A report on Lineage switch at relapse of CD19 CAR-T therapy for Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia

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A report on Lineage switch at relapse of CD19 CAR-T therapy for Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia

CD19-targeted chimeric antigen receptor (CAR)-T cell therapy has transformed outcomes for patients with B-cell acute lymphoblastic leukemia (B-ALL), offering long-term remission for many. But a rare, poorly understood form of relapse—where leukemic cells “switch lineage” from B-cell to myeloid—highlights gaps in our understanding of CAR-T resistance. In 2020, researchers from the Department of Hematology at The First Affiliated Hospital of Nanjing Medical University published a case study in the Chinese Medical Journal detailing this phenomenon in a patient with Philadelphia chromosome-positive B-precursor ALL (Ph+ B-ALL), a subtype driven by the BCR-ABL fusion gene. Their findings shed light on how CAR-T pressure, genetic mutations, and chemotherapy may interact to drive lineage switch—and how one patient achieved unexpected success after transformation to acute myeloid leukemia (AML).

The Patient’s Journey: From Ph+ B-ALL to AML

The patient, a 46-year-old woman, was admitted to the hospital in January 2014 with a 1-month history of chest pain. Lab tests revealed abnormal blood counts (white blood cells: 12.01 × 10⁹/L, hemoglobin: 92 g/L, platelets: 47 × 10⁹/L), and bone marrow (BM) smears showed 95.2% blast cells. Flow cytometry (FCM) confirmed B-cell lineage: blasts expressed CD34, CD10, CD19, CD20, CD22, CD38, and human leukocyte antigen DR (HLA-DR). Fluorescence in situ hybridization (FISH) detected the Philadelphia chromosome (BCR-ABL fusion gene), and quantitative real-time polymerase chain reaction (qRT-PCR) showed a high BCR-ABL p190 transcript level (184.1%). She was diagnosed with Ph+ B-ALL.

She began standard induction chemotherapy (rituximab, vincristine, daunorubicin, cyclophosphamide, prednisone) combined with oral dasatinib (100 mg/day) on January 27, 2014. One cycle achieved complete remission (CR): BM tests showed no detectable BCR-ABL. She completed six cycles of consolidation therapy (cyclophosphamide, cytarabine, 6-mercaptopurine) from April to November 2014, followed by maintenance with methotrexate (7.5 mg/week) and 6-mercaptopurine (25 mg/day).

In March 2016, BM and FCM confirmed a relapse of ALL. She received a tumor-reduction regimen (rituximab, cyclophosphamide, vincristine, prednisone) to prepare for CAR-T therapy, achieving CR again by April 7, 2016. She then underwent lymphodepleting chemotherapy (fludarabine 37 mg/day × 3, cyclophosphamide 370 mg/day × 3) and received 3 × 10⁶ CD19 CAR-T cells on April 13, 2016. She developed only a low fever—resolved with anti-infection treatment—and was discharged two weeks later. For three years, BM exams showed no signs of relapse.

In May 2019, she returned with fatigue. BM aspirate revealed 88% myeloid progenitors. FCM now showed abnormal myeloblasts expressing CD34, CD13, CD33, CD38, CD117, CD15, and HLA-DR—no B-cell markers. Karyotype was normal, and BCR-ABL was undetectable. Next-generation sequencing (NGS) identified two key genetic changes: a FLT3-internal tandem duplication (FLT3-ITD) mutation (variant allele fraction 21.99%) and a paired box gene 5 (PAX5) single nucleotide polymorphism (SNP, p.T264I, 99.94% allele fraction). She was diagnosed with secondary AML.

She started induction chemotherapy with the DCAG regimen (decitabine, low-dose cytarabine, aclarubicin, granulocyte colony-stimulating factor) on May 22, 2019. One cycle achieved CR, and four consolidation cycles (July–November 2019) eliminated the FLT3-ITD and PAX5 SNP. As of the study’s publication, she remained in CR under regular follow-up.

How This Case Differs from Prior Reports

Lineage switch after CAR-T therapy is extremely rare—prior to this study, only four cases had been reported in B-ALL: three with mixed lineage leukemia (MLL) rearrangement and one pediatric patient with TCF3-ZNF384 fusion. The Nanjing team compared their case to these reports (summarized in Table 1 of the original study):

  • Timing: Switch occurred 1–36 months post-CAR-T; the Nanjing patient’s 3-year interval was among the longest.
  • Cytokine Release Syndrome (CRS): All three MLL patients had severe or mild CRS (high IL-6 levels), but the Nanjing patient had no CRS.
  • Prognosis: Most prior cases had poor outcomes—patients died shortly after AML transformation. The Nanjing patient’s response to DCAG was unique: she achieved CR quickly, and mutations resolved with consolidation.

What Drives Lineage Switch?

While the exact mechanism remains unknown, researchers propose three key factors:

  1. Genetic Drivers: Animal studies (Jacoby et al., 2016) show lineage switch depends on oncogenic drivers—not just loss of CD19. PAX5, a critical B-cell transcription factor, represses myeloid genes like FLT3. The Nanjing patient’s PAX5 SNP and FLT3-ITD likely disrupted B-cell commitment, pushing blasts to myeloid lineage.
  2. Cytokine Effects: High IL-6 levels (from CRS) may deplete B-cell progenitors and promote myeloid differentiation (Maeda et al., 2009). Prior MLL cases with CRS support this link.
  3. Chemotherapy Impact: The 5-year interval between the patient’s exposure to cyclophosphamide and AML relapse raises the possibility of therapy-related AML. Chemotherapy may select for hidden myeloid subclones or alter differentiation pathways.

Why This Matters for CAR-T Patients

Lineage switch represents a unique form of CAR-T resistance, where leukemic cells evade CD19 targeting by changing their cell type. While most cases involve MLL-rearranged leukemia, this Ph+ B-ALL case shows the phenomenon can occur in other subtypes. The patient’s success with DCAG offers hope for tailored treatments—but it also highlights the need for:

  • Genetic Testing at Relapse: Identifying mutations like PAX5 and FLT3-ITD can guide therapy.
  • Long-Term Monitoring: Lineage switch may occur years after CAR-T, so extended follow-up is critical.
  • Mechanistic Research: Understanding how CAR-T pressure and genetics interact could prevent or treat this rare relapse.

The study was reviewed and approved by the ethics committee of The First Affiliated Hospital of Nanjing Medical University (No. 2020-QT-06). The patient provided written consent for the publication of her clinical information.

  1. Gardner R, Wu D, Cherian S, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 2016;127:2406–2410. doi.org/10.1182/blood-2015-08-665547
  2. Lucero OM, Parker K, Funk T, et al. Phenotype switch in acute lymphoblastic leukaemia associated with 3 years of persistent CAR T cell directed-CD19 selective pressure. Br J Haematol 2019;186:333–362. doi.org/10.1111/bjh.15812
  3. Oberley MJ, Gaynon PS, Bhojwani D, et al. Myeloid lineage switch following chimeric antigen receptor T-cell therapy in a patient with TCF3-ZNF384 fusion-positive B-lymphoblastic leukemia. Pediatr Blood Cancer 2018;65:e272659. doi.org/10.1002/pbc.27265
  4. Jacoby E, Nguyen SM, Fountaine TJ, et al. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat Commun 2016;7:12320. doi.org/10.1038/ncomms12320
  5. Maeda K, Malykhin A, Teague-Weber BN, et al. Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus-prone B6.Sle1.Yaa animals. Blood 2009;113:4534–4540. doi.org/10.1182/blood-2008-12-192559
  6. Li LZ, Sun Q, Fang Y, et al. A report on Lineage switch at relapse of CD19 CAR-T therapy for Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia. Chin Med J 2020;133:2001–2003. doi.org/10.1097/CM9.0000000000000962

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