Lineage Switch in an Infant B-Lymphoblastic Leukemia With t(1;11)(p32;q23); KMT2A/EPS15, Following Blinatumomab Therapy

2021 ◽  
pp. 109352662110013
Author(s):  
Jing Du ◽  
Karen M Chisholm ◽  
Karen Tsuchiya ◽  
Kasey Leger ◽  
Brittany M Lee ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Cellular Reprogramming ◽  
Cell Transplant ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Lineage Switch ◽  
Infant Girl ◽  
Generation Sequencing

We report a 6 month-old infant girl with t(1;11)(p32;q23), KMT2A/EPS15-rearranged B-acute lymphoblastic leukemia (B-ALL) that was refractory to traditional ALL-directed chemotherapy. Following administration of blinatumomab, she experienced lineage switch from B-ALL to acute myeloid leukemia (AML). Myeloid-directed chemotherapy resulted in clearance of AML by flow cytometry, though a residual CD19+ B-ALL population persisted (0.14%). Following bridging blinatumomab, the patient achieved B-ALL and AML remission, as measured by flow cytometry. The patient subsequently underwent allogeneic hematopoietic stem cell transplant. Unfortunately, she relapsed with CD19+ B-ALL one-month post-transplantation. Next generation sequencing study of IGH/IGL using ClonoSEQ® analysis detected 3 dominant sequences all present in her original B-ALL, lineage switched AML, and post-transplant relapsed B-ALL, though the latter showed an additional 4 sequences, three of which were present at low abundance in the original diagnostic sample. The presence of the same clones throughout her disease course suggests cellular reprogramming and differentiation following chemotherapy and immunotherapy. This is the first reported case of lineage switch of B-ALL with t(1;11) and also the first report of a lineage switch case that used ClonoSEQ® to define the clonality of the original B-ALL, lineage switched AML, and relapsed B-ALL.

Multicolor Flow Cytometry and Multi-Gene Next Generation Sequencing Are Complimentary and Highly Predictive for Relapse in Acute Myeloid Leukemia Following Allogeneic Hematopoietic Stem Cell Transplant

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 834-834
Author(s):  
Bartlomiej M Getta ◽  
Sean Devlin ◽  
Molly A. Maloy ◽  
Abhinita Mohanty ◽  
Maria Arcila ◽  
...  
Keyword(s):  
Stem Cell ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Variant Allele Frequency ◽  
Hematopoietic Stem ◽  
Time To Relapse ◽  
Generation Sequencing ◽  
Acute Myeloid

Abstract Aim: Evaluation of tandem minimal residual disease (MRD) assessment using multi-gene next generation sequencing (NGS) and multi-parameter flow cytometry (MFC) in acute myeloid leukemia (AML) pts undergoing allogeneic hematopoietic stem cell transplant (allo-HCT). Methods: MRD was measured on the same bone marrow aspirate using 10-color MFC and a targeted myeloid specific 28-gene NGS panel pre and post allo-HCT in available samples from 122 consecutive pts with AML transplanted between 2014 and 2015. Any level of MRD measured by MFC in the blast compartment was regarded as positive, while somatic mutations detected above a pre-defined variant allele frequency (VAF) threshold on bulk marrow by multi-gene NGS were regarded as positive. Mutations identified on diagnostic or relapse samples were tracked throughout the disease course. FLT3-ITD and TKD mutations were detected in a stand-alone PCR based assay and VAF was not quantified. Results: NGS (HR: 2.37 (95% CI 1.06-5.28) and HR: 3.23 (95% CI 1.21-8.62)) and MFC (HR: 2.44 (95% CI 1-5.97) and HR: 4.62 (95% CI 1.32-16.09)) predicted overall survival (OS) and time-to-relapse respectively with median observation time of 12 months among survivors. MRD detection using both assays was associated with relapse, with MRD detected by MFC being the most predictive (table 1). NGS was applicable to 85% of tested pts with probable pathogenic mutations seen at diagnosis, while all pts tested at diagnosis had abnormal blasts detected by MFC. Transplant factors including donor source, conditioning intensity, stem cell source and GVHD prophylaxis were not associated with transplant outcomes while complex and monosomal karyotype were associated with OS and time-to-relapse (table 1). Pre allo-HCT concordance rate of MRD detection using the two assays was 70% (table 2). 12 (20%) pts had detectable MRD by MFC and not NGS. Five of these patients had NGS assessment at diagnosis and on manual review of NGS results 3 of these 5 had diagnostic mutations detected on pre allo-HCT samples at VAF below threshold to call mutations. Six (10%) were MFC negative but had detectable mutations by NGS, which were typically clonal hematopoiesis (CH) type mutations with VAF ranging between 3-20%, only 1/6 of these has relapsed post allo-HSCT. MRD pre allo-HCT using both MFC and NGS was associated with relapse; however, the risk was highest in pts who had pre transplant MRD detected concurrently using both techniques and cumulative incidence of relapse was lowest in those who were MRD negative using both techniques (Figure 1A & B). No significant change in mutant DNMT3A, TET2 and JAK2 variant allele frequency (VAF) was seen between assessment at diagnosis and pre transplant, while a significant reduction in NPM1 and IDH VAF was noted. For pts in CR or CRi pre allo-HCT MRD burden quantified using MFC (on blasts) was markedly lower than the corresponding VAF of residual mutations (on bulk marrow) measured in the same sample (Figure 1C) with VAF of residual mutation ranging between 10-20% suggesting that a large bulk of cells at the time of CR were derived from the abnormal clone. We tracked pathogenic mutations identified on diagnostic samples in pts who had marrow MFC and NGS MRD assessment after transplant. In pts who relapsed, multi-gene NGS detected mutations earlier than MFC although at very low allele burden (<1%) (Figure 3D). Low VAF (<2%) DNMT3A mutations were detected after transplant in 10/11 evaluable pts who had these mutations on pre transplant assessment while MFC was negative in 9/10 of those with low VAF DNMT3A mutations detected after transplant. Of the 10 pts with detectable DNMT3A mutations after transplant only 2 have relapsed and both had mutations in TP53. This suggests that the clinical significance of persistent low allelic burden DNMT3A mutations needs further clarification, as they may not be strongly predictive of relapse even if detected after transplant. Conclusion: Despite different assay sensitivity MFC and multi gene NGS had a concordance of 70% for detecting pre allo-HCT MRD in AML.Assessing pre Allo-HCT MRD with MFC and multi-gene NGS improves the ability to predict relapse and OS. MFC had more universal applicability, while NGS could identify residual CH-type mutations with greater sensitivity than MFC and identify MRD at earlier time points than MFC post-HCT. Using a more extensive gene panel is likely to improve the sensitivity of MRD detection and may improve correlation with MFC Disclosures Levine: Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Roshal:BD Biosciences: Consultancy.

Mixed phenotype acute leukemia and lineage switch from lymphoblastic leukemia to myeloid leukemia in the course of Philadelphia-negative myeloproliferative neoplasm – case reports and literature review

2020 ◽  
Vol 51 (2) ◽  
pp. 112-118 ◽  
Author(s):  
Agnieszka Ożańska ◽  
Marta Sobas ◽  
Donata Szymczak ◽  
Tomasz Wróbel
Keyword(s):  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Case Reports ◽  
Lymphoblastic Leukemia ◽  
Myeloproliferative Neoplasm ◽  
Primary Myelofibrosis ◽  
Hematopoietic Stem ◽  
Lineage Switch ◽  
Mixed Phenotype

AbstractPhiladelphia-negative myeloproliferative neoplasms (Ph-neg MPNs) are characterized by clonal hematopoiesis derived from a mutated hematopoietic stem cell. Ph-neg MPNs rarely transforms into acute leukemia, and in most cases, the transformation leads to the development of acute myeloid leukemia (AML). The incidence of mixed-phenotype leukemia (MPAL) or acute lymphoblastic leukemia (ALL) with lineage switch is much rarer. The unidentified lineage of blast cells is due to the immaturity of their undifferentiated progenitors with co-expression of myeloid and lymphoid antigens. The prognosis of secondary acute leukemia transformed from Ph-neg MPN is very unfavorable, especially in MPAL or lineage switch from ALL to AML cases. Moreover, there are no therapeutic protocols for these specific leukemia subtypes. Therefore, we believe that all cases of MPAL or lineage switch leukemia should be reported. This article presents the case of a patient with JAK2-positive essential thrombocythemia (ET) transformed to MPAL, and a patient with triple-negative primary myelofibrosis (PMF) (negative for JAK2, CALR, and MPL) transformed to ALL with subsequent lineage switch to AML.

scholarly journals Antifungal Prophylaxis With Posaconazole in Immunocompromised Children Younger Than 13 Years

2021 ◽  
Vol 27 (1) ◽  
pp. 57-62
Author(s):  
Julio Maquera-Afaray ◽  
Medalit Luna-Vilchez ◽  
Blanca Salazar-Mesones ◽  
Diana Portillo-Alvarez ◽  
Luis Uribe-Ramirez ◽  
...  
Keyword(s):  
Medical Records ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Fungal Infections ◽  
Lymphoblastic Leukemia ◽  
Gastrointestinal Symptoms ◽  
Antifungal Prophylaxis ◽  
Cell Transplant ◽  
Hematopoietic Stem

OBJECTIVE Prophylaxis with posaconazole (PP) is effective in the prevention of invasive fungal infections in immunocompromised adult patients. However, evaluation of its effectiveness and safety in children is limited. The aim of the study was to describe the use of posaconazole as antifungal prophylaxis in children. METHODS We reviewed the medical records of immunocompromised patients younger than 13 years with hematologic diseases and post hematopoietic stem cell transplant (HSCT) who received antifungal PP at the Instituto Nacional de Salud del Niño San Borja (INSN-SB) in Lima, Peru, from January 2014 to December 2018. RESULTS Fifty-six courses of PP were identified in 47 patients with a median age of 7.5 years (IQR, 4–10), 51.6% (n = 24) of whom were female. The main underlying medical conditions were aplastic anemia (n = 19, 33.9%), acute lymphoblastic leukemia (n = 18, 32.1%), acute myeloid leukemia (n = 14, 25.0%), and 34.1% had undergone HSCT. The median dose of posaconazole was 13.62 mg/kg/day (IQR, 12.0–16.8), and the median duration of PP was 24 days (IQR, 16–82). Gastrointestinal symptoms included abdominal pain (17.9%), nausea (16.1%), diarrhea (7.1%), and vomiting (3.6%). Elevated alanine aminotransferase and aspartate aminotransferase levels were observed in 9/35 patients (25.7%) and 10/51 (19.6%) patients, respectively. Five cases of breakthrough fungal infection were identified (8.9%). CONCLUSIONS Patients younger than 13 years who received PP showed an increase in transaminase values, and the development of breakthrough fungal infections.

scholarly journals Oral mucositis in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation in relation to the conditioning used prior to transplantation

2021 ◽  
Author(s):  
Aleksandra Wysocka-Słowik ◽  
Lidia Gil ◽  
Zuzanna Ślebioda ◽  
Agnieszka Kręgielczak ◽  
Barbara Dorocka-Bobkowska
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Transplantation ◽  
Oral Mucositis ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
World Health ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Acute Myeloid

AbstractThis study was designed to investigate the frequency and severity of oral mucositis in patients with acute myeloid leukemia after allogeneic hematopoietic cell transplantation, in relation to the type of conditioning used. Eighty patients diagnosed with acute myeloid leukemia were assigned to two groups based on the conditioning regimen used before transplantation. The intensity of oral inflammatory lesions induced by chemotherapy (oral mucositis) was evaluated according to a 5-point scale recommended by World Health Organization. Oral mucosa was investigated in all patients before the transplantation and during two subsequent stages of the post-transplantation procedure in relation to the conditioning regimen used. Mucositis in the oral cavity was observed in the majority of patients (66%) in the first week after transplantation, whereas the largest percentage of patients suffering oral lesions (74%) occurred in the second week after transplantation. A significantly higher percentage of patients with mucositis was observed in the group which underwent myeloablation therapy (74% of MAC and 50% of RIC patients in the first week; 83% of MAC and 53% of RIC patients in the second examination).The severity of mucositis after transplantation was higher in the MAC patients compared to the RIC patients. The highest mean value of the mucositis index was recorded in the second week in the MAC group (1.59). In AML sufferers receiving allo-HSCT, oral mucositis is a significant complication of the transplantation. This condition is more frequent and more severe in patients after treatment with myeloablation therapy.

scholarly journals Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation

2021 ◽  
Vol 9 (2) ◽  
pp. e001818 ◽  
Author(s):  
Chantal Saberian ◽  
Noha Abdel-Wahab ◽  
Ala Abudayyeh ◽  
Hind Rafei ◽  
Jacinth Joseph ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Checkpoint Inhibitors ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

BackgroundImmune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT.MethodsA retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed.ResultsFour patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2–4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01).ConclusionsICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.

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