HemaBites

HemaBites showcase hematology news and short commentaries on recent high-impact articles published in international journals. This blog will keep you up to date with the latest developments and discoveries in the field of hematology.

Monday, September 10, 2018

​New frontier in the treatment of anemia ​​​​
Francesca Vinchi
Lindsley F. Kimball Research Institute (LFKRI), New York Blood Center - NYBC, New York, USA.

Erythropoietin (EPO) and its recombinant forms are used for the treatment of anemia, thanks to EPO’s ability to stimulate the differentiation of red blood cell (RBC) precursors into mature RBCs. Patients who may benefit from EPO therapy include those who develop anemia consequent to chronic kidney disease, AIDS, cancer chemotherapy or hematologic disorders (multiple myeloma, myelodysplastic syndromes). Alternative therapeutic options are needed for patients who show poor EPO response or develop other forms of EPO-non-responsive anemia, including hemolysis, sepsis and genetic bone marrow failure. 
The recent identification of a key pathway that controls erythroblast survival has paved the way for the formulation of novel therapeutic strategies for those patients who cannot benefit from EPO therapy. Using human CD34+ hematopoietic stem cell (HSC)-derived erythroblasts and P38α​ conditional knock-out mice, Hu and co-workers demonstrated that the mitogen-activated protein kinase P38α ​acts as an intrinsic brake during anemia recovery, by self-restraining erythroblast survival and limiting potential excessive erythropoiesis led by erythropoietic signals. Importantly, P38α loss in mice accelerates the recovery of hemolysis and chemotherapy-driven anemia by reducing erythroblast apoptosis. This mechanism is mediated by P38α deficiency-induced activation of JNK, which serves as an EPO-independent pro-survival signal. JNK prevents Cdk1-induced degradation of the epigenetic silencer Ezh2. In turn Ezh2 stabilization decreases the expression of the pro-apoptotic BCL2 family member, Bim, thus promoting erythroblast survival. In parallel, JNK maintains high P53 levels, by increasing protein stability, thus exerting an anti-tumor function. Therefore, in cancer-related anemias, P38α​ inhibitors, as well as JNK activators, would have the dual benefit of promoting erythropoiesis, by suppression of a pro-apoptotic pathway and activation of a pro-survival one, and also counteracting tumor progression, by increasing P53 levels (in patients with non-mutated P53).


Reference​
Hu P, Nebreda AR, Hanenberg H, Kinnebrew GH, Ivan M, Yoder MC, Filippi MD, Broxmeyer HE, Kapur R. “P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim”. Nature Communications 2018 Aug 29;9(1):3518. doi: 10.1038/s41467-018-05955-2.​

Thursday, August 30, 2018

Rituximab halves the risk of high-grade transformation in follicular lymphoma ​

Simon Hallam
St.Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom

 

Transformation of follicular lymphoma (FL) into a clinically more aggressive, histologically high-grade lymphoma is a much-feared event historically associated with short survival. The anti-CD20 monoclonal antibody rituximab has improved progression-free and overall survival in treatment-naïve FL but its impact on rates of subsequent high-grade transformation (HGT) has been harder to establish due to small numbers of events in individual prospective trials.

The Aristotle study, launched by the European Lymphoma Institute and the European Hematology Association Lymphoma Group, is a pooled analysis of the archives of multiple prospective clinical trials and population-based registries. It interrogated the case records of 10,001 adults diagnosed with FL between 1997 and 2013, recording the incidence of biopsy-proven HGT as a first event after first-line therapy, aiming to establish a cumulative hazard of histological transformation conditional on exposure to rituximab.

8,116 cases were eligible for evaluation, of which 509 had an event of HGT. The cumulative hazard of HGT amongst all patients was 5.8% at 5 years and 7.7% at 10 years, with significant variation dependent on exposure to rituximab. The 10-year cumulative hazard of HGT was 8.7% for those not exposed to rituximab, 5.9% if given rituximab during induction therapy only, and 3.6% for those given rituximab during induction and maintenance therapy. Histological grade 3a FL at diagnosis, age older than 60 years, and a Follicular Lymphoma International Prognostic Index score of greater than 1 were associated with a higher risk of HGT, but choice of chemotherapy regimen was not.

After a median follow-up of 59 months, survival after HGT was 43% at 5 years and 32% at 10 years, and was not significantly impacted by exposure to rituximab during first-line therapy.

This impressive undertaking is the largest study of its kind and the first to credibly establish the reduced risk of biopsy-proven HGT consequent on exposure to rituximab during first-line therapy for FL. These data inform critical discussions with patients anxious about the jeopardy of their chronic condition, and reinforce the benefits of pursuing and completing rituximab maintenance.


Reference:
 
Federico, M. et al. Rituximab and the risk of transformation of follicular lymphoma: a retrospective pooled analysis. The Lancet Haematology (2018). doi:10.1016/S2352-3026(18)30090-5

Wednesday, August 15, 2018

Early detection of acute myeloid leukemia​

Jan Cools, VIB-KU Leuven Center for Cancer Biology, Editor-in-chief HemaSphere, Contact: jan.cools@kuleuven.be

Acute myeloid leukemia (AML) is characterized by the presence of several mutations and chromosomal rearrangements at diagnosis. It has been postulated that a stepwise accumulation of these genomic lesions occurs and that the first mutations could have been acquired years before AML is diagnosed. Two studies now support this hypothesis and identified which oncogenic mutations are typically acquired first.1,2

In one study, women from the Women's Health Initiative were followed for a bout 10 years and in 212 women AML was eventually diagnosed.1 Deep sequencing was performed on peripheral blood DNA and compared to age-matched controls that did not develop AML. The investigators discovered that mutations in IDH1, IDH2, TP53, DNMT3A, TET2 and spliceosome genes significantly increased the chances of developing AML. Importantly, all cases with TP53 mutations (n = 21) and IDH1/IDH2 mutations (n = 15) detected in the blood developed AML later on. In a second study, blood from 95 individuals was analyzed up to 6 years before AML was diagnosed and compared to a control group.2 Individuals who developed AML showed more mutations per sample, higher variant allele frequencies (indicative for a higher number of mutated cells), and showed enrichment for mutations in specific genes. This was also clearly different than the clonal hematopoiesis that is often observed in older individuals.3

These studies indicate that the development of AML is likely a slow process and that it is possible to detect oncogenic mutations in the blood of healthy individuals who are at risk to develop AML. Future studies will need to address if an early screening could be beneficial and how it can contribute to improve the outcome of AML patients.​

References

  1. Desai P, et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med. 2018;24(7):1015-1023.
  2. Abelson S, et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature. 2018;559(7714):400-404.
  3. Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 2014; 371: 2477-2487.

Thursday, July 26, 2018

Professor Franco Ma​ndelli ​​1931-2018

Franco Mandelli.jpg

The world-renowned Professor Franco Mandelli, a true "founder" of Italian hematology, passed away on July 15, 2018 at the age of 87.

Professor Mandelli was born in Bergamo and graduated in medicine with full marks and honors at the University of Milan.

A visionary and pioneer, he organized the first international conferences on acute leukemia, held repeatedly in Rome in the late '70s and '80s, as well as the First International Symposium on Acute Promyelocytic Leukemia in 1993.

"Over the decades, Professor Mandelli has really changed hematology in Italy, fostering research and advancing clinical care in many fields. His contributions to the management of acute promyelocytic leukemia (APL), just to quote one of his main scientific interests, are well-recognized by the international community," says Professor Gianluca Gaidano, Board member of the European Hematology Association (EHA).

Professor Mandelli led the Italian Munticenter Group GIMEMA from 1982 onwards and anticipated the feasibility and potential of clinical studies conducted by large cooperative groups. His legacy lives on in the work of the many Italian hematologists he mentored during his long and extraordinary career.

In 1967, he was appointed as Professor of Hematology at Rome Policlinico Umberto. He moved to Sapienza University Hospital in 1975 where he established the Institute of Hematology in 1979.  This institute with an adult and a pediatric ward, a stem cell transplantation unit, an emergency unit as well as a unit for hemorrhagic and thrombotic diseases, was directed by Professor Mandelli until 2003. Since 2011 he has been Professor Emeritus at Sapienza University.

Outside this important work, Professor Mandelli also created a guest house "Residenza Vanessa" for patients not living in Rome.   

In addition, he was President of  the Italian Association against Leukemia, Lymphoma and Myeloma, a major charity in Italy dedicated to hematoncologic patients and promoting care and research of blood disorders in many ways and through very innovative initiatives.

Professor Mandelli's work, dedication and empathy will be dearly missed within the Italian as well as within the international hematology community.

 


Wednesday, July 18, 2018

Catching some rays: UV damage protection in fish hematopoietic stem cells.
Michael D. Milsom1,2
1. Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg Germany.
2. Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.

 
Kidney_Milsom.pngThe hematopoietic system is particularly sensitive to the action of DNA damaging agents, as evidenced by the fact that myelosuppression is frequently observed in humans upon exposure to ionizing radiation or DNA-damaging chemotherapeutic drugs such as alkylating agents. Indeed, multiple lines of experimental investigation have shown that it is important to protect hematopoietic stem and progenitor cells (HSPCs) from DNA damage in order to avoid both short and long-term adverse effects, such as bone marrow failure and leukemic transformation. In a recently published study, the Zon group have uncovered a mechanism that has evolved in fish in order to protect their HSPCs from the ultraviolet (UV) irradiation co​ntained within sunlight. Unlike in mammals, where the primary location of the adult HSPC niche is within the bone marrow, the adult HSPCs of many fish species reside predominantly within the kidney marrow. Kapp and colleagues made the observation that an umbrella-like structure of melanocytes exists above the kidney marrow in a range of species of fish. They were able to show that this umbrella does indeed protect HSPCs from UVB-induced DNA damage, and is important for sustaining production of mature blood cells. The authors speculate that the need to protect HSPCs from UV damage may explain why the mammalian HSPC niche is located within bones.

Image provided by Leonard Zon and Nymus3D

Animated video explaining the work: https://www.youtube.com/watch?v=e6-CrJOr8zY 

Link and full citation of article:
https://www.nature.com/articles/s41586-018-0213-0
Kapp F.G., et al., Protection from UV light is an evolutionarily conserved feature of the hematopoietic niche. 2018, Nature, 558(7710): pp445-448