Myeloproliferative Neoplasms: Chronic Myeloid Leukemia, Essential Thrombocythemia, and Primary Myelofibrosis
Hematology · Hematopoietic Stem Cells and Their Disorders 🎯 Practice these cards
Each classic MPN is defined by its driver mutation: CML by the ____ fusion, PV by a ____ mutation (~97% of cases), and ET and PMF by ____, ____, or ____ mutations.
Each classic myeloproliferative neoplasm is defined by its driver mutation: CML by the BCR-ABL1 fusion kinase; PV, PMF, and ET by mutations that constitutively activate JAK2 signaling (the kinase essential for erythropoietin and thrombopoietin receptor function). PV carries JAK2 V617F in ~97% (most of the remainder have JAK2 exon 12 mutations); ET and PMF share three canonical drivers — JAK2 V617F (~50-60%), CALR (~30-40%), and MPL (~4-9%) — with up to ~10% of ET and ~10% of PMF cases triple-negative. Peripheral blood mutation testing is therefore a first-line diagnostic test.
The Philadelphia chromosome is the reciprocal translocation ____ that fuses the ____ proto-oncogene on chromosome 9 with the BCR gene on chromosome 22, generating the constitutively active ____ tyrosine kinase (usually the 210-kDa p210 form in CML).
CML is defined by the Philadelphia (Ph) chromosome, the reciprocal translocation t(9;22)(q34.1;q11.2) that fuses the ABL1 proto-oncogene on chromosome 9 with the BCR gene on chromosome 22. The resulting BCR-ABL1 oncoprotein — usually the 210-kDa p210 form — is a constitutively active tyrosine kinase that drives proliferative and anti-apoptotic signaling (RAS/MAPK, JAK-STAT, PI3K pathways). In ~10% of otherwise classic CML the Ph chromosome is not visible on standard G-banding (variant or masked translocations), but FISH or PCR still detects BCR-ABL1 and these patients respond to TKIs normally.
Neutrophilia with a left shift has two big explanations — leukemoid reaction and CML; the presence of ____ without a reactive cause strongly favors CML, and the most common physical finding in CML is ____.
Neutrophilia with a left shift has two big explanations: a leukemoid reaction (severe infection, inflammation, or physiologic stress) and CML. The presence of basophilia (with or without eosinophilia) in the absence of a clinical reason for reactive leukocytosis strongly favors CML and should trigger BCR-ABL1 testing. More than half of patients are diagnosed incidentally from asymptomatic neutrophilia; splenomegaly is the most common physical finding (early satiety, abdominal fullness, left upper quadrant discomfort). CML accounts for roughly 15% of adult leukemias at an incidence of ~2 per 100,000 persons per year.
In CML, accelerated phase is defined by ____ blasts in blood or marrow and blast phase by >=20% blasts; blast phase is effectively a secondary acute leukemia, and roughly ____ of blast-phase cases are lymphoid.
Untreated CML runs a triphasic course: chronic phase (<10% blasts, indolent, highly TKI-responsive; ~90% of patients present here), accelerated phase (10-19% blasts, also signaled by rising basophils, new clonal cytogenetic abnormalities, or therapy-unrelated thrombocytopenia), and blast phase (>=20% blasts). The blast phase is effectively a secondary acute leukemia — myeloid in ~75% of cases but lymphoid in roughly one quarter, which matters because lymphoid blast phase responds to ALL-type chemotherapy combined with TKIs. Extramedullary sheets of blasts also qualify as blast phase.
In CML, a complete cytogenetic response corresponds to BCR-ABL1 <=____ on the International Scale, a major molecular response (MMR) is <=____, and a sustained ____ is the gateway to attempting treatment-free remission.
Once TKI therapy begins, CML management is guided by molecular response rather than symptoms. BCR-ABL1 transcript levels are measured by PCR on peripheral blood and reported on the International Scale (IS). A complete cytogenetic response (no Ph-positive metaphases) corresponds roughly to BCR-ABL1 <=1% IS (MR2) and is the milestone most consistently tied to survival; a major molecular response (MMR, MR3, <=0.1% IS) further reduces relapse and transformation risk; and a deep molecular response (MR4 <=0.01% IS or MR4.5) is the gateway to attempting treatment-free remission. A slow molecular response is not by itself treatment failure.
Before imatinib, median survival in CML was ____ years; in the TKI era the estimated 10-year survival exceeds ____ and annual mortality has fallen from 10-20% to about 1-2%.
TKIs revolutionized CML: before imatinib, median survival was 3-7 years; today the estimated 10-year survival exceeds 85% — approaching that of the age-matched general population — and annual mortality has fallen from 10-20% to about 1-2%. Every patient requires treatment at diagnosis. Six oral TKIs are approved: imatinib; second-generation dasatinib, nilotinib, and bosutinib; and third-generation ponatinib and asciminib. All four classic frontline TKIs produce similar survival; second-generation agents achieve deeper, faster molecular responses, useful when treatment-free remission is the goal.
____ is a first-in-class STAMP inhibitor that targets the ABL1 ____ rather than the ATP-binding site; in the ASC4FIRST trial its 48-week major molecular response rate was ____ versus ____ with investigator-selected TKIs.
Asciminib is a first-in-class STAMP inhibitor that targets the ABL1 myristoyl pocket rather than the ATP-binding site, retaining activity where ATP-site TKIs fail. The phase 3 ASC4FIRST trial (405 newly diagnosed chronic-phase patients) showed asciminib produced higher 48-week major molecular response rates than investigator-selected TKIs — 67.7% vs 49.0% overall (~69% vs ~40% against imatinib) — with fewer grade >=3 adverse events. Following these results, asciminib became a frontline option in 2025 (US first-line approval widely reported June 2025) and the 2025 ELN recommendations incorporate it into personalized first-line selection.
The ABL1 ____ gatekeeper mutation blocks imatinib and all second-generation TKIs, leaving ____ or ____ as the effective TKI options, with serious consideration of transplantation.
True resistance to imatinib occurs in only ~10% of patients at 10 years; when responses are lost, first check adherence, then perform ABL1 kinase-domain mutation testing, which identifies a targetable mechanism in ~half of resistant cases (>100 mutations described). The T315I gatekeeper mutation blocks imatinib and all second-generation TKIs and requires ponatinib or asciminib, with serious consideration of transplantation. Other mutations steer agent choice: Y253H/E255K/V/F359V favor dasatinib or bosutinib; V299L/T315A/F317L favor nilotinib.
Stopping TKIs after more than 2-3 years of deep molecular response yields durable treatment-free remission in roughly ____ of CML patients, rising above ____ after 5 or more years of DMR.
For patients who sustain a deep molecular response, TKI discontinuation is a realistic goal: stopping after more than 2-3 years of DMR yields durable treatment-free remission in roughly 40-60% of patients, rising above 80% after 5 or more years of DMR. TFR attempts require intensive molecular monitoring (monthly-to-bimonthly PCR early on), and TKIs are restarted only if transcripts rise above the MMR threshold on confirmatory testing. In the final EURO-SKI analysis of 728 patients stopping TKIs, molecular recurrence-free survival was 61% at 6 months and 46% at 36 months; each additional year of DMR added ~3% to the probability of maintaining MMR at 6 months. The 2025 ELN now lists TFR as a primary treatment goal alongside survival.
Before diagnosing ET, reactive thrombocytosis must be excluded — headed by ____ — and the physical finding of ____ is not a feature of ET and should redirect the workup toward another MPN.
ET is a clonal stem cell disorder expressed as sustained platelet overproduction. Reactive (secondary) thrombocytosis is far more common than ET and must be excluded before pursuing a clonal diagnosis: iron deficiency heads the list, along with chronic bleeding, infection/inflammation, malignancy, and the post-splenectomy state. Two pearls: splenomegaly is NOT a feature of ET and should redirect the workup toward another MPN (PV, PMF, or CML); and very large platelet masses can produce spurious hyperkalemia (platelet potassium released during clotting in the tube) — a laboratory artifact without ECG changes.
In ET, a platelet count greater than ____ paradoxically raises bleeding risk because the enlarged platelet mass adsorbs and destroys high-molecular-weight ____ multimers, producing acquired von Willebrand disease.
Extreme clonal thrombocytosis (platelets >1 million/microL) paradoxically raises bleeding risk: the enlarged platelet mass adsorbs and destroys high-molecular-weight von Willebrand factor multimers, producing acquired von Willebrand disease — and aspirin can worsen hemorrhage in that setting. Any ET patient with platelets above this threshold should be assessed for acquired von Willebrand disease before starting aspirin; bleeding risk dominates management at these counts.
In ET, low-risk disease is defined as age ____, no history of ____, and ____ mutation-negative; high-risk patients receive low-dose aspirin plus cytoreductive therapy, usually ____.
ET therapy is determined by thrombotic risk, not the platelet number alone. Low-risk patients — age <60, no history of venous or arterial thrombosis, and JAK2-negative — can be observed or given low-dose aspirin for vasomotor symptoms. High-risk patients — age >60, JAK2-positive, and/or prior thrombosis — receive aspirin plus cytoreductive therapy, usually hydroxyurea. Interferon alfa is the preferred platelet-lowering agent in younger patients and during pregnancy (hydroxyurea is potentially teratogenic); anagrelide is second-line. Acute venous thromboembolism generally requires lifelong anticoagulation in addition to ET-directed therapy.
In PMF the peripheral smear is ____ — teardrop red cells, nucleated red cells, and immature myeloid forms — and bone marrow aspiration typically fails, yielding a ____, because of reticulin/collagen fibrosis.
PMF is a clonal stem cell disorder characterized by bone marrow fibrosis, extramedullary hematopoiesis, and splenomegaly (often massive). The fibrosis is reactive, not neoplastic: clonal megakaryocytes release cytokines (including TGF-beta-1) that recruit polyclonal fibroblasts to lay down reticulin and collagen. The peripheral smear is leukoerythroblastic — teardrop-shaped red cells, nucleated red cells, and immature myeloid forms — reflecting blood production outside the marrow. Bone marrow aspiration typically fails (dry tap) because of fibrosis; the biopsy shows clustered atypical megakaryocytes with extensive reticulin/collagen deposition. Diagnosis requires excluding CML and secondary myelofibrosis (metastatic carcinoma, miliary TB, others).
The core IPSS risk factors in PMF are age over 65, hemoglobin below ____, leukocyte count above ____, circulating blasts >=____, and constitutional symptoms.
PMF prognosis is estimated with the International Prognostic Scoring System (IPSS, at diagnosis) and its dynamic successors DIPSS and DIPSS-Plus (usable at any point). Core risk factors: age >65, anemia (hemoglobin <10 g/dL), leukocytosis (>25,000/microL), circulating blasts >=1%, and constitutional symptoms; DIPSS-Plus adds unfavorable karyotype, platelet count <100,000/microL, and transfusion dependence. The outcome spread is stark: low-risk disease carries ~15-year estimated survival, while high-risk disease averages only ~16 months; ~10% of patients transform to aggressive acute leukemia. Type 1 CALR-mutated disease has a survival advantage over JAK2/MPL-mutated disease; triple-negative PMF has the worst prognosis.
____, FDA-approved in September 2023, is the first myelofibrosis therapy specifically indicated for patients with anemia; it inhibits JAK1/JAK2 and also blocks ____, lowering hepcidin, and in the MOMENTUM trial it outperformed ____ on symptoms, spleen response, and transfusion independence.
Momelotinib, approved by the FDA in September 2023, is the first myelofibrosis therapy specifically indicated for patients with anemia: an oral JAK1/JAK2 inhibitor that also blocks ACVR1, lowering hepcidin and improving iron-restricted erythropoiesis. In the phase 3 MOMENTUM trial of JAK-inhibitor-experienced, anemic patients with intermediate- or high-risk MF, momelotinib outperformed danazol on all three endpoints — constitutional symptoms, spleen response, and transfusion independence — at 24 weeks. Other JAK inhibitors: ruxolitinib and fedratinib improve symptoms and spleen volume regardless of JAK2 mutation status; pacritinib is particularly useful when thrombocytopenia limits other JAK inhibitors.
In the MANIFEST-2 trial, adding ____ — a ____ (bromodomain) inhibitor — to ruxolitinib nearly doubled the rate of spleen volume reduction >=35% at week 24 in JAK-inhibitor-naive myelofibrosis (____ vs 35.2%).
MANIFEST-2, a phase 3 trial in ~430 JAK-inhibitor-naive patients, showed that adding pelabresib — a BET (bromodomain) inhibitor — to ruxolitinib nearly doubled the rate of spleen volume reduction >=35% at week 24 (65.9% vs 35.2% with placebo plus ruxolitinib) and improved symptom scores, at the cost of more grade >=3 thrombocytopenia and anemia. Following these results, FDA approval of pelabresib plus ruxolitinib for first-line myelofibrosis was reported in July 2025. Allogeneic HSCT remains the only potentially curative treatment for PMF, reserved for fit patients with features predicting poor short-term survival.
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