HO Questions Flashcards
What is the single strongest prognostic factor in acute lymphoblastic leukemia (ALL)?
a. Age
b. Initial WBC count
c. Sex
d. Early treatment response as assessed by minimal residual disease (MRD) at end of induction therapy
e. Presence of CNS leukemia (CNS3)
Answer D is correct. Multivariate analyses consistently show that end induction MRD is the strongest prognostic factor in ALL. Age (answer A) and initial WBC count (answer B) remain prognostic but are not as powerful as MRD in multivariate analyses. Sex (answer C) remains prognostic of outcome in very large trials, with boys having inferior outcome to girls; however, sex is of only limited prognostic significance, with relative risks of 1.1 to 1.2 (which cannot be detected unless a very large number of patients is analyzed). CNS involvement (answer E) is prognostic of outcome in some but not all contemporary trials. It is more important as an indicator of a need for more CNS-directed therapy than as a prognostic factor.
Novel immunotherapeutics currently are being used in acute lymphoblastic leukemia (ALL) therapy, including bispecific T-cell engaging therapies. Cytokine release syndrome is a known complication of this therapy. What cytokine is associated with the acute onset of the inflammatory response seen in this acute complication?
a. IL-7 b. C3 c. IL-6 d. IL-4 e. IL-3
Answer C is correct. Abnormal macrophage activation can occur in the context of blinatumomab therapy, particularly in the setting of high disease burden. Cytokine release syndrome (CRS) is best managed with supportive care. Laboratory values consistent with hemophagocytic lymphohistiocytosis include elevated ferritin, cytopenias, and hypofibrinogenemia. Elevated levels of IL-6 are associated with CRS and the use of tocilizumab, an IL-6 receptor antibody, can ameliorate the symptoms. IL-7 (answer A) is a signaling molecule involved in B-cell differentiation. C3 (answer B) is not generally assessed in CRS. IL-4 (answer D) induces differentiation of naive helper T cells to Th2 cells. IL-3 (answer E) promotes development of myeloid progenitor cells through binding of the IL-3 receptor.
A 17-year-old boy presents with a 1-week history of cough and increasing shortness of breath. His pediatrician notes decreased breath sounds bilaterally and obtains a chest x-ray, which shows an anterior mediastinal fullness. He is transported to your hospital and has a CBC showing a white blood cell count of 180,000/dL with less than 50% circulating blasts. His coagulation parameters are also abnormal, with an international normalized ratio (INR) of 1.8 and a partial thromboplastin time (PTT) of 40 seconds. Immunophenotyping demonstrates an early T-cell precursor subtype. Which of the following characteristics portends the worse prognosis for this patient?
a. High presenting white blood cell count
b. Age at presentation
c. Abnormal coagulation tests
d. Persistent disease at the end of consolidation therapy
e. Early thymic precursor (ETP) immunophenotype
The correct answer is D. There is no prognostic significance to age or presenting white blood cell count for patients with T-cell acute lymphoblastic leukemia (ALL). It is common to see anterior mediastinal masses in T-cell ALL, and coagulopathies are common and can sometimes cause delays in diagnostic lumbar punctures. When first reported, the early thymic precursor (ETP) phenotype was considered a poor prognostic factor in retrospective studies, but more recently presented data do not support that ETP ALL represents a subtype of T ALL with a worse prognosis. However, as with other ALL subtypes, response to therapy is one of the most important predictors of future relapse. For T-cell ALL, end induction (also known as time point 1 in some European studies) minimal residual disease is not as prognostic as end consolidation (also known as time point 2 in some European studies).
A newly diagnosed patient with acute lymphoblastic leukemia (ALL) has a twin. Which of the following circumstances are associated with the highest risk for ALL development in that twin?
a. A 3-year-old boy with ALL and ETV6-RUNX1 (TEL-AML1) fusion who has an identical twin brother b. A 6-month-old boy with ALL and KMT2A::AFF1 (KMT2A::AF4) fusion who has a twin sister
c. A 6-year-old boy with ALL and MLL-AFF1 (MLL-AF4) fusion who has an identical twin brotherA 6-year-old boy with ALL and KMT2A::AFF1 (KMT2A::AF4) fusion who has an identical twin brother
d. A 6-month-old boy with ALL and KMT2A::AFF1 (MLL::AF4) fusion who has an identical twin brother
e. A 2-year-old boy with ALL and TCF3::PBX1 (E2A::PBX1) fusion who has an identical twin brother
Answer D is correct; the concordance rate for leukemia is highest for identical twins diagnosed in the first year of life. The concordance rate is about 50% in the first year of life and drops to a very low percentage by age 5 years. Concordance occurs because of in utero twin-to-twin transfer of either overt leukemia cells or cells with an initiating leukemia event (typically a translocation), with new secondary events acquired independently in each twin. Because 75% to 80% of infants with ALL have KMT2A translocations, most but not all cases of concordant ALL in twins are associated with KMT2A translocations. ETV6::RUNX1 and KMT2A translocations typically occur in utero in patients diagnosed with leukemia in the first few years of life; the identical twins of the patients in answers A and C are at some risk at 3 (A) and 6 (C) years, but probably only 5% to 10% for A and a very low risk for C. The twin of the patient in answer B is fraternal and at much lower risk than the identical twin in answer D. TCF3::PBX1 is much less likely to occur in utero than ETV6::RUNX1 and KMT2A translocations, so the twin of the patient in answer E is at low but not zero risk.
A mother brings her 3-year-old son to the emergency department for excessive bruising. She gave him a bath before bedtime on Sunday night, and he was fine. On Monday morning, when she dressed him, she noticed tiny red spots on his skin. During the day, he developed extensive bruising without known trauma. He is otherwise well, has no fever, and has been playing happily. He is described as being very active and always climbing on things. He has a prior history of a humerus fracture at 18 months and a femur fracture at 30 months.
What is the most likely explanation for this history?
a. Acute lymphoblastic leukemia (ALL)
b. Acute myeloid leukemia (AML)
c. Nonaccidental trauma
d. Idiopathic thrombocytopenic purpura (ITP) e. Viral infection
Answer D is correct. In cases of ITP, the parents often can describe exactly when the onset of petechiae and bruising occurred, and children typically are otherwise well. ALL and AML (answers A and B) are possible, but the acute onset of petechiae and bruising is evidence against these diagnoses. In addition, most children with newly diagnosed acute leukemia have other complaints such as bone pain, lethargy, irritability, and fever. Although the prior history of fractures raises concern about nonaccidental trauma (answer C), the factors above argue against this diagnosis, and a CBC should reveal isolated thrombocytopenia. Viral infections (answer E) can be associated with cytopenias, but one would not expect the child to be otherwise well.
The National Cancer Institute (NCI)/Rome risk factors are used to group patients with acute lymphoblastic leukemia (ALL) into standard- and high-risk groups. Which of the following patients has standard-risk ALL?
a. A 9-year-old boy with WBC count 45,000/μL and B-lineage ALL
b. An 11-and-a-half-month-old girl with WBC count 5,000/μL and B-lineage ALL c. An 11-year-old girl with WBC count 5,000/μL and B-lineage ALL
d. A 13-year-old boy with WBC count 5,000/μL and T-cell ALL
e. A 3-year-old boy with WBC count 55,000/μL and B-lineage ALL
Answer A is correct. Standard-risk patients are those with age 1.01 to 9.99 years and initial WBC count less than 50,000/μL. Patient B is an infant younger than 1 year. Patient C has high-risk ALL due to age greater than 10 years. The NCI criteria apply only to B-lineage ALL, and patient D has T-ALL. Patient E has high-risk ALL based on a WBC count greater than 50,000/μL.
A 13-year-old girl with relapsed acute lymphoblastic leukemia (ALL) is undergoing reinduction chemotherapy. She develops high fevers with neutropenia approximately 3 weeks into her course, and a CT scan of her chest demonstrates four isolated pulmonary nodules that are about 1 cm in dimension. Her galactomannan is positive. What is the most appropriate antimicrobial coverage for her?
a. Caspofungin
b. Voriconazole
c. Fluconazole
d. Nystatin
Answer B is correct. The empiric therapy of pulmonary nodules during febrile neutropenic episodes has been revolutionized by the availability of voriconazole, a triazole antifungal medication. Caspofungin is second-line for aspergillosis, fluconazole has no activity against aspergillus, and Zosyn or another antibiotic would have already been in use in this patient.
Which of the following patients is expected to have the best prognosis?
a. A 3-year-old boy with an initial WBC count of 2,000/mcL, ETV6-RUNX1 (TEL-AML1) fusion, and minimal residual disease (MRD) 0.14% at end induction
b. A 3-year-old girl with an initial WBC count of 2,000/μL, TCF3::PBX1 (E2A::PBX1) fusion, and MRD 0.04% at end induction
c. A 3-year-old girl with an initial WBC count of 9,000/μL, ETV6::RUNX1 (TEL::AML1) fusion, and MRD 0.07% at end induction
d. A 3-year-old girl with an initial WBC count of 2,000/μL, hyperdiploidy with trisomies of chromosomes 4 and 10, and MRD 0.04% at end induction
e. A 3-year-old girl with an initial WBC count of 9,000/μL, hyperdiploidy with trisomies of chromosomes 4 and 10, and MRD less than 0.01% at end induction
Answer E is correct. Age, sex, initial WBC count, blast cell genetics, and day 29 MRD response all are prognostic of outcome. Patients aged 2 to 6 years with a WBC count less than 10,000 have the best prognosis. All of the patients in this example fall into this category. Initial WBC is a continuous variable, but it is hard to parse out the difference between 2,000/μL and 9,000/μL. The most favorable genetic features are ETV6::RUNX1 (TEL::AML1) fusion (present in answers A and C) and hyperdiploidy with favorable chromosomes trisomies (with 4 and 10 being most important; present in answers D and E). However, MRD response is the strongest prognostic factor, with patients with MRD less than 0.01% clearly doing best (present only in answer E).
Which of the following characteristics excludes a diagnosis of B-cell precursor acute lymphoblastic leukemia (ALL)?
a. Presence of T-cell receptor gene rearrangements
b. Expression of cytoplasmic CD3
c. Expression of surface CD13/33
d. Mediastinal mass
e. WBC count greater than 500,000/μL
Answer B is correct. Cytoplasmic CD3 expression is a diagnostic criterion for T-cell acute lymphoblastic leukemia (T-ALL) and cannot be present in B-cell precursor ALL. T-cell receptor gene rearrangements (answer A) occur in B- precursor ALL and are often used to monitor minimal residual disease. CD33 expression (answer C) is common in B-cell precursor ALL. Both a mediastinal mass (answer D) and hyperleukocytosis (answer E) are much more common in T-ALL than in B-cell precursor ALL, but neither precludes a diagnosis of B-cell precursor ALL.
Which of the following factors is most prognostic for the highest-risk subgroup of infants younger than 1 year with acute lymphoblastic leukemia (ALL)?
a. CNS involvement
b. Initial WBC count 50,000/μL
c. NUTM1 translocations
d. Age younger than 3 months
e. KMT2A translocations and age younger than 3 months
Answer E is correct. The strongest prognostic factors in infants with ALL are age (younger than 3 months is worse than 3 months to younger than 6 months, which is worse than 6 to 12 months) and the presence of a KMT2A translocation. Infants with both age younger than 3 months and KMT2A translocations have an extremely poor outcome. CNS involvement (answer A) is much more common in infants with ALL than in older children, does not have prognostic significance. The average WBC count is much higher in infants than in older children with ALL, and most have a WBC count of 50,000/μL or greater (answer B). This (answer B) is of prognostic importance but is nowhere near as strong as age less than 3 months and MLL translocations. Some studies (Interfant-99) have found that WBC 300,000/μL or higher is a particularly poor prognostic marker. More recently, infants with NUTM1 alterations are found to have more favorable prognoses.
A 16-year-old Hispanic boy presents with fever, fatigue, and swollen glands. A CBC demonstrates a WBC count of
89,000/µL and cytogenetics revealed a t(Y;14)(p11;q32). Which of the following fusion genes is most likely to be
present?
a. MLL-AF9
b. BCR-ABL1
c. IGH-CRLF2
d. TCF3-PBX1
e. EWS-FLI1
Answer C is correct. The presence of a chromosome translocation in most or all cells generally is indicative of a
malignancy, although balanced translocations (Robertsonian translocations) can be seen in individuals without
malignancies. The IGH/CRLF2 rearrangement indicative of Ph-like acute lymphoblastic leukemia (ALL) is more
common in Hispanic adolescents and is associated with high expression of CRLF2. The locations of the other
fusion genes are not on chromosome 14 or chromosome Y. EWS-::FLI1 (answer E) is a fusion gene found in Ewing
sarcoma.
Which of the following chromosome translocations is most likely to be seen in pediatric T-cell acute lymphoblastic
leukemia (T-ALL)?
a. t(9;22)(q34;q11)
b. t(8;22)(q24;q11)
c. t(1;19)(q23;p13)
d. t(9;11)(q34; q23)
e. t(11;14)(p13;q11.2)
Explanation
Answer E is correct. The t(11;14)(p13;q11.2) fuses the T-cell receptor alpha/delta (TCRA/D) locus with LMO2,
which occurs in about 7% of pediatric T-ALL cases and does not appear to have prognostic significance. The
t(9;22)(q34;q11) or Philadelphia chromosome (answer A) occurs in about 4% of pediatric B-cell precursor ALL.
The Philadelphia chromosome is also seen rarely in T-ALL, but with a frequency less than 1%. The
t(8;22)(q24;q11) fuses c-MYC to the immunoglobulin lambda gene on chromosome 22 (answer B) and is a rare
recurrent translocation in Burkitt leukemia and lymphoma, not T-ALL. The t(1;19)(q23;p13) (answer C) creates
TCF3::PBX1 (E2A::PBX1) fusion and is seen in about 5% of B-cell precursor ALL cases. The t(9;11)(q34;q23)
(answer D) creates KMT2A::AF9 fusion and is seen commonly in acute myeloid leukemia and less commonly in Blineage ALL (especially infants).
A 15-year-old male with B-lineage ALL receives induction therapy. On day 24, he begins complaining of
abdominal pain and nausea. Serum lipase is 940 U/L, TB 3.0, DB 2.0, and AST 320. Abdominal ultrasound
demonstrated a swollen pancreas with some cystic structures. What induction chemotherapy likely caused this
constellation of findings?
a. Vincristine
b. Cytarabine
c. Asparaginase
d. Daunomycin
e. IT Methotrexate
he answer is C, asparaginase. Asparaginase is a key agent used to treat ALL. It depletes asparagine, a nonessential amino acid, in both lymphoblasts and healthy cells. While the exact mechanism of how asparaginase
causes pancreatitis is not fully known, there is a higher incidence of pancreatitis secondary to asparaginase in
older patients.
A 12-year-old boy has T-cell acute lymphoblastic leukemia (ALL) with an initial WBC count of 500,000/µL and
CNS3 status with CSF WBC 200/µL (100% blasts) and RBC 10/µL. The treatment regimen specifies that CNS
radiation should be given.
What would the proper radiation regimen consist of?
a. 2,400 cGy to whole brain, excluding the globes of the eyes, and 1,200 cGy to spine
b. 1,800 cGy to whole brain, excluding the globes of the eyes, and 1,200 cGy to spine
c. 1,800 cGy to whole brain, excluding the globes of the eyes
d. 1,800 cGy to whole brain, including the entire globes of the eyes
e. 1,800 cGy to whole brain, including the posterior halves of the globes of the eyes
Answer E is correct. Radiation therapy for ALL no longer routinely includes spinal radiation, which eliminates
answers A and B. The standard dosage for patients with clear CNS involvement (as present in this case) generally
is considered to be 1,800 cGy, with the target volume including the entire brain and meninges, including the
frontal lobe and posterior halves of the globes of eyes, with optic disc and nerve, extending superior to vertex
and posterior to occiput. Caudal border will be below the skull base at C2 vertebral level. Some groups (St. Jude,
UKALL, and DCOG) now believe that even patients with CNS3 involvement do not need CNS irradiation, but this is
not the majority opinion at this time.
Which of the following patients should not be treated with therapy used commonly for pediatric acute
lymphoblastic leukemia (ALL)?
a. A 10-year-old boy with a large mediastinal mass, pleural and pericardial effusions, normal peripheral
blood cell counts, and 3% T-lymphoblasts in the bone marrow
b. A 4-year-old girl with L2 morphology ALL with lymphoblasts expressing cytoplasmic mu heavy chains
c. A 3-year-old boy with ALL that expresses CD10, CD19, CD13, and CD33
d. A 20-year-old woman with B-precursor ALL and a white blood cell count of 40,000/µL
e. A 4-year-old boy with WBC count 45,000/µL, hepatosplenomegaly, and 50% lymphoblasts with deeply
basophilic cytoplasm and cytoplasmic vacuoles, surface kappa light chains, and a t(2; 8)(p12;q24)
Answer E is correct. Burkitt leukemia is defined by L3 morphology, with deeply basophilic cytoplasm and
cytoplasmic vacuoles and the presence of translocations that join the c-Myc locus at 8q24 to an immunoglobulin
heavy or light chain gene. The immunoglobulin kappa gene is located at 2p12. These patients require different
therapy than other patients with ALL and typically are treated in the same way as patients with advanced stage
Burkitt lymphoma using therapy that is intensive but short in duration and not including ALL maintenance
chemotherapy. The patient described in answer A has stage III T-cell lymphoma, which is typically treated the
same as is T-cell ALL. The patient described in answer B has pre-B cell ALL, and the patient described in answer C
has ALL with expression of myeloid markers. The latter is not unusual and not associated with an adverse
prognosis, so he should be treated like any other patient with ALL. The young woman described in answer D will
fare much better if treated on a pediatric rather than adult ALL protocol.
Your patient with acute myeloid leukemia (AML) is receiving an intensive course of chemotherapy with high-dose cytarabine. She has been neutropenic for 4 days, has developed severe mucositis, and is now hypotensive.
Which of the following is most likely to be isolated from this patient’s blood culture?
a. Pneumocystis jiroveci
b. Staphylococcus epidermidis c. Aspergillus fumigatus
d. Herpes simplex virus (HSV) e. Streptococcus viridans
Children with AML are at high risk of developing bacteremia and specifically S. viridans, also known as alpha hemolytic strep. The incidence increases significantly with mucositis or high-dose cytarabine in patients with AML, and they should be covered with empiric antibiotics used in each institution’s neutropenic fever guidelines. S. epidermidis is a common cause of bacteremia but is rarely associated with hypotension. Aspergillus can be seen in this population but typically in patients with longer periods of neutropenia, and it typically does not cause hypotension as a presenting symptom. Although HSV is associated with mucositis, hypotension is not a characteristic finding. Pneumocystis is not a common complication of AML therapy and is not specifically linked with this scenario. Other organisms with similar presentation not listed above include Staphylococcus aureus, and the gram-negative organisms and empiric antibiotic choices should also be directed against these organisms.
A 5-year-old boy presents with acute myeloid leukemia (AML) and a WBC count of 120,000/mm3. Cytomolecular genetics reveals a NUP98 fusion and all other testing is negative. She is treated with 10 days of daunorubicin, AraC, and etoposide for induction therapy. On day 30, a bone marrow aspiration shows 30% leukemic blasts. She enters remission after treatment with idarubicin, fludarabine, and high-dose AraC. She has no HLA-matched siblings, but an unrelated donor search reveals a large number of potential matches.
Which course of treatment is most likely to result in the best outcome?
a. Give one additional course of induction therapy followed by three more courses of intensification chemotherapy.
b. Perform an autologous hematopoietic stem cell transplant (HSCT) now.
c. Give one more course of intensification chemotherapy and then perform a matched unrelated donor
HSCT.
d. Give one more course of intensification chemotherapy and then 1 year of maintenance chemotherapy.
Patients with intermediate-risk AML who have residual leukemia after the first induction course have been shown to have a high risk of relapse with chemotherapy alone. Allogeneic HSCT is likely the optimal therapy in this setting. Continuing chemotherapy alone will be very unlikely to result in cure, and maintenance chemotherapy is not a standard component of most AML treatment protocols. Similarly, autologous HSCT is also unlikely to provide a curative approach to therapy, because of the potential for contaminating leukemia cells in the graft and the lack of a graft versus leukemia effect. Because it will take time to arrange an unrelated allogeneic donor, giving another course of chemotherapy to maintain remission followed by HSCT would be the best of the available treatments.
A family requests consultation with you after their 2-year-old boy with trisomy 21 recently is diagnosed with acute myeloid leukemia (AML). They are struggling with a decision whether to have their child treated, and, if they do agree to treatment, what it should include. The initial presentation included findings that the leukemia was positive for CD41 and CD61, fluorescence in situ hybridization was only positive for trisomy 21, the initial white count was 75,000/mm3, the liver and spleen were moderately enlarged, and the child is otherwise well and stable.
,br/>Based on current literature, what do you recommend that the regimen chosen should include?
a. Induction chemotherapy with anthracyclines and cytarabine, at least one course of intensive cytarabine,
and intermittent dosing of intrathecal cytarabine over the course of treatment
b. No therapy, because this will spontaneously resolve c. Low-dose cytarabine alone
d. Induction chemotherapy with anthracyclines and cytarabine, concluding with a bone marrow transplant if a sibling donor is available
e. Because of the poor prognosis in these children with this type of leukemia, only palliative treatment
This patient has the typical acute megakaryoblastic leukemia seen in children with Down syndrome. The patient’s age is younger than 4 years. Although the outcome for AML in children with Down syndrome who are younger than 4 years is favorable, it does require therapy, and therefore answers B and E are incorrect. Answer B, observation, is indicated in low- or moderate-risk transient myeloproliferative disorder (TMD), which is restricted to the first 90 days of life, and answer C would be appropriate in high-risk TMD. Studies have shown that the best outcome for a child with this presentation is seen with answer A. Remissions in children with Down syndrome treated with low-dose cytarabine are not sustained. Children with Down syndrome who received a matched sibling transplant actually had a worse outcome than those who received high-dose cytarabine during intensification.
A 7-year-old girl is found to have a white count of 55,000/mm3 with 20% neutrophils, 10% lymphocytes, and 70% blasts. Bone marrow aspirate and biopsy shows 75% blasts. The blasts on flow cytometry show CD33, CD13, and CD34 to be positive; CD7 to be minimally positive; and TdT, CD3 (surface and cytoplasmic), and CD10 to be negative.
Which of the additional testing options below is most important to further define risk-based therapy in this patient’s leukemia?
a. Cytogenetics/fluorescence in situ hybridization (FISH) for BCR-ABL1, iAMP21, and ploidy
b. Cytogenetics/FISH for inv(16) and t(8;21), and FLT3 mutation testing
c. WBC greater than 50,000/mm3, cytogenetics for ploidy, and immunohistochemistry for myeloperoxidase d. Cytogenetics/FISH for t(11;19) and +21, and sequencing for RAS mutation status
e. Cytogenetics/FISH for t(1;22) and trisomy 8, and sequencing for GATA1 mutation status
This patient’s bone marrow aspirate, biopsy, and flow cytometry are diagnostic of acute myeloid leukemia (AML). Therefore, the important prognostic factors on which initial risk stratification is based include favorable cytogenetics and molecular markers (inv(16), t(8;21), NPM1, CEBPA), unfavorable cytogenetics and molecular markers (monosomy 7, monosomy 5 or deletion 5q, FLT3-ITD high allelic ratio), and induction response. The other choices are prognostic for patients with acute lymphoblastic leukemia (answer A) or do not factor into prognostic classifications for AML (answers C through E).
A 12-year-old girl presents with a WBC count of 750,000/mm3 with 1% blasts and other immature myeloid cells at different stages of differentiation. Her only significant sign or symptom is abdominal pain and a “swollen belly.” The platelet count is 220,000/mm3, and the hemoglobin is 11 g/dL. The uric acid is 3.
What is the most likely diagnosis and optimal treatment for this patient?
a. Chronic myeloid leukemia (CML) in accelerated phase; treat with imatinib and hydroxyurea. b. CML in chronic phase; treat with imatinib.
c. Myelodysplastic syndrome transforming into acute myeloid leukemia (AML); treat with induction chemotherapy followed by family donor ablative bone marrow transplantation once remission is achieved.
d. CML in accelerated phase; treat with imatinib followed by matched family donor bone marrow transplantation.
e. AML; treat with induction chemotherapy.
The high WBC with a “normal” maturation of the myeloid lineage in the peripheral blood (including only a small percentage of myeloblasts) along with minimal symptoms, in this case due to splenomegaly, is most characteristic of CML in chronic phase. The normal platelet count and hemoglobin are also consistent with this. Accelerated phase CML is characterized by at least 10% but less than 30% leukemic blasts in the peripheral blood or bone marrow. In addition, thrombocytopenia with a platelet count of less than 100,000/mm3 usually accompanies accelerated phase CML. AML is usually associated with increased blasts, anemia, and thrombocytopenia without the “normal” maturation of the myeloid lineage observed on the peripheral smear. Imatinib (or a “second-generation” tyrosine kinase inhibitor, such as dasatinib or nilotinib) is almost always adequate initial therapy, which will result in an effective cytoreduction in chronic phase CML and, in a majority of cases, leads to a cytogenetic remission, although fewer molecular remissions are obtained. However, allogeneic hematopoietic stem cell transplant (HSCT) remains the only known curative therapy for CML at this time. Until more information about drugs such as imatinib is obtained, in terms of long-term follow-up, the role of allogeneic HSCT is controversial.
A 15-year-old boy presents for a follow-up visit for localized Ewing sarcoma of the pelvis. He was diagnosed 18 months ago and completed therapy 6 months ago. Therapy included 14 cycles of standard chemotherapy and radiation for local control. He was last seen 3 months ago and had negative scans and normal blood work. He presents today with recent onset of fatigue, a white count of 90,000/mm3, hemoglobin of 6.9 g/dL, platelets of 40,000/mm3, and hepatosplenomegaly. You suspect that he has therapy-related acute myeloid leukemia (AML).
Of the following, which chemotherapy drug is the most likely culprit, and which cytogenetic abnormality is most likely to be present in the leukemia?
a. Doxorubicin; monosomy 7 b. Etoposide; t(9;11)
c. Ifosfamide; t(9;11)
d. Etoposide; monosomy 7 e. Ifosfamide; monosomy 7
Therapy-related myeloid neoplasms (therapy-related myelodysplastic syndrome [t-MDS] or t-AML) are a dreaded, and fortunately rare, complication of treatment with chemotherapy. The two major classes of chemotherapy with the highest risk of t-MDS/AML are alkylating agents (eg, cyclophosphamide, ifosfamide) and topoisomerase inhibitors (eg, etoposide, doxorubicin). The t-MDS/AML arising from these two classes of agents typically differs in two important ways. First, t-MDS/AML arising after exposure to alkylators typically has a long latency (3 to 5 years) with a long preleukemic MDS phase, whereas that arising after exposure to topoisomerase II inhibitors typically has a short latency (6 to 18 months) with a more explosive presentation. Second, t-MDS/AML arising after alkylator exposure often carries high-risk cytogenetic lesions such as monosomy 7 or 5q-, whereas cases arising after topoisomerase II inhibitor exposure typically are most likely to harbor an MLL rearrangement, most commonly t(9;11). Given the short latency and rapid progression in this case, answer B contains the most likely etiology and cytogenetic results.
A 15-year-old girl has just been diagnosed with chronic myeloid leukemia, and you have initiated therapy with the tyrosine kinase inhibitor (TKI) imatinib at 400 mg daily.
What can you anticipate in this case?
a. Complete hematologic and cytogenetic remission within 1 month and resolution of splenomegaly within 6 months; you plan to continue imatinib for a total of 9 months.
b. Complete hematologic remission within 3 months, complete cytogenetic remission (CCyR) within 12 months, and major molecular response (MMR) within 18 months; monitor by peripheral blood RT-qPCR for BCR/ABL every 3 to 6 months while continuing imatinib indefinitely if MMR persists.
c. Complete hematologic remission within 2 weeks and cytogenetic remission within 4 weeks; you will monitor RT-qPCR for BCR/ABL monthly during the 1-year maintenance therapy with imatinib.
d. Complete hematologic remission within 6 months and CCyR within 12 months; after CCyR is achieved, you will discontinue RT-qPCR monitoring.
Initial response to TKI therapy is typically gradual and proceeds in the following order: resolution of splenomegaly and normalization of blood counts, cytogenetic remission of the marrow, and diminution of peripheral blood BCR/ABL by RT-qPCR to low or undetectable levels. The expected rate of this resolution is correct in answers B and D. Monitoring for recurrence is recommended by use of peripheral blood RT-qPCR, which is most sensitive. Thus, the correct answer is B. For now, the duration of imatinib or other TKI administration is thought to be indefinite, although ongoing adult long-term follow-up studies that include discontinuation of TKIs will shed more light on this.
A 3-year-old girl is referred to you for evaluation of thrombocytopenia. She has trisomy 21 and was noted to have transient myeloproliferative disorder as an infant, which resolved spontaneously without the need for chemotherapy. A bone marrow is performed, which demonstrates increased blasts and fibrosis. The immunophenotyping marker that is most likely to be positive is:
a. CD4 b. CD19 c. CD22 d. CD41 e. TdT
This patient with trisomy 21 and history of transient myeloproliferative disorder is at significant risk for developing acute myeloid leukemia, specifically acute megakaryoblastic leukemia (AMKL). Twenty percent of patients with Down syndrome and TMD will develop AML, which typically presents in the first 3 years of life with isolated thrombocytopenia or pancytopenia, and bone marrow fibrosis is often present. AMKL associated with Down syndrome has a superior prognosis compared to non-Down AMKL and is treated with less intensive chemotherapy than traditional AML. Answer A is incorrect because CD4 is associated with T-ALL. Answers B and C (CD19 and CD22) are B-cell markers, and answer D (TdT) is an immature lymphoid marker. The correct answer (D) is CD41, which is a megakaryocytic marker characteristic of AMKL, as are CD42 and CD61. Although patients with Down syndrome also have an increased lifetime risk of developing ALL, this question seeks to reinforce the association between TMD and AMKL in Down syndrome.
You have a new 15-year-old male patient with a white count of 28,000/mm3 and 11% myeloblasts, hemoglobin of 7.2 g/dL, and platelet count of 30,000/mm3. A bone marrow aspirate reveals 18% blasts that have Auer rods and are surface marker positive for CD33. You receive a call from the cytogenetics lab that the bone marrow karyotype is positive for t(8;21) in 17 out of 20 metaphases. Your staff asks whether this represents a diagnosis of acute leukemia in the current classification scheme for this type of hematologic malignancy.
a. No, because for a diagnosis of acute leukemia you must have 30% or more blasts in the marrow. b. No, because for a diagnosis of acute leukemia you must have 20% or more blasts in the marrow. c. No, because the cytogenetics do not include +21, monosomy 7, or trisomy 8.
d. Yes, because Auer rods are present.
e. Yes, because the cytogenetics includes a characteristic AML-defining mutation.
The patient has a myeloid neoplasm by virtue of the presenting histochemical findings and cell surface markers. The current classification (ie, World Health Organization [WHO]) uses a minimum of 20% blasts in the marrow for a designation of acute myeloid leukemia (AML) versus myelodysplastic syndrome if there are fewer than 20% blasts. In the old French-American-British classification scheme, this cutoff had been 30% or more for a diagnosis of AML. A crucial feature of the WHO classification is that a patient need not have 20% blasts in the marrow for a diagnosis of AML if they have one of the classic AML cytogenetic findings by conventional karyotype or by fluorescence in situ hybridization (ie, t(8;21), t(15;17), inv(16), 11q23 translocation (KMT2A rearrangements), NPM1 mutations, MECOM, NUP98 rearrangements).
You are seeing a 19-year-old man who was diagnosed with chronic myeloid leukemia 2 years ago. He has been taking imatinib 400 mg daily since diagnosis. He has no siblings, but there are multiple potential matched unrelated donors in the registry. He has been fully compliant with his imatinib, and side effects have been minimal. Bone marrow and peripheral blood 6 months after the patient began imatinib were negative for BCR- ABL 1 by fluorescence in situ hybridization (FISH), and FISH in peripheral blood has remained negative up until the 21-month check. Peripheral blood qRT-PCR for BCR-ABL 1 was 0.03% (international scale) 1 year after the patient began imatinib and has remained less than 0.1% up until the 21-month check. On 24-month testing, however, peripheral blood FISH is positive at 6% and qRT-PCR is positive at 11.3%. Blood counts remain normal.
What is your next step?
a. Immediately finalize a matched unrelated donor and proceed to transplant.
b. Increase the imatinib dosage to 800 mg daily.
c. Add interferon to imatinib.
d. Send peripheral blood for ABL resistance mutation testing and switch from imatinib to dasatinib.
This patient has developed secondary resistance to imatinib after achieving a complete cytogenetic and major molecular response. Although increasing the imatinib dosage has been effective for some patients in this situation, the second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib are more likely to reestablish an optimal response. ABL sequencing to detect resistance mutations can help guide alternative TKI choice. For example, patients with T315I mutations should receive ponatinib. Although stem cell transplant with a suitable donor may be indicated if alternative TKI therapy proves ineffective, proceeding straight to transplant in this setting would be premature. Interferon rarely has been used since the advent of TKI therapy because of an unfavorable side effect profile.
A 13-year-old Hispanic girl is found to have an elevated white count of 25,000/mm3 with 80% Auer rod-containing granular blasts that by flow cytometry express very bright CD33 but are negative for human leukocyte antigen- DR isotype. Marrow aspirate shows nearly 100% replacement with blasts. The fluorescence in situ hybridization lab calls you to report that they have evidence of a PML-RARA translocation in the leukemic blasts.>br/>
How do you plan to initiate therapy?
a. Perform a lumbar puncture to determine leukemic involvement because of its high risk in this phenotype, then proceed with induction chemotherapy and all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapy followed by bone marrow transplant in first remission.
b. Determine whether coagulopathy is present before obtaining CSF, then start therapy with ATRA, ATO, and chemotherapy on day 1.
c. Start ATRA alone, then begin ATO and chemotherapy days later, followed by bone marrow transplant in first remission.
d. Start induction chemotherapy alone, obtain HLA typing, and start a donor search because of the poor prognosis associated with this leukemic phenotype in association with the high white count.
e. Use ATRA and ATO alone, because the patient’s low white count in this phenotype indicates a good prognosis without the need for conventional chemotherapy.
This represents a diagnosis of acute promyelocytic leukemia (APL; M3 in the French-American-British classification), which has an overall favorable prognosis because of its high event-free survival rates with ATRA, arsenic trioxide, and, in high-risk cases, chemotherapy. Thus, stem cell transplant is not indicated in first remission. However, the white count is greater than 10,000/mm3 at diagnosis, suggesting a higher risk APL rather than lower risk. Although ATRA has made dramatic improvements in APL outcome, its use as a single agent sustains remission for only a limited period of time before patients relapse. Until recently, chemotherapy was also thought to be necessary for sustained remissions. Recent data have indicated that prolonged remissions may be possible in lower risk cases with ATRA and arsenic trioxide alone. Differentiation syndrome is a complication of using ATRA alone when the white count is high and should be used concurrently with chemotherapy for patients with initially high white counts. Otherwise, ATRA may be started alone, followed in a few days by traditional chemotherapy. Coagulopathy due to disseminated intravascular coagulation is present in a high percentage of patients with APL, and therefore this should be evaluated before performing a lumbar puncture to avoid the risk of bleeding. Also, central nervous system disease is rare in APL.
A 1-month-old boy presents with bruising, pallor, poor feeding, and lethargy. He is noted to be tachypneic and hypoxic and has a diffuse interstitial infiltrate on chest X-ray. CBC reveals a WBC count of 650,000/mm3 (95% myeloblasts), hemoglobin of 7 g/dL, and platelet count of 36,000/mm3.
What is the most likely cause of the infiltrate and respiratory symptoms and the most appropriate initial treatment?
a. Hyperleukocytosis; initiation of induction chemotherapy
b. Hyperleukocytosis; leukapheresis or manual exchange transfusion and initiation of induction
chemotherapy
c. Respiratory syncytial virus bronchiolitis; ribavirin d. Mycoplasma pneumonia; azithromycin
e. Reactive airway disease; prednisone and albuterol
WBC counts greater than 100,000/mm3 are associated with the clinical syndrome of hyperleukocytosis, especially when the cause of the elevated white count is acute myeloid leukemia. Clinical features of hyperleukocytosis can include CNS findings (eg, lethargy, focal neurologic deficits, intracranial bleeding, hemorrhagic stroke), respiratory findings (tachypnea, dyspnea, hypoxia, and diffuse interstitial infiltrates), and renal dysfunction (often complicated by concomitant tumor lysis syndrome). The pathophysiology of hyperleukocytosis includes increased viscosity of blood and resultant congestion within the capillary beds of the affected organs. Hyperleukocytosis is a medical emergency that requires immediate “debulking” of the circulating tumor burden, which is best accomplished by manual exchange transfusion or by leukapheresis. Initiation of chemotherapy should proceed as soon as possible but should not be the first step in management. The other choices are less likely in the clinical scenario presented.
An 18-year-old man has been newly diagnosed with acute myeloid leukemia with myelomonocytic characteristics and a marrow blast percentage of 33%. Cytogenetics reveals a 5q deletion. For this patient, what should the optimal therapy include?
a. An anthracycline, intensive cytarabine, and allogeneic hematopoietic stem cell transplant (HSCT)
b. Intensive cytarabine, an anthracycline, and 1 year of maintenance chemotherapy
c. An anthracycline, cyclophosphamide, etoposide, and HSCT
d. Four-drug induction, consolidation, interim maintenance, delayed intensification, and maintenance chemotherapy
e. HSCT without preceding chemotherapy
This patient has a diagnosis of acute myeloid leukemia (AML). The backbone of AML therapy includes the intensive administration of anthracyclines and cytarabine without maintenance therapy. Therefore, answers B, C, and D are not appropriate. Optimal therapy for a patient with AML and a high-risk cytogenetic abnormality such as monosomy 7, 5q deletion, or FLT3/ITD high allelic ratio includes remission induction and then allogeneic stem cell transplantation with the best available donor. Proceeding directly to HSCT with 33% blasts in the bone marrow (answer E) would be associated with a very high risk of relapse
Fluorescence in situ hybridization testing on the peripheral blood of a 3-month-old boy with newly diagnosed acute leukemia reveals rearrangement of the MLL gene at 11q23. Flow cytometry and morphology are consistent with acute myeloid leukemia (AML) with monocytic differentiation. The patient has an identical twin brother, who is currently asymptomatic, and three older healthy siblings. There is no family history of leukemia or other blood disorders.
What do you tell the family regarding the healthy twin?
a. The probability of the healthy twin developing AML is very low (less than 1%) and is no different from the risk of the older siblings developing AML.
b. The probability of the healthy twin developing AML is about 10%, and if he does develop AML, it will probably take years for the AML to develop.
c. The probability of the healthy twin developing AML is very high (more than 50%), but it will probably take years for the twin to develop AML.
d. The probability of the healthy twin developing AML is very high (more than 50%) and is likely to occur within weeks to months, so the twin should be followed very closely, with frequent (every 1 to 2 weeks) exams and blood work.
The concordance rate of leukemia in monozygotic twins is variable depending on the age that the first twin develops leukemia. In this case, the first twin was diagnosed in infancy and, like most infant leukemias, his was characterized by rearrangement of the MLL gene at 11q23. The concordance rate in such cases is very high (and therefore answers A and B are not the best answers), and typically the second twin develops leukemia within weeks to months of the first twin’s diagnosis (and therefore answer C is not the best answer). This indicates that infant leukemias typically initiate in utero (and so the preleukemic clone or fully leukemic clone is shared between the twins because of the common placental circulation that is commonly seen in monozygotic twins) and that preleukemic clones with MLL rearrangements are extremely likely to rapidly progress to full-blown leukemia. Answer B describes a situation in which the first twin was diagnosed in childhood rather than infancy. Answer A describes a situation in which the twins were dizygotic (fraternal), and the placental circulations were separate.
A 9-year-old boy enters the emergency room with a 1-week history of decreasing strength and numbness in his lower extremities along with midthoracic back pain. He has had no fever, bruising, or history of trauma. Examination reveals decreased strength in the lower extremities, reduced deep tendon reflexes, and downgoing toes. There is slight tenderness in the midthoracic region of his back. An MRI reveals a T6 paraspinal mass with spinal cord compression. A CBC reveals a WBC count of 28,000/mm3 with 23% circulating myeloblasts, a platelet count of 25,000/mm3, and a hemoglobin of 10 g/dL.
Which of the following choices is the most appropriate next step in the evaluation and treatment?
a. Urgent radiation oncology and neurosurgical consultation to address the paraspinal mass, followed by
diagnostic bone marrow aspiration
b. Flow cytometry of peripheral blood followed by appropriate chemotherapy regimen c. Diagnostic bone marrow aspiration followed by radiation to paraspinal mass
d. Flow cytometry of peripheral blood followed by radiation to paraspinal mass
e. Diagnostic bone marrow aspiration followed by appropriate chemotherapy regimen
This patient has acute myeloid leukemia (AML) that is complicated by a paraspinal chloroma (solid mass of AML cells). The clinical syndrome of spinal cord compression is a medical emergency that requires immediate local treatment (external beam irradiation or surgery). Steroid treatment is commonly initiated but is not as likely as emergent radiation to help and may cause unnecessary side effects. Thus, steroids should not be considered a substitute for radiation in this setting. The diagnostic procedures are important but must await the treatment of the medical emergency.
