Abstract
Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) accounts for 20–30% of adult patients with ALL, characterized by translocation of t(9, 22). Tyrosine kinase inhibitors (TKIs) have significantly improved the outcome even though there are still some problems including relapse due to drug-resistant mutations and suboptimal molecular remission depth. Previously, we reported the safety and efficacy of sequential infusion of CD19/22 chimeric antigen receptor T-cell (CAR-T) immunotherapy in the treatment of relapsed/refractory (R/R) B-cell neoplasms including cases with Ph+ ALL. Given possible deeper reaction, more patients were expected to reach optimal minimal residual disease (MRD) response. An alternative method, duplex droplet digital PCR (ddPCR) with high sensitivity was established, which could provide absolute quantification of MRD without the need for calibration curves. Here, we retrospectively collected 95 bone marrow samples from 10 patients with R/R Ph+, who received 19/22 CAR-T-cell cocktail therapy. Notably, sequential molecular remission for more than 3 months (SMR3), a significant indicator based on ddPCR after CAR-T infusion was established, which was defined as a sequential molecular remission for not <3 months with negative MRD. In this cohort, no recurrence was observed in six patients achieving SMR3, where four of whom accepted allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CAR-T cell regimen. Unfortunately, the other four patients who did not reach SMR3 relapsed, and did not receive extra specific treatment except CAR-T regimen. To sum up, ddPCR may be an alternative, especially when nucleic acid was insufficient in clinical practice. No achievement of SMR3 may be an early warning of potential relapse after CAR-T and indicating the initiation of other therapies including allo-HSCT.
Highlights
Acute lymphoblastic leukemia (ALL) is one of the most common childhood leukemia [1, 2]
The morphologic diagnosis was confirmed in all cases by Quantitative real-time PCR (qPCR), karyotypic analysis, and fluorescence in situ hybridization (FISH), as previously reported
SMR3, a significant indicator based on droplet digital PCR (ddPCR) after 19/22 Chimeric antigen receptor T cell (CAR-T) cell therapy was established, which was defined as a sequential molecular remission for not
Summary
Acute lymphoblastic leukemia (ALL) is one of the most common childhood leukemia [1, 2]. Ph chromosome derived from the reciprocal translocation of t(9, 22) (q34; q11.2), leading to the expression of chimeric BCR-ABL1 gene, accounts for more than 20–30% of all adult cases with ALL. Over the last few years, chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising new therapeutic approach, which has robust activity against relapsed/refractory (R/R) B-cell lineage ALL [10,11,12]. The potential effectiveness of CD19/22 CAR-T-cell in treating R/R B-cell neoplasms, including such high-risk genetic or chromosome aberrations as Ph+ ALL, has been demonstrated by our center previously [13]. Given deeper reaction demonstrated by CAR-T, it is expected that more patients can reach complete molecular response. Quantitative real-time PCR (qPCR) methods are routinely used to monitor BCR-ABL1 transcript levels in patients with Ph+ ALL [17].
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