Early pharmacological intervention in acute promyelocytic leukemia: can we still improve outcomes?

Survival after acute paediatric (014 years), adolescent (15-19 years) and young adult (20-39 years) leukaemia has improved substantially over the last five decades, particularly for acute lymphoblastic leukaemia (ALL) and acute promyelocytic leukaemia, a subtype of acute myeloid leukaemia. This progress represents one of the most successful achievements in the history of medicine and has been attributed to the development of effective chemotherapy regimens, improvement in supportive care, better risk stratification, use of targeted therapies, and advances in haematopoietic stem cell transplantation. Currently, long-term survival for children diagnosed with acute lymphoblastic leukaemia is 80%-90% in developed countries. Strikingly, survival among adolescents and young adults with this disease is about 60% and 40% respectively. In addition, in these countries, 5-year survival for young patients with acute myeloid leukaemia (excluding acute promyelocytic leukaemia) remains approximately 60% in the modern era of treatment. This project aimed to evaluate how survival and, when appropriate, early death (death occurring within 30 days of diagnosis) after acute leukaemia varied during almost 25 years in California, the most populous and racially/ethnically diverse state in the United States (US). A second aim was to investigate the association between sociodemographic and selected clinical factors and outcomes. Using high-quality data from the California Cancer Registry, I evaluated survival trends from acute lymphoblastic leukaemia among patients aged 0-19 years, and survival and early death trends after acute myeloid leukaemia among patients aged 0-39 years. I also investigated whether early death has decreased among young patients after the approval by the US Food and Drug Administration of all-trans retinoic acid (ATRA) for the treatment of acute promyelocytic leukaemia. The overall results of this thesis showed improvement in survival over time for all age groups and subtypes of leukaemia. Early death after acute promyelocytic and myeloid leukaemias declined during the study period. However, these outcomes varied widely by age at diagnosis and were associated with sociodemographic and clinical factors. Racial/ethnical survival inequalities were identified and found to persist even after adjustment for other covariates. These inequalities were more marked among patients of Hispanic (acute lymphoblastic leukaemia) and black race/ethnicity (for acute lymphoblastic and myeloid leukaemias). Patients living in lower socioeconomic neighbourhoods had worse survival than those living in higher socioeconomic neighbourhoods (for acute lymphoblastic and myeloid leukaemias). Early death and worse survival were associated with initial care at hospitals not affiliated with National Cancer Institute-designated cancer centres (for acute myeloid leukaemia) and lack of health insurance (for acute myeloid and promyelocytic leukaemias). Intriguingly, over the 25-year study period, adolescents and young adults with acute leukaemia continued to have worse survival than children. These results suggest that lack of timely access to treatment and suboptimal care have influenced outcome among vulnerable patients. In conclusion, survival and early death after acute leukaemia has greatly improved among young patients in California. However, inequalities in outcomes remain and are likely a result of multiple factors. My studies highlight the importance of population-based data to reveal the actual burden of the disease in this population and help clinicians, policy makers, government, and researchers better understand the predictors of outcomes. I expect my work to contribute to the development of strategies aimed at improving survival from acute leukaemia, especially among

The history of acute promyelocytic leukaemia.

CPSF6-RARG-positive acute myeloid leukaemia resembles acute promyelocytic leukaemia but is insensitive to retinoic acid and arsenic trioxide

Outcome of Adolescents and Young Adults Compared With Pediatric Patients With Acute Myeloid and Promyelocytic Leukemia.

Chk2 is a kinase critical for DNA damage-induced apoptosis and is considered a tumor suppressor. Chk2 is essential for p53 transcriptional and apoptotic activities. Although mutations of p53 are present in more than half of all tumors, mutations of Chk2 in cancers are rare, suggesting that Chk2 may be inactivated by unknown alternative mechanisms. Here we elucidate one such alternative mechanism regulated by PML (promyelocytic leukemia) that is involved in acute promyelocytic leukemia (APL). Although p53-inactivating mutations are extremely rare in APL, t(15;17) chromosomal translocation which fuses retinoic acid receptor (RARalpha) to PML is almost always present in APL, while the other PML allele is intact. We demonstrate that PML interacts with Chk2 and activates Chk2 by mediating its autophosphorylation step, an essential step for Chk2 activity that occurs after phosphorylation by the upstream kinase ATM (ataxia telangiectasia-mutated). PML/RARalpha in APL suppresses Chk2 by dominantly inhibiting the auto-phosphorylation step, but inactivation of PML/RARalpha with alltrans retinoic acid (ATRA) restores Chk2 autophosphorylation and activity. Thus, by fusing PML with RARalpha, the APL cells appear to have achieved functional suppression of Chk2 compromising the Chk2-p53 apoptotic pathway.

Lessons taught by acute promyelocytic leukemia cure

PML-RARα/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia

Outcomes for Hispanic Patients with Acute Leukemia Treated at Academic Centers

A High Prevalence of Obesity in Acute Promyelocytic Leukemia (APL): Is Obesity a Risk Factor for APL? Implication of Targeted Therapy to Control Obesity and APL Prevention.

Synergistic effect of ATRA and As 2 O 3 was confirmed by several research works in vivo and in vitro.The first clinical trial was completed by SIH in 2001.CR rate was same from Current trends in leukemia, lymphoma and myeloma White Plains, NY, USA.

Clinical Significance of Mitochondrial DNA Content in Acute Promyelocytic Leukemia

Invasive Fungal Infections in Acute Promyelocytic Leukemia Patients. Results of a Prospective Multicenter Study in Italy

High Post-Remission WT1 Expression Is a Predictive Marker for Subsequent Molecular Relapse and Poor Survival Outcome in Adult Patients with Acute Promyelocytic Leukemia (APL)

United Arab Emirates first population-based acute leukemia registry

TO THE EDITOR: We read with great interest the article by Kelaidi et al concerning clinical trials for acute promyelocytic leukemia (APL) performed by the European APL group. This article is meaningful because the efficacy of maintenance therapy was separately analyzed in patients with high-risk APL who were defined as APL with presenting WBC count higher than 10 10/L and patients with low/intermediate-risk APL presenting WBC count lower than 10 10/L. We would like to make comments regarding risk-adapted maintenance therapy for APL. Maintenance therapy consisting of all-trans retinoic acid, 6mercaptopurine, and methotrexate has been adopted in some trials since the European APL group proved its efficacy. Kelaidi et al updated this data, and the benefit of this combination maintenance therapy in patients with high-risk APL was confirmed. In contrast, this therapy had a marginal benefit to preventing relapse to patients with low/intermediate-risk APL. This knowledge has been described for the first time. Risk-adapted strategies have been performed mainly concerning consolidation therapy and induction therapy in clinical trials for APL all over the world. There are no other reports in which it was mentioned that the benefit of this maintenance therapy was correlated with presenting WBC count. The European LeukemiaNet APL guidelines commented that the relative benefit of maintenance therapy depends on the prior induction and consolidation therapy and promyelocytic leukemia/ retinoic acid receptor-alpha (PML/RAR) mRNA status after consolidation therapy. In fact, combination maintenance therapy did not confer disease-free survival advantage for patients with negative PML/ RARA mRNA after three courses of consolidation therapy in the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) group, although the European APL group has performed maintenance therapy for patients with unknown PML/RARA mRNA status after two courses of consolidation therapy. Taking these into consideration, we should pay attention to the fact that the combination maintenance therapy has never been proven to be effective for patients with low/intermediate-risk APL. Moreover, the introduction of arsenic trioxide and gemtuzumab ozogamicin into first-line treatment for APL may reduce significance of maintenance therapy. In addition, this combination therapy often causes serious adverse events such as pancytopenia and liver dysfunction. Therefore, it is probable that the combination maintenance therapy should be omitted or amended in patients with low/intermediate-risk APL although many clinical study groups including the European APL group have continued to adopt this therapy for all patients with APL. The Southwest Oncology Group now examines whether this omission is beneficial for patients with low/intermediate-risk APL (ClinicalTrials.gov number, NCT00492856). Because the efficacy of maintenance therapy is dependent on the prior therapy as described above, the other study groups should prospectively and separately examine whether maintenance therapy has a clinical benefit for patients with low/ intermediate-risk and high-risk APL who have received the induction and consolidation therapy of their own. We believe that the answer to this topic would be of great significance in guiding therapy for patients with APL.