factor ATM. In summary, the relapse patients of our cohort were characterized by somatic mutations affecting the RAS pathway, epigenetic and developmental programs and germline mutations in DNA repair pathways.

Central nervous system relapse in adults with acute lymphoblastic leukemia.

7080 Background: Recurrence of acute lymphoblastic leukemia (ALL) in the central nervous system (CNS) in adults is associated with poor outcome. Few reports have analyzed the impact of contemporary...