Chronic Leukemias Flashcards
Criteria to initiate treatment for CLL
- Disease-related symptoms
- Development of cytopenias (hemoglobin less than 10 g/dl or platelet counts less than 100,000/uL)
- Massive spleen (>6cm below rib) and/or adenopathy (>10cm)
- Autoimmune cytopenias poorly responsive to standard therapies
- Symptomatic or functional extranodal involvement
- Lymphocyte doubling time (although this in isolation is not necessarily an indication to treat)
Subtypes of BCR-ABL1
MPN with the closest to normal morphology
Essential thrombocythemia
Marrow may be very minimally perturbed!
ET-associated mutations
90% have one of JAK2, CALR, and MPL.
10% have a more general myeloid mutation like TET2 or DNMT3A.
Essential thrombocythemia with staghorn megakaryocytes
What do you do if the JAK2 comes back negative in suspected PV?
- Try a more sensitive assay! The VAF may be very low.
- If still negative, you must demonstrate a subnormal EPO level to make the diagnosis
Polycythemia vera
“Panmyelosis” with an increase in all myeloid lineages, not just erythroids
Megas are more clustered, more hyperchromatic, “bulbous,” and with less prominent nuclear lobation
Primary myelofibrosis
Very aggressive clustering of megakaryocytes and bulbous, “cloud-like”, hyperchromatic nuclei.
Dilated bone marrow sinuses and increased reticulin, sometimes with intrasinusoidal hematopoiesis.
Early primary myelofibrosis
Hypercellular marrow with bulbous and hyperchromatic megakaryocytes of varying size with clustering.
Increased M:E ratio.
Elevated platelets are also usually present!
Key differences between early PMF and ET in a patient who presents with chronic thrombocytosis
ET: Normocellular marrow, giant megakaryocytes with staghorn nuclei.
Early PMF: Hypercellular marrow, bulbous megekaryocytes with nuclear hyperchromasia and prominent clustering.
Chronic neutrophilic leukemia
- Leukocytosis with >25 x 10^9 neutrophils / L
- No dysplasia of neutrophils (normal, mature morphology)
- Less than 5% immature myeloids in the blood
- No significant basophilia or eosinophilia
- Splenomegaly often present
Caused by mutations in CSF3R (present in 85% of cases). If CSF3R mutation is defected, the ICC abs neutrophil requirement drops to 13 x 10^9.
Must be negative for BCR::ABL1.
Progression in ET/PV/PMF
Note: In the ICC, we also define 10-19% blasts as “accelerated phase”
Paraneoplastic eosinophilias
Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions
Notably, all involve pluripotent stem cells that retain the capacity to differentiate into myeloid and lymphoid neoplasms. Important to subclassify because they respond to TKIs.
Chronic eosinophilic leukemia / idiopathic hypereosinophilic syndrome
Persistent eosinophilia >1,500 with associated bone marrow eosinophilia
Exclusion of CML, secondary causes, paraneoplastic causes, and MLN with specific tyrosine kinase rearrangement.
In this case, call HES when there is no evidence of clonality, but organ damage is present. Call CEL when there is evidence of clonality. In the ICC, increased PB (>2%) or BM (>5%) blasts is also sufficient to prove clonality, but must be less than 20% (otherwise it becomes AML).
Accelerated CLL/SLL
Rare histologic variant of CLL/SLL with a more aggressive clinical course. Less than 1% of all CLL/SLL cases. Thought to be an intermediate or transitional state between typical CLL/SLL and Richter transformed CLL/SLL. It should be suspected in the case of rapidly expanding lymphadenopathy and a CLL/SLL immunophenotype without morphologic DLBCL.
Characterized by expanded and confluent proliferation centers with elevated proliferation indices. Morphologic criteria (only one required):
1) expanded proliferation centers (broader than a
20x microscopic field)
2) increased mitotic activity (>2.4 mitotic fig-
ures per PC)
3) high Ki-67 index (>40% per PC)
From a molecular perspective, more likely to display TP53 mutation, 17p and 11q deletions, and complex karyotype.
Patient with CLL/SLL
Proliferation center in CLL/SLL
Mixture of small lymphocytes, prolymphocytes, and paraimmunoblasts.
Prolymphocytes are small to intermediate in size with condensed chromatin and small nucleoli. Paraimmunoblasts are larger cells with dispersed chromatin, a prominent central eosinophilic nucleolus and expanded cytoplasm.
The PC may show increased expression of Ki-67, as well as c-Myc, E2F, Notch-1 and cyclin-D1, highlighting its role in tumor proliferation.
Pseudo-Richter transformation
Nowadays, patients on SLL/CLL are often treated with Bruton tyrosine kinaes intibitors (like ibrutinib).
Abrupt cessation of BTK inhibitors can result in morphologic changes in SLL/CLL resembling Richter transformation, but in the absence of an exacerbated clinical course.
So, remember, Richter transformation is NOT a histologic diagnosis. It has to be integrated with the clinical history.
Types of Richter transformation
DLBCL-type (most common)
Hodgkin-type (less common)
Plasmablastic lymphoma (rare, EBV-associated)
High-grade B cell lymphoma (rare)
B-lymphoblastic leukemia/lymphoma (rare)
Patient with CLL/SLL
Prolymphocytic progression of CLL/SLL
If the total proportion of prolymphocytes (medium-sized cells with basophilic cytoplasm and a prominent nucleolus) is > 15% in peripheral blood.
In previous WHO editions, >55% prolymphocytic cases were classified as B-PLL, but now are considered progression of CLL/SLL.
The ddx is blastoid mantle cell lymphoma, which must be excluded in these cases.
Patient with CLL/SLL
There is a legitimate DDx here.
This could be a Hodgkin-type Richter transformation of the patient’s known CLL/SLL, or could represent a de novo Hodgkin lymphoma.
This is especially true in patients who have just received chemotherapy for CLL/SLL or another malignancy - the immune suppression can result in EBV-activation and an EBV-associated cHL or DLBCL.
