Progress in treatment and in the understanding of disease biology has been continuous in acute lymphoblastic leukemia (ALL) over the last 50 years. At present, the survival rate in children with ALL is excellent, and in adults it has markedly improved. These achievements relied largely on the progressive optimization of steroid and chemotherapy administration schemes and on the adaptation of treatment intensity to the initial risk and early response to treatment. Despite this progress and the availability of hematopoietic stem cell transplantation, subsets of patients with ALL still have high relapse rates, especially infants and adults, and the cure rate is well below that for which we should aim. It is likely that dose and schedule optimization of available chemotherapeutic options has reached a plateau, stressing the need for new concepts and innovative therapeutic approaches. The good news is that the pace of discovery has dramatically accelerated in recent years, and the ALL field has moved into a new era. This should ultimately have an impact on the patient through better risk stratification and well-designed innovative therapeutic interventions. Recent translational research findings and potentials are highlighted in the review series “acute lymphoblastic leukemia,” which we launch in this issue of Blood. These reviews were written by authors who were instrumental in bringing the research concepts to the clinic.
The reviews are as follows:
Stephen P. Hunger and Charles G. Mullighan, “Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine”
Takaya Moriyama, Mary V. Relling, and Jun J. Yang, “Inherited genetic variation in childhood acute lymphoblastic leukemia”
Jacques J. M. van Dongen, Vincent H. J. van der Velden, Monika Brüggemann, and Alberto Orfao, “Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standarized technologies”
Elias Jabbour, Susan O'Brien, Farhad Ravandi, and Hagop Kantarjian, “Monoclonal antibodies in acute lymphoblastic leukemia”
Shannon L. Maude, David T. Teachey, David L. Porter, and Stephan A. Grupp, “CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia”
In a first review, Hunger and Mullighan show how the comprehensive analysis of the ALL genome and transcripts in large cohorts of patients has revolutionized the way we see oncogenesis in this disease. Beyond hyperdiploidy, ETV6-RUNX1 fusion, and other classical lesions, there is a whole world (previously unsuspected) of somatic mutations, short deletion, translocations, and epigenetic lesions that can riddle the coding and noncoding ALL genome, and, when drivers, collectively shape the cells as leukemic. Multiple preferential combinations, nicely called “constellations,” are found within the classical and newly revealed oncogenic subtypes. Some lesions are already targetable today with available agents like some of those involving kinases in the newly recognized Ph-like leukemias. Others can be markers of unfavorable prognosis in retrospective clinical trials, such as Ikaros gene (IKZF1) deletion. An extra level of complexity is related to the intraclonal heterogeneity of the disease, eg, the existence of several subclones, which reveals a dynamic process that can also have strong implications for relapse mechanisms. The authors carefully discuss how the information coming from ALL-cell analysis could be addressed in the future to detect high-risk ALL and implement precision medicine in a timely manner in patients.
In the second review, Moriyama et al review our current understanding of the inherited (germ-line) genetic variations in childhood ALL. Candidate gene and genome-wide association studies have shown that genetic variants are major determinants of interpatient variability in ALL susceptibility, drug response, and toxicity with ALL therapy. Although the information on susceptibility is highly valuable to understand the cause of ALL in the various subtypes, the relative risks are modest and may not justify, at the moment, the implementation at the time of clinical workup. There are notable exceptions such as the high rate of germ-line TP53 variants (Li Fraumeni syndrome) in the rare low-hypodiploid ALL subtype. The situation may change in the future by integrating the myriad variant combinations in precision medicine for prediction and therapy.
Monitoring the minimal residual disease (MRD) addresses some of the issues raised by both the heterogeneity of ALL and the host diversity through measurement of the integrated response to a given treatment. MRD is the strongest prognosis factor in ALL, and it guides the treatment intensity assignment in clinical practice. van Dongen et al have been instrumental for many years in developing and standardizing the MRD diagnostics based on PCR analysis of rearranged immunoglobulin and T-cell receptor gene methods. In this review, the authors also discuss the new possibilities and challenges that are related to multidimensional flow cytometry and high-throughput sequencing techniques. Interestingly, MRD measurements can also be used as surrogate end points when testing innovative drugs, such as antibodies and small molecules.
In the next review, Jabbour et al provide an overview of the development of monoclonal antibodies in ALL. Several leukemia-associated (although not specific) antigens (eg, CD19, CD20, and CD22) are expressed in a large majority of patients with ALL, and antibodies are being developed to target these antigens. Antibodies can also be used in different formats, including the naked antibodies such as rituximab and ofatumumab, bispecific antibodies such as blinatumumab, or attached to toxins such as inotuzumab ozogamycin. These agents can be used alone or in combination with chemotherapy, and several studies have shown clinical efficacy in many settings, from relapse disease to management of MRD. The current data, possible future uses, and challenges facing the incorporation of these agents into the treatment of ALL are eloquently reviewed in this manuscript.
In a last paper of the series, Maude et al review the use of transfer of T cells engineered to express a chimeric antigen receptor (CAR) against CD19 in B-cell precursor ALL. CAR T cells have emerged as a powerful targeted immunotherapy in the relapsed or refractory cases that otherwise poorly respond to therapies. Adoptive immunotherapy is an effective means of eradicating leukemia, but delivery of immunotherapy has remained challenging. CARs have been developed as a means to eliminate the risk of graft-versus-host disease associated with the use of allogeneic T cells. Multiple challenges had (and still have) to be overcome to be able to produce effective CARs, including identification of proper targets, means to improve the replicative capacity and persistence of the effector cells (to improve durability of responses), and the use of optimal gene transfer technologies and cell culture systems. Several versions of CARs have been taken to the clinic, demonstrating very high response rates. Despite the multiple challenges still remaining, it is clear that this approach is already a reality for patients with ALL and other B-cell malignancies. Efforts in making these cells more widely available, the responses more durable, and the adverse events more manageable will translate into perhaps one of the most important advances in the management of ALL.
