Hematologic Malignancies
Utkarsh H. Acharya, DO, FACP
Tejaswini Dhawale, MD
James S. Blachly, MD
Johnnie J. Orozco, MD, PhD
Keri Maher, DO
Clifton Mo, MD
David Bond, MD
A 40-year-old woman presents with ecchymoses and gingival bleeding. She exhibits new onset pancytopenia and coagulopathy. Peripheral blood immunophenotyping shows 80% of events in the blast gate expressing CD13, CD33, and MPO; negative for CD34 and HLA-DR.
What are the next two most important diagnostic and therapeutic interventions?
View Answer
Administer ATRA (all-trans retinoic acid) and obtain PML-RARA FISH and/or PCR to confirm the diagnosis of acute promyelocytic leukemia (APL).
Treatment of suspected APL with ATRA should begin immediately.
APL has a characteristic immunophenotype and in most cases expresses the PML-RARA fusion gene resulting from t(15;17).
Treatment of APL includes ATRA, arsenic trioxide, and, in high-risk cases (WBC > 10 × 10(9)/L), anthracycline.
DIC is common at diagnosis of APL and must be dealt with aggressively.
Suggested Readings:
Sanz MA, Fenaux P, Tallman MS, et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019;133(15):1630-1643. doi:10.1182/blood-2019-01-894980.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
Which four (two cytogenetic groups and two genetic groups) non-APL acute myeloid leukemias (AML) are classified as “favorable” by the European Leukemia Net and others?
View Answer
t(8;21) and inv(16)/t(16;16) Core-binding factor AML; NPM1 mutated without FLT3-ITD or with FLT3-ITDlow; and CEBPA biallelic mutated are considered favorable risk and are typically treated with chemotherapy (for fit patients).
Hematopoietic stem cell transplant is not typically recommended in first complete remission (CR1) for favorable-risk patients as opposed to unfavorable patients (eg, FLT-3 mutated, complex karyotype, secondary AML, and therapy-related AML).
Suggested Readings:
Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447. doi:10.1182/blood-2016-08-733196.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
What important side effect or toxicity do the IDH1 and IDH2 inhibitors ivosidenib and enasidenib, respectively, share with all-trans retinoic acid (ATRA)?
View Answer
Differentiation syndrome is an important toxicity associated with IDH1/IDH2 inhibitors in the management of acute myeloid leukemia.
Differentiation syndrome is characterized by ultrarapid maturation of arrested myeloid precursors followed by high tissue (often lungs) affinity and homing. Rising WBC and respiratory failure are characteristic.
Treatment includes immediate dexamethasone. Unlike ATRA, the very long half-lives of the IDH inhibitors makes withdrawal unlikely to be effective.
Suggested Readings:
Norsworthy KJ, Mulkey F, Scott EC, et al. Differentiation syndrome with ivosidenib and enasidenib treatment in patients with relapsed or refractory IDH-mutated AML: A U.S. Food and Drug Administration Systematic Analysis. Clin Cancer Res. 2020;26(16):4280-4288. doi:10.1158/1078-0432.CCR-20-0834.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 58-year-old man with t(8;21) RUNX1-RUNXT1 acute myeloid leukemia is receiving consolidation with high-dose Ara-C during this hospital admission. He stumbles and falls on the fourth hospital day while walking to the bathroom.
Which component of the physical examination is most likely to reveal a cause for his fall?
View Answer
Cerebellar testing will likely reveal cause of his fall given recent treatment with high-dose cytarabine (Ara-C).
High-dose Ara-C (“HiDAC”) is often given for consolidation in AML and can be associated with cerebellar toxicity.
Physician or nursing staff should conduct at least daily cerebellar examinations in patients receiving HiDAC.
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 62-year-old woman who was previously in good health and is an aerobics instructor presents with pancytopenia. The bone marrow shows 30% myeloblasts, dysplastic granulocytic precursors, and dysmegakaryopoiesis. An echocardiogram shows EF of 55%-60%.
What is this patient’s diagnosis and the most appropriate therapy for her?
View Answer
Diagnosis: AML with myelodysplasia-related changes (AML-MRC).
Management: This subtype of AML responds poorly to conventional chemotherapy (“7 + 3” daunorubicin and cytarabine). The FDA approved a fixed molar ratio of daunorubicin-cytarabine liposomal (marketed in the United States as Vyxeos™) for adults with therapy-related AML or AML-MRC based on phase 3 data showing superior complete response rates and overall survival versus conventional 7 + 3.
Suggested Readings:
Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684-2692. doi:10.1200/JCO.2017.77.6112.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
Seven years after a diagnosis of breast cancer, which was treated with surgical resection and dose-dense Adriamycin-cyclophosphamide-Taxol, a 64-year-old woman presents with WBC of 15 × 109/L, Hb 10 g/dL, Plt 50 × 109/L, and 25% peripheral myeloblasts. Cytogenetics show -7 and genetics shows TP53 mutation.
What is the diagnosis, and which agent most likely led to these findings?
View Answer
Diagnosis: Therapy-related acute myeloid leukemia (t-AML) secondary to alkylating therapy. t-AML has a historically unfavorable/poor-risk feature requiring consolidative allogenic hematopoietic stem cell transplantation in the first complete remission.
Causes of t-AML:
Alkylating agents like cyclophosphamide characteristically create genome damage, including −7/del(7q), −5/del(5q), 17p abnormalities, complex karyotype, or TP53 mutation and present with latency of 5 to 7 years.
t-AML due to topoisomerase inhibitors like anthracyclines typically develop and present in 2 to 3 years and feature gene fusions like core-binding factor, PML-RARA, or KMT2A (MLL) rearrangement (11q23).
Suggested Readings:
Heuser M. Therapy-related myeloid neoplasms: does knowing the origin help to guide treatment? Hematology Am Soc Hematol Educ Program. 2016;2016(1):24-32. doi:10.1182/asheducation-2016.1.24.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 40-year-old man undergoes a diagnostic bone marrow biopsy due to Hb of 10 g/dL and platelets of 100 × 109/L. This reveals 14% myeloblasts and a karyotype 46,XY,t(8;21)(q22;q22)[3]/46,XY[17].
What is his diagnosis?
View Answer
Diagnosis: Acute myeloid leukemia.
AML is differentiated from MDS by bone marrow blasts ≥20%, except for AML with recurrent genetic abnormalities t(15;17), t(8;21), inv(16), or t(16;16) for which no specific blast percentage is required.
t(15;17) defines PML-RARA and is diagnostic of APL; the other three comprise RUNX1-RUNXT1 and CBFB-MYH11, or “core-binding factor” AML.
Suggested Readings:
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. doi:10.1182/blood-2016-03-643544.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
Which anti-bcl2-targeted small-molecule therapy for acute myeloid leukemia (AML) carries the greatest risk for tumor lysis syndrome (TLS)?
View Answer
Venetoclax carries a risk for tumor lysis syndrome in AML.
Venetoclax is FDA approved in combination with 5-azacitidine, decitabine, or low-dose cytarabine for treatment of older or unfit AML patients.
In AML, venetoclax dosing should be ramped up over 3 to 4 days, with daily laboratory tests to look for biochemical evidence of tumor lysis. WBC should be ≤25 × 109/L at initiation of venetoclax to decrease risk. Hydroxyurea can be used to depress the WBC.
Suggested Readings:
DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. doi:10.1182/blood-2018-08-868752.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 10-day course of decitabine has the most evidence of benefit for which genetic group of acute myeloid leukemia (AML) patients?
View Answer
TP53-mutated acute myeloid leukemia (AML) is responsive to a 10-day course of decitabine.
TP53-mutated AML responds very poorly/has a short duration after conventional 7 + 3 anthracycline with cytarabine therapy.
Decitabine is also used in older patients or those unfit for intensive induction with 7 + 3.
Suggested Readings:
Welch JS, Petti AA, Miller CA, et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med. 2016;375(21):2023-2036. doi:10.1056/NEJMoa1605949.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 34-year-old man was diagnosed with T-cell acute lymphoblastic leukemia (ALL) having a presenting WBC of 120 × 109/L, while a 41-year-old woman was diagnosed with B-ALL in conjunction with a presenting WBC of 60 × 109/L.
All else being equal, which of these patients is predicted to have the worst prognosis and which prognostic factors are important to consider?
View Answer
The 41-year-old woman with a diagnosis of B-ALL has a poorer prognosis based on B-histology, WBC >50k, female sex, and age>35 years.
Female sex, age (increasing continually above the age of 35 years), B-histology, and elevated WBC >30, 50, or 100 (depending on study) in B-ALL have all been identified as factors predicting poor outcomes.
Other poor-risk factors include complex karyotype and IKZF1 deletion.
Philadelphia chromosome (BCR-ABL1 fusion) was historically poor-risk, but tyrosine kinases inhibitors have improved outcomes.
Suggested Readings:
Curran E, Stock W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015;125(24):3702-3710. doi:10.1182/blood-2014-11-551481.
Rowe JM, Goldstone AH. How I treat acute lymphocytic leukemia in adults. Blood. 2007;110(7): 2268-2275. doi:10.1182/blood-2007-05-038950.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 29-year-old man was diagnosed with precursor B acute lymphocytic leukemia and treated with a pediatric-style regimen that includes induction with daunorubicin, PEG-asparaginase, prednisone, and vincristine. On the eighth day of induction treatment, he complains of severe abdominal pain radiating to the back, anorexia, nausea, and vomiting.
What is his most likely diagnosis?
View Answer
Diagnosis: Pancreatitis caused by PEG-asparaginase.
PEG-asparaginase may cause pancreatitis, elevated transaminases, elevated bilirubin, hypertriglyceridemia, depleted fibrinogen, and bleeding. Any of these can be life threatening, but coagulopathy is particularly worrisome, and the fibrinogen and coagulation parameters should be followed closely in all patients.
Suggested Readings:
Stock W, Douer D, DeAngelo DJ, et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma. 2011;52(12):2237-2253. doi:10.3109/10428194.2011.596963.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 25-year-old man presented to his physician with rapidly progressive lymphadenopathy. A CBC revealed WBC of 98 × 109/L of which 90% were blasts, which were very large, had moderate cytoplasm, and vacuoles. The pathologist has called to tell you that she is signing out the case as acute lymphoblastic leukemia and the blasts are of the L3 type.
What is your next step in management, and what associated cytogenetic abnormalities would you expect to find?
View Answer
Management: Admit the patient for urgent treatment of Burkitt leukemia in the setting of circulating L3 lymphoblasts. L3 lymphoblasts are Burkitt-like, and most cases of Burkitt leukemia are now recognized as an overlap with Burkitt lymphoma, an aggressive Myc-driven non-Hodgkin lymphoma. These patients are at high risk for tumor lysis syndrome or rapidly fatal progression and should start therapy ideally within 24 to 48 hours of coming to attention.
Cytogenetic abnormalities associated with Burkitt lymphoma: t(8;14), t(2;8), and t(8;22).
Suggested Readings:
Leukemia.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
Which clinical factors should most influence the decision to start hypomethylating agent for patients with myelodysplastic syndrome?
View Answer
Clinically relevant cytopenias in MDS should induce the initiation of hypomethylating therapy.
Azacitidine or decitabine should be considered after there is clinically relevant thrombocytopenia, neutropenia with recurrent infection, or clinically relevant anemia not a candidate for (EPO > 500) or not responsive to erythropoiesis-stimulating agents.
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 44-year-old woman was evaluated by a hematologist because of pancytopenia. Her bone marrow examination showed 3% blasts, minimal trilineage dyspoiesis, and a karyotype 46,XX,del(5)(q13q32)[10]/46,XX[20].
What is the most appropriate treatment for this diagnosis?
View Answer
Lenalidomide is indicated in the treatment of “MDS with isolated del(5q).”
Deletion of casein kinase 1A1 gene on 5q leads to exquisite lenalidomide sensitivity. These patients may respond for years to single-agent lenalidomide.
Other MDS patients (particularly low risk) may respond to lenalidomide rarely, but it is not a first-line agent for other types of MDS.
Suggested Readings:
Krönke J, Fink EC, Hollenbach PW, et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature. 2015;523(7559):183-188. doi:10.1038/nature14610.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 67-year-old man presents with a complaint of early satiety. On examination, he is noted to have splenomegaly with laboratory tests revealing a mild leukocytosis with 20% monocytes, which has been persistent over the course of a year. Bone marrow shows 3% blasts, 10% monoblasts or promonocytes, 4% eosinophils, and 4% basophils. He has mild anemia and thrombocytopenia and now needs 1-unit PRBC per month.
How would final diagnosis and treatment differ if a FISH panel including PDGFRA and PDGFRB were negative versus positive?
View Answer
Diagnosis: The patient likely has chronic myelomonocytic leukemia (CMML), but to make the diagnosis it requires negative BCR-ABL1, PDGFRA, PDGFRB, or FGFR1 fusion, and negative PCM1-JAK2 fusion.
Management considerations: CMML is treated with hypomethylating agents, while fusion-driven myeloproliferative neoplasm (or MDS-MPN overlap, or MDS/MPN unclassifiable) containing PDGFRA, PDGFRB, or FGFR1 fusions may be responsive to imatinib.
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 58-year-old previously healthy and active gentleman is referred to the emergency department after laboratory tests done at a routine primary care physician visit result with a WBC of 150 × 109/L. He is diagnosed with normal karyotype acute myeloid leukemia (AML). His genetic profile shows DNMT3A R882H (VAF 0.4) and FLT3-ITD (allele ratio 99). He achieves a complete remission to induction therapy.
What is the most appropriate consolidative therapy?
View Answer
Consolidative allogeneic hematopoietic stem cell transplant should be performed in clinically fit, high-risk, acute myeloid leukemia patients after they achieving first complete remission.
FLT3-ITD is a predictor of particularly poor outcome, and patients who are transplant candidates should be transplanted in first remission (CR1).
Midostaurin is a FLT3-inhibitor that is FDA approved to be used in combination with cytarabine and daunorubicin induction and cytarabine consolidation therapy for newly diagnosed adult FLT3-mutated AML (RATIFY phase III trial). The value of midostaurin in post-stem cell transplant maintenance therapy is under investigation.
Suggested Readings:
Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi:10.1056/NEJMoa1614359.
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 72-year-old woman is seen in clinic for a history of worsening bilateral lower extremity edema and dyspnea on exertion. Physical examination is notable for an elevated JVP, rales in the bilateral lower lung fields, splenomegaly, and 2+ lower extremity edema. Laboratory tests reveal leukocytosis with an absolute eosinophil count of 9 × 109/L and an elevated serum B12 of 1634 pg/mL. Molecular genetic analysis of the peripheral blood identifies the presence of an FIP1L1-PDGFRA fusion.
What treatment would you recommend?
View Answer
Imatinib is indicated for hypereosinophilic syndrome associated with mutations resulting in PDGFRA and PDGFRB fusions including FIP1L1-PDGFRA (most common), KIF5B-PDGFRA, ETV6-PDGFRB, and point mutations in PDGFRA.
For patients with suspected cardiac involvement, corticosteroids (>1 mg/kg) should be administered concurrently with imatinib during the first few days of therapy to prevent myocardial necrosis.
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 66-year-old man is recently diagnosed with essential thrombocytosis.
What is the most likely mutated gene?
View Answer
The gene most often mutated in myeloproliferative neoplasms is JAK2; others are CALR and MPL.
Polycythemia vera: nearly all are JAK2 V617F mutated with JAK2 Exon 12 occurring less frequently.
Essential thrombocytosis: mutational frequencies are ˜60% to 65% JAK2 V617F, 20% to 25% CALR, and 3% to 5% MPL mutations.
Primary myelofibrosis: mutational frequencies are ˜50% to 60% JAK2, 20% to 25% CALR, and <10% MPL.
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 70-year-old man with chronic obstructive lung disease, smoking history, and sleep apnea is seen in the emergency department, where vitals show oxygen saturation 88% on room air and WBC of 9000/µL, Hb of 18.5 g/dL, and platelets of 390,000/µL.
What diagnostic next step can differentiate primary versus secondary erythrocytosis?
View Answer
Erythropoietin level is expected to be very low (to undetectable) in polycythemia vera (PV), whereas secondary erythrocytosis will have elevated erythropoietin levels.
JAK2 mutation + and low erythropoietin is diagnostic of PV
Causes of secondary erythrocytosis: lung disease, high altitude, paraneoplastic syndromes (eg, renal cell carcinoma)
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 45-year-old man is recently diagnosed with polycythemia vera (PV). Laboratory studies show WBC 11,200/µL, Hb 19/Hct 57, platelets 490,000/µL.
Does he need treatment?
View Answer
Unlike other myeloproliferative neoplasms, PV is treated at time of diagnosis.
Phlebotomy to goal <45% (consider <42% in women), without iron supplementation
Low-dose ASA in all patients
Hydroxyurea if high risk (>60-year-old, history of thrombosis)
Ruxolitinib or pegylated interferon is considered if intolerant of hydroxyurea or poor response to phlebotomies
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 67-year-old man with a history of left lower extremity venous thrombus is diagnosed with JAK2-mutated essential thrombocytosis.
Which high-risk factors would favor combined cytoreductive therapy with hydroxyurea and aspirin?
View Answer
Age>60 years, prior history of thrombosis (arterial or venous), and JAK2-mutated essential thrombocytosis (ET) confer higher risk disease and require cytoreduction + aspirin.
Low-risk ET patients do not require cytoreductive treatment at diagnosis (age < 60 years, no history of thrombosis, no JAK2-mutated/CALR-mutated disease) but may be offered ASA versus observation based on accompanying cardiovascular indications/vasomotor symptoms.
First-line cytoreductive options for ET: hydroxyurea, anagrelide, interferon alpha (used in pregnancy)
Consider testing for acquired von Willebrand disease when platelets >1 × 106/µL due to risk of paradoxical bleeding (which may be exacerbated with aspirin).
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 65-year-old woman with constitutional symptoms is diagnosed with primary myelofibrosis.
What disease risk factors would be required to calculate her dynamic international prognostic scoring system (DIPSS) and how would it influence management?
View Answer
Calculating DIPS score in primary myelofibrosis (PMF) relies on age (65 or older is higher risk), WBC (25 or greater is higher risk), hemoglobin (hgb <10 g/dL is higher risk), peripheral blood blasts (>1% is higher risk), and constitutional symptoms (presence of higher risk). Based on the aggregate composite score, patients are deemed as low, intermediate, or high risk with inferior long-term survival in non-low-risk groups for which an allogeneic hematopoietic stem cell transplant should be considered.
Hematopoietic stem cell transplant is only curative treatment for robust, high-risk primary myelofibrosis patients.
Nontransplant management for symptomatic JAK2-positive or -negative disease: Ruxolitinib (reduces spleen size and constitutional symptoms).
Low-risk PMF, consider hydroxyurea for leukocytosis or thrombocytosis.
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
In what phase is chronic myeloid leukemia most frequently diagnosed?
View Answer
Chronic
<10% blasts in PB and marrow
May see eosinophilia, basophilia, thrombocytosis
Accelerated
Impaired neutrophil differentiation (10%-19% blasts in peripheral blood/marrow)
Splenomegaly
Cytopenias, clonal evolution
Peripheral blood basophils ≥20%
Cytogenetic evolution
Blast crisis (treated as secondary AML)
≥20% blasts in peripheral blood or marrow
Includes extramedullary manifestations
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
Match the following options with the correct statements regarding myeloproliferative disorders.
1. __ Defined by the presence of greater than 20% myeloid blasts
2. __ Most commonly occurring phase at the diagnosis of CML
3. __ Defined by the presence of greater than 10% myeloid blasts (but less than 20% blasts)
4. __ Tyrosine kinase inhibitor that may be used in chronic and accelerated phase chronic myelogenous leukemia with propensity for prolonging QT interval
5. __ Defined by the presence of less than 10% myeloid blasts
6. __ Tyrosine kinase inhibitor indicated in T315I-mutant disease and with potential to result in thrombotic complications
7. __ Tyrosine kinase inhibitor that is associated with pulmonary hypertension and pleural effusions
8. __ Mutation frequently occurring in patients with chronic myelogenous leukemia
9. __ Mutation frequently occurring in patients with chronic neutrophilic leukemia
10. __ Mutation frequently occurring in patients with hypereosinophilic syndrome and the target of imatinib
11. __ Less frequently occurring mutation in patients with polycythemia vera
A. Chronic phase CML
B. Accelerated phase CML
C. Blast phase CML
D. Dasatinib
E. Nilotinib
F. Ponatinib
G. CSFR mutation
H. PDGFR-FLIPI mutation
I. BCR-ABL mutation
J. JAK2 Exon 12
View Answer
Match the following options with the correct statements regarding myeloproliferative disorders.
1. (C) Defined by the presence of greater than 20% myeloid blasts
2. (A) Most commonly occurring phase at the diagnosis of CML
3. (B) Defined by the presence of greater than 10% myeloid blasts
4. (E) Tyrosine kinase inhibitor that may be used in chronic and accelerated phase chronic myelogenous leukemia with propensity for prolonging QT interval
5. (A) Defined by the presence of less than 10% myeloid blasts
6. (F) Tyrosine kinase inhibitor indicated in T315I-mutant disease and with potential to result in thrombotic complications
7. (D) Tyrosine kinase inhibitor that is associated with pulmonary hypertension and pleural effusions
8. (I) Mutation frequently occurring in patients with chronic myelogenous leukemia
9. (G) Mutation frequently occurring in patients with chronic neutrophilic leukemia
10. (H) Mutation frequently occurring in patients with hypereosinophilic syndrome and the target of imatinib
11. (J) Less frequently occurring mutation in patients with polycythemia vera
A. Chronic phase CML
B. Accelerated phase CML
C. Blast phase CML
D. Dasatinib
E. Nilotinib
F. Ponatinib
G. CSFR mutation
H. PDGFR-FLIPI mutation
I. BCR-ABL mutation
J. JAK2 Exon 12 mutation
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 35-year-old woman presents with WBC 66,000/µL (differential: 86% mature neutrophils, 2% myelocytes, 1% metamyelocytes, 1% basophils, 2% monocytes, 8% lymphocytes), Hgb of 10, with platelet count of 455,000/µL. Blood tests have confirmed the presence of BCR-ABL fusion gene by PCR, and marrow had 3% myeloid blasts.
What is the diagnosis, and how should she be treated?
View Answer
Diagnosis: Chronic myelogenous leukemia (CML) is diagnosed based on a myeloid-predominant leukocytosis with presence of the BCR-ABL fusion gene [t(9;22)] evident in 95% of patients with CML. Management: All chronic phase CML (<10% myeloblasts in bone marrow) patients receive tyrosine kinase inhibitor (TKI) on diagnosis to prevent progression to AML.
Treat with TKI: first line
imatinib (first generation)
dasatinib (second generation)
nilotinib (second generation)
consider bosutinib (second generation)
Suggested Readings:
Abraham J, Gulley JL. The Bethesda Handbook of Clinical Oncology. 5th ed. Wolters Kluwer; 2018.
DeVita VT, Rosenberg SA, Lawrence SL. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer; 2018.
A 70-year-old male has TP53-mutated chronic lymphocytic leukemia (CLL) that has now relapsed after initial therapy with ibrutinib. He has bulky lymphadenopathy, unintentional weight loss, and anemia. Second-line therapy with venetoclax is initiated at 400 mg once daily. He presents to the emergency department several days later with nausea, vomiting, and low urine output.
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