scholarly journals Blinatumomab + Ponatinib for Relapsed Ph1-Positive Acute Lymphoblastic Leukemia: The French Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4014-4014 ◽  
Author(s):  
Marie-Anne Couturier ◽  
Xavier Thomas ◽  
Francoise Huguet ◽  
Céline Berthon ◽  
Célestine Simand ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
New Drugs ◽  
Molecular Response ◽  
Complete Molecular Response

Abstract Prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1+ ALL) has been considerably improved since the beginning of the BCR-ABL1 tyrosine kinase inhibitors (TKI) era 20 years ago. However, the prognosis of patients with a refractory/relapsed (including molecular relapse) disease is still very dismal. New drugs or combination of new drugs may improve outcomes of these patients. For example, ponatinib, a 3rd-generation oral TKI, known to have activity against BCR-ABL1 T315I mutations, has shown some efficacy in this context. Similarly, a recent study has reported very encouraging results of the bispecific anti-CD3/CD19 monoclonal antibody blinatumomab as single-agent in refractory/relapsed Ph1+ ALL. Data regarding the efficacy and tolerance of a combination of blinatumomab+ponatinib (blina/pona) are still scarce. This was a retrospective study with the aim to report outcomes of patients receiving a combination of blina/pona for refractory/relapsed Ph1+ ALL in France. Fifteen adults from 8 French centers were identified and data were collected by physicians of each centers, then gathered for the purpose of this study. There were 9 males and 6 females, with a median age of 53 years (range:17-72). All patients, but 2 with blast crisis of chronic myeloid leukemia, had de novo Ph1+ ALL. Four cases had BCR-ABL1 T315I mutation. Patients received the blina/pona combination, either after a first (n=8) or a second (n=7) cytologic relapse. There was no refractory patient in theses series. Previous allograft and autograft has been performed in 7 and 2 patients, respectively. The majority of patients (n=12) had previously received 2 or more lines of TKI. The median time between the first cycle of blina/pona and diagnosis was 14 months (range: 8-40). The median number of blinatumomab cycle (28 mg/day by continuous infusion for 28 days every 6 weeks) administered per patient was 3 (range: 1-6) while ponatinib was concomittantly administered continuously at an initial dose of 45 mg once daily in 11 pts (73%) and 30 mg in 4 pts (27%). Median duration of ponatinib administration was 4 months (range: 1.1-10.9) from first blinatumomab cycle. The toxicity profile was safe: all patients received a complete first cycle without grade 3-4 adverse events. After cycle 1, blinatumomab was stopped in 47% of cases because of neurologic events in 4 and infections in 3; ponatinib was stopped in 33% of cases because of neurologic events in 3, fluid retention in 1 and severe arteriopathy in 1 patient with other vascular disease risk factors. All neurologic events resolved after stopping blinatumomab or ponatinib. The majority of patients were evaluated after one cycle (n=11, after cycle 2 n=3, after cycle 3 n=1). All but one patients (93%) obtained a cytologic complete remission (CR), of whom 12/14 (86%) achieved a complete molecular response. However, 2 patients were documented with CNS relapse at the time of blina/pona evaluation although in bone marrow molecular remission. Both obtained clearance of leukemic blasts after intrathecal infusion of chemotherapy. Then, 5 patients underwent allogeneic transplant (including 2 patients already allotransplanted before blina/pona) and 1 patient received donor lymphocyte infusion. Seven cases pursued maintenance therapy with ponatinib as single agent after stopping blinatumomab. With a median follow-up of 8 months (range: 2.6-30.2) for alive patients, median overall and leukemia-free survivals from first cycle of blina/pona were 8.5 months (range: 1.7-30.2) and 8 months (range: 1.3-30.2), respectively. At last follow-up (July 2018), only 4 relapses had occurred at a median of 3.3 months (range: 1.3-8.3) from first blina/pona cycle and 6 patients had died (3 bacterial infections, 1 fungal infection, 1 secondary cancer and 1 ALL relapse). All alive patients (n=9) but one (cytologic CR but detectable minimal residual disease) are in complete molecular response. Four patients are still under ponatinib medication at last follow-up. The combination of blinatumomab+ponatinib appears effective and tolerable in relapsed Ph1+ALL patients and may replace chemotherapy salvage regimens. The combination should be tested in first-line therapy in the future. Our results have also to be confirmed prospectively on a larger cohort of patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Induction of Effector and Memory Cellular Immunity in a Patient with Long-Term Complete Molecular Response to Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

2020 ◽  
Vol 13 (2) ◽  
pp. 990-996
Author(s):  
Tatsuro Jo ◽  
Haruna Shioya ◽  
Hiroo Tominaga ◽  
Takahiro Sakai ◽  
Shizuka Hayashi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Gene Repertoire ◽  
Monosomy 7 ◽  
Long Time ◽  
Lineage Markers ◽  
Complete Molecular Response

This case report is about a patient who suffered from Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia. The blasts were positive for myeloid-lineage markers including CD13 and CD33, as well as B-cell-lineage markers. Minor bcr-abl1 mRNA was detected by real-time quantitative polymerase chain reaction. Chromosomal abnormality monosomy 7 was also observed, in addition to Ph1. Despite treatment difficulties that were anticipated based on these findings, the patient had long-time complete molecular response (CMR) for approximately 5 years using chemotherapy and two tyrosine kinase inhibitors, imatinib and dasatinib. Lymphocytes were elevated after the patient switched from imatinib to dasatinib, and a T-cell receptor (TCR) V beta gene repertoire analysis revealed oligoclonal expansion of effector and memory cytotoxic T lymphocytes (CTLs), including Wilms tumor 1-specific CTLs. More specifically, the two memory CTLs expressing TCR V beta 3 and V beta 7.1 gradually increased after dasatinib administration. The activation and maintenance of anti-leukemia immunity may have allowed the patient to obtain long-time CMR. These results highlight that obtaining memory CTLs for leukemia cells may lead to safe withdrawal from dasatinib in the patient.

Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Showing Complete Molecular Response Following Imatinib (Glivec®) - combined chemotherapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3971-3971
Author(s):  
Inas Ahmed Asfour ◽  
Shereen Ahmed El Shazly
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Molecular Level ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Treatment Strategies ◽  
Normal Karyotype ◽  
Molecular Response ◽  
Molecular Remission ◽  
Complete Molecular Response

Abstract The Philadelphia (Ph) chromosome is the result of a reciprocal translocation between chromosomes 9 and 22 [t (9; 22)] and is characterized at the molecular level by expression of the BCR-ABL fusion gene. It is the most frequent genetic aberration in adult acute lymphoblastic leukemia (ALL), being detectable in 30–40%of patients with B-precursor ALL. In our initial work we report two cases of grossly negative (Ph) ALL, that showed a complete molecular response after an imatinib based chemotherapy. In the first case we report a 17-year-old male who was admitted because of bony aches and fever. A diagnosis of acute lymphoblastic leukemia was made on the basis of a 95% infiltration of leukemic cells in his bone marrow. Standard G-banding chromosome analysis of bone marrow cells revealed a normal karyotype. And subsequent fluorescent in situ hybridization (FISH) examination showed a 20% positivity for the Philadelphia chromosome. As for the second case we report a 19 years old male patient who was presented with complaints of recurrent epistaxis and bony aches. He was also found to have acute lymphoblastic leukemia due to bone marrow infiltration with 55% blasts that showed a normal karyotype using the G- banding, and a positive Philadelphia chromosome-using FISH method - in 31 % of the examined cells. Both patients received combination chemotherapy incorporating imatinib mesylate; Glivec® in a dose of 400 mg/day continuously all through the induction, consolidation and subsequent re-enforcement courses. They both achieved complete hematological, cytogenetic as well as molecular remission that was maintained-thus far- for a total period of 20 and 11 months respectively. We postulated that there might have been two clones, both a Ph-positive clone and Ph-negative clone, with subsequent sensitivity of this Ph positive clone to the incorporated targeted treatment, as was evidenced by disappearance of the Ph-positive cells in subsequent FISH analysis and the negativity of the real time quantitative polymerase chain reaction (RT-QPCR) for BCR/ABL gene. Several investigators have studied the role of Hematopoeitic stem cell transplantation (HSCT) in the context of Ph+ ALL patients, which showed superior results when compared to conventional chemotherapy in means of remission induction as well as relapse rates, Dombret et al.2002. The highly successful introduction of the first ABL-kinase inhibitor imatinib into the treatment of Philadelphia chromosome positive chronic myeloid leukemia (CML) has led to clinical testing of imatinib in Ph+ALL. It has recently been approved for Ph+ALL in Europe and Japan. Given the much more aggressive nature of Ph+ALL when compared with chronic or even accelerated phase CML, a variety of imatinib-based treatment strategies have been explored in ALL(Ottman et al.,2007). Yet thus far the exploration of these treatment modalities in the very rare entity of gross normal karyotype and molecular level cytogenetic aberrations remains to be elucidated. Conclusion: Molecular remission on tyrosine kinase inhibitors in patient with ALL Ph +ve may open the door to revising the treatment strategies offered thus far for that subset of patients, as a new stratifying factor. Our work offers a unique protocol for utilizing imatinib as an integral part of the chemotherapy protocols normally offered for these patients, but yet at a lower dose, and raises the question of whether they should be transplanted in accordance with the current guidelines and if so when? More patients experience and controlled randomized trials are needed and eagerly awaited.

scholarly journals Poor Outcome of CRLF2 Rearranged Philadelphia Negative Acute Lymphoblastic Leukemia Adults Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5290-5290 ◽  
Author(s):  
Yasser H Elnahass ◽  
Omar A Fahmy ◽  
Mohamed Abdel Mooti Samra ◽  
Fatma A Elrefaey ◽  
Mahmoud T Bokhary ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Bone Marrow Aspiration ◽  
Poor Outcome ◽  
Egyptian Patients ◽  
Diagnostic Work

Abstract BACKGROUND: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph'-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1 positive ALL and a poor outcome. Rearrangements of cytokine receptor like factor 2 (CRLF2) are identified in approximately 50% of Ph'-like and 10% of B-other ALL patients. AIM: To identify the incidence of CRLF2 rearrangements and the frequency of relapse in a cohort of B-other Precursor B-ALL adults Egyptian patients who were treated with conventional therapy at National Cancer Institute, Cairo University. METHODS: The routine diagnostic work-up at diagnosis included Bone marrow aspiration, immunophenotyping, karyotyping, fluorescent in situ hybridization (FISH) for BCR-ABL1 and KMT2A (MLL) and CRLF2 rearrangements (IGH-CRLF2 or P2RY8-CRLF2), and molecular analyses of BCR-ABL1 translocations. Patients within the age group 18-25 years received Total XV protocol while patients >25 years received Hoelzer's protocol. RESULTS: Forty patients were included (22 males, 18 females). Median age at diagnosis was 25 years (18 -65). Median TLC was 14.9 x109/L (1.1 - 201), median Hb was 9.9 gm/dl (5-12.9), median platelet count was 47 x 109/L (19-359) and median BM blasts count was 90% (30-100). CRLF2 rearrangement was detected in 4/40 (10%) patients. All CRLF2 positive patients (100%) relapsed at 6 months vs. 11/36 (30%) CRLF2 negative (p<0.001). At 6 months follow up, disease free survival (DFS) was 70% in CRLF2 negative patients vs. 0% in CRLF2 rearranged (p=0.04). At 1 year follow up, overall survival (OS) was 30 (75%) for CRLF2 negative vs. 0 (0%) for CRLF2 positive patients (p=0.01). CONCLUSION: CRLF2 rearrangements constitute a high risk independent prognostic factor in adult precursor B-ALL patients denoting a poor outcome and should be studied in ALL Ph' negative patients. Additional TKI therapy should be included for this category of patients in our protocols to improve outcome. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Patterns of Relapse in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Who Achieve Complete Molecular Response with Chemotherapy Plus a Tyrosine Kinase Inhibitor

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3977-3977
Author(s):  
Nicholas J. Short ◽  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
Rebecca Garris ◽  
Susan M. O'Brien ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase Inhibitor ◽  
Median Time ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
First Remission ◽  
Complete Molecular Response

Abstract Background: Achievement of a complete molecular response (CMR) in patients (pts) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is associated with improved survival. We sought to evaluate the patterns of molecular and overt relapse in pts who achieved CMR with chemotherapy plus a tyrosine kinase inhibitor (TKI). Methods: We identified 164 adult pts with Ph+ ALL who received frontline hyper-CVAD plus a TKI at our institution between 4/2001 and 6/2016 and had minimal residual disease (MRD) testing after approximately 3 months of therapy; 98 pts (60%) achieved CMR and are the subject of this analysis. MRD assessment was performed using BCR-ABL1 by RQ-PCR on a remission bone marrow (BM) (sensitivity = 0.01%). CMR was defined as the absence of a quantifiable BCR-ABL1 transcript. Overt relapse was defined as recurrence of BM blasts ≥5% or CNS leukemia.MRD relapse was defined as a BCR-ABL1/ABL1 transcript level >0.01% on two occasions or one level ≥0.1%, identified in the peripheral blood or BM and in the absence of overt relapse. Results: The median duration of follow-up was 43 months (range, 6-171 months). The TKI received was imatinib in 13 (13%), dasatinib in 46 (47%), and ponatinib in 39 (40%). 19 pts (19%) underwent allogeneic stem cell transplant (SCT) in first remission, 17 of whom were in CMR at the time of SCT. Overall 21 pts (21%) experienced overt relapse with a median time from first remission to relapse of 17 months (range 10-59 months); only 2 of these pts underwent SCT in CR1. All but 3 overt relapses occurred within 30 months of first remission; these 3 pts experienced CNS-only relapse, after 32, 46, and 59 months of remission. The median overall survival (OS) from time of overt relapse was 14 months; the 2-year OS rate was 15%. 79 pts had at least one MRD assessment after achievement of CMR and are evaluable for analysis of MRD relapse (Figure 1). Overall, 15 pts (19%) met criteria for MRD relapse. The median time from achievement of CMR to MRD relapse was 13 months (range, 2-54 months). The median OS for pts with MRD relapse was 22 months, and the 2-year OS rate was 34%. Of the 15 pts who developed MRD relapse, 9 (60%) also developed overt relapse and 6 (40%) did not. Among the 9 pts with MRD relapse followed by overt relapse, the median time to overt relapse was 54 days (range, 21-705 days). 1 pt on dasatinib had the dose increased but overt relapse occurred 5 months after MRD relapse. In the remaining 8 pts, no preemptive treatment for MRD relapse was given. Among the 6 pts with MRD relapse who did not develop overt relapse, 2 had been off TKI therapy; upon re-initiation of a TKI, both again achieved CMR. 2 pts underwent SCT and are currently alive without overt relapse 21 and 42 months after MRD relapse, 1 pt had persistent low-level BCR-ABL1/ABL1 levels <0.1% but eventually attained CMR again without change of therapy, and 1 pt died in CR 1 month after MRD relapse. Among 64 pts who did not develop MRD relapse, 11 (17%) experienced overt relapse. 4 of these pts had had a previous positive MRD test (i.e. BCR-ABL1/ABL1 ratio >0.01%)but not meeting criteria for MRD relapse: 3 had preceding low-level MRDon one occasion not meeting criteria for MRD relapse (ratios: 0.03, 0.07 and 0.08), and 1 had an unquantifiable positive test that preceded overt relapse. Among the 7 pts who relapsed without a prior positive MRD test, 6 experienced overt relapse with concomitant positive test for BCR-ABL1 ≥0.1% and 1 experienced BM relapse with negative PCR (though confirmed Ph+ by cytogenetics and FISH). In 3 pts, change of TKI with or without SCT appeared to prevent overt hematologic relapse. 1 pt on dasatinib with a BCR-ABL1/ABL1 ratio of 0.08 (but not meeting criteria for MRD relapse) was given intensification of hyper-CVAD and switched to ponatinib; this pt did not undergo SCT and is still alive without overt relapse 14 months after possible MRD relapse. 2 pts on dasatinib who experienced CNS-only relapse had their TKI changed (1 to nilotinib, 1 to ponatinib) and SCT was performed. Both pts died from SCT-related complications in second CR with survival from time of MRD relapse of 22 and 19 months, respectively. Conclusion: In pts with Ph+ ALL who achieve CMR, PCR-based monitoring of BCR-ABL1 can identify pts with MRD relapse at high risk for overt relapse and death. While various therapeutic strategies for pts who experience MRD relapse can be successful, the optimal treatment in this setting remains to be established. Figure 1 Figure 1. Disclosures Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

scholarly journals Interim Results of a Phase II Study of Dasatinib and Prednisone As an Oral, Chemo-Free Induction and Consolidation Regimen for Adults with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4402-4402
Author(s):  
Mixue Xie ◽  
Ying Lu ◽  
Guifang Ouyang ◽  
Liming Zhang ◽  
Huixian Hu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Phase Ii ◽  
Conflicts Of Interest ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Hematopoietic Stem

Abstract Background Tyrosine kinase inhibitors (TKIs) combined with intensive chemotherapy as a first-line treatment regimen significantly improved the prognosis of Philadelphia (Ph) chromosomal positive acute lymphoblastic leukemia (Ph+ALL). However, it has been reported that 74% of patients fail to complete 8 cycles of chemotherapy, and the early mortality rate during induction was as high as 13%. Our previous retrospective study determined an oral, chemo-free regimen (dasatinib plus prednisone) as induction and consolidation yields 100% of complete remission (CR) rates in Ph+ ALL with minimal induction death (Li XY, et al. Br J Haematol. 2020;189:e231-e234). To further verify the effectiveness of this completely oral and chemo-free regimen, we conducted a phase II, one-arm and multicenter trial (ChiCTR200038053). Methods Adults ≥16 years of age with new diagnosed Ph+ALL were eligible. Induction (Course I) used dasatinib 100 mg daily on days 1-28 and prednisone 1mg/kg/daily on days 1-21, 0.5 mg/kg/daily on days 22-28. Patients not in CR/CRi received Course I as second induction again. Two courses of consolidation (Course II and III) used dasatinib 100 mg daily on days 1-28 and prednisone 1mg/kg/daily on days 1-7. CNS prophylaxis used intrathecal cytarabine and dexamethasone. Patients 16-65 years old underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) if they had a HLA-matched donor; otherwise they received 6 cycles of hyper-CVAD chemotherapy alternating regimen-B (methotrexate, cytarabine) and regimen-A (cyclophosphamide, doxorubicin, vincristine, dexamethasone). The dose of chemotherapy was reduced by a third in patients 60-70 years old and by half in patients over 70 years. The primary objectives were to determine induced complete remission rate and major molecular response of the dasatinib/prednisone oral, chemo-free regimen. Results To date, 32 patients from 10 centers enrolled. Median age was 54 years (range: 15-84). The dominant BCR-ABL1 isoform was p190 in 72%, p210 in 18%, rare types in 6.3% and not reported in 3.1%. Patients received an average of 2.5 courses of dasatinib/prednisone regimen (Course I-III). Most patients were tolerable the dose of dasatinib, and two patients were reduced to 50mg daily due to severe pleural effusion. Allo-HSCT was performed in 10 patients, 50% after remission and 50% after marrow relapse. As shown in Figure 1, the CR rate was 97% with one induction death due to sepsis. The major molecular response (MMR was defined as: 3-log reduction in BCR-ABL1 transcript) was 50% and the complete molecular response (CMR was defined as: the absence of a detectable BCR-ABL1 transcript with 0.01% sensitivity/4.5-log) was 40% either at 3 months after starting induction or before HSCT, respectively. From Course I to Course II, the CMR increased from 18.5% to 48%, but accompanied by an increase in marrow relapse rates, which were 16% and 18.75% at course II and course III, respectively. Marrow relapse occurred in 9 patients, all occurred within 6 months after starting induction. T315I mutation in ABL1 KD was detected in 5 of 7 marrow relapses (72%). With a median follow up of 232 days (range: 77-392 days), 1-year OS and 1-year event-free survival (events were defined as marrow relapse and death) was 97% and 54%, respectively (Figure 2). The cumulative molecular relapse rate (defined as BCR-ABL1:ABL1 ratio rises after reaching the CMR level) was 35% at 3 months, 48% at 6 months, and 54% at 1 year (Figure 2). Conclusions The chemotherapy-free, oral combination of dasatinib and prednisone appears promising induction efficacy in de novo Ph+ ALL; the high CR rates and acceptable molecular response rates were similar to results reported by GIMEMA LAL2116 study (Foà R, et al. N Engl J Med. 2020;383:1613-1623). However, two subsequent consolidation courses of the chemo-free regimen led to early molecular relapse with T315I mutations, which urged us to modify the study protocol such as strengthening consolidation therapy or incorporating promising drug blinatumomab. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of complete molecular response on survival in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia

Blood ◽  
2016 ◽  
Vol 128 (4) ◽  
pp. 504-507 ◽  
Author(s):  
Nicholas J. Short ◽  
Elias Jabbour ◽  
Koji Sasaki ◽  
Keyur Patel ◽  
Susan M. O’Brien ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Long Term Outcomes ◽  
Key Points ◽  
Complete Molecular Response ◽  
Philadelphia Chromosome Positive

Key Points In patients with Ph+ ALL, achievement of CMR at 3 months is independently associated with improved survival. CMR at 3 months may identify patients with Ph+ ALL who have excellent long-term outcomes without SCT in first CR.

scholarly journals Igh-V(D)J NGS-MRD Measurement in Pediatric B-Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4923-4923
Author(s):  
Suying Lu ◽  
Jia Zhu ◽  
Junting Huang ◽  
Juan Wang ◽  
Feifei Sun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Induction Therapy ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Clinicopathological Characteristics ◽  
Marrow Cells

Abstract Introduction B-acute lymphoblastic leukemia (B-ALL) is the most common cancer of childhood. Early response to induction chemotherapy is one of the important prognostic factors in B-ALL. However, the analytic sensitivity for flow cytometry (FC) is only 10 -4. The feasibility of using next-generation sequencing (NGS) of immunoglobulin for the determination of minimal residual disease (MRD) in B-ALL has been demonstrated. This study aimed to investigate the performance of NGS techniques measuring immunoglobulin heavy chain (IgH)-variable, diversity, and joining (V[D]J) clonal rearrangements compared with FC in detecting MRD for children with B-ALL and to predict the clinical outcome of B-ALL patients. Methods Newly diagnosed younger than 18 years old B-ALL patients who received the treatment strategy of South China children's leukemia Group (SCCLG)-ALL 2016 were recruited. DNA extracted from bone marrow cells at all available time points for each patient was submitted to Simcere diagnostics for sequencing using Illumina NovaSeq platform. We performed IgH V(D)J NGS and FCM on the bone marrow serially obtained at diagnosis (D0), 15 days at induction therapy (D15), 33 days at induction therapy (D33) and then at the end of induction therapy (EOI). We defined MRD positive (MRD +) by IgH V(D)J NGS and FCM as more than 1 blast cell among 10 4 and 10 6 bone marrow cells, respectively. The sensitivity of MRD detection by IgH V(D)J NGS and FCM, and the association of MRD status with clinicopathological characteristics were investigated. Statistical analysis was performed through SPSS Statistics 22. Enumeration data and correlation between MRD data and clinicopathological characteristics were compared by Chi-square test or Fisher's exact test. This trial was registered at www.clinicaltrials.gov as # NCT04977895. Results As of July 27, 2021, 22 patients (median age, 4.5 years; range, 3.0-7.3) were enrolled in the study. Three patients (13.6%) had a t (9;22) translocation consistent with Philadelphia chromosome positive disease. According to risk stratifications, 8 (36.4%), 8 (36.4%), and 2 (9.1%) patients were classified as low risk (LR), intermediate risk (IR), and high risk (HR) groups, respectively. The remaining 4 patients are still under treatment and have not been classified. We identified leukemic IgH clones in 100% of the diagnostic samples and 68.2% (15/22) of the patients were polyclonal. In 11 patients whose samples of all the four timepoints (D0, D15, D33, EOI) have been tested in parallel by FCM and IgH V(D)J NGS, the frequencies of patients with MRD + were 30.4% vs. 90.9% at D15 (P＜0.05) by FCM and IgH V(D)J NGS. IgH V(D)J NGS MRD monitoring could identify MRD + patients with frequency of 45.5% and 18.2% among patients achieved MRD negativity by FCM at D33 (P＜0.05) and EOI (P = 0.46). With an MRD detection limit of 10 -6, 90.9% (10/11), 36.4% (4/11) and 18.2% (2/11) patients were MRD negative by FCM but positive by the NGS test at D15, D33 and EOI, respectively. This suggested that the sensitivity of IgH V(D)J NGS was significantly higher than that of FCM. Correlation of the measured MRD between the two methods in the entire cohort (r = 0.7934, P &lt; 0.0001) as well as in the concordant cases (r = 0.5558, P = 0.0032) was very high. There was a high discordant rate with NGS identifying more patients MRD + at this threshold. Furthermore, NGS MRD was positive but the FCM MRD was negative in 13 samples (P &lt; 0.0001). In addition, positive MRD status of D33 by NGS was significantly associated with the age of B-ALL patients, patients under 6 years more frequently harbored detectable MRD compared with those ≥ 6 years old (87.5% vs. 11.1%, P &lt; 0.01). There was no patient relapsed after a medium follow-up of 10.5 months. Conclusions We demonstrated the higher sensitivity of IgH-V(D)J NGS in MRD detection of B-ALL, which implies that NGS MRD monitoring could be helpful for more accurate risk stratifications and more precise treatment according to risk stratifications. Further study with a larger sample size and a longer follow-up period is need. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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