Chromosome-positive B-cell Acute Lymphoblastic Leukemia Research Articles

CAR-T Therapy Followed by Hematopoietic Stem Cell Transplantation Can Improve Survival in Children Relapsed/Refractory Philadelphia Chromosome-positive B-cell Acute Lymphoblastic Leukemia.

Philadelphia chromosome (Ph)-positive B-cell acute lymphoblastic leukemia (ALL) has a high complete remission (CR) rate, but relapse and prolonged measurable residual disease remain serious problems. We sought to describe the CR rate measurable residual disease negative rate and address the results and safety of pediatric patients who underwent after receiving chimeric antigen receptor (CAR) specific for CD19 (CAR-19) followed by hematopoietic stem cell transplantation (HSCT) for the treatment of Ph-positive ALL. A descriptive study was conducted at Peking University People's Hospital from September 2013 to January 2021. 13 patients with relapsed/refractory Ph-positive B-ALL who received CAR-T therapy followed by allo-HSCT were included. We concentrated on the overall patient survival and CR rate. The median time between CAR-T therapy and allo-HSCT was 58 days. Among all the patients, the CR rate was 100%, the flow cytometry negativity rate was 84.62%, and the BCR-ABL negativity rate was 53.85% at 1 month after CAR-T infusion. All the patients achieved a major molecular response in 6 months after HSCT. After a median follow-up of 45 months, the 3-year OS rate was 66.7%, and the 3-year DFS rate was 61.5%. The 3-year OS rate of patients with BCR-ABL-positive pre-HSCT was significantly lower than that in the BCR-ABL-negative group (40.0% vs. 85.7%, P=0.042). Also, the same trend was observed for the 3-year DFS rate but did not differ significantly (40.0% vs. 75.0%, P=0.233). CAR-T therapy followed by allo-HSCT can be a safe and effective treatment for Ph-positive B-ALL pediatric patients.

Targeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia

Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting immune niches may ameliorate disease progression and tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive B-ALL (Ph+ B-ALL). Here, we show that T helper type 17 (Th17) cells and IL-17A expression are distinctively elevated in Ph+ B-ALL patients. IL-17A promotes the progression of Ph+ B-ALL. Mechanistically, IL-17A activates BCR-ABL, IL6/JAK/STAT3, and NF-kB signalling pathways in Ph+ B-ALL cells, resulting in robust cell proliferation and survival. In addition, IL-17A-activated Ph+ B-ALL cells secrete the chemokine CXCL16, which in turn promotes Th17 differentiation, attracts Th17 cells and forms a positive feedback loop supporting leukemia progression. These data demonstrate an involvement of Th17 cells in Ph+ B-ALL progression and suggest potential therapeutic options for Ph+ B-ALL with Th17-enriched niches.

Treatment de-escalation in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia: the emerging role of chemotherapy-free regimens.

The management of Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) has witnessed major progress over the past two decades. Initially, the incorporation of the first-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) imatinib into intensive chemotherapy regimens improved outcomes compared with chemotherapy alone. The combinations of chemotherapy with second- or third-generation TKIs further improved outcomes, with higher rates of complete molecular remission (CMR) and superior survival. The combination of ponatinib plus chemotherapy resulted in durable remissions and prolonged long-term survival, even in patients who did not receive allogeneic stem cell transplantation (SCT). The promising results seen with later-generation TKIs have caused many to re-evaluate the role of allogeneic SCT for patients who achieve CMR with potent TKI regimens. Recently, the chemotherapy-free combinations of blinatumomab plus TKIs were shown to be safe and effective in newly diagnosed Ph-positive ALL, sparing patients the toxicities associated with intensive chemotherapy. In particular, encouraging early results have been seen with the combination of blinatumomab plus ponatinib, suggesting that this regimen may represent a chemotherapy-free and SCT-sparing strategy for patients with Ph-positive ALL. Herein, we discuss the current evidence for frontline therapies of Ph-positive ALL, the treatment de-escalation strategies over time, and the role of allogeneic SCT in view of the emergence of newer chemotherapy-free regimens using potent TKIs.

Neurolymphomatosis of the median nerve, optic nerve, L4 spinal nerve root and cauda equina in patients with B-cell malignancies: a case series

BackgroundNeurolymphomatosis is rare. Neoplastic lymphocytes are seen to invade nerves (cranial or peripheral), nerve roots or other related structures in patients with hematological malignancy. It is a separate entity from central nervous system lymphoma. Neurolymphomatosis has most commonly been described in association with B-cell non-Hodgkin lymphoma. Neurolymphomatosis in the context of Burkitt lymphoma and the post-renal transplant setting has not been described before.Case reportsWe report for the first time in the Arabian Gulf countries and nearby Arab states four cases of neurolymphomatosis (one Asian, and the other 3 are from Arabic nationals) occurring between 2012 and 2017 involving the median nerve, optic nerve, nerve root and cauda equina in patients with Burkitt lymphoma, Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma.ConclusionsNeurolymphomatosis is rare and can be difficult to diagnose by biopsy but reliably confirmed by a combined imaging approach. Prior treatment with high-dose dexamethasone might suppress 18F-fluorodeoxyglucose (FDG) activity and decrease the sensitivity of positron emission tomography/computed tomography (PET/CT). The prognosis is generally poor but using high-dose methotrexate as well as high-dose chemotherapy and autologous stem cell transplantation may be an effective way to treat neurolymphomatosis.

Case Report: Late Onset of Myelodysplastic Syndrome From Donor Progenitor Cells After Allogeneic Stem Cell Transplantation. Which Lessons Can We Draw From the Reported Case?

BackgroundMyelodysplastic syndromes and acute leukemias after allogeneic stem cell transplantation (allo-SCT) are mainly caused by recurrence of the primitive leukemic clones. More rarely, they originate from donor hematopoietic stem cells, developing the so-called donor cell leukemia (DCL) or myelodysplastic syndromes (DC-MDSs). DCL and DC-MDS can be considered as an in vivo model of leukemogenesis, and even if the pathogenetic mechanisms remain speculative, a genetic predisposition of donor progenitor cells, an altered host microenvironment, and the impairment of immune surveillance are considered the main causes.Case PresentationWe report a case of DC-MDS diagnosed 5 years after an allo-SCT from a matched related donor (patient’s sister) in a patient with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL). The sex-mismatch allowed us to identify the donor cell origin. At the onset, the DC-MDS was characterized by chromosome seven monosomy and NRAS, RUNX1, and BCOR mutations. Because of a familiar history of colorectal neoplasia and the variant allele frequency (VAF) of NRAS mutation at the onset, this mutation was searched on germline DNA in both the donor and the recipient, but the result was negative. Moreover, after transplant (+4 months), the patient developed severe and long-lasting chronic graft-versus-host disease (cGVHD), requiring multiple lines of treatments. Because of the severe immunosuppression, recurrent infections occurred and, lately, the patient died due to septic shock.ConclusionThis case report highlights the need, whenever possible, to evaluate the donor origin of the posttransplant myelodysplasia and acute leukemias. The potential key role of the impaired immune surveillance and of long-lasting immunosuppression appears to be emerging in the development of this case of DC-MDS. Finally, this case reminds the importance to investigate the familiar genetic predisposition in donors with a familiar history of neoplasia.

Concurrent Imatinib Dosing With High-dose Methotrexate Leads to Acute Kidney Injury and Delayed Methotrexate Clearance in Pediatric Patients With Philadelphia Chromosome-positive B-Cell Acute Lymphoblastic Leukemia.

Imatinib, a tyrosine kinase inhibitor has improved survival in pediatric patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia. There are no formal drug interactions listed between methotrexate and tyrosine kinase inhibitors. Four pediatric patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia had delayed methotrexate clearance during their first cycle of high-dose methotrexate while receiving imatinib, resulting in acute kidney injury. For subsequent high-dose methotrexate cycles, imatinib was withheld resulting in decreased acute kidney injury, shorter time to methotrexate clearance, less toxicity, and shorter hospitalizations. For pediatric patients with acute lymphoblastic leukemia receiving imatinib, we recommend escalated supportive care measures including increased hyperhydration and leucovoruin frequency. For patients with toxicities secondary to delayed clearance or need for glucarpidase, we recommend holding imatinib with subsequent high-dose methotrexate courses.

DYRK1A Is Regulated By Oncogenic KMT2A and Required for Survival of KMT2A-Rearranged Acute Lymphoblastic Leukemia

Background: Research efforts have focused upon uncovering critical leukemia-associated genetic alterations that may be amenable to therapeutic targeting with new drugs. Targeting the oncogenic BCR-ABL1 fusion protein in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (B-ALL) with tyrosine kinase inhibitors to shut down constitutive signaling activation and induce leukemia cell cytotoxicity has remarkably improved patients' survival and has established a precision medicine paradigm for kinase-driven leukemias. However, multiple subtypes of B-ALL are driven through non-tyrosine fusion proteins, including the high-risk KMT2A-rearranged (KMT2A-R) subtype common in infants with B-ALL, leaving many patients with insufficient treatment options. Objectives: KMT2A-R B-ALL is associated with chemoresistance, relapse, and poor survival with a frequency of 75% in infants and 10% in older children/adults with B-ALL. Current intensive multiagent chemotherapy regimens induce significant side effects yet fail to cure the majority of patients, demonstrating continued need for novel therapeutic approaches. The goals of our study were to i) identify signaling molecules required for KMT2A-R B-ALL cell survival, ii) select ALL-associated targets that are not essential in normal tissues, and iii) develop new treatment strategies that may benefit patients with KMT2A-R ALL. Results: We performed a genome-wide kinome CRISPR screen using the pediatric KMT2A-R cell line SEM and identified DYRK1A among other signaling molecules as required for leukemia cell survival. DYRK1A is a member of the dual-specificity tyrosine phosphorylation-regulated kinase family and has been reported as a critical oncogene in a murine Down syndrome (DS) model of megakaryoblastic leukemia. In normal hematopoiesis, DYRK1A controls the transition from proliferation to quiescence during lymphoid development. Deletion of DYRK1A results in increased numbers of B cells in S-G2-M phase, yet also significantly reduces cell proliferation. Meta-analysis of ChIP-Seq data from two KMT2A-AFF1 cell lines (SEM and RS4;11) and a human KMT2A-Aff1-FLAG-transduced ALL model demonstrates that both N-terminal (KMT2AN) and C-terminal (AFF1C) and the FLAG-tagged KMT2A-Aff1 fusion directly bind to the DYRK1A promoter. Gene expression and RT-PCR analyses of SEM cells treated with inhibitors against two important KMT2A fusion complex proteins, DOT1L (histone methyltransferase) and menin (tumor suppressor), demonstrate that only menin inhibition induced DYRK1A downregulation. Interestingly, deletion of germline KMT2A in murine B-cells did not decrease DYRK1A expression. Taken together, these results suggest direct transcriptional regulation through the KMT2A fusion complex. Surprisingly, RNA and protein expression of DYRK1A was reduced in KMT2A-R ALL compared to other B-ALL subtypes. We then identified MYC as a potential negative regulator of DYRK1A that could explain the lower RNA and protein expression levels observed. A gain-of-function experiment showed marked downregulation of DYRK1A when MYC was ectopically expressed in murine B-cells, while loss of MYC resulted in DYRK1A upregulation. Parallel analysis of publicly available gene expression data from children with high-risk B-ALL (NCI TARGET database) showed significantly higher MYC RNA expression levels in KMT2A-R ALL as compared to other ALL subtypes, further validating our findings that MYC acts as a negative regulator of DYRK1A. Finally, to assess pharmacologic inhibition, we treated multiple KMT2A-rearranged ALL cell lines with the novel DYRK1A inhibitor EHT 1610 and identified sensitivity to DYRK1A inhibition. We then queried the Achilles database and identified that DYRK1A is not a common essential gene in normal tissues, suggesting minimal potential for on-target/off-tumor effects of DYRK1A inhibition. Conclusions: We identified a novel mechanism in KMT2A-R ALL in which DYRK1A is positively regulated by the KMT2A fusion protein and negatively regulated by MYC. Genetic deletion and pharmacologic inhibition of DYRK1A resulted in significant growth disadvantage of KMT2A-R ALL cells. While further studies are needed, we predict that combining DYRK1A inhibitors with chemotherapy could decrease relapse risk and improve long-term survival of patients with KMT2A-R B-ALL. Disclosures Crispino: MPN Research Foundation: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy; Scholar Rock: Research Funding; Forma Therapeutics: Research Funding. Tasian:Incyte Corportation: Research Funding; Gilead Sciences: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy.

Prognostic Significance of IKZF1, PAX5, and CDKN2A Deletions in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated with Hyper-CVAD/MA with Dasatinib or Ponatinib

Background Clinical outcomes of patients with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) have improved with combination of tyrosine kinase inhibitors (TKIs) with intensive chemotherapies. However, patients with IKZF1 deletion (del) has been shown to manifest poor prognosis when treated with imatinib-based regimens (Martinelli et al. J Clin Oncol. 2009, Veer et al. Blood 2014). Prognostic significance of IKZF1 del in the context of more potent TKIs, such as dasatinib or ponatinib, is not known. Methods We studied 62 patients with previously untreated Ph+ B-ALL who were part of the phase II clinical trials of Hyper-CVAD alternating with high-dose methotrexate and cytarabine (Hyper-CVAD/MA) plus dasatinib (N = 27) or Hyper-CVAD/MA plus ponatinib (N = 35). Details of the treatment protocols have been previously published elsewhere (Ravandi et al. Blood 2010 and Jabbour et al. Lancet Haematol 2018). DNA from diagnostic bone marrow samples were analyzed by genome-wide SNP arrays using Infinium Omni2.5 array (Illumina, N = 39), Infinium CytoSNP-850K array (Illumina, N = 20), or by whole exome sequencing (N= 3) for copy number analyses. Somatic point mutations were also detected by Agilent's SureSelect Custom 295 gene panel with median 500x depth. Results The baseline clinical characteristics of the 62 Ph+ B-ALL patients are described in Table 1. There were no significant differences in major clinical features between dasatinib- and ponatinib-treated groups. Overall, IKZF1 del, CDKN2A del, and PAX5 del were detected in 30 (48.3%), 16 (25.8%), and 9 (14.5%) patients, respectively. Frequency of IKZF1 and CDKN2A deletions were comparable between dasatinib- and ponatinib-treated groups, but PAX5 deletions were more frequently detected in dasatinib-treated group (dasatinib vs. ponatinib, 25.9% vs. 5.7%, P = 0.034) (Table 1). Somatic point mutations were rare in Ph+ B-ALL and 20 (32.3%) of the patients were found to have at least one point mutations. DNMT3A (N = 4) was most frequently detected among the cohort followed by CHEK2 (N = 2), EP300 (N = 2), SETD2 (N = 2), and TET2 (N = 2). Irrespective of the treatment regimen, 100% of the patients attained complete remission (CR) after 1 cycle of therapy. 29 (48.3%) and 41 (68.3%) patients attained CR with negative minimal residual disease (MRD) with RT-PCR at 1 month and 3 months, respectively. Patients with IKZF1 del had significantly lower chance of attaining CR with negative MRD compared to IKZF1 wild type (WT) patients at 1 month (IKZF1 del vs. WT, 26.7% vs. 70.0% , P = 0.002). However, at 3 months, no difference of complete molecular response (CMR) was observed (IKZF1 del vs. WT, 71.0% vs. 65.5%, P = 0.783). Other deletions or point mutations did not affect MRD negative status. With the median follow up duration of 59 months (95% confidence interval [CI]: 54-67), the median overall survival (OS) of the entire cohort was 80 months (95% CI: 76-not reached) and the 5-year OS rate of the entire cohort was 70.3% (95% CI: 57.1-80.2). In the entire cohort, patients with IKZF1 del had a strong trend of poor OS compared to IKZF1 WT patients (IKZF1 del vs. WT, median survival: 76 months vs. not reached, 5-year OS: 57.8% vs. 81.2%, P = 0.082), while PAX5 and CDKN2A deletion status did not affect OS. Among the dasatinib-treated subgroup, IKZF1, PAX5, and CDKN2A del status did not affect OS. Among the patients with IKZF1 del, ponatinib-treated subgroup had better prognosis than dasatinib-treated subgroup (dasatinib vs. ponatinib, median survival: not reached vs. 80 months, 5-year OS: 40.0% vs. 77.2%, P = 0.0337) [Table 2]. In ponatinib-treated subgroup, CDKN2A del was associated with significantly worse OS (CDKN2A del vs. WT, median survival: both not reached, 5-year OS: 66.7% vs. 96.0%, P = 0.0259), while IKZF1 del was associated with a trend of worse OS (IKZF1 del vs. WT, median survival: both not reached, 5-year OS: 77.0% vs. 95.0%, P = 0.161). One of limitations of this study is the number of cases is small. Discussion In the patients with Ph+ B-ALL treated with Hyper-CVAD/MA plus dasatinib or ponatinib, IKZF1 del did not affect CMR at 3 months while it was associated with a trend toward worse OS. In the patients harboring IKZF1 del, ponatinib-treated subgroup had better prognosis than dasatinib-treated subgroup. Further investigation is needed to determine the prognostic significance of IKZF1 del in individual treatment subgroup. Disclosures Short: AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Research Funding. Kantarjian:Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Astex: Research Funding; Takeda: Honoraria; Ariad: Research Funding; Immunogen: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jain:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Ravandi:Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Selvita: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding. Konopleva:Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Calithera: Research Funding; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties. Garcia-Manero:Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Helsinn: Research Funding; Amphivena: Consultancy, Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding.

Molecular remission using low-dose immunotherapy for relapsed refractory Philadelphia chromosome-positive precursor B-cell acute lymphoblastic leukemia post-allogeneic stem cell transplant

Adults with relapsed/refractory acute lymphoblastic leukemia have a poor prognosis. While current immunotherapies are promising, they are toxic, with graft-versus-host disease a major complication of allogeneic therapy. Here, we report a patient with high-risk relapsed/refractory Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (ALL) following chemotherapy induction, matched related donor allogeneic hematopoietic stem cell transplantation (allo-HCT), donor lymphocyte infusion and two tyrosine kinase inhibitors. The patient achieved a complete molecular and cytogenetic remission with minimal adverse events or evidence of GVHD following recombinant human IL-2 (rIL-2), in combination with a tyrosine kinase inhibitor (TKI). There was a ninefold increase in natural killer (NK) cell activity and natural killer T cells (NKT) cells (CD2+CD26+). Personalized low dose recombinant human IL-2-mediated NK cell stimulation represents an effective, nontoxic immunotherapy administered in the outpatient setting for relapsed acute lymphoblastic leukemia and warrants further investigation.

Aberrant activation-induced cytidine deaminase expression in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia

Activation-induced cytidine deaminase (AID) is expressed in germinal center B cells and plays a critical role in somatic hypermutation and class-switch recombination of immunoglobulin genes. Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) carries a poor prognosis and is specifically treated with tyrosine kinase inhibitors. Interestingly, AID has been shown to be aberrantly expressed and functional in Ph+ ALL and is thought to contribute to genetic instability. We hypothesized that AID might be detectable in routinely processed bone marrow biopsies by immunohistochemistry (IHC) and assist in identifying Ph+ ALL. We found that AID was expressed in 26 (70%) of 37 cases of Ph+ ALL but only 1 (2.9%) of 38 cases of Ph- ALL cases. There was a significant difference in AID expression between these 2 ALL groups (P < .001, Fisher exact test). The expression of AID was confirmed by RT-PCR (reverse-transcriptase polymerase chain reaction) and correlated with IHC scoring. AID protein is expressed in a large proportion of Ph+ ALL cases at levels detectable by IHC in clinical samples and might be useful to rapidly identify cases likely to have a BCR/ABL1 fusion.