Know ALL was pleased to speak to Charles Mulligan, St Jude Children's Research Hospital, Memphis, US. We asked, How do genetic changes contribute to acute lymphoblastic leukemia (ALL) development?

Mulligan summarizes how genes are involved in the development of ALL, highlighting genetic predispositions and increased risk in certain groups of people. He discusses the nature of some genetic changes and the environmental factors that may influence the development of ALL. Finally, he outlines the genetic differences in ALL for varying ages and how genetic understanding aids the development of more effective treatments.

During ESH 3rd How to Diagnose and Treat Acute Leukaemias ,Know ALL was pleased to speak with Emily Curran, University of Cincinnati, Cincinnati, US. We asked, What is Ph-like acute lymphoblastic leukemia (ALL), and how is it treated?

Curran begins by distinguishing between Ph positive ALL and Ph-like ALL and explaining how it can often be missed at diagnosis. She discusses new approaches utilizing targeted treatments like dasatinib and imatinib to improve outcomes for this patient group. Finally she highlights that for some patients stem cell transplants can be a good treatment choice, due to the high risk of relapse.

Dr. James G. Schwade: A recent study discusses an alternative to cranial irradiation for children with Acute Lymphoblastic Leukemia, which may alleviate some of the neuropsychological side effects.

Fadi Haddad, MD, University of Texas MD Anderson Cancer Center, Houston, TX, discusses the evolution of treatment strategies for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), highlighting the rationale, design, and results of a Phase II study evaluating the combination of ponatinib and blinatumomab in newly diagnosed and relapsed/refractory (R/R) patients (NCT03263572). Dr Haddad explains that the advent of tyrosine kinase inhibitors (TKIs) in Ph+ALL and the introduction of blinatumomab has led to a paradigm shift in the treatment of these patients. In particular, the third-generation TKI ponatinib has shown remarkable activity in patients carrying the T315I mutation. Dr Haddad explains that the results of the Phase II trial evaluating ponatinib and blinatumomab are highly promising and have the potential to define this combination as a new standard of care (SOC) that does not involve chemotherapy or stem cell transplantation (SCT). This interview took place at the Tenth Annual Meeting of the Society of Hematologic Oncology (SOHO) held in Houston, TX.

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Although insulin and IGF1 were known to enhance ALL survival/proliferation in vitro for decades, their role in ALL has not been fully explored, except in T-ALL. Addition of insulin/IGFs alone has a small effect on ALL survival/proliferation. However, in association with one of the low affinity IGF binding proteins, IGFBP7, insulin/IGF have a significant effect on ALL biology both by stimulating the leukemia microenvironment and the leukemia cells itself. It is well documented that the interaction of acute lymphoblastic leukemic (ALL) cells with bone marrow (BM) stromal cells has a positive impact on leukemia cell survival and enhances ALL resistance to chemotherapy. We found that BM stromal cells stimulate ALL’s expression of IGFBP7. Diagnostic BM plasma from children with ALL had higher levels of IGFBP7 than controls. The extracellular IGFBP7 plus insulin/IGF, enhances asparagine synthetase expression and asparagine secretion by BM stromal cells, thus protecting ALL cells against one of the main drugs used in leukemia treatment: asparaginase. But besides this paracrine effect, IGFBP7 exerts also an autocrine action on ALL cells as well. ALL cells express the INSR and IGF1R receptors for insulin/IGFs. We found that IGFBP7 binds and inhibits the internalization of IGF1R, but not INSR, when in response to insulin/IGF1. This resulted in prolonging activation of IGF1R signaling and enhanced ALL survival and proliferation. Moreover, sustained activation of the IGF1R-PI3K-Akt axis concurred to GLUT1 upregulation, enhanced energy metabolism and increased glycolytic metabolism in ALL. All these findings were validated using clinical samples of B- and T-ALL. Importantly, we were able to show that IGFBP7 is targetable. We produced a monoclonal antibody against IGFBP7 and showed that IGFBP7 neutralization had a significant impact in ALL proliferation/survival in vitro and ALL progression in vivo. Mice treated with the anti-IGFBP7 antibody had a longer survival time. In conclusion, our observations reveal a hitherto unknown role for IGFBP7 in ALL biology, revealing a new candidate for drug development.

Treatment for Acute Leukemia from Hi9 by Dr.Narender Kumar | Consultant Medical Oncologist
Treatments may include: Chemotherapy. Chemotherapy, which uses drugs to kill cancer cells, is typically used as an induction therapy for children and adults with acute lymphocytic leukemia. Chemotherapy drugs can also be used in the consolidation and maintenance phases.
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