scholarly journals Therapeutic Targets in Childhood B-Acute Lymphoblastic Leukemia : What about HER2/Neu?

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Margaux Camuset ◽  
Alice Huault ◽  
Audrey Grain ◽  
Beatrice Clemenceau ◽  
Fanny Rialland ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Age Groups ◽  
Therapeutic Targets ◽  
Antigen Expression ◽  
Multiparameter Flow Cytometry ◽  
Significant Difference ◽  
Measurable Residual Disease

Relapsed B-lineage acute lymphoblastic leukemia (ALL) in children is associated with poor prognosis. Therefore, it seems essential to stratify patients according to prognostic factors in order to adapt therapies. The evaluation of minimal/measurable residual disease (MRD) during chemotherapy constitutes the most powerful prognostic factor in all age groups, indeed, patients with early low MRD having better outcomes. New immunotherapies based on monoclonal antibodies have recently been developed and are giving promising results in chemoresistant forms with limited toxicities. Indeed, CD20, CD38, CD22 and, less developed, HER2/neu constitute therapeutic targets. However, few studies have reported on the expression level of these markers and compared it to the normal counterpart, precursor B-cells or hematogones. Such investigations would be useful to appreciate the potential efficacy of immunotherapies targeting these markers. Moreover, it could help for the detection of minimal/measurable residual disease during follow-up. A cohort of 125 B-ALL patients (1-25 years old) was retrospectively enrolled in this study, treated between January 2011 and February 2020. Samples collected from bone marrow or peripheral blood were studied in multiparameter flow cytometry (MFC). Cells were analyzed with a Canto II flow cytometer (BD Biosciences), and Diva (BD Biosciences) software was used to assess the expression of the antigenic markers. The same MFC assay had been performed over the whole period, allowing for fluorescence intensities comparison. Additionally, results from 36 normal bone marrow samples were examined, to compare the level of antigen expression by hematogones. CD20, CD38 and CD22 were expressed in respectively 53.6%, 99.2% 98.4% of the cases, rather homogeneously and at intermediate levels. The mean fluorescence intensity of CD38 was much higher on hematogones than blasts, which made it a leukemia-associated immunophenotype (LAIP) for 101 patients (81.4%). HER2/neu, a marker of breast cancer also expressed in a subset of ALL, was present in 16 samples (13.4%), but not detectable on hematogones, and can thus always be considered a LAIP. Interestingly, in this subgroup, patients had a significantly lower 5-year EFS compared to patients without expression of HER2/neu (63% versus 80.5%, p=0.02) (Figure 1). No significant difference in the expression of tested potential therapeutic markers was found between age groups. In conclusion, these 4 antigens have sufficient expression intensities to make them potential therapeutic targets, which could be an interesting alternative for the treatment of refractory/relapsed childhood B-ALL. For example, trastuzumab could be a potential immunotherapy in the HER2/neu expressing group, especially regarding their poorer prognosis. Moreover, CD38 and HER2/neu are good candidates for monitoring MRD. These results are of interest as it has been shown that monitoring MRD early was prognostic on patients' outcome. Figure Disclosures Chevallier: Incyte Corporation: Honoraria.

scholarly journals Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia

2021 ◽  
Vol 5 (16) ◽  
pp. 3147-3151
Author(s):  
Lori Muffly ◽  
Vandana Sundaram ◽  
Connie Chen ◽  
Ilana Yurkiewicz ◽  
Eric Kuo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Median Time ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clinical Relapse ◽  
Cellular Therapies ◽  
Car T ◽  
Measurable Residual Disease

Abstract Monitoring of measurable residual disease (MRD) is essential to the management of acute lymphoblastic leukemia (ALL) and is typically performed through repeated bone marrow (BM) assessments. Using a next-generation sequencing (NGS) MRD platform, we performed a prospective observational study evaluating the correlation between peripheral blood (PB) and BM MRD in adults with ALL receiving cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor T-cell [CAR-T] therapies). Among the study cohort (N = 69 patients; 126 paired PB/BM samples), we found strong correlation between PB and BM MRD (r = 0.87; P < .001), with a sensitivity and specificity of MRD detection in the PB of 87% and 90%, respectively, relative to MRD in the BM. MRD became detectable in the PB in 100% of patients who subsequently relapsed following HCT, with median time from MRD+ to clinical relapse of 90 days, and in 85% of patients who relapsed following CAR T, with median time from MRD+ to clinical relapse of 60 days. In adult patients with ALL undergoing cellular therapies, we demonstrate strong concordance between NGS-based MRD detected in the PB and BM. Monitoring of ALL MRD in the PB appears to be an adequate alternative to frequent invasive BM evaluations in this clinical setting.

scholarly journals Flow Cytometry-Based Pre-Transplant Minimal Residual Disease Detection Strongly Impacts on the Outcome of Haploidentical Transplantation with Αβ T Cell Depletion in Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4618-4618
Author(s):  
Larisa Shelikhova ◽  
Maria Ilushina ◽  
Alexander Popov ◽  
Zhanna Shekhovtsova ◽  
Dmitriy Balashov ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Median Time ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Multiparameter Flow Cytometry ◽  
Allogeneic Hsct ◽  
Minimal Residual

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is indicated for patients with relapsed or refractory acute lymphoblastic leukemia. Patients with persistence of minimal residual disease (MRD) before HCT are at increased risk of disease relapse. Multiparameter flow cytometry (MFC) is the most commonly used method of MRD detection in clinical practice. This study aimed to evaluate MRD status before HCT on outcome of ALL patients receiving allogeneic HSCT from haploidentical donors with TCRαβ+/CD19+ depletion of the graft. Materials and methods A total of 120 pts with ALL (T-lineage ALL (T-ALL)- 37, B cell precursor (BCP)-ALL-83, 45 female, 75 male, median age 8.7 years (0.5-20) underwent allogeneic HSCT between June 2013 and June 2019. All pts received Haplo graft and were in morphologic remission. Disease status at transplant was CR1 in 35 pts, CR2 in 68 pts and CR>2 in 17 pts. Transplantation in CR1 was performed according to risk stratification scheme in the current institutional ALL protocol (Moscow-Berlin 2008, 2015). MRD detection in the bone marrow prior to НSСТ was performed in all pts by MFC according the AIEOP BFM FLOW Network SOP. MRD negativity was defined as <0.001% of all bone marrow nucleated cells. Seventy-nine patients were MRD negative before HSCT, 41 were MRD-positive. The median MRD level (among MRD-positive patients) prior HCT was 0.025%. Thirty (25%) pts received treosulfan-based myeloablative preparative regimen, while TBI-based regimen was used in 90 (75%) pts. Two regimens of GvHD prophylaxis were used. Regimen 1 (n=27): thymoglobulin 5mg/kg, rituximab 200 mg/m2 and bortezomib on day +2, +5; regimen 2 (n=93): tocilizumab at 8 mg/kg on day -1 and post-transplant bortezomib, 89 pts receive additional abatacept at 10 mg/kg on day +2, +7, +14, +28. TCR αβ+/CD19+ depletion of HSCT with CliniMACS technology was implemented in all cases. The median dose of CD34+ cells was 9.3 x106/kg (range 4.3-19.8), αβ T cells - 30x103/kg (range 1-361). Median time of follow-up for survivors was 1.6 years (range: 0.13 - 4.8). Results Primary engraftment was achieved in 116 of 120 pts (3 pts died before engraftment due to septic events, one relapsed early), the median time to neutrophil and platelet recovery was 13 and 14 days, respectively. All engrafted pts had verified morphologic remission and achieved sustained complete donor chimerism by day +30, seven of them had detectable MRD (5 of them were MRD-positive before HCT). Transplant-related mortality was 5 % (95% CI: 2-11). The cumulative incidence (CI) of relapse at 1.5 years was 25%(95%CI:18-35) for the whole cohort. Among patients, who had MRD-negative remission prior to HSCT, CI of relapse was 14 % (95%CI:8-26) with median time of relapse of 0.54 months, as compared to MRD-positive cohort, with CI of relapse of 44 % (95%CI:31-63) with median time to relapse 0.29 months, p=0.0004. pEFS (event=death or relapse) was 70% (95%CI: 61-78) for the whole cohort, in MRD (-) group pEFS was 79% (95%CI: 68-88), as compared to 56%(95%CI:40-72) in the MRD(+) group, p=0.025. CI of relapse in BCP-ALL pts, who had MRD-negative remission prior to HCT was 12 %(95%CI:6-25), in MRD(+) group 49% (95%CI:33-72), p=0.0002, in T-ALL pts in MRD (-) and MRD (+) groups CI of relapse was 17 % (95%CI:6-51) and 38 % (95%CI:20-76), respectively, p=0.14. Conclusion These results suggest that MRD detection by multiparameter flow cytometry prior to HSCT is a highly significant prognostic factor in the setting of haploidentical HSCT on the platform of ab T cell depletion. We expect that further improvement of the outcome can be achieved based on the combination of current safe haplo HSCT platform and novel targeted immunotherapy approaches. Figure Disclosures Maschan: Miltenyi Biotec: Other: lecture fee.

scholarly journals Co-culture model of B-cell acute lymphoblastic leukemia recapitulates a transcription signature of chemotherapy-refractory minimal residual disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stephanie L. Rellick ◽  
Gangqing Hu ◽  
Debra Piktel ◽  
Karen H. Martin ◽  
Werner J. Geldenhuys ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Tumor Cells ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Adherent Cells ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Minimal Residual

AbstractB-cell acute lymphoblastic leukemia (ALL) is characterized by accumulation of immature hematopoietic cells in the bone marrow, a well-established sanctuary site for leukemic cell survival during treatment. While standard of care treatment results in remission in most patients, a small population of patients will relapse, due to the presence of minimal residual disease (MRD) consisting of dormant, chemotherapy-resistant tumor cells. To interrogate this clinically relevant population of treatment refractory cells, we developed an in vitro cell model in which human ALL cells are grown in co-culture with human derived bone marrow stromal cells or osteoblasts. Within this co-culture, tumor cells are found in suspension, lightly attached to the top of the adherent cells, or buried under the adherent cells in a population that is phase dim (PD) by light microscopy. PD cells are dormant and chemotherapy-resistant, consistent with the population of cells that underlies MRD. In the current study, we characterized the transcriptional signature of PD cells by RNA-Seq, and these data were compared to a published expression data set derived from human MRD B-cell ALL patients. Our comparative analyses revealed that the PD cell population is markedly similar to the MRD expression patterns from the primary cells isolated from patients. We further identified genes and key signaling pathways that are common between the PD tumor cells from co-culture and patient derived MRD cells as potential therapeutic targets for future studies.

scholarly journals Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 2984-2990 ◽  
Author(s):  
Stella M. Davies ◽  
Michael J. Borowitz ◽  
Gary L. Rosner ◽  
Kristin Ritz ◽  
Meenakshi Devidas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Response To Therapy ◽  
Oncology Group ◽  
Risk Status ◽  
Prognostic Features ◽  
Minimal Residual

Abstract Minimal residual disease (MRD) as a marker of antileukemic drug efficacy is being used to assess risk status and, in some cases, to adjust the intensity of therapy. Within known prognostic categories, the determinants of MRD are not known. We measured MRD by flow cytometry at day 8 (in blood) and at day 28 (in bone marrow) of induction therapy in more than 1000 children enrolled in Pediatric Oncology Group therapy protocols 9904, 9905, and 9906. We classified patients as “best risk” if they had cleared MRD by day 8 of therapy and as “worst risk” if they had MRD remaining in bone marrow at day 28, and tested whether MRD was related to polymorphisms in 16 loci in genes hypothesized to influence response to therapy in acute lymphoblastic leukemia (ALL). After adjusting for known prognostic features such as presence of the TEL-AML1 rearrangement, National Cancer Institute (NCI) risk status, ploidy, and race, the G allele of a common polymorphism in chemokine receptor 5 (CCR5) was associated with more favorable MRD status than the A allele (P = .009, logistic regression), when comparing “best” and “worst” risk groups. These data are consistent with growing evidence that both acquired and host genetics influence response to cancer therapy.

Sign in / Sign up

Export Citation Format

Share Document