What Is the Role of HSCT in Philadelphia-Chromosome-Positive and Philadelphia-Chromosome-Like ALL in the Tyrosine Kinase Inhibitor Era?

Abstract

Previously, the outcome of paediatric Philadelphia-chromosome-positive (Ph⁺) ALL treated with conventional chemotherapy alone was poor, necessitating the use of haematopoietic stem cell transplantation (HSCT) for the best outcomes. The recent addition of tyrosine kinase inhibitors (TKIs) alongside the chemotherapy regimens for Ph⁺ ALL has markedly improved outcomes, replacing the need for HSCT for lower risk patients. An additional poor prognosis group of Philadelphia-chromosome-like (Ph-like) ALL has also been identified. This group also can be targeted by TKIs in combination with chemotherapy, but the role of HSCT in this population is not clear. The impact of novel targeted immunotherapies (chimeric antigen receptor T cells and bispecific or drug-conjugated antibodies) has improved the outcome of patients, in combination with chemotherapy, and made the role of HSCT as the optimal curative therapy for Ph⁺ ALL and Ph-like ALL less clear. The prognosis of patients with Ph⁺ ALL and persistent minimal residual disease (MRD) at the end of consolidation despite TKI therapy or with additional genetic risk factors remains inferior when HSCT is not used. For such high-risk patients, HSCT using total-body-irradiation-containing conditioning is currently recommended. This review aims to provide an update on the current and future role of HSCT for Ph⁺ ALL and addresses key questions related to the management of these patients, including the role of HSCT in first complete remission, MRD evaluation and related actions post HSCT, TKI usage post HSCT, and the putative role of HSCT in Ph-like ALL.

Keywords: BCR-ABL-like ALL; Philadelphia chromosome; acute lymphoblastic leukaemia; graft-vs.-host disease; graft-vs.-leukaemia effect; haematopoietic stem cell transplantation; tyrosine kinase inhibitors.

Figure 1

Mechanism of action of tyrosine kinase inhibitors. AKT, protein kinase B; cGvHD, chronic graft-vs.-host disease; ERK1/2, extracellular signal-regulated kinase 1/2; GRB2, growth factor receptor-bound protein 2; MEK1/2, mitogen-activated protein kinase 1/2; mTOR, mammalian target of rapamycin; Pi, phosphorylation; PI3K, phosphatidylinositol-3-kinase; TK, tyrosine kinase.

Figure 2

Proposed treatment algorithm for HSCT in paediatric Ph⁺ and Ph-like ALL. *There are no defined criteria for high-risk Ph-like ALL at present. ALL, acute lymphoblastic leukaemia; CAR, chimeric antigen receptor; HSCT, haematopoietic stem cell transplantation; IB, consolidation; MRD, minimal residual disease; Ph⁺, Philadelphia chromosome; TKI, tyrosine kinase inhibitor.

Figure 3

Our recommendations for the use of MRD to plan HSCT in paediatric Ph⁺ and Ph-like ALL. ANC, absolute neutrophil count; ALL, acute lymphoblastic leukaemia; BM, bone marrow; CAR, chimeric antigen receptor; HSCT, haematopoietic stem cell transplantation; IgH, immunoglobulin H; MRD, minimal residual disease; NGS, next-generation sequencing; PCR, polymerase chain reaction; Ph⁺, Philadelphia chromosome; TCR, T cell receptor; TKI, tyrosine kinase inhibitor.