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How I diagnose and manage Philadelphia chromosome-like acute lymphoblastic leukemia
Ferrata Storti Foundation
Haematologica 2019 Volume 104(11):2135-2143
Avraham Frisch1 and Yishai Ofran1,2
1Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, and 2Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
ABSTRACT
Advances in our understanding of mechanisms of leukemogenesis and driver mutations in acute lymphoblastic leukemia (ALL) lead to a more precise and informative sub-classification, mainly of B-cell ALL. In parallel, in recent years, novel agents have been approved for the therapy of B-cell ALL, and many others are in active clinical research. Among the newly recognized disease subtypes, Philadelphia-chromosome- like ALL is the most heterogeneous and thus, diagnostically challenging. Given that this subtype of B-cell ALL is associated with a poorer prognosis, improvement of available therapeutic approaches and protocols is a burn- ing issue. Herein, we summarize, in a clinically relevant manner, up-to-date information regarding diagnostic strategies developed for the identification of patients with Philadelphia-chromosome-like ALL. Common therapeutic dilemmas, presented as several case scenarios, are also discussed. It is cur- rently acceptable that patients with B-cell ALL, treated with an aim of cure, irrespective of their age, be evaluated for a Philadelphia-chromosome-like signature as early as possible. Following Philadelphia-chromosome-like recognition, a higher risk of resistance or relapse must be realized and treat- ment should be modified based on the patient's specific genetic driver and clinical features. However, while active targeted therapeutic options are limited, there is much more to do than just prescribe a matched inhibitor to the identified mutated driver genes. In this review, we present a compre- hensive evidence-based approach to the diagnosis and management of Philadelphia-chromosome-like ALL at different time-points during the dis- ease course.
Introduction
In recent years several new agents have been approved for the treatment of acute lymphoblastic leukemia (ALL), resulting in a tremendous improvement in long- term survival of patients. Concurrently, refinements in risk stratification have enabled escalation and de-escalation of therapy, thus minimizing treatment-related mortality, while maintaining high response rates. While the traditional method for subgrouping B-cell ALL (B-ALL) is based on cytogenetic and mutation analyses, it has been demonstrated that each of the known subgroups has a unique gene expression profile. Subsequent studies identified a B-ALL group which expresses the BCR/ABL signature in the absence of the BCR/ABL fusion, and hence this group was defined as Philadelphia chromosome-like (Ph-like) ALL.
Surprisingly, a search for genetic alterations driving these types of leukemia has revealed multiple mutations and/or aberrations, involving different signal transduc- tion pathways. Clinically, patients with Ph-like ALL have been recognized as being at a high risk for a poor response to therapy or relapse.1-3 Herein we describe the challenges in the diagnosis and appropriate treatment selection for this heteroge- neous group of patients.
Correspondence:
YISHAI OFRAN
y_ofran@rambam.health.gov.il
Received: April 29, 2019. Accepted: September 3, 2019. Pre-published: October 3, 2019.
doi:10.3324/haematol.2018.207506
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/11/2135
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