Conventional cytotoxic chemotherapy used to treat acute lymphoblastic leukemia (ALL) results in high cure rates in pediatric patients but is suboptimal in the treatment of adult patients. The 5-year ...overall survival is approximately 90% in children and 30% to 40% in adults and elderly patients. Adults with ALL tend to have higher risk factors at diagnosis, more comorbidities, and increasing age that often requires dose reductions. Major advancements have been made in redefining the pathologic classification of ALL, identifying new cytogenetic-molecular abnormalities, and developing novel targeted agents in order to improve survival. The addition of new monoclonal antibodies and tyrosine kinase inhibitors to conventional chemotherapy in the frontline setting has resulted in increased rates of complete remission and overall survival. These new developments are changing the treatment of adult ALL from a "one therapy fits all" approach to individualized treatment based on patient's cytogenetic and molecular profile.
The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the ...European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.
Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with a bimodal distribution. The progresses made in understanding its biology led to the development of targeted therapies. In this ...review, we summarize the current and future approaches in management of adult ALL. Tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 tyrosine kinase, monoclonal antibodies targeting cell surface antigens (CD19, CD20, and CD22), bispecific antibodies, and chimeric antigen receptor (CAR)-T therapy are breakthrough treatments. They resulted in FDA approvals of blinatumomab in 2014, inotuzumab ozagamicin in 2017, and tisagenlecleucel in 2017 for relapsed/refractory ALL. Currently, long-term survival is achieved in more than 50% of patients with precursor B-ALL (50-70% in patients with Philadelphia chromosome (Ph)-positive ALL), 50-60% T-ALL, and 80% mature B-ALL. Ongoing efforts exist to optimize therapeutic options in both the relapsed/refractory as well as the frontline settings. In the era of precision medicine, the future lies in using less cytotoxic and more targeted agents.
Progress is occurring at a dizzying rate across all leukemias. Since the authors' review of the topic in Cancer in 2018, numerous discoveries have been made that have improved the therapy and ...outcomes of several leukemia subsets. Hairy cell leukemia is potentially curable with a single course of cladribine followed by rituximab (10‐year survival, ≥90%). Acute promyelocytic leukemia is curable at a rate of 80% to 90% with a nonchemotherapy regimen of all‐trans retinoic acid and arsenic trioxide. The cure rate for core‐binding factor acute myeloid leukemia (AML) is ≥75% with fludarabine, high‐dose cytarabine, and gemtuzumab ozogamicin. Survival for patients with chronic myeloid leukemia is close to that for an age‐matched normal population with BCR‐ABL1 tyrosine kinase inhibitors (TKIs). Chronic lymphocytic leukemia, a previously incurable disease, may now be potentially curable with a finite duration of therapy with Bruton tyrosine kinase inhibitors and venetoclax. The estimated 5‐year survival rate for patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) exceeds 70% with intensive chemotherapy and ponatinib, a third‐generation BCR‐ABL1 TKI, and more recent nonchemotherapy regimens using dasatinib or ponatinib with blinatumomab are producing outstanding results. Survival in both younger and older patients with ALL has improved with the addition of antibodies targeting CD20, CD19 (blinatumomab), and CD22 (inotuzumab) to chemotherapy. Several recent drug discoveries (venetoclax, FLT3 and IDH inhibitors, and oral hypomethylating agents) are also improving outcomes for younger and older patients with AML and for those with higher risk myelodysplastic syndrome.
Major progress is occurring at a very rapid pace in leukemia. This review summarizes the important recent discoveries in these disorders.
Summary
The past decade has witnessed tremendous progress in the treatment of acute lymphoblastic leukaemia (ALL), primarily due to the development of targeted therapies, including tyrosine kinase ...inhibitors targeting BCR‐ABL1 tyrosine kinase, monoclonal antibodies targeting cell surface antigens (CD19, CD20 and CD22), bispecific antibodies and chimeric antigen receptor T‐ cell therapy. A number of new therapies have been approved by the US Food and Drug Administration in the past 5 years, including blinatumomab in 2014, inotuzumab ozagamicin in 2017 and tisagenlecleucel in 2017 for relapsed/refractory ALL. This has led to tremendous improvement in long‐term survival, of more than 50% in patients with precursor B‐ALL 50–70% in patients with Philadelphia chromosome (Ph)‐positive ALL), 50–60% in T‐ALL and 80% in mature B‐ALL. Research is ongoing to optimize the benefit of targeted therapeutics with the goal of decreasing the use of cytotoxic therapies.
Aggressive natural killer-cell leukemia (ANKL) is a rare, lethal disease with pathologic features that are underdescribed in the literature, particularly in Western nations. In addition, although ...data on the molecular pathogenesis of ANKL has been reported, evaluation of such data in a clinicopathologic context remains limited. Patients diagnosed with ANKL were identified retrospectively. Detailed demographic and clinicopathologic data were analyzed. We assessed novel markers by immunohistochemistry and performed targeted next-generation sequencing analysis. The study group included 9 men and 3 women with a median age at diagnosis of 47.5 years (range, 20 to 75 y). Two distinct patterns of bone marrow involvement were identified: interstitial and sinusoidal. The neoplastic cells were positive for CD56 and CD94, and negative for surface CD3, CD5, and CD57 in all cases assessed. They were also positive for CD2 (10/12), c-MYC (6/8), BCL2 (6/8), CD16 (5/7), EBER (9/12), CD7 (6/11), pSTAT3 (3/8), CD8 (2/6), PD-L1 (2/8), CD4 (2/11), CD8 (2/6), and CD158 (1/5). Aberrant p53 expression was identified in most (7/8) cases; p53 was strongly expressed in 4 cases. Conventional cytogenetic analysis showed clonal abnormalities in 5 of 12 cases. TP53 mutations were detected in 3 of 6 cases, whereas ASXL1 and TET2 mutations were each detected in 2 of 6 cases. Patients had very poor outcomes despite intensive chemotherapy, with a median survival of 2 months. ANKL exhibits 2 distinct patterns of tissue involvement. Neoplastic cells in ANKL are commonly positive for c-MYC and EBER, and they have a high frequency of p53 overexpression, frequently with corresponding TP53 mutations.
Background
Phenotypic characterization of immune cells in the bone marrow (BM) of patients with acute myeloid leukemia (AML) is lacking.
Methods
T‐cell infiltration was quantified on BM biopsies from ...13 patients with AML, and flow cytometry was performed on BM aspirates (BMAs) from 107 patients with AML who received treatment at The University of Texas MD Anderson Cancer Center. The authors evaluated the expression of inhibitory receptors (programmed cell death protein 1 PD1, cytotoxic T‐lymphocyte antigen 4 CTLA4, lymphocyte‐activation gene 3 LAG3, T‐cell immunoglobulin and mucin‐domain containing‐3 TIM3) and stimulatory receptors (glucocorticoid‐induced tumor necrosis factor receptor‐related protein GITR, OX40, 41BB a type 2 transmembrane glycoprotein receptor, inducible T‐cell costimulatory ICOS) on T‐cell subsets and the expression of their ligands (41BBL, B7‐1, B7‐2, ICOSL, PD‐L1, PD‐L2, and OX40L) on AML blasts. Expression of these markers was correlated with patient age, karyotype, baseline next‐generation sequencing for 28 myeloid‐associated genes (including P53), and DNA methylation proteins (DNA methyltransferase 3α, isocitrate dehydrogenase 1IDH1, IDH2, Tet methylcytosine dioxygenase 2 TET2, and Fms‐related tyrosine kinase 3 FLT3).
Results
On histochemistry evaluation, the T‐cell population in BM appeared to be preserved in patients who had AML compared with healthy donors. The proportion of T‐regulatory cells (Tregs) in BMAs was higher in patients with AML than in healthy donors. PD1‐positive/OX40‐positive T cells were more frequent in AML BMAs, and a higher frequency of PD1‐positive/cluster of differentiation 8 (CD8)‐positive T cells coexpressed TIM3 or LAG3. PD1‐positive/CD8‐positive T cells were more frequent in BMAs from patients who had multiply relapsed AML than in BMAs from those who had first relapsed or newly diagnosed AML. Blasts in BMAs from patients who had TP53‐mutated AML were more frequently positive for PD‐L1.
Conclusions
The preserved T‐cell population, the increased frequency of regulatory T cells, and the expression of targetable immune receptors in AML BMAs suggest a role for T‐cell–harnessing therapies in AML.
T‐cell subsets are preserved in the bone marrow of patients with acute myeloid leukemia. The expression of targetable immune checkpoints by T cells suggests that therapies harnessing T cells may benefit these patients.
PDF
