Myeloproliferative Disorders Flashcards
Two common forms of myeloproliferative disorder progression
- Acute leukemia, in which marrow is replaced by blasts
- Myelofibrosis, in which marrow is replaced by collagen deposited by reactive fibroblasts
Philidelphia Chromosome
Fusion of chromosome 9 and 22 to form the Bcr-Abl protein, the driver of chronic myelogenous leukemia.
Pathologic features of chronic myelogenous leukemia
- Drives proliferation of granulocytes, for whatever reason does not affect erythrocytes
- Commonly involves extramedullary hematopoiesis in the spleen
- Peripheral blood smear shows neutrophilia and left-shift with varying degrees of eosinophilia, basophilia, monocytosis, and thrombocytosis plus mild anemia
- Abnormal neutrophil morphology (shown is a peripheral blood smear)
Major ways in which CML stands out among myeloproliferative neoplasms
- Virtually all untreated patients progress to a phase identical to acute leukemia (blast crisis), usually over 3-5 years
- The acute leukemia may resemble an acute myeloid leukemia or an acute lymphoblastic leukemia
Why can CML produce acute myeloid AND acute lymphoid leukemias?
Because it arises from a hematopoietic stem cell, not a myeloid progenitor
Clinical presentation of CML
- Often first presents as splenomegaly symptoms (early satiety and splenomegaly) and hypermetabolism (B symptoms)
- Half of new diagnoses asymptomatic and identified in routine boodwork
- Can be managed well on imatinib, but the only cure is stem cell transplantation
Graft-versus-leukemia effect
Following allogeneic stem cell transplant, allogeneic lymphocytes have an easier time recognizing and destroying preexisting leukemia cells that survived conditioning.
Donor leukocytes can also be given following the stem cell transplant to further attack the leukemia with significant effect, however this maneuver increases the risk of graft-versus-host disease
What drives polycythemia vera?
An activating mutation in JAK2
Proliferation of normal vs polycythemia vera cells in response to EPO
Diagnosis of PCV
- Requires evidence of JAK2 mutation and increased hemoglobin
- Bone marrow biopsy shows moderate hypercellularity
- Blood smear characteristically shows pancytosis (often with basophilia), not just erythrocytosis
- EPO levels are low, distinguishing PCV from overproduction of EPO
- Decreased marrow iron stores due to erythropoiesis
Hemodynamics of PCV
- Blood viscosity is increased
- Distention of the venous circulation results in a plethoric complexion
- Often associated with bleeding or thrombosis problems
- Pruritis, especially aquagenic pruritis, is common
- Erythromelalgia
Aquagenic pruritis
Pruritis that gets worse with water exposure, such as when showering
Erythromelalgia
Burning sensation in the hands or feet that is caused by microvascular occlusion.
Polycythemia vera sometimes progresses to ____.
Polycythemia vera sometimes progresses to acute myeloid leukemia or myelofibrosis.
This suggests that the cell of origin is a myeloid precursor
Progression of PCV to myelofibrosis is associated with. . .
. . . severe anemia and increasing splenomegaly.
Once this occurs, the disease becomes very difficult to treat
Treatment of PCV
- Median survival time is only 1 year
- However, if hematocrit is lowered, this improves dramatically
- Attempts to lower hematocrit are made by regular phlebotomy and gentle chemotherapy with hydroxyurea
- Only cure is HSC transplant
What drives essential thrombocytosis?
An activating mutation in JAK2 or MPL (the TPO receptor, upstream of JAK2)
Pathologic features of essential thrombocytosis
- Thrombocytosis
- Giant thrombocytes on smear
- Megakaryocyte hyperplasia in bone marrow
Diagnosis of essential thrombocytosis
- By definition, >450,000 thrombocytes per microliter
- Lacking of features of CML and PCV
- JAK2 and MPL mutations on sequencing
- In the absence of an attributable mutation, it is a diagnosis of exclusion (rule out chronic inflammation and iron deficiency, which cause reactive thrombocytosis)
Unlike most other myeloproliferative neoplasms, essential thrombocytosis ___.
Unlike most other myeloproliferative neoplasms, essential thrombocytosis usually does not progress to acute leukemia.
Treatment of essential thrombocytosis
- Centered on lowering risk of thrombotic complications
- All patients receive low-dose aspirin
- Those with very high platelet counts (>1,500,000/mm3), a history of thrombosis, or advanced age (>60) appear to benefit from gentle chemotherapy with hydroxyurea, which lowers platelet counts.
Driving mutations in primary myelofibrosis
JAK2 and MPL, the same as essential thrombocytosis
Pathologic features of primary myelofibrosis
- Early in its course, often associated with leukocytosis and thrombocytosis, with hypercellularity of granulocytic progenitors and megakaryocytes
- As disease progresses, reactive fibroblasts take over marrow, responding to PDGF and TGFb secreted by abnormal megakaryocytes
- Extramedullary hematopoiesis follows (hepatosplenomegaly)
- Then marked anemia characterized by transfusion dependence
- Leukoerythroblastosis (tear drop cells on smear, nucleated erythroid progenitors, and early granulocytic elements)
Diagnosing primary myelofibrosis
- Bone marrow biopsy showing fibrosis, sometimes reorganized to bone (osteosclerosis)
- Leukoerythroblastosis is an indirect sign
- Clustering of megakaryocytes
Primary Myelofibrosis may progress to ___.
Myelofibrosis may progress to osteosclerosis (end-stage fibrotic) or acute myeloid leukemia (end-stage cancerous).
Since extramedullary hematopoiesis is a hallmark of primary myelofibrosis, myeloid leukemias that arise from it usually arise from extramedullary sites, most commonly lymph nodes.
What is shown on this bone marrow biopsy?
Myelofibrosis
Splenectomy in primary myelofibrosis
There are pros and cons.
Often, splenomegaly gets so bad in these patients that it impairs eating, resulting in dangerous amounts of weight loss, and also in severe pain.
However, if you remove the spleen, you are removing a large source of extramedullary hematopoiesis, and a large TPO sink. This results in decreased hemoglobin levels and increased risk of thrombosis.
Treating primary myelofibrosis
- Supportive care with transfusions as needed
- Splenectomy has pros and cons
- Bone marrow transplant an option for younger patients
- JAK2 inhibitors currently under study
What drives chronic eosinophilic leukemia?
Activating mutations in the PDGF receptor alpha or beta genes, which are RTKs.
Pathologic features of chronic eosinophilic leukemia
- characterized by an increase in eosinophilic precursors in the marrow, eosinophilia in the peripheral blood, splenomegaly, and tissue dysfunction due to fibrosis
-
Fibrosis is the result of mediators released by neoplastic eosinophils
- Heart often affected (creates restrictive cardiomyopathy)
- Scleroderma-like skin changes
- May present with mastocytosis as well, in which case mast cells are also part of the clone
Diagnosing chronic eosinophilic leukemia
- Mutations are helpful, but not always present
- Can be made by excluding reactive causes of eosinophilia (allergy, helminth infection, paraneoplasm, autoinflammatory disease)
- Must be proven clonal
Treating chronic eosinophilic leukemia
- Luckily, imatinib also works against PDGF receptor kinases, so it is a viable treatment here producing rapid responses. It remains to be seen if this response will be sustained over time.
Myelodysplastic syndromes
Diverse group of hematopoietic neoplasms caused by acquired mutations that disrupt the normal maturation of myeloid progenitors, leading to cytopenias in the peripheral blood
In myelodysplastic syndrome, hematopoiesis is ineffective, meaning that many marrow progenitors undergo apoptosis before they give rise to formed elements, and those cells that are produced are often malformed (dysplastic)
Sometimes called refractory anemia
Genotoxic myelodysplastic disorder
Exposure to genotoxins, like radiation,certain chemotherapies, and certain environmeltal and occupational exposures (especially benzene), may precipitate a myelodysplatic syndrome
Three variables that control prognosis in myelodysplastic syndromes
- Number and severity of cytopenias
- Number of blasts present in the marrow
- Types of cytogenetic aberrations that are present
Clinical presentation of myelodysplastic syndromes
- Most present as vague symptoms related to anemia (fatigue, shortness of breath) and thrombocytopenia (bruising, petechiae)
-
Dysplasia of one or more cells on blood smear
- Misshapen nuclei, ringed sideroblasts, pseudo-Pelger-Huët anomaly, abnormal cytoplasmic granulation, multinucleated or small megakaryocytes with simple nuclei
- One or more cytopenias on bloodwork
- Tend to be older patients, with peak incidence ~80 years of age
What is shown in this bone marrow biopsy?
A dysplastic megakaryocyte
What is shown in this picture?
Ringed sideroblasts
These are mitochondria that are iron-laden, representative of a family of myelodysplastic disorders.
The stain here is Prussian Blue, an iron stain
What is shown in this picture?
A Pseudo-Pelger-Huët cell
aka, a dysplastic neutrophil with only two lobes
What is shown in this bone marrow biopsy?
An erythroid dysplasia, here showing erythroid progenitors with multiple nuclei
Treating myelodysplastic disorders
- Only definitive therapy is stem cell transplant, however this cannot be safely performed in older patients, which are the patients that tend to get these diseases
- Aggressive chemotherapy is ineffective
- Most patients receive palliative treatments with supportive care in form of transfusions, often accompanied by iron chelation- High risk of iron overload
- Anemia and 5q mutations only respond well to lenalidomide, a thalidomide analog
- A subset respond well to 5-azacytidine (a histone methylation inhibitor)
Myelodysplastic syndromes are associated with what type of mutations?
50% are associated with chromosomal gains and losses (as opposed to true sequence mutations)
There also tends to be involvement of epigenetic lesions
Drivers in myeloproliferative neoplasm vs acute leukemia
Acute leukemia: Transcription factor is lost, leading to excess proliferation in the absence of differentiation
Myeloproliferative neoplasm: Tyrosine kinase regulation is lost, leading to disproportionate differentiation and proliferation down a mature pathway even in the absence of growth factor.
Myeloproliferative vs myelodysplastic diseases
Myeloproliferative: Clonal proliferation with effective differentiation and maturation
Myelodysplastic: Clonal proliferation with ineffective differentiation and maturation
Mutations that drive MPNs and drugs to target these
Note that though JAK2 inhibitors can interact with PCV, they are not permitted by the FDA for this indication, because chronic phlebotomy turns out to be a far better and cheaper treatment for these patients.
Simple way about thinking about the presentation of CML
Chronic myeloid left-shift
MPN to leukemia progression diagram
Note that PCV and ET usually progress to myelofibrosis over leukemia
Bcr-Abl is seen in. . .
CML and ALL (though the fusion sites tend to be slightly different, CML protein is longer)
However, almost all CML is caused by Bcr-Abl while ALL has multiple causes.
Marrow in MDS
Tends to be hypercellular, since hematopoietic drive is there, but that hematopoiesis is ineffective: So there is a disconnect between the factory and the shelves.
MDS patient presents with isolated deletion of 5q on sequencing. What is the indicated treatment?
Lenalidomide
CHIP
Clonal hematopoiesis of intedeterminate potential
Clonal mutations in the same proteins we see in MDS, but are not sick or cytopenic. However, they have an increased risk in developing a hematologic malignancy in the next 10 years.
Also predisposes to atherosclerosis
Sometimes ___ looks like PCV.
Sometimes reactive erythrocytosis + some inflammatory condition looks like PCV.
Reactive erythrocytosis may happen in response to any chronic deoxygenation.
Conditioning treatment
- Supportive care
- Non-absorbable antibiotic do reduce intestinal flora
- Intensive chemotherapy
