Recent Advances in the Management of Acute Lymphoblastic Leukaemia.

OPINION STATEMENT: The last few years have seen unprecedented advances in treatment options for patients diagnosed with acute lymphoblastic leukaemia (ALL) in adulthood. New targeted drug therapies have been shown in randomised trials to offer significant survival improvements above standard-of-care (SoC) for relapsed disease, whilst being relatively well tolerated. Chimeric antigen receptor T cell therapy (CAR-T) has offered spectacular promise amongst the young adult population, with the possibility of cure for refractory disease. It has reversed the paradigm that transplant is the only curative option at relapse. Data is awaited regarding its effectiveness in the older adult population. Nelarabine represents an advance, but there remains a pressing need to develop new therapies with efficacy against T-ALL, especially in the relapse setting.Outcomes for younger adults have improved with the adoption of paediatric-like regimens, with a focus on dose intensity and heavy use of pegylated asparaginase. Defining who falls into the "young adult" category and would benefit from this approach remains a controversial area. In elderly patients with ALL, the introduction of tyrosine kinase inhibitors (TKIs) and reduction in standard chemotherapy intensity (especially for those with Philadelphia-positive disease) have significantly reduced treatment-associated mortality and resulted in durable remissions with good quality of life.Bone marrow transplantation remains a key therapy in adult ALL, and is still the treatment of choice for relapsed disease. The mortality associated with a myeloablative approach can be substantially lowered by reduced intensity conditioning, without an apparently significant reduction in efficacy.

Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo.

The strategy of enzymatic degradation of amino acids to deprive malignant cells of important nutrients is an established component of induction therapy of acute lymphoblastic leukemia. Here we show that acute myeloid leukemia (AML) cells from most patients with AML are deficient in a critical enzyme required for arginine synthesis, argininosuccinate synthetase-1 (ASS1). Thus, these ASS1-deficient AML cells are dependent on importing extracellular arginine. We therefore investigated the effect of plasma arginine deprivation using pegylated arginine deiminase (ADI-PEG 20) against primary AMLs in a xenograft model and in vitro. ADI-PEG 20 alone induced responses in 19 of 38 AMLs in vitro and 3 of 6 AMLs in vivo, leading to caspase activation in sensitive AMLs. ADI-PEG 20-resistant AMLs showed higher relative expression of ASS1 than sensitive AMLs. This suggests that the resistant AMLs survive by producing arginine through this metabolic pathway and ASS1 expression could be used as a biomarker for response. Sensitive AMLs showed more avid uptake of arginine from the extracellular environment consistent with their auxotrophy for arginine. The combination of ADI-PEG 20 and cytarabine chemotherapy was more effective than either treatment alone resulting in responses in 6 of 6 AMLs tested in vivo. Our data show that arginine deprivation is a reasonable strategy in AML that paves the way for clinical trials.

Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.

Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients, predisposing them to life-threatening infections and bleeding. The mechanism by which AML mediates this complication is unknown but one widely accepted explanation is that AML depletes the BM of hematopoietic stem cells (HSCs) through displacement. We sought to investigate how AML affects hematopoiesis by quantifying residual normal hematopoietic subpopulations in the BM of immunodeficient mice transplanted with human AML cells with a range of genetic lesions. The numbers of normal mouse HSCs were preserved whereas normal progenitors and other downstream hematopoietic cells were reduced following transplantation of primary AMLs, findings consistent with a differentiation block at the HSC-progenitor transition, rather than displacement. Once removed from the leukemic environment, residual normal hematopoietic cells differentiated normally and outcompeted steady-state hematopoietic cells, indicating that this effect is reversible. We confirmed the clinical significance of this by ex vivo analysis of normal hematopoietic subpopulations from BM of 16 patients with AML. This analysis demonstrated that the numbers of normal CD34(+)CD38(-) stem-progenitor cells were similar in the BM of AML patients and controls, whereas normal CD34(+)CD38(+) progenitors were reduced. Residual normal CD34(+) cells from patients with AML were enriched in long-term culture, initiating cells and repopulating cells compared with controls. In conclusion the data do not support the idea that BM failure in AML is due to HSC depletion. Rather, AML inhibits production of downstream hematopoietic cells by impeding differentiation at the HSC-progenitor transition.