Clinical Vignettes 1
43-year-old Hispanic female presents to the emergency department with profound fatigue. In addition, over the past 3 days she began to experience menorrhagia. Vital signs: 99.7 °F, pulse 108, respiratory rate 19, blood pressure 110/70. She demonstrates slight pallor. Lab analysis shows hemoglobin 8.4 with a normal reticulocyte count. Her leukocyte count is 3000 and her platelet count is 20,000. Fibrinogen 55, PTT elevated, D-dimer 500, prolonged thrombin time. Peripheral smear shows helmet cells, micro spherocytes, very small number of leukemic cells in the peripheral blood which are CD13/CD33 positive and CD34 negative. What is the next most appropriate step in her management?
A) begin all-trans retinoic acid as soon as possible
B) begin arsenic trioxide as soon as possible
C) begin high-dose cytarabine as soon as possible
D) begin standard induction therapy with cytarabine plus anthracycline (7+3 therapy) as soon as possible
Answer: A
Patient in the vignette is suffering from low risk (WBC<10k) acute promyelocytic leukemia with DIC. APL is considered a medical emergency due to the high mortality frequently seen soon after presentation. If clinical suspicion for APL is high prior to confirmation of the t15;17 translocation, therapy should be initiated immediately as this may prevent the lethal complications of bleeding in these patients.
27-year-old Caucasian female presents to the emergency department with new onset fatigue and bruising. She is found to have cytopenias with hemoglobin 8.8, platelets 22, WBC 6.0. Peripheral blood smear shows population of large atypical cells showing occasional Auer rods with large lobed nuclei and violet granules. Peripheral blood flow cytometry reveals a population of cells positive for CD13, CD33, and CD56 and negative for CD34 and HLA–DR. You are concerned for APL and immediately start ATRA. Stat FISH is negative for t(15;17). You suspect a possible cryptic or variant APL translocation. Which of the following is the most common cryptic or variant APL translocation?
A) t(11;17)(q23;q21.1)- PLZF-RARA
B) t(17;17)(q21;q21)- STAT5b-RARA
C) t(11;17)(q13;q21)-NuMa-RARA
D) t(5;17)(q35;q21.1)-NPM1-RARA
Answer: A
Approximately 98% of APL will have a classic t(15;17) chromosomal translocation. Rarely, cases with otherwise classic APL phenotype will not demonstrate the classic t(15;17) and are often referred to as cryptic or variant APL, officially known as AML with variant RARA translocation. The most commonly reported variant is t(11;17)(q23;q21.1) in which the RARA gene is fused to the gene encoding PLZF (promyelocytic leukemia zinc finger). This fusion protein is typically reported to be not responsive to ATRA therapy.
51-year-old male with AML status post induction chemotherapy with idarubicin and Ara-C. 15s in complete remission with induction chemotherapy and received consolidation therapy with an allogeneic transplant from a matched sibling donor for his high risk AML. He had busulfan and cyclophosphamide for conditioning. He has been compliant with his immunosuppressive medications. He also recently started valacyclovir for viral prophylaxis. 15 days status post transplant, the patient presents with severe right upper quadrant pain with new onset ascites. On presentation, his bilirubin is 2.8. To date, his bilirubin has been normal. What is the most likely explanation for these findings?
A) Acute GVHD
B) Chronic GVHD
C) Hepatic sinusoidal obstruction syndrome
D) side effect from valacyclovir
E) chemotherapy induced heart failure
Answer: C
Hepatic sinusoidal obstruction syndrome occurs in part due to injury of the small veins in the liver. If you see ascites, hepatomegaly, or elevation of bilirubin less than 3 weeks after transplant, one should rule out this condition. Severe sinusoidal obstruction syndrome can lead to multiorgan failure. Cyclophosphamide and busulfan conditioning has been reported to cause sinusoidal obstruction. Gemtuzumab ozogamicin can also cause sinusoidal obstruction. Treatment is largely supportive.
MOA of Midostaurin
FLT3 inhibitor
48-year-old man presents to clinic with a recent diagnosis of AML. At the time of his presentation, his performance status is ECOG 0. He is experiencing mild fatigue, with no other clinical stigmata related to his disease process. What would be your recommendation for induction therapy?
A) standard dose cytarabine 100–200mg/m2 continuous infusion x7 days with idarubicin 12mg/m2 or daunorubicin 60–90mg/m2 x 3 days
B) standard dose cytarabine 200mg/m2 continuous infusion x7 days with daunorubicin 60mg/m2 x 3 days and cladribine 5mg/m2 x 5 days
C) high-dose cytarabine (HiDAC) 2g/m2 every 12 hours for 6 days or 3g/m2 every 12 hours x4 days with idarubicin 12mg/m2 or daunorubicin 60mg/m2 x 3 days
D) fludarabine 30mg/m2 IV days 2-6, HiDAC 2g/m2 over 4 hours starting 4 hours after fludarabine on days 2–6, idarubicin 8mg/m2 IV days 4-6, and G-CSF SC daily days 1-7
Answer: A
In younger patients with AML, 2 phases of chemotherapy are generally administered (induction phase and consolidation phase). Primary goal of induction chemo is to enable the body's bone marrow to function properly by removing malignant cells. Goal is to decrease the total leukemic cell burden to less than 10^9 cells. Current NCCN guidelines for induction chemotherapy recommend standard dose cytarabine 100-200mg/m2 continuous infusion x7 days with idarubicin 12mg/m2 or daunorubicin 60–90mg/m2 x 3 days.
A 39-year-old Hispanic male has had fatigue for the past 2 months. On presentation to the hospital, he was found to have a hemoglobin of 10.1, platelet count 110,000, and a WBC of 17,500 with 54% blasts. He has no serologic or clinical evidence of DIC. Bone marrow biopsy reveals APML with cytogenetics showing t(15;17). LFTs are normal. Creatinine 1.4. Which of the following features triage is similar to having higher risk disease?
A) WBC
B) Platelet count
C) Gender
D) Ethnicity
E) Kidney function
Answer A
For APML, a WBC>10,000 triage is a patient having high risk disease. Having a white blood cell count confers a higher risk of differentiation syndrome once ATRA is started.
62-year-old male with AML achieved a complete response status post induction chemotherapy with daunorubicin and Ara-C (3+7). He has felt to have intermediate risk disease and receives consolidation therapy with an allogeneic transplant from a matched sibling donor. He receives busulfan and cyclophosphamide for conditioning. 2 weeks after his transplant, he developed venoocclusive disease of his liver concomitantly with lung dysfunction. Which should be offered as therapy?
A) steroids
B) rituximab
C) donor lymphocyte infusion
D) defibrotide sodium
E) heparin
Answer D
Venoocclusive disease is a rare complication of stem cell transplantation that can occur in up to 15% of patients. Hepatic venoocclusive disease is an early and life-threatening complication affecting the sinusoidal endothelial cells of the liver, which can typically occur within the first 21 days following stem cell transplant. The mortality rate can be up to 50%. Defibrotide sodium is FDA approved for the treatment of adult and pediatric patients with hepatic venoocclusive disease with renal or pulmonary dysfunction.
APML is associated with a high risk of...
DIC and intracranial hemorrhage
MOA of Gemtuzumab ozogamicin
anti-CD33
56-year-old male presents to the emergency department with fatigue over the past 3-4 months associated with dyspnea on exertion. He has also noticed bruising and easy bleeding. Vital signs: Pulse 112, temp 101.2 °F, respiratory rate 17, blood pressure 128/86. Labs: Hemoglobin 7.8, leukocyte count 40,000, platelet count 13,000. Peripheral smear shows large cells with a high nuclear to cytoplasmic ratio, with violet/purple granules within the cytoplasm. Molecular analysis demonstrates a fusion gene (PML-RARA). Based on the above, what would be your recommended treatment with.
A) induction therapy with cytarabine (7-day continuous infusion) plus an anthracycline (given days 1–3) (7+3 therapy) followed by allogeneic hematopoietic cell transplantation
B) induction therapy with cytarabine (7-day continuous infusion) plus an anthracycline (given days 1–3) (7+3 therapy) followed by autologous hematopoietic cell transplantation
C) induction therapy with ATRA plus anthracycline-based chemotherapy followed by consolidation therapy with 2 cycles of consolidation therapy with ATO, followed by 2 cycles of daunorubicin plus ATRA
D) induction therapy with ATRA plus ATO followed by consolidation therapy with 4 cycles of ATO, followed by 7 cycles of ATRA
Answer: C
Per NCCN, this patient will be considered high risk based on his WBC>10K. The recommendation for high-risk APL is:
Induction therapy with ATRA 45mg/m2 in divided doses daily until clinical remission plus daunorubicin 50/mg/m2 x 4 days plus cytarabine 200mg/m2 x 7 days. Then at count recovery consider LP and proceed with consolidation.
Consolidation therapy with ATO 0.15mg/kg/d x 5 days for 5 weeks x 2 cycles then ATRA 45mg/m2 x 7 days + daunorubicin 50/mg/m2 x 3 days for 2 cycles
A 58-year-old African-American male with a recent diagnosis of AML is under your care on the acute leukemia ward. He has favorable risk AML. He is currently on day 3 of standard induction therapy with cytarabine + anthracycline without dose reduction. During rounds, the patient states he is unable to walk straight and is having mild difficulty sitting without his wife helping him. Which of the following is the best explanation for the patient's constellation of symptoms?
A) hyponatremia secondary to intravascular volume loss
B) stroke in the patient's right frontal lobe
C) neurotoxicity secondary to cytarabine
D) neurotoxicity secondary to anthracycline
Answer C
Patients undergoing induction therapy with cytarabine should be closely monitored for the development of neurotoxicity. This is particularly true in patients with renal impairment and appropriate dose adjustments should be made based on daily creatinine clearance levels. If patients develop neurotoxicity, cytarabine should be discontinued immediately.
58-year-old male recently diagnosed with AML with inversion (16). He was started on standard 7+3 induction chemotherapy. A bone marrow biopsy is performed 21 days after induction is completed and shows hypoplasia. You await recovery and a repeat bone marrow biopsy reveals no leukemia. No FLT3 mutation is seen and the patient is MRD negative. What you offer for consolidation therapy?.
A) none
B) intermediate dose Ara-C (300mg/m2 bid) every 12 hours x 4 cycles
C) high dose Ara-C (3 grams/m2 bid) every 12 hours, TIW, x 4 cycles
D) Autologous transplant
E) Allogeneic transplant
Answer C
Even if the patient has an outstanding response to induction chemotherapy, if they do not receive some type of consolidation treatment, he or she will suffer disease relapse. For a patient who has a favorable karyotype, one should consider high-dose Ara-C for consolidation therapy instead of an allogeneic transplant. A CALGB study compared standard, intermediate, or high-dose cytarabine therapy and core binding factor AML benefited greatly from high-dose cytarabine treatment.
Name two favorable-risk cytogenetics
1) t(8;21)(q22;q22.1); RUNX1-RUNX1T1
2) CBF inv (16) (p13.1q22) or t(16;16)
3) Mutated NPM1 without FLT3-ITD or with FLT3-ITD (low)
4) Biallelic mutated CEBPA
5) t(15;17)
MOA of Venetoclax
BCL2 inhibitor
55-year-old male was admitted to the hospital after presenting with fatigue and bruising and found to have new pancytopenia and circulating blasts. Flow cytometry from peripheral blood revealed a myeloid immunophenotype (positive for CD13, CD33, CD11c, HLA–DR, CD34) and confirmed AML (62% blasts). Cytogenetics and molecular studies are pending. Patient has good performance status (ECOG 1) and wishes for aggressive therapy. He is recommended induction chemo with cytarabine and an anthracycline (7+3 induction). The patient asks about the role of midostaurin; you recommend which of the following?
a) start midostaurin now and continue for 12 months
b) awaiting molecular study results; consider midostaurin if FLT3 TKD mutation is found
c) awaiting molecular study results; consider midostaurin if FLT3 ITD mutation with allelic mutation fraction >0.7 is found
d) awaiting molecular study results; consider midostaurin if any FLT3 mutation is found
Answer D
Standard of care for for patients with AML remains induction chemo with cytarabine and an anthracycline (7+3). Midostaurin was approved by the FDA in April 2017 for patients with newly diagnosed AML who are FLT3 mutation positive in combination with standard 7+3 induction therapy. Per the CALGB/RATIFY trial, the benefit of midostaurin was observed across FLT3 mutation subgroups (including TKD and ITD mutations, whether with high or low mutational allele burdens)
52-year-old male is undergoing induction chemo with cytarabine 200 mg/m2 continuous infusion x7 days and idarubicin 12mg/m2 x3 days. He has 4 days into receiving therapy when he develops acute hypoxia and dyspnea. Chest x-ray is performed and reveals a complete whiteout of both lungs. PE protocol is negative. He is not have any fever or signs of infection. DIC labs are all normal. Platelet count is normal and he has no signs of uremia. He has not on any anticoagulants. What is the most likely etiology?
A) diffuse lung injury
B) occult PE
C) multifocal pneumonia
D) diffuse alveolar hemorrhage
E) ARDS
Answer: D
Diffuse alveolar hemorrhage can occur in patients with AML during the induction phase of chemotherapy. Etiologies that can predispose to this condition include thrombocytopenia, underlying infection, coagulopathy, and systemic anticoagulation. Commonly presenting symptoms include dyspnea, fever, and coughing. Diagnosis is primarily based on radiological and bronchoscopic findings. Blasts can invade the lung and gums of the mouth; when these blasts are located in the lung and are subsequently killed by chemotherapy they can indirectly cause marked inflammation and alveolar hemorrhaging.
45-year-old male presents to your clinic with a recent diagnosis of AML. At the time of presentation, he is currently status post standard induction therapy with cytarabine plus an anthracycline (7+3 therapy) and subsequently underwent a unilateral bone marrow biopsy 7 days following his last dose of treatment. Results of the bone marrow biopsy demonstrated a complete response to induction therapy. At the time of his original diagnosis, his cytogenetics demonstrated a monosomy 7 clone. Based on the above information what would be the recommendation for his next step in therapy?
a) additional course of induction therapy with sorafenib
b) high-dose cytarabine consolidation therapy for 3–4 cycles
c) allogeneic hematopoietic cell transplantation
d) autologous hematopoietic cell transplantation
Answer: C
In patients with AML, under the age of 60, and classified as unfavorable/adverse risk (ex: monosomy 7) at the time of diagnosis who are status post induction chemotherapy with bone marrow biopsy demonstrating complete response should proceed with allogeneic hematopoietic cell transplantation (allogeneic is preferred to autologous as this provides a graft versus leukemia effect resulting in lower rates of relapse compared to autologous HCT)
Name two intermediate-risk cytogenetics
1) mutated NPM1 and FLT3-ITD (high)
2) Wild type NPM1 without FLT3-ITD or with FLT3-ITD (low)
3) t(9;11)(p21.3;q23.3); MLLT3-KMT2A
4) Cytogenetic abnormalities not classified as favorable or adverse
MOA of Gilteritinib
FLT3 inhibitor
You are in the process of treating a 50-year-old male with a recent diagnosis of AML. He has undergone standard induction therapy with cytarabine and an anthracycline. He undergoes a bone marrow biopsy 7 days following his last dose of treatment which shows 22% residual leukemic blasts and then undergoes a second cycle of induction therapy. Following completion of his second cycle another bone marrow biopsy shows a complete response. The patient is anxious to know his prognosis and asks what is the difference in outcome between patients that achieved a complete response after 1 cycle of induction therapy versus patients that achieve a complete response following 2 cycles of induction therapy?
A) patient's who achieve a complete response following 1 cycle of induction therapy have superior survival versus patients that achieve a complete response following 2 cycles of induction therapy
B) patients who achieve a complete response following 2 cycles of induction therapy have superior survival versus patients that achieve a complete response following 1 cycle of induction therapy
C) there is no difference in outcomes between patients who achieve a complete response following 1 cycle of induction therapy versus 2 cycles of induction therapy if a complete response is obtained following treatment
D) the outcome data is not available, and should be studied in a clinical trial
Answer C
In the report published by Rowe et al. (Cancer, 2010), they found that among patients enrolled in ECOG studies between 1983-1993 that long-term outcome was similar for patients who required 1 or 2 cycles of induction therapy to achieve complete response and their outcome was independent of other prognostic variables, such as age or karyotype.
58-year-old male recently diagnosed with AML with inversion 16 is started on standard 7+3 induction chemotherapy. Repeat bone marrow biopsy is MRD negative. He then started on consolidation therapy with high-dose Ara-C. His first cycle went well without any issues. During his second cycle, he develops an acute onset of cerebellar toxicity including nystagmus and marked slurred speech. It was thought to be due to cytarabine toxicity. What should be recommended for further therapy?
A) stop therapy for 1 week to allow for recovery then continue therapy at the same dose
B) stop therapy for 1 week to allow for recovery then continue therapy at a 25% dose reduction
C) stop therapy for 4 weeks then continue therapy at a 50% dose reduction
D) stop therapy with high-dose Ara-C. Find an alternative consolidation therapy.
E) None
Answer D
If the patient develops cerebellar toxicity with cytarabine, then the high-dose Ara-C should be immediately stopped. One should not try to rechallenge the patient with this medication for future cycles. Going forward for this patient, could consider performing a consolidative autologous transplant as he cannot receive further high-dose Ara-C. He has had one cycle of high-dose Ara-C therapy and there is data on the effectiveness of autologous transplant as consolidation therapy for AML patients who have good risk cytogenetics. Be very careful in giving any patient high-dose Ara-C if they have renal failure. Neurotoxicity occurred more commonly in patients treated with twice daily dosing of Ara-C if they had renal insufficiency.
A 49-year-old presents with a recent diagnosis of AML. He is status post standard induction therapy with cytarabine + anthracycline (7+3 therapy) and underwent a unilateral bone marrow biopsy 7 days following his last dose of treatment which showed a complete response to induction therapy. At the time of his original diagnosis, he demonstrated t(8;21)(q22;q22.1) in the RUNX1-RUNX1T1 genes. Based on the above information, will be a recommendation for his next step in therapy?
A) additional course of induction therapy
B) high-dose cytarabine consolidation therapy
C) matched sibling or alternative donor hematopoietic cell transplantation
D) performed polymerase chain reaction
Answer B
In patient's with AML, under the age of 60, and classified as favorable risk at the time of diagnosis who are status post induction chemotherapy with bone marrow biopsy demonstrating a complete response should proceed with consolidation high-dose cytarabine chemotherapy. Core binding factor leukemias are more common in younger patients and have shown favorable outcomes with cytarabine based consolidation alone without allogeneic hematopoietic cell transplantation.
Name two poor-risk cytogenetics
1) t (6;9)
2) t (v;11q23.3); KMT2A rearranged
3) t (9;22); BCR-ABL1
4) inv (3) or t(3;3)
5) -5 or del(5q); -7; -17/abn(17p)
6) Wild type NPM1 and FLT3-ITD (high)
7) Mutated RUNX1
8) Mutated ASXL1
9) Mutated TP53
10) complex (>3 clonal chromosomal abnormalities)
11) Monosomal karyotype
MOA of Glasdegib
Hedgehog inhibitor