Let's talk about bone marrow fibrosis in myelofibrosis.
When we hear fibrosis, we think lung (IPF) or liver (cirrhosis), devastating conditions.
The beauty about marrow fibrosis: it's reversible with allogeneic BMT.
Bone marrow fibrosis (BMF) is characterized by the increased deposition of reticulin fibers and in some cases collagen fibers. Scoring of BMF is primarily dependent on manual grading by the hematopathologist based on the density and type of fibrosis. 1/19
Besides myelofibrosis, there are several hematologic and non-hematologic disorders that are associated with increased BMF that differ in composition (either reticulin-only or reticulin plus collagen). 2/19
Myelofibrosis (MF) is a Philadelphia-negative chronic myeloproliferative neoplasm, characterized by variable degrees of BMF, abnormal proliferation of hematopoietic progenitor cells (HPC), cytopenias, splenomegaly, increased risk of thrombosis and blast transformation. 3/19
History part 2: In 1951, thanks to William Dameshek, it was shown that primary MF shares clinical and pathological features with essential thrombocythemia and polycythemia vera, which also can progress to MF: recently confirmed by discovery of a common mutational background.4/19
History part 2: Since 2005, we know that up to 90% of patients harbor at least 1 of so-called “driver” mutations: V617F in JAK2 gene, W515L/K in MPL gene, and 52 bp deletion (type 1 mutation) or 5 bp insertion (type 2 mutation) in CALR gene.5/19
Back to fibrosis.
Although the exact pathogenesis of MF is not fully understood, let's quickly go through potential drivers and treatment options for BMF.
Goals of MF treatment can be divided into 2 categories: clonal eradication and treatments targeting various signaling pathways and mediators implicated in BMF.
Allogeneic BMT is the only curative treatment, eradicates the malignant HSC clone, leading to reversal of BMF👇
7/19
Inflammation:
could be involved in determining genetic damage to HSC, through oxidative damage to DNA by reactive oxygen species (ROS).
TGF-β1/miR-382-5p/SOD2 axis deregulation linked to ROS overproduction.
Galunisertib potentially reduces oxidative stress induced by TGF-β1. 8/19
Inflammation:
provides a continuous stimulus for Gli1+ myofibroblasts to nurture the process of BMF. Genetic ablation of Gli1+ cells abolished MF and rescues BM failure; and pharmacological targeting of Gli1+ cells with GANT61 ameliorated MF. 9/19
Cytokines:
TGF-β signaling plays a central role in the pathogenesis of BMF in MF. Luspatercept is a TGFβ trap that consists of the extracellular domain of the activin receptor II B fused to the Fc domain of human IgG1. Early results showed Hb increases but no data on BMF. 10/19
Interactions:
Leptin receptor-expressing stromal cells can differentiate into myofibroblasts. Imatinib or conditional deletion of platelet-derived growth factor receptor a (Pdgfra) from Lepr+ stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. 11/19
Genetics:
big topic, will make it concise and focus on new drugs with upcoming fresh and (in part) exciting results at #ASH22#mpnsm 12/19
Telomerase inhibition:
Imetelstat is a 13-mer lipid-conjugated oligonucleotide that complimentary binds the template region of telomerase. Despite only modest spleen responses, there was a reduction in BMF in 15 evaluable patients (40.5%).
->very limited evidence. 13/19
MDM2:
a key negative regulator of the TP53 pathway, inhibiting TP53 transcription, facilitating export of TP53 from the nucleus, and promoting the degradation of TP53. MDM2i Navtemdalin showed improvement of at least 1 grade in BMF in 1/4, now explored in phase 2/3 study. 14/19
HDM2:
Siremadlin, potent and selective HDM2 inhibitor, restores p53-mediated apoptosis. Results on spleen volume 👇
Impact on BMF to be shown. #ASH22 ash.confex.com/ash/2022/webpr… 15/19
BET:
facilitates transcription of genes regulated by NF-κB, c-Myc, and TGF-β. BETi pelabresib showed BMF reduction in 16/57 patients; 1/2 maintained through week 48 or beyond. #ASH22 ash.confex.com/ash/2022/webpr… 16/19
BCL:
JAK-STAT pathway constitutive activation increases BCL-2 and BCL-xL expression. Navitoclax (BCLi) and ruxolitinib showed BMF reduction in 26/32 (81%) patients. Complete resolution of BMF in 2/9 patients, baseline was grade 2 and 3. #ASH22ash.confex.com/ash/2022/webpr… 17/19
Immunotherapy:
a highly potent monoclonal antibody that binds to mutated CALR and inhibits oncogenesis in cells expressing CALR, demonstrating that this moAbnormalizes TPO-R signaling in patient-derived HSCs and in a in vivo model. #ASH22ash.confex.com/ash/2022/webpr… 18/19
Finally, is BMF reduction even relevant? 1. BMT does not care about BMF grade->no impact on post-BMT outcome. 2. Anemia improvement was not linked with BMF changes->question the use of BMF assessment at as a surrogate for clinical benefit. #ASH22ash.confex.com/ash/2022/webpr… 19/19
In conclusion, we did not fully understand the role of BMF yet. Allo BMT as only complete disease modifier, while new drugs seem to be associated with BMF reduction. Whether this is only an epi-phenomenon of is unclear. So, let's be careful to use BMF as endpoint.
Intro:
- caused by protozoa parasites of genus Plasmodium
- transmitted throughout most of the tropics
- in 84 countries and territories
- in 2023, WHO reported 247 million cases (up from 245 million in 2020)
- 619 thousand deaths (down from 625,000 in 2020) 1/
Plasmodium life-cycle:
-female Anopheles mosquitoes acquire parasites from infected person during blood meal
-subsequent human bite, transmit infection to new host👉injection of sporozoites
-infects hepatocytes
-replicates
👉exoerythrocytic merozoite
👉invades erythrocytes 2/
Rule 1: Lead by example
As a mentor, your actions speak louder than words. Demonstrate the ethics, dedication, and passion you wish to instill in your mentees.
Practice what you preach🙏
Rule 2: Listen actively
Effective mentoring starts with listening. Understand your mentee's needs, fears, and aspirations. This builds trust and opens up more honest communication.
Short intro to sickle cell disease (SCD):
-group of inherited red blood cell disorders
-affects ~ 1 in 500 African American and 1 in 36,000 Hispanic American children
-results in anemia
-main clinical feature is acute painful crisis
👉 often requires hospitalization
2/15
Acute pain:
-one of the most common types of vaso-occlusive events in SCD
BUT
-not all patients are in true crisis
BUT
-pain shouldnt be allowed to progress to crisis
AND
-most patients grow with pain, so ask them how severe it is❗️
-do not to delay analgesia
3/15
Intro:
-rare but underestimated bleeding disorder
-lab and clinic similar to inherited form
-usually occurs more frequently in adults with no history of bleeding
-renewed interest
👉association with 🫀disorders (eg aortic stenosis), cancer, autoimmune disease...
2/14
History I - (inherited) VWS:
-1924
-5-year-old girl from 🇫🇮 brought to hospital in Helsinki, seen by physician Erik Adolf von Willebrand
-assessed 66 members of her family
-reported in a 1926 a previously undescribed bleeding disorder, called "Hereditary pseudohemophilia"
3/14
😱Gastrointestinal (GI) manifestations in hematology😱
A short visual 🧵with diagnosis
1/19
Intro:
-lympho-/myeloproliferative disorders
-nodal and/or extranodal
-GI tract one of the most common extranodal sites
-diagnosis of GI hematologic malignancy challenging
👉esp in absence of documented nodal/extranodal disease
👉due to higher incidence of other pathologies
2/19
Importance of imaging:
-although tissue biopsy is often required to reach the definitive diagnosis, imaging plays a crucial role in raising suspicion of underlying hematologic malignancy
-imaging also guides biopsies, staging, and evaluating response to treatment
3/19
History part I:
-1928, Maurice Richter reported generalized swelling of lymph nodes, liver + spleen in a patient with chronic lymphocytic leukemia (CLL)
-due to infiltration by rapidly growing cells
👉termed it generalized reticular cell sarcoma
-patient died after 22 days
2/20
History part II:
-1964, Lortholary described case series of 14 patients with CLL developing malignant reticulopath
👉occurrence of diffuse large B cell lymphoma (DLBCL)
👉named it Richter's transformation (RT)
-DLBCL most common
-also Hodgkin lymphoma, T cell lymphoma
3/20