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Acute Lymphoblastic Leukemia Case 1
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Author: Richard A. Larson
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A 70-year-old man presented with a white cell count of 46.5 × 109/L (60% blasts), hemoglobin of 95 g/L, and platelet count of 80 × 109/L and was diagnosed by fluorescence in situ hybridization (FISH) with Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). The molecular analysis predicted expression of P190. The immunophenotype showed expression of CD19, CD22, CD10, and CD25. He is a one pack per day smoker and has coronary artery disease and hypertension.
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In addition to intrathecal methotrexate, which of the following would you recommend for remission induction?
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Several large multicenter trials have shown high complete response rates (>95%) using only dasatinib and dexamethasone as remission induction therapy for older adults with Ph+ ALL. Many of these patients have also achieved deep molecular responses without requiring cytotoxic chemotherapy. Ponatinib has been associated with vascular adverse events, including myocardial infarction, strokes, and peripheral vascular disease, and these are more common in patients with preexisting cardiovascular risk factors. HyperCVAD includes doxorubicin, which is known to have cardiovascular toxicity. Chemotherapy for this patient may not add to the benefit achieved with the combination of a tyrosine kinase inhibitor and glucocorticoids alone.
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Acute Lymphoblastic Leukemia Case 2
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Author: Richard A. Larson
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A 35-year-old Hispanic woman presented with a white cell count of 65 × 109/L (92% blasts), hemoglobin of 102 g/L, and platelet count of 45 × 109/L. The immunophenotype showed expression of CD19, CD20, CD22, CD34, terminal deoxynucleotidyl transferase (TdT), and CRLF2. Fluorescence in situ hybridization (FISH) for BCR/ABL1 was negative. Cytogenetics showed a normal karyotype. Molecular studies showed a cryptic translocation of CRLF2 with the IGH gene. A mutation in JAK2 was identified by next-generation sequencing.
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The immunophenotype indicates a Ph-like B-cell ALL; there is no expression of myeloid or T-cell markers. Ph-like B-cell ALL lacks the BCR-ABL1 fusion or t(9;22) by cytogenetic, FISH, or molecular analyses, but it shares the same gene-expression profile with typical BCR-ABL1–positive ALL. In half of these patients, the CRLF2 gene is involved in a cryptic translocation with the IGH gene or is fused to the P2RY8 gene; both rearrangements lead to overexpression of CRLF2. Mutations in JAK2 or JAK1 are detected in 30% to 40% of these patients, and many of the remaining have activating mutations in cytokine receptor and kinase signaling pathways. Ph-like ALL is a high-risk subset of ALL.
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Acute Lymphoblastic Leukemia Case 3
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Author: Richard A. Larson
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A 55-year-old woman has precursor B-cell ALL with a normal karyotype that has relapsed after 3 years in remission. Her white cell count is 24 × 109/L (65% blasts), hemoglobin is 116 g/L, and platelet count is 130 × 109/L. Flow cytometry shows expression of CD19, CD20, CD10, and CD52. There was no expression of CD22 or myeloid or T-cell markers. She has no comorbidities and a good performance status. She has a human leukocyte antigen–matched sibling.
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In addition to intrathecal methotrexate, which of the following would you recommend?
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This patient had a long first remission and is likely to achieve a second remission after which she should undergo an allogeneic hematopoietic cell transplant using her sibling as the donor. Blinatumomab has a high rate of inducing remissions in patients with relapsed ALL with a low incidence of significant toxicity. It will not interfere with a subsequent transplant. Her ALL blasts do not express CD22, the target for inotuzumab, which has also been approved for relapsed ALL. When used as single agents, rituximab (antiCD20) and alemtuzumab (antiCD52) have minimal activity against relapsed ALL. Liposomal vincristine is approved for third line treatment of ALL; neurotoxicity is its major adverse effect.
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For a more detailed discussion, see Chapter 90 in Williams Hematology, 10th edition.
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Chronic Lymphocytic Leukemia Case 1
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Authors: John C. Byrd; Adam S. Kittai; Farrukh T. Awan
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A 72-year-old man of European descent had a routine medical examination as a prelude to taking out a life insurance policy. He had well controlled hypertension for the previous 10 years and was taking a calcium channel blocker. He was otherwise completely well. His father had been diagnosed with chronic lymphocytic leukemia (CLL) at age 75 years and died at the age of 78 years from a cerebrovascular event. Clinical examination was normal with no lymphadenopathy or organomegaly.
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A blood test taken at the time of the insurance medical revealed a hemoglobin of 14.3 g/L, a WBC of 10.7 × 109/L, a neutrophil count of 2.9 × 109/L, a lymphocyte count of 6.9 × 109/L, and a platelet count of 270 × 109/L. The urea and electrolytes, liver function tests, and calcium and phosphate estimations were all normal
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Immunophenotyping of the blood lymphocytes showed that 33% were CD3 positive with a normal CD4:CD8 ratio, and 59% were CD19 positive. These B cells exhibited weak expression of CD20 and CD79b and showed light chain restriction (96% of B cells expressed surface κ light chains).
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Which of the following is correct?
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A more extended B-cell immunophenotype is likely to show
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A. CD5+, CD23+, and CD10+.
B. CD5+, CD23-, and CD10-.
C. CD5+, CD23+, and CD10-.
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Which of the following is not correct?
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A. A bone marrow biopsy is always required before a diagnosis of MBL is made.
B. It is more common in males.
C. The rate of progression to CLL is approximately 1-2% per annum.
D. Patients with MBL are often mildly immunosuppressed.
E. Patients with MBL have a higher rate of secondary malignancies.
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MBL is a precursor state to CLL. It is defined as a clonal expansion of B cells in which the B-cell count in the blood is less than 5 × 109/L; there are no cytopenias, no lymphadenopathy, or organomegaly; and the patient is asymptomatic. In this patient's case, although the lymphocyte count is 6.9 × 109/L, the B-cell count is 4.1 × 109/L in accord with the diagnostic criteria for MBL. This case is an example of "high-count MBL" by virtue of the B-cell count being greater than 0.5 × 109/L. MBL is rarely found in individuals younger the age of 40 years, but it is progressively more common at ages over that. Some studies suggest that it can be found in nearly three-quarters of individuals older than the age of 90 years if a sensitive threshold is used for identification of B-cell clones. It is particularly common in individuals with a family history of CLL as with this patient.
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The most common phenotype of MBL is the same as typical CLL namely CD19+, CD20dim, CD5+, CD23+, and CD10-.
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A bone marrow biopsy is not usually necessary when the phenotype of the lymphocytes is "CLL-like." Most, but not all, studies show an increased incidence in males. The rate of progression is about 1% per year but is higher (~2%) in those patients, such as this one with "high-count MBL." Although patients with MBL usually have normal immunoglobulin, levels there is an increased risk of serious infections. There is also an increased risk of second malignancies.
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This patient was reviewed several times at 6-month intervals, and because there was no change in blood counts or physical findings, yearly review was instigated. He remains well 5 years since diagnosis.
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Chronic Lymphocytic Leukemia Case 2
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Authors: John C. Byrd; Adam S. Kittai; Farrukh T. Awan
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A 76-year-old woman of European descent presented to her family doctor complaining of a recent lack of energy and enlarging lymph nodes in the neck, axillae, and groin. She otherwise considered herself to be very fit for her age. There was no relevant past medical or family history. She was on no medications. On examination, there was disseminated lymphadenopathy with the largest nodes measuring 5 cm in size. The liver was not palpable, but the spleen was palpable 4 cm below the costal margin.
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The Hb was 98 g/L, the WBC was 55.1 × 109/L, neutrophil count was 2.6 × 109/L, lymphocyte count was 51 × 109/L, and platelet count was 94 × 109/L. A blood film was typical of CLL with abundant smear cells. Immunophenotyping revealed that the lymphocytes were CD19+, CD20 dim +, CD5+, CD23+, CD10-, sIg weakly positive with κ light chain restriction. Renal and liver function tests were normal as were the immunoglobulin (Ig) levels. There was a just detectable IgM paraprotein. Fluorescent in situ hybridization (FISH) revealed a deletion of chromosome 17p, and a mutation in the residual TP53 gene was subsequently found. The IGHV gene was also mutated. The β2M level was 2.9 mg/L.
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Which of the following are not indications for the initiation of therapy?
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A. Symptomatic disease
B. Progressive marrow failure with hemoglobin less than 100 g/L or platelets less than 100 × 109/L
C. Rise in lymphocyte count greater than 50% in 2 months or a lymphocyte doubling time of less than 6 months.
D. Hypogammaglobulinemia
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Which of the following is not an independent prognostic factors in CLL?
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Which of these treatments is most appropriate for this patient?
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Many patients, especially those with early stage disease, do not require treatment initially. Indications for treatment include symptoms such as significant fatigue, unintended weight loss greater than 10% in 6 months and persisting fevers or night sweats. Massive lymphadenopathy or splenomegaly or a rapidly rising lymphocyte count are deemed to be features of "active" disease and are also indications for therapy. An absolute lymphocyte count, rather than the rate of change, is not an indication for therapy. Anemia with a hemoglobin less than 100 g/L or a platelet count less than 100 × 109/L is generally considered to be an indication for treatment. Hypogammaglobulinemia is not an indication for therapy. This patient fulfils the criteria for initiation of therapy by virtue of the marrow failure.
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Despite advances in the molecular characterization of CLL, the clinical stage retains prognostic significance: either Binet stage A versus B and C or Rai stage 0 versus I–IV. Loss of chromosome 17p, which is usually associated with a mutation in the other TP53 allele is a poor prognostic factor whereas mutated IGHV status is a good prognostic factor. An elevated ?2M is a poor prognostic factor with the usual cut-off taken to be 3.5 mg/L. The leukocyte count is not prognostic.
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This patient thus has a mixture of good and poor prognostic factors: advanced age, advanced stage, and mutated TP53 are poor prognostic factors, whereas mutated IGHV and relatively low β2M are good prognostic features. These good prognostic features are, however, "trumped" by the TP53 status.
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Standard forms of chemotherapy are ineffective in patients with TP53 mutations, so ibrutinib or an alternative Bruton tyrosine kinase inhibitor is the treatment of choice. Idelalisib is more immunosuppressive than ibrutinib and is reserved for patients developing resistance or not tolerating ibrutinib. Venetoclax is another option in this situation.
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The patient was treated with ibrutinib and had a good response, although she did not achieve a complete remission (CR). After about 18 months, her nodes began to enlarge again, and her hemoglobin, which had normalized on therapy, began to fall. A mutation in the BTK gene (C481S) was discovered, which is a well-recognized cause of the development of resistance to ibrutinib. She has subsequently been treated with a combination of venetoclax and obinutuzumab and has again responded. This response has lasted 10 month so far.
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Chronic Lymphocytic Leukemia Case 3
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Authors: John C. Byrd; Adam S. Kittai; Farrukh T. Awan
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A 53-year-old man of Asian descent noticed enlarged lymph nodes in both sides of the neck 1–2 years previously, and these nodes had increased in size to about 3.0 cm in diameter. In addition, he had become aware of enlarged nodes, about 2 cm is size, in both inguinal regions. He also described discomfort in the left hypochondrium and was feeling nonspecifically unwell. On examination, he appeared to be anemic, and lymphadenopathy was noted, which included enlarged lymph nodes in both axillae. The largest node in the right axilla measured 4 cm in size. The liver was palpable 3 cm below the costal margin with a smooth edge, and the spleen was palpable 7 cm below the costal margin.
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The blood count showed a hemoglobin of 91 g/L, a WBC of 54.5 × 109/L with a neutrophil count of 1.9 × 109/L, and a lymphocyte count of 51 × 109/L. The platelet count was 99 × 109/L. The lymphocyte immunophenotype was CD19+, CD20dim+, CD5+ CD23+, CD10- FMC7-. Urea and electrolytes, liver function tests, and a calcium and phosphate level were all normal.
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Fluorescent in situ hybridization studies revealed a del(13q), which is associated with a good prognosis. There was no del(17), and sequencing revealed no mutation in the TP53 gene. The IGHV gene was mutated. The β2M was 1.9 mg/L. This patient fulfils criteria for initiation of therapy.
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What treatment would you recommend for this patient?
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Which of these are frequent complications (>1% of patients) of fludarabine therapy?
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A. Nausea and vomiting
B. Severe myelosuppression, which may be prolonged
C. Severe immunosuppression and consequent infections
D. CNS toxicity
E. Autoimmune hemolytic anemia (AIHA)
F. All of the above
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Which of these is not a frequent complication (>1% of patients) of ibrutinib therapy?
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A. Musculoskeletal pains
B. Myelosuppression
C. Unusual bruising or bleeding
D. Atrial fibrillation or flutter
E. Stevens-Johnson syndrome
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FCR is probably the optimal therapy for a relatively young patient such as this with good-risk disease. This is because there is a high response rate to FCR with a significant number of patients achieving deep and long-lasting CRs (possibly cures). An alternative is ibrutinib which is generally well tolerated but must be given for long periods. The response rate is very high, but deep CRs are not usually achieved. Very promising results have been reported with a time-limited venetoclax and rituximab combination, but follow-up is still too short for this to replace FCR as standard of care.
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Severe nauseas and vomiting can occur after fludarabine administration, but it is mild in most patients. Myelosuppression is usual and can in occasionally be prolonged for weeks or even months. Fludarabine causes severe T-cell depletion, and the marked immunosuppression can lead to opportunistic infections. Prophylactic antipneumocystis therapy and acyclovir are usually given during fludarabine therapy and for a period afterward. Fludarabine-induced CNS toxicity takes many forms. Headaches, general weakness, paresthesias, sleep disorders, and depression are all common. At higher doses than those usually used today, there were reports of blindness, coma, and even death. Autoimmune conditions, including AIHA and immune thrombocytopenia, are frequent after fludarabine therapy, possibly caused by depression of regulatory T cells. There is disagreement about the precise incidence. Anti-CD20 antibodies are useful if AIHA or immune thrombocytopenia occurs.
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Musculoskeletal aches and pains are common and probably occur in about one-third of patients. Myelosuppression is a common complication, but it can usually be dealt with by brief drug discontinuation and dose reduction. It should be noted, however, that discontinuation of ibrutinib can cause a "tumor flare." Abnormal bleeding is also common unrelated to a low platelet count. Atrial fibrillation and flutter are not infrequent, but the mechanism is not clear. Severe allergic reactions, including Stevens-Johnson syndrome, are rare events after use of ibrutinib.
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The patient achieved a deep CR with six cycles of FCR with no minimal residual disease as determined by polymerase chain reaction and flow cytometry. The patient has now been in remission for 3 years.
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For a more detailed discussion, see Chapter 91 in Williams Hematology, 10th edition.
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Hairy Cell Leukemia Case 1
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Authors: Michael R. Grever; Gerard Lozanski
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A 52-year-old man presented with recurrent cellulitis. His physician ordered blood counts that showed a WBC of 2.5 × 109/L with an absolute neutrophil count of 0.8 × 109/L. His hemoglobin was 85 g/L, and his platelet count was 89 × 109/L. His blood flow cytometry showed a monoclonal population of cells positive for CD20, CD11c, CD25, and CD103. His marrow biopsy was consistent with infiltration by hairy cell leukemia. He was treated with cladribine intravenously for 7 days. His therapy was complicated by febrile neutropenia, but this resolved on broad-spectrum antibiotic therapy, and his blood counts returned to normal over a period of several weeks. He continued to work for approximately 8 years with close medical follow-up. Over the past, year, his hemoglobin has remained within the normal range, but his neutrophil count declined to 2.2 × 109/L and his platelet count to 110 × 109/L. He was initially observed, and over several months, his neutrophil count declined further to 0.7 × 109/L and his platelet count to 68 × 109/L.
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In patients who have been successfully treated with either cladribine or pentostatin and subsequently achieve a second remission, the following statements are correct:
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A. A marrow biopsy is important to determine the extent of residual disease.
B. Second remissions are usually shorter than the first remission unless consolidated by rituximab.
C. After restoration of an absolute neutrophil count to greater than 1.5 × 109/L, prophylaxis for herpes zoster reactivation is not necessary.
D. Serial determinations of soluble IL-2 receptor can be used to follow the course of the disease.
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Achievement of a CR is associated with prolonged time to next treatment. If there is a substantial residual leukemia despite restoration of blood counts, consideration should be given to the possibility of more therapy. Rituximab administration after induction with a purine analog usually results in reduced residual disease. The sequence of administration of a purine analog and rituximab is under investigation. Ongoing studies will test whether rituximab should be administered simultaneously or sequentially with the purine analog. However, use of a purine analog alone for disease in relapse usually results in a shorter second remission. The risk for developing reactivation of herpes zoster after treatment for hairy cell leukemia is related to lymphocyte recovery after the purine analog, not the neutrophil recovery. Patients are often maintained on prophylaxis for herpes zoster reactivation for months after completion of antileukemic therapy. The soluble IL-2 receptor levels correlate with activity of the hairy cell leukemia. The level can be used to monitor response to treatment.
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Hairy Cell Leukemia Case 2
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Authors: Michael R. Grever; Gerard Lozanski
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A 55-year-old man was found to have abnormal blood counts on an annual medical check-up. His WBC was 3.9 × 109/L. His neutrophil count was 1.3 × 109/L. He had abnormal cells observed on his blood film. Although he was clearly monocytopenic, he had mononuclear cells that showed a rounded nucleus with gray cytoplasm with irregular shaggy borders. His platelet count was 130 × 109/L. Flow cytometry of his blood showed characteristic immunophenotypic markers of hairy cell leukemia (CD20+, CD11c+, CD25+, CD103+, CD123+). A marrow biopsy confirmed that he had classic hairy cell leukemia that was BRAFV600E+. He had mild enlargement of his spleen on ultrasound but not on physical examination.
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In distinguishing classic hairy cell leukemia from other splenic lymphoid malignancies, which of the following items are important?
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A. Identification of the BRAFV600E mutation in malignant cells
B. Monocytopenia on a blood film
C. Immunophenotypic profile of the malignant cells is CD20+, CD11c+, CD25+, CD103+, CD123+
D. All of the above
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If the blood counts fall to potentially dangerous levels, which of the following determinations are necessary before starting induction therapy with cladribine
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A. Is there evidence of ongoing infection?
B. Is serum creatinine within normal limits?
C. Is there serologic evidence of hepatitis B?
D. All of the above
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Approximately 90% of patients with classic hairy cell leukemia have a mutation in the BRAFV60+0E gene. Monocytopenia is a prominent feature of classic hairy cell leukemia and is probably a contributing factor to the increased incidence of infections. The use of immunophenotypic profiling is critical in determining the exact type of lymphoid malignancy.
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It is prudent to ensure that active infection is adequately controlled before administering induction with cladribine. Cladribine can induce prolonged and profound neutropenia. Therefore, if infection is not controlled before administration of this agent, the patient may experience life-threatening complications from infection. If it is necessary to treat the leukemia before infection has been eradicated, use of low-dose pentostatin has been successful. Interferon has also been used to improve the neutrophil count before administering a purine analog. Finally, some experimental success has been observed using vemurafenib in classic hairy cell leukemia in the face of infection. This "off-label use" of this inhibitor of BRAFV600E has been reported in case reports to improve the blood counts enabling control of infection, and then induction of a response in the leukemia can be later consolidated with standard therapy. Both cladribine and pentostatin are cleared by a renal route. Therefore, it is imperative to ensure normal renal function before their use. In patients receiving immunosuppressive therapy, there can be reactivation of hepatitis B with serious liver injury. If the patient is found to have had hepatitis B, it is advisable to consult with a hepatologist before administration of immunosuppressive agents.
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For a more detailed discussion, see Chapter 92 in Williams Hematology, 10th edition.
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Large Granular Lymphocytic Leukemia
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Authors: Jonathan E. Brammer; Anjali Mishra; Aharon G. Freud; Pierluigi Porcu
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A 61-year-old woman complained to her family doctor of pain in both knees on walking and having great difficulty, because of pain, in kneeling down and standing up again. There was no swelling of either knee, but there was some palpable crepitus on flexion of both knees. The knees were radiographed and showed narrowing of the joint spaces, subchondral sclerosis, and a small osteophyte on the medial aspect of the right knee. A diagnosis of osteoarthritis was made. There was no history of recent viral or other infections and no relevant previous or family history. Examination revealed no lymphadenopathy or hepatomegaly, but the spleen was palpable 2 cm below the costal margin
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The family doctor had also requested a number of blood tests, and these showed a hemoglobin of 127 g/L, a WBC of 5.9 × 109/L with a neutrophil count of 0.65 × 109/L, and a lymphocyte count of 5.1 × 109/L, and a platelet count of 180 × 109/L. Inspection of the blood film confirmed the neutropenia and revealed an increase in large granular lymphocytes (LGLs); the estimated LGL count was 1.3 × 109/L (reference range, 0.2–0.4 × 109/L).
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Urea and electrolytes, calcium and phosphate, and liver function tests were all normal. An autoantibody screen revealed a positive rheumatoid factor but no other autoantibodies. The immunoglobulin levels were normal, and there was no paraprotein.
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Referral was made to the local hospital hematology clinic, where a provisional diagnosis of large granular lymphocytic leukemia (LGLL) with associated neutropenia was made, and further investigations were ordered.
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If this is LGLL, what is the most likely phenotype of the abnormal lymphocytes
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A. CD3+, CD4-, CD8+, CD16+, CD56-
B. CD3+, CD4-, CD8+, CD16+, CD56-
C. CD3+, CD4-, CD8+, CD16-, CD56-
D. CD3- (surface), CD16+, CD56+
E. CD3- (surface), CD16-, CD56-
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Should this patient receive immediate therapy?
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Which therapeutic options should not be considered?
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Phenotype a is the most frequent form of LGLL, so called T-LGLL.
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Phenotype d is the second most common form of LGLL and is known as chronic lymphoproliferative disorder of natural killer cells (CLPD-NK). Both are clinically similar indolent diseases associated with immune neutropenia and anemia. CLPD-NK must be distinguished from the very aggressive acute NK cell leukemia (ANKL).
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The phenotype in this patient was CD3+, CD4-, CD8+, CD16+, CD56-. CD5 was also expressed but at a low level. The leukemic nature was confirmed by the demonstration of monoclonality by polymerase chain reaction analysis of the T-cell receptor γ chain.
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This patient does not meet the criteria for the initiation of treatment. She does not have severe neutropenia (<0.5 × 109/L), intermediate neutropenia (0.5 – 1.5 × 109/L) with recurrent infections, symptomatic anemia, marked thrombocytopenia (<50 × 109/L) or any autoimmune condition requiring therapy. Although her rheumatoid factor is positive, she does not have rheumatoid arthritis.
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The patient was followed up for 5 years with no change in the blood count. Subsequently, the neutrophil count dropped over a period of about 6 months to 0.1 × 109/L, and this was coincident with a rise in the lymphocyte count to 10.2 × 109/L. A decision was made to initiate therapy.
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Oral methotrexate or oral cyclophosphamide is used most frequently as initial therapy, and if these are ineffective, oral cyclosporine is often tried. Glucocorticoids may induce a response, but such a response is usually short-lived and therefore not used. A moderately intensive combination chemotherapy regimen, such as CHOP, is not appropriate because initial therapy in such an indolent disease in which the majority of patients will die with but not because of their T-LGLL. A peptide inhibitor of the interleukin common γ chain (BNZ-1), which is thought to work via inhibition of interleukin-15, may also be efficacious.
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This patient was treated with daily oral cyclophosphamide at a dose of 100 mg/day. Progressive improvement followed, and by 4 months, the full blood count was normal. The blood film still showed some LGL, and the polymerase chain reaction demonstrated the persistence of a population of clonal T cells. The cyclophosphamide was stopped, and the patient has remained in clinical remission for the past 3 years.
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For a more detailed discussion, see Chapter 93 in Williams Hematology, 10th edition.
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Hodgkin Lymphoma Case 1
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Authors: Michael A. Spinner; Eric Mou; Ranjana H. Advani
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A previously healthy 28-year-old man presents with an enlarging lump in his right neck, which he first noticed while shaving 6 months ago. He feels well without fevers, night sweats, weight loss, or pruritus. Physical examination shows a 3 × 3 cm right anterior cervical lymph node and multiple smaller 1 cm lymph nodes in the right neck. Excisional biopsy of the dominant right cervical lymph node shows classic Hodgkin lymphoma, nodular sclerosis subtype. Labs show normal blood counts, chemistries, and erythrocyte sedimentation rate (ESR). A baseline positron emission tomography/computerized tomography (PET/CT) scan shows hypermetabolic adenopathy in the right neck and mediastinum with no bulky disease sites and no evidence of disease below the diaphragm. A chest x-ray examination shows a mediastinal mass ratio less than 0.33.
++
Which treatment regimen would you recommend for this patient?
++
++
++
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This patient has early stage (IIA) favorable classic Hodgkin lymphoma by the National Comprehensive Cancer Network (NCCN), European Organisation for the Research and Treatment of Cancer (EORTC), and German Hodgkin Study Group (GHSG) criteria given age younger than 50 years, no B symptoms, normal ESR, and only two nodal sites (right neck and mediastinum) without bulky disease or extranodal involvement. Combined modality therapy is the standard of care for most patients with early stage disease based on numerous randomized trials and a meta-analysis demonstrating a small but significant progression-free survival (PFS) benefit compared with chemotherapy alone. For patients meeting the GHSG criteria for early stage favorable disease, the standard of care is two cycles of ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) + 20 Gy involved-site radiotherapy (ISRT) based on the randomized phase 3 GHSG HD10 trial. Mature follow-up of the HD10 trial confirmed the noninferiority of two cycles of ABVD + 20 Gy ISRT compared with four cycles of ABVD + 30 Gy ISRT for early stage favorable disease with excellent outcomes (10-year PFS and overall survival of 87% and 94%, respectively). If this patient was a young woman with axillary lymph node involvement, then a chemotherapy alone approach would be reasonable to avoid the risk of secondary breast cancer from radiotherapy.
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Hodgkin Lymphoma Case 2
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Authors: Michael A. Spinner; Eric Mou; Ranjana H. Advani
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A 23-year-old woman presents with 6 months of diffuse pruritus, drenching night sweats, 25-lb weight loss, progressive cough, dyspnea, and orthopnea. On examination, she is ill appearing with a frequent cough and is unable to lie flat. Laboratory studies are notable for a leukocytosis with white blood cell count of 20.4 × 109/L (88% neutrophils, 5% lymphocytes), Hgb of 118 g/L, platelet count of 420 × 109/L, albumin of 3.1 g/dL, and ESR of 65 mm/hr. A chest radiograph shows a large anterior mediastinal mass, and a CT scan of the chest shows confluent mediastinal and right hilar adenopathy measuring 13 × 11 × 5 cm with mass effect on the lower trachea. An endobronchial ultrasound (EBUS)–guided biopsy of the mediastinal mass shows classic Hodgkin lymphoma. A baseline PET/CT shows hypermetabolic adenopathy above and below the diaphragm along with hypermetabolic foci in the spleen.
++
Which treatment regimen would you recommend for this patient?
++
A. Two cycles of ABVD followed by four cycles of AVD if an interim PET scan is negative
B. Two cycles of escalated BEACOPP (bleomycin, etoposide, Adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) followed by four cycles of ABVD if an interim PET scan is negative
C. Two cycles of escalated BEACOPP followed by two additional cycles of escalated BEACOPP if an interim PET scan is negative
D. Six cycles of brentuximab vedotin + AVD
E. All of the above are appropriate treatment options
++
++
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This patient has advanced stage (IIIBSX) classic Hodgkin lymphoma with an International Prognostic Score (IPS) of 3 for leukocytosis, lymphopenia, and low serum albumin. All of the treatment regimens indicated are reasonable options for advanced stage disease and are supported by randomized phase 3 trial data.
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Option a is supported by the UK Risk-Adapted Therapy in Hodgkin Lymphoma (RATHL) trial. This trial showed than bleomycin can be omitted if an interim PET scan is negative (Deauville 1-3) after two cycles of ABVD. Options b and C are supported by the Advanced Hodgkin Lymphoma (AHL) LYSA and GHSG HD18 trials, respectively. In these trials, patients who had a negative interim PET scan after two cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) could have therapy deescalated to ABVD or receive only two additional cycles of escalated BEACOPP. In young women, escalated BEACOPP should be used with caution given the risk of sterility. Option d is supported by the ECHELON-1 trial, which showed a modest PFS benefit for brentuximab + AVD compared with ABVD. In a prespecified subgroup analysis, the PFS benefit was greater for patients with stage IV disease and high IPS scores of 4–7. Importantly, there was also more toxicity in the brentuximab + AVD arm, including a higher incidence of peripheral neuropathy and neutropenia mandating growth factor support. While all of the above regimens are options for advanced stage disease, the choice of therapy should be individualized based on the balance of efficacy and expected toxicity.
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Hodgkin Lymphoma Case 3
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Authors: Michael A. Spinner; Eric Mou; Ranjana H. Advani
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A 34-year-old man presents with a slowly enlarging lump in the left axilla, which he first noted several years ago. His general practitioner orders an ultrasound, which shows a 2.5- × 3.5-cm left axillary lymph node with two smaller adjacent 1-cm left axillary nodes. Excisional biopsy of the dominant left axillary node shows nodular lymph node architecture with scattered large atypical "popcorn cells" with prominent nucleoli embedded within B cell–rich nodules and with surrounding T-cell rosettes. The large atypical cells are strongly positive for CD20 and PAX5 and are negative for CD30, CD15, and EBER. The findings are consistent with nodular lymphocyte-predominant Hodgkin lymphoma. The patient is asymptomatic and has no other palpable adenopathy outside of the left axilla. A baseline PET/CT is ordered, and the biopsy slides are sent to an academic medical center for expert hematopathology review.
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Which of the following features if present would confer a worse prognosis for this patient?
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Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) typically presents with early stage disease with peripheral adenopathy and has an indolent course. Advanced stage disease is associated with inferior PFS and a higher risk of transformation to diffuse large B-cell lymphoma. Splenic involvement and histopathologic variant patterns C–F are poor prognostic factors, which are also associated with large cell transformation. Elevated ESR (option a) is not associated with prognosis in NLPHL.
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For a more detailed discussion, see Chapter 96 in Williams Hematology, 10th edition.
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Follicular Lymphoma Case 1
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Authors: Clémentine Sarkozy; Philippe Solal-Céligny; Guillaume Cartron
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A 42-year-old woman presented in July 2018 with a 1.5- × 2.0-cm enlarged left inguinal node, which she had first noticed 4 months earlier. She was single with two children and worked in a bank. She had no relevant previous history and was on no medications. She was asymptomatic and examination was otherwise normal. A needle core biopsy was performed, which demonstrated grade 1–2 follicular lymphoma (FL). Immunophenotyping showed positivity for CD20 and BCL2. Twenty% of cells were positive for Ki67. Her hemoglobin was 125 g/L, WBC was 7.5 × 109/L, neutrophil count was 4.4 × x109/L, and platelets were 285 × 109/L. The estimated creatinine clearance was 89 mL/min. An abdominal/pelvic computerized tomography (CT) scan revealed the presence of two left inguinal nodes (15 × 19 mm and 20 × 28 mm) without any other enlarged nodes.
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Which of the following do you consider as not mandatory to evaluate the anatomical extent of the disease?
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A. Marrow biopsy
B. Neck and chest CT scan
C. Lactate dehydrogenase (LDH)
D. Positron emission tomography (PET) scan
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Which of these therapeutic options do you think is most appropriate?
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A. Watch and wait (WW) approach
B. Radiotherapy of left inguinal area (42 Gray)
C. Radioimmunotherapy
D. Immuno-chemotherapy without anti-CD20 monoclonal maintenance
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A decision is made to defer treatment, with close follow-up. Which of the following statements is correct?
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A. Approximately 20% of patients in her situation will not have needed treatment 10 years after diagnosis.
B. There is no need of periodic assessment of disease by CT scan.
C. PET is the only examination to (reliably) detect progressive disease.
D. If inguinal nodes progress and there are no other signs of progression, low-dose radiotherapy (eg, 2 x 2 Gy) could be proposed.
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Cervical CT is also needed to complete imaging assessment. PET/CT is recommended to track a possible hidden transformation (ie, high SUV) that would be an indication for a second biopsy. Marrow infiltration needs to be assessed with a biopsy given that PET/CT is not sensitive enough in FL in the absence of transformation. Finally, the LDH evaluation is required to determine the FLIPI score but does not give accurate information about the anatomical extent of the disease.
++
The staging investigations confirm Ann Arbor stage I.
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The patient is asymptomatic, with nonbulky and noncompressive localized disease; therefore, WW is an option. Curative radiation could also be discussed because recent data showed long-term progression-free survival (PFS) for localized FL treated with radiation alone. However, 24-Gray and involved site radiation (ISRT) have been shown to be as effective and less toxic than higher doses and involved-field radiation therapy. Rituximab alone is also an option if the patient is not willing to undertake a WW strategy or has any contraindication to ISRT. Given the asymptomatic nature of the disease, chemotherapy would not be recommended.
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Around 20% of asymptomatic patients for whom a WW strategy is applied will remain treatment free 10 years after diagnosis. Annual CT scans are recommended for follow-up by some authorities, but PET/CT is not indicated in follow-up. However, if there is no clinical progression over an extended period, imaging could be omitted providing a clinical examination is carefully carried out at annual review. If inguinal nodes progress without other signs of disease progression, radiotherapy is an option but not with low-dose radiation (ie, 2 fractions of 2 Gy). Because the patient is receiving her first therapy, a potentially curative dose should be given (ie, 24 Gy).
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Follicular Lymphoma Case 2
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Authors: Clémentine Sarkozy; Philippe Solal-Céligny; Guillaume Cartron
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A 67-year-old woman presented in April 2017 with a massive swelling in the left parotid region. She also complained of feeling unwell for several months with intermittent low-grade fevers. She was retired and lived alone. She had moderate asthma and was taking a cysteinyl leukotriene receptor inhibitor. She also had heartburn for which she was taking lansoprazole. In the past, she had had an appendectomy and abdominal wall liposuction. Her Eastern Cooperative Oncology Group (ECOG) performance status was deemed to be 1.
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On examination, her temperature was 38 °C and a 100- × 40-mm mass was palpable in the left parotid region, with left-sided cervical lymphadenopathy measuring 100 × 70 mm and right-sided cervical lymphadenopathy measuring 40 × 50 mm. A left-sided 10- × 10-mm subclavicular node was also palpable. The spleen was just tippable, and there was no hepatomegaly.
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Laboratory investigations revealed hemoglobin of 120 g/L, WBC of 15.36 × 109/L, neutrophil count of 12.6 × 109/L, and platelet count of 410 × 109/L. Urea and electrolytes, calcium and phosphate, and liver function tests were all normal. The LDH was elevated at 438 IU/L (normal <214 IU/L) as was the β2M level at 5 mg/L (normal <2.8 mg/L). Serology for hepatitis and human immunodeficiency viruses were negative. The left ventricular ejection fraction was 65%.
++
A biopsy of the parotid mass was performed and revealed grade 1–2 FL. The immunostaining is shown in Figure 98–1A. The Ki67 stain was scored as 50% of cells positive.
++
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A marrow biopsy also showed infiltration by FL.
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The CT scan at diagnosis is shown in Figure 98–1B.
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The PET scan at diagnosis is also shown (Fig. 98–1C).
++
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Which of the following immuno-stains is usually positive in FL?
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A. CD5+
B. CD25+
C. CD10+
D. CD43+
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++
Which of the clinical, biological, or imaging factors do not suggest histologic transformation?
++
A. SUV max
B. LDH
C. BCL2 expression level
D. General symptoms
++
++
In case of unproven histologic transformation which of the following chemoimmunotherapy regimens would you suggest?
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A. Rituximab cyclophosphamide, vincristine, and prednisone (R-CVP)
B. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM)
C. Rituximab, cyclophosphamide, hydroxydaunorubicin (Adriamycin), vincristine (Oncovin), and prednisone (R-CHOP)
D. Rituximab, fludarabine, and cyclophosphamide (R-FC)
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FL cells typically express monoclonal surface immunoglobulin (IgM with or without IgD, IgG, or rarely IgA), B cell–associated antigens (CD19, CD20, CD22, and CD79a), BCL2, and usually BCL6 and CD10 but not CD5 or CD43.
++
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In this patient, a high SUV, LDH above the upper limits of normal, and B symptoms (fever of 38 °C) lead to a suspicion of histological transformation. BCL2 staining is positive in more than 80% of FL and not associated with transformation.
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In a patient with FL with suspected but not proven histologic transformation, either R-CHOP or BR could be given because these regimens are effective in both untransformed and transformed FL. R-CHOP is more efficacious than BR in proven transformed FL and is probably the treatment of choice in a patient with no contraindications to anthracyclines. R-FCM is not used when transformation is suspected. The relatively young age of this patient (67 years) and her good performance status should probably preclude R-CVP administration, which would be preferred for older adult and unfit patients.
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Follicular Lymphoma Case 3
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Authors: Clémentine Sarkozy; Philippe Solal-Céligny; Guillaume Cartron
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In 2017, an 82-year-old retired male cattle and sheep farmer presented with a lump in his right axilla. Seven years earlier, he had presented with an enlarged node in the right side of his neck, and stage II diffuse large B-cell lymphoma (DLBCL) had been diagnosed. He was treated with six cycles of full-dose rituximab, cyclophosphamide, hydroxydaunorubicin (Adriamycin), vincristine (Oncovin), and prednisone (R-CHOP). A complete remission was achieved, and after 3 years in remission, he was discharged from further follow-up. He lived with his wife, son, and daughter in-law.
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He had type 2 diabetes, had received four coronary artery stents for angina, and had mild heart failure. He had also been diagnosed with an adenocarcinoma of the prostate gland 5 years earlier, and this had been treated with external-beam radiotherapy.
++
His oral medications included bisoprolol 10 mg/d, perindopril 2.5 mg/d, aspirin 75 mg/d, metformin 500 mg × twice daily, and omeprazole 20 mg/d.
++
His ECOG score was deemed to be 1.
++
On examination, there was a mass in the right axilla measuring 7.0 × 5.0 cm. He also had an enlarged 3.0- × 0.30-cm node in the right inguinal region. There was no other palpable lymphadenopathy or hepatosplenomegaly.
++
Laboratory tests showed a hemoglobin of 110 g/L, WBC of 8.72 × 109/L, neutrophil count of 7.4 × 109/L, and lymphocyte count of 1.1 × 109/L. The platelet count was 375 × 109/L.
++
The serum LDH was 180 IU/L (normal < 214 IU/L), and the serum β2M level was raised at 3 mg/L (normal <2.8 mg/L). Electrolyte levels were normal, and the estimated creatinine clearance was 45 mL/min. Serology for hepatitis viruses and HIV was negative.
++
The left ventricular ejection fraction was 47%.
++
A biopsy of the axillary node revealed grade 1–2 FL positive for CD20 and BCL2. The Ki67 was scored as 15% positive.
++
A marrow biopsy also showed involvement by low grade FL cells. The CT scan at diagnosis is show in in Figure 98–2.
++
++
What is the Follicular International Prognostic Index (FLIPI) score for this patient?
++
++
++
What does the medical history of this patient suggest?
++
A. He exhibited transformed FL in March 2010 and then FL relapsed in 2017.
B. Type 2 diabetes is usually observed in patients with FL.
C. Exposure to carcinogens at work could have contributed to the development of his lymphoma.
D. A careful enquiry should be made seeking a familial lymphoma predisposition.
++
++
Which of the following treatment options for this patient results in a higher probability of PFS?
++
++
++
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This is based on a hemoglobin below 120 g/L, stage 3 and age older than 60 years.
++
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The history suggests de novo transformed FL in March 2010 and relapse of the FL component in 2017. According to the Interlymph Consortium, farmers are at more at risk of developing a lymphoma presumably because of pesticide exposure. The increased risk is seen in arable farmers but not in animal farmers. There is no reason to suspect familial predisposition in this case.
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In view of the time that has elapsed between treatment for a DLBCL and the emergence of FL, the patient should receive chemoimmunotherapy with an anti-CD20 antibody, either rituximab or obinutuzumab. The chemotherapy to be given could be CVP or bendamustine because an anthracycline cannot be administered. Maintenance with a CD20 antibody should also be considered. Overall, obinutuzumab–bendamustine for six cycles followed by obinutuzumab every 2 months for 2 years would probably give the best chance of long-term survival.
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For a more detailed discussion, see Chapter 98 in Williams Hematology, 10th edition.
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Mantle Cell Lymphoma Case 1
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A 56-year-old male executive, who considered himself to be fit, developed a cramp in his right hamstring while out jogging. While massaging the hamstring, he found a hard mass deep within the muscle. He saw his physician, who thought the mass was not a hematoma. The mass was 6 × 4 cm in size, and the physician arranged for it to be biopsied. The biopsy resulted in a referral to an oncologist, who also found a 2-cm node in the right inguinal region and 1-cm nodes in the left inguinal region and both axillae. The spleen was palpable 2 cm below the costal margin. There was no hepatomegaly. There was no relevant previous medical history, and he was taking no medications.
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The hemoglobin was 141 g/L and WBC 7.2 × 109/L, with a neutrophil count of 2.9 × 109/L and a lymphocyte count of 3.7 × 109/L. Urea, electrolytes, and liver function tests were normal. The lactate dehydrogenase (LDH) level was 128 IU/L (normal <214 IU/L). The core biopsies of the right hamstring mass indicated that it was mantle cell lymphoma (MCL).
++
What is most likely to be the immunophenotype of this tumor?
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A. CD20+, CD3-, CD5-, CD23-, BCL2-, BCL6-, CD10-
B. CD20+, CD3-, CD5+, CD23-, BCL2-, BCL6-, CD10-
C. CD20+, CD3-, CD5-, CD23-, BCL2+, BCL6-, CD10-
D. CD20+, CD3-, CD5+, CD23-, BCL2+, BCL6-, CD10-
E. CD20+, CD3-, CD5-, CD23+, BCL2+, BCL6-, CD10-
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++
Integrating the MCL international prognostic index (MIPI) with the Ki67 value (MIPIc), in which risk category does this patient reside?
++
++
++
Which therapy would you advise?
++
++
++
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MCL has an immunophenotype resembling the normal mantle zone of the lymph node. It is a B-cell malignancy (CD20+, CD3-) but expresses the CD5 antigen, which is normally expressed on T cells and only a minority of B cells. BCL2 is strongly positive. CD23 is not usually expressed, which helps differentiate this proliferation from chronic lymphocytic leukemia, another CD5+ B-cell malignancy. BCL6 and CD10 are markers of germinal center cells and are not usually expressed by mantle cells.
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In addition, the immunocytochemistry showed that the tumor cells were strongly surface immunoglobulin positive with light chain restriction, SOX11 positive, and expressed cyclin, D1 and 34% of the cells were Ki67 positive. Fluorescence in situ hybridization (FISH) revealed the presence of a t(11;14)(q13;q32).
++
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The MIPI is based on scores assigned for age, performance status, LDH and WBC. In this patient, the combined score is only 2 (1 point for age 50–59 years and 1 point for WBC 6.7–9.9 × 109/L), which is indicative of low-risk disease. The Ki67 percentage, however, exceeds 30%, which raises the risk category to low intermediate.
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The patient is relatively fit and young and should tolerate intensified immunochemotherapy, which should include an anthracycline because of the high Ki67 value, often alternating with a high-dose cytosine arabinoside regimen. The benefit of consolidation with an ASCT has been proven in a randomized trial in terms of progression-free survival, and a meta-analysis suggests that there is also an overall survival benefit.
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The patient received three cycles of a "mega-CHOP" regimen alternating with three cycles of high-dose cytosine arabinoside (Ara-C). This was consolidated with high-dose therapy and an autologous transplant. A complete remission was obtained and has been maintained for 6 years, but the patient should not be considered as cured.
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Mantle Cell Lymphoma Case 2
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An 81-year-old retired man presented with progressively enlarging lymph nodes in both sides of the neck and in the right axilla. He also complained of intermittent fevers, loss of appetite, and loss of weight, which proved to be 12% of his usual weight. On examination, his pulse was 82 beats/min and was irregularly irregular. His blood pressure was 145/ 80 mm Hg. He had enlarged lymph nodes in both sides of the neck, both axillae (right greater than left), and the femoral and inguinal regions. The largest node in the right submandibular region was 6 cm in diameter. The liver was palpable 2 cm below the costal margin, and the spleen was palpable 6 cm below the costal margin. He had a myocardial infarction 7 years earlier and he had chest discomfort and shortness of breath on climbing stairs, although was still able to participate in many of his usual activities. He had been told previously that he had mild renal failure. His medications were a statin, a β-blocker, and warfarin.
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The hemoglobin was 91 g/L, and the WBC was 8.2 × 109/L with a neutrophil count of 4.4 × 109/L and a lymphocyte count of 3.6 × 109/L. The creatinine was raised, and the estimated creatinine clearance was 29 mL/min. Liver function tests and calcium and phosphate levels were normal. The lactate dehydrogenase level was 230 IU/L (normal <214 IU/L).
++
An electrocardiogram confirmed atrial fibrillation and a previous myocardial infarct.
++
A cervical node was excised, and histology revealed a diffuse infiltration of small- to intermediate-sized lymphocytes with irregular cleaved nuclei, dense chromatin, and indistinct nucleoli. The immunophenotype was CD20+, sIg+, CD5+, CD23-, SOX 11+, and cyclin D1 positive. The proportion of cells staining positively with Ki67 was 11%. FISH revealed the presence of a t(11;14)(q13;q32). A diagnosis of MCL was made.
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This patient requires therapy. Which treatment regimen would you not recommend?
++
++
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What treatment would be appropriate now?
++
++
++
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R-CHOP is not well tolerated in a person of this age with significant comorbidities and is contraindicated with a history of a previous myocardial infarction.
++
This patient was treated with a low-dose bendamustine and rituximab regimen. This therapy caused some abdominal discomfort and diarrhea, but the treatment did not need to be interrupted. He had a good, albeit partial, response to this therapy and was started on a rituximab maintenance regimen. After 9 months, the nodes in the neck started to enlarge again.
++
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Having failed an immunochemotherapy regimen within a short time, a targeted therapy would usually be preferred. In most patients, the treatment of choice would be ibrutinib, which is particularly efficacious in cases with a low Ki67 score. However, he is taking warfarin because of his atrial fibrillation, and ibrutinib can cause an increased bleeding tendency. Ibrutinib can induce atrial fibrillation or flutter, but this is less of a concern because he is already fibrillating. Temsirolimus is usually given together with chemotherapy and is less effective on its own. Although the response rate to idelalisib is relatively high, the duration of response is usually short.
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The patient was treated with ibrutinib at standard dose with very close monitoring of the international normalized ratio to prevent overanticoagulation. He had a response that was again partial. The treatment was continued until has disease again progressed 10 months later. While decisions about further therapy were being considered, he died of a myocardial infarction.
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Mantle Cell Lymphoma Case 3
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A 69-year-old woman presented to her family physician with an infected ingrowing toenail. She had the same problem 8 years earlier. Antibiotics were prescribed. A blood test was also taken, and this revealed a hemoglobin of 110 g/L, a WBC of 21.8 × 109/L, with a neutrophil count of 2.2 × 109/L and a lymphocyte count of 19.1 × 109/L, and a platelet count of 140 × 109/L. The blood film confirmed the lymphocytosis, and most of the lymphocytes were of small size without conspicuous nucleoli. Occasional slightly larger cells contained cytoplasmic vacuoles. There were no smudge cells. The blood sugar was normal, as were the urea and electrolytes and the liver function tests. The lactate dehydrogenase level was 270 IU/L (normal <214 IU/L).
++
She was referred to the hospital hematology department, where examination revealed an enlarged spleen 7 cm below the costal margin. There were a few small nodes in the inguinal regions, all less than 1 cm in size. The immunophenotype of the lymphocytes in the blood was CD20+, sIg+, CD3-, CD5+, CD23-, SOX11-, cyclin D1+. Ki67 was 12%. FISH studies revealed the presence of a t(11;14)(q13;q32). There was no deletion of chromosome 17p. A diagnosis of MCL was made.
++
Which of the following statements about MCL is correct?
++
A. MCL is twice as common in males as in females.
B. Advanced disease at presentation is found in about 50% of patients.
C. Absence of cyclin D1 staining excludes a diagnosis of MCL.
D. Absence of SOX11 staining excludes a diagnosis of MCL.
++
++
How would you manage this patient?
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++
++
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MCL is twice as common in males overall, but in the leukemic variant, such as this, the sex ratio is more balanced. Advanced disease at presentation is found in about 90% of cases. Infiltration of the gut, often in the form of polyposis coli, is present in up to 60% of cases if a colonoscopy is performed, with symptomatic bowel disease being present in about 25%. Cyclin D1 expression is occasionally absent, and in these rare cases, there is usually overexpression of cyclin D2 or D3. SOX 11 staining, although sometimes useful in the diagnosis of MCL, is present in about 90% of cases, and negativity, as in this case, does not exclude the diagnosis.
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Although MCL is usually an aggressive form of lymphoma, in about 10% to 15% of cases, it follows an indolent course. The indolent form of the disease typically presents without lymphadenopathy but with splenomegaly and lymphocytosis. SOX11 is frequently negative in the indolent form of the disease. In this patient with no significant symptoms, non-nodal disease, SOX11 negativity, and no evidence of a TP53 abnormality (although TP53 sequencing had not been performed), watchful waiting is probably the most appropriate course of action providing the patient is happy with this approach.
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The patient is still being observed 2 years since diagnosis, and although the lymphocyte count has risen by 30%, the hemoglobin, neutrophil, and platelet counts are stable, and she remains asymptomatic.
++
For a more detailed discussion, see Chapter 99 in Williams Hematology, 10th edition.
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Marginal Zone B-Cell Lymphomas Case 1
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Authors: Alessandro Broccoli; Pier Luigi Zinzani
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A 58-year-old school principal presented to her family doctor with nonspecific epigastric pains, which were made worse by stressful situations and large meals. These pains had been present for about 1 year but had become worse in the past 2 months and were no longer responding well to the antacid lozenges that she had been taking. There was no other relevant history or family history. She was on no medications apart from an occasional aspirin for “stress headaches.”
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The physical examination was normal. Her family doctor started her on a trial of a proton pump inhibitor (PPI) and arranged to see her 3 weeks later. He also sent off some blood tests.
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The blood tests showed a hemoglobin of 113 g/L, a WBC of 7.8 × 109/L with a neutrophil count of 3.9 × 109/l and a lymphocyte count of 3.2 × 109/L, and a platelet count of 480 × 109/L. The MCV was 73 fL (reference range, 80–98 fL), and the blood film showed hypochromia and poikilocytosis. The serum creatinine, electrolytes, and liver function tests were normal.
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When she returned to her family doctor, she reported that the pain was a little better but had not gone away. In view of this and the probable iron deficiency, he referred her to a gastroenterologist. The gastroenterologist performed an upper gastrointestinal endoscopy and found nodularity of the stomach antrum with superficial erosions and two shallow ulcers. An additional ulcer was seen in the first part of the duodenum. Multiple biopsies of normal and abnormal mucosa were taken. These (including some of the biopsies from normal--appearing mucosa) showed an infiltrate of small to medium-sized lymphocytes with irregularly shaped nucleoli, dispersed chromatin, and inconspicuous nucleoli. There were scattered centroblasts and mature plasma cells and so-called lymphoepithelial lesions with invasion and necrosis of the glandular epithelium. Immunohistochemistry revealed that the abnormal cells expressed CD20, CD79a, CD21, and sIgM and were negative for CD5, CD23, CD10, and cyclin D1. These findings were indicative of marginal zone lymphoma (MZL). Fluorescence in situ hybridization revealed no chromosomal structural abnormalities. Further staging tests including a whole-body computerized tomography (CT) scan and a marrow biopsy showed no disease beyond the stomach. Thus, her disease was classified as stage IE. The lactic dehydrogenase (LDH) level was normal.
++
Which of the following statements about MZL is not correct?
++
A. Extranodal marginal zone lymphoma (EMZL) accounts for about 70% of all MZL cases.
B. Helicobacter pylori is found in the stomachs of more than 90% of patients with gastric EMZL.
C. There is a limited repertoire of immunoglobulin (Ig) VH genes in MZL.
D. Involvement of the marrow and distant nodes occurs in about 50% of cases.
++
++
++
The PPI was continued, and a 2-week course of amoxicillin and clarithromycin was given to try and eradicate the H. pylori infection.
++
With regard to H. pylori eradication, which of the following are correct?
++
A. There is an increasing problem with H. pylori resistance to amoxicillin.
B. The choice of which antibiotics to use should be based on local resistance patterns.
C. Testing for H. pylori eradication with a “breath test” should be carried out 1 week after completing the course of antibiotics.
D. The PPI should be continued until the breath test has been carried out.
E. Triple therapy successfully eradicates H. pylori in more than 90% of cases.
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++
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The breath test at 6 weeks was negative, confirming eradication of H. pylori. A repeat endoscopy showed improvement in the superficial erosions and ulcers, but the antrum still appeared nodular, and an endoscopic ultrasound showed persistent thickening of the gastric wall. Biopsies confirmed persistence of EMZL.
++
What therapies would generally be considered to be inappropriate?
++
++
++
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EMZL accounts for about 70% of MZL cases, splenic marginal zone lymphoma (SMZL) for about 20% of cases, and nodal marginal zone lymphoma (NMZL) for fewer than 10% of cases. H. pylori is found in the stomach in more than 90% of gastric EMZL cases, and the restricted IgVH gene usage in the lymphoma cells reinforces the role of chronic antigen stimulation in the disease pathogenesis. Marrow and disseminated nodal involvement occurs in fewer than 20% of cases.
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There is an increasing problem of H. pylori resistance to clarithromycin with a resistance rate of 12.6% in the United States. Resistance to amoxicillin can occasionally occur, but the incidence is stable. The breath test for H. pylori should be carried out after 6 weeks and at least 2 weeks after the PPI has been discontinued because PPIs can cause false negatives. If it is essential to continue an antacid because of severe epigastric pains, an H2 receptor antagonist should be used. Triple therapy is currently successful at eradicating H. pylori in about 80% of cases.
++
++
H. pylori eradication only results in long-term resolution of the lymphoma in 50% to 70% of cases. After failure of "triple therapy," there are many reasonable approaches which include a, b, c and e but there is a lack of randomized comparisons other than a trial demonstrating that the combination of chlorambucil and rituximab results in improved progression free survival compared with either agent alone. R-CHOP is not recommended for first line therapy.
++
++
This patient was treated with IFRT and obtained a complete remission, which has been maintained for 4 years.
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Marginal Zone B-Cell Lymphomas Case 2
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Authors: Alessandro Broccoli; Pier Luigi Zinzani
++
A 62-year-old woman was seeing her family doctor for a periodic evaluation of her mild hypertension, which was being successfully treated with a thiazide diuretic. She had no other relevant history and was taking no other medications. At this visit, she complained of vague abdominal fullness. On examination, the patient was found to have a spleen enlarged 7 cm below the left costal margin. The liver was not palpable, and she had no lymphadenopathy. She was referred to the hematology clinic, where a complete blood count revealed a hemoglobin of 109 g/L, a WBC of 7.9 × 109/L, with a neutrophil count of 1.8 × 109/L, a monocyte count of 0.7 × 109/L, a lymphocyte count of 6.3 × 109/L, and a platelet count of 109 × 109/L. The blood film confirmed the lymphocytosis and the lymphocytes were medium sized with some plasmacytic differentiation and had irregular surface projections. The immunophenotype was CD20+, sIgM+, CD3- CD5-, CD23-, CD10- and cyclin D1-. Serum urea, electrolytes, calcium, phosphate, and liver function tests were normal. The lactate dehydrogenase level was increased at 410 IU/L (normal <214 IU/L). The immunoglobulin (Ig) levels were normal, but an IgM paraprotein was just detectable on serum protein electrophoresis. The IgHV genes were not mutated. Cytogenetic studies revealed a deletion of chromosome 7q. A computerized tomography scan showed the enlarged spleen and also splenic hilar nodes, the largest of which was 2.2 cm in size. There was no other organomegaly or lymphadenopathy.
++
A diagnosis of splenic SMZL was made.
++
Which of the following statements are correct?
++
A. SMZL involves the red pulp of the spleen.
B. Deletions or translocations of 7q32 are the commonest structural abnormalities seen in SMZL.
C. The IgM paraprotein is unusual and suggests a diagnosis of lymphoplasmacytic lymphoma.
D. Notch mutations are present in about 25% of cases of SMZL.
++
++
Which treatments should be considered in this patient?
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++
++
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SMZL involves the white pulp of the spleen. Translocations of chromosome 7q or del(7q), as in this patient, are found in about 40% of cases, but the commonest structural abnormality is a complete or partial trisomy 3q. IgM paraproteins are found in about 40% of cases of SMZL, and only if the level was high would this raise a suspicion of lymphoplasmacytic lymphoma. About 30% of cases of SMZL have nonmutated IgVH genes, and about 25% have a Notch mutation.
++
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There is no consensus on the treatment of this indolent condition, and there is no evidence that treatment prolongs overall survival. With this in mind and the fact that this patient has only minor symptoms, watchful waiting would be appropriate. When treatment is required, rituximab monotherapy will often induce a response, but from the data in EMZL, it is likely that the response would be longer lasting if rituximab was combined with a chemotherapeutic agent such as chlorambucil, cyclophosphamide, or bendamustine. R-CHOP is not indicated in this indolent condition. Splenectomy may be considered if the patient develops significant symptomology attributable to hypersplenism or discomfort from a massive spleen even though this will not impact the blood and marrow disease. This patient has only mild hypersplenism.
++
This patient was initially observed for 2 years, and during this time, the spleen enlarged further, and she became uncomfortable. The hemoglobin fell to 89 g/L, the neutrophil count to 0.5 × 109/L, and the platelet count to 95 × 109/L. A splenectomy was performed, with normalization of the hemoglobin, neutrophil, and platelet counts, but a rise in the lymphocyte count to 20.4 × 109/L ensued. The patient felt better and remained so for a further 2.5 years, but the hemoglobin and platelet count are now again declining. Initiation of rituximab or immunochemotherapy is being discussed with the patient.
++
For a more detailed discussion, see Chapter 100 in Williams Hematology, 10th edition.
++
Authors: Andrew G. Evans; Jonathan W. Friedberg; Carla Casulo
++
A previously fit and healthy young man, aged 19 years, presented to the hospital emergency department with a 1-week history of rapid decline in well-being. He had lost his appetite, was nauseated, and had increasing abdominal discomfort, and over past last few days had become aware of increasing abdominal distention. He was intermittently febrile. He had never travelled outside the United States. On examination, his temperature was 38.9 °C, his pulse rate was 104 beats/min, and his blood pressure was 100/60 mm Hg. He appeared moderately dehydrated. He had no peripheral lymphadenopathy. His abdomen was clearly distended with an enlarged and tender liver (6 cm below the costal margin) and splenomegaly 4 cm below the costal margin. Abdominal percussion revealed very apparent shifting dullness. Bowel sounds were present. His hemoglobin was 14.5 g/L, and his white cell count was 8.8 × 109/L with a neutrophil count of 5.4 × 109/L and a lymphocyte count of 2.9 × 109/L. The platelet count was 390 × 109/L. A blood film showed occasional intermediate-sized lymphoid cells with round nuclei, multiple nucleoli, and strongly basophilic cytoplasm with numerous cytoplasmic vacuoles. The serum sodium level was 139 mmol/L (reference range, 135–146 mmol/L), potassium was 6.3 mmol/L (reference range, 3.5–5.0 mmol/L), urea was 14.1 mmol/L (reference range, 2.5–7.8 mmol/L), and creatinine was 176 μmol/L (reference range, 59–104 μmol/L). The calcium level was 1.96 mmol/L (reference range, 2.20–2.60 mmol/L), and the phosphate was 1.78 mmol/L (reference range, 1.12–1.45 mmol/L). The uric acid level was 0.64 mmol/L (reference range, 0.15–0.42 mmol/L). The bilirubin was 27 μmol/L (reference range, 1–17 μmol/L), aspartase transaminase was 72 IU/L (reference range, 5–40 IU/L), and alkaline phosphatase was 210 IU/L (reference range, 30–130 IU/L). The lactate dehydrogenase (LDH) level was 690 IU/L (normal <214 IU/L). A marrow aspirate and biopsy showed infiltration of the marrow by the same abnormal lymphocytic cells as seen in the blood. The level of infiltration was estimated to be 10%. The immunophenotype of these cells was CD20+, sIgM+, CD5-, CD23-, BCL6 +, CD10+ CD38+, Mum-1-, CD138-, BCL2-, and Tdt-. An ascitic fluid aspiration was performed and showed high numbers of similar abnormal cells. A lumbar puncture revealed normal cerebrospinal fluid.
++
Which of the following is correct?
++
A. This young man has endemic Burkitt lymphoma (eBL).
B. The presence of abnormal cells in the blood indicates that this is a leukemic variant of Burkitt lymphoma (BL).
C. The tumor cells will probably contain the EBV genome.
D. The tumour cells will almost certainly have a translocation involving the MYC gene and an immunoglobulin gene.
++
++
++
The diagnosis was affirmed by the finding of a t(8;14)(q24;q32) within the marrow cell sample, and a gene expression profile (GEP) revealed a typical BL molecular pattern. Mutational screening revealed a mutation of the ID3 gene, a member of the inhibitor of DNA binding gene family, which is frequent in BL and rare in diffuse large B-cell lymphoma (DLBCL). This patient has evidence of TLS (eg, elevated uric acid, potassium, phosphate, and LDH and decreased calcium) before starting chemotherapy.
++
With regard to the GEP profiling, which of the following is incorrect?
++
A. The GEP can distinguish between BL and DLBCL even when the latter has a MYC translocation.
B. The BL molecular signature is based on a high level of MYC target genes.
C. The BL molecular signature is based on a low level of nuclear factor-κB target genes.
D. The BL molecular signature is based on the presence of germinal center marker genes.
E. None of the above
++
++
With regard to the cytogenetics, which of the following chromosomal structural changes does not play a role in the pathogenesis of BL in addition to the t(8;14)?
++
A. t(14;18), IGH–BCL2 fusion
B. t(11;18), BIRC3–MALT1 fusion
C. t(2;8), IGK–MYC fusion
D. 11q copy gain/loss
E. BCL6 (3q26) gene rearrangement
++
++
++
The TLS was treated aggressively with rigorous IV rehydration and administration of intravenous rasburicase, which is more rapidly effective than allopurinol in lowering the uric acid level. Very intensive chemotherapy was then given with two cycles of cyclophosphamide, vincristine, doxorubicin, and methotrexate alternating with two cycles of iphosphamide, etoposide, and high-dose cytosine arabinoside (CODOX-M/IVAC). Intrathecal cytotoxic agents were also given because of the risk of CNS disease. This regimen introduces multiple agents, some of which are non–cross-resistant; the cyclophosphamide is fractionated, and the minimum period possible is allowed between each cycle to prevent intercycle regrowth of this highly proliferative tumor.
++
Which of the following statements regarding treatment outcomes in BL is FALSE?
++
A. Despite encouraging overall response rates, certain lower intensity, dose-adjusted regimens (eg, R-EPOCH) may have decreased efficacy in preventing CNS recurrence.
B. In the era of highly active antiretroviral therapy (HAART), HIV-positive patients should be treated similar to nonimmunocompromised patients.
C. Outcomes remain favorable for adults aged 40–70 years old in the United States, with 5-year survival rates well in excess of 60%.
D. Autologous stem cell transplantation is best reserved as a consolidation of patients who experience relapsed or refractory disease.
E. Among children treated with intensive chemotherapy regimens, 5-year survival rates exceed 90%, although worse outcomes are associated with advanced stage disease and multiple primary sites at presentation.
++
++
++
This patient has BL of the sporadic type. It is not considered to be the leukemic variant because the malignant cell infiltration in the marrow is less than 25%. Whereas nearly all cases of eBL contain the EBV genome, this is found in only about 15% of cases of the sporadic form and about 30% of cases associated with immunodeficiency. A hallmark of BL is a translocation between the MYC gene and an immunoglobulin gene, usually the IgH gene (t(8;14)(q24;q32), resulting in MYC protein overexpression.
++
++
The GEP distinguishes between BL and DLBCL on the basis of the parameters in b, c, and d.
++
++
The t(11;18) is frequently present in gastric MALT lymphomas, not Burkitt lymphoma. Abnormality of 11q identifies a unique subset of BL with an aggressive course.
++
++
Registration studies clearly show that the success rate is considerably lower than 60% in individuals older than the age of 40 years. Autologous transplantation has no role in consolidation of a first complete remission, and although it can sometimes be used as consolidation of a later response, it should be noted that in this type of lymphoma, it is difficult to induce a second remission (or first remission in primary refractory disease) that lasts long enough to carry out the transplant procedure. Similar considerations apply to the use of allografts.
++
++
A complete remission was obtained and has been maintained for 2 years. It is unusual for relapse to occur beyond this time.
++
For a more detailed discussion, see Chapter 101 in Williams Hematology, 10th edition.
+++
Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sézary Syndrome) Case 1
++
Authors: Larisa J. Geskin; Megan Trager
++
A 67-year-old man of European descent with a 5-year history of "eczema" presented with pruritic erythematous scaly patches and thin plaques comprising approximately eight% of his TBSA. A skin biopsy was consistent with MF, with a dominant clone carrying a T-cell receptor (TCR) gene rearrangement. Blood flow cytometry shows no evidence of circulating neoplastic cells.
++
What would not be considered a first line treatment for this patient?
++
++
++
Which of the following tests is useful, but not essential, for a diagnosis of CTCL?
++
A. Biopsy of suspicious skin sites
B. Flow cytometry
C. Immunohistochemistry staining for CD2, CD3, CD4, CD5, CD7, CD20, CD30
D. Molecular analysis for TCR gene rearrangement
++
++
++
Oral bexarotene would not be considered because this patient has stage IA disease with limited skin involvement. He has patches and plaques covering less than 10% TBSA with no lymph node, visceral, or blood involvement. For stage IA disease, skin-directed therapy is recommended as the first-line treatment. Phototherapy with narrow-band ultraviolet B (NBUVB), topical meclorethamine, and topical glucocorticoids are all skin-directed therapies that could be used first line in this patient. NBUVB is recommended over ultraviolet A (UVA) for thin patches and plaques, as in this case. Oral bexarotene is a systemic therapy that would not be used first line in a patient with stage IA disease.
++
++
Flow cytometry is not essential. According to the NCCN guidelines, biopsy of a suspicious site, dermatopathology review of the slides, use of an extensive immunohistochemistry (IHC) panel (CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30), and molecular analysis to detect clonal T-cell antigen receptor gene rearrangements are required for diagnosis. Some useful, but not essential, tests include assessment of the blood for Sézary cells by cell flow analysis, IHC for CD25, CD56, TIA1, granzyme B, TCRβ, and TCRγ, biopsy of lymph nodes or extracutaneous sites, and assessment of human T- cell leukemia virus 1.
+++
Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sézary Syndrome) Case 2
++
Authors: Larisa J. Geskin; Megan Trager
++
A 70-year-old man presents with tumors, patches, and plaques comprising 22% TBSA. A biopsy of one of the tumors shows CD30 positive disease. He is started on a systemic therapy and soon after complains of numbness in his fingers.
++
Which drug was he most likely treated with?
++
++
++
++
This patient, who has CD30+ tumor stage disease, was most likely treated with BV. BV is an antibody that binds to CD30. Peripheral sensory neuropathy is a well-known side effect.
++
For a more detailed discussion, see Chapter 102 in Williams Hematology, 10th edition.
+++
Mature T-Cell and Natural Killer Cell Lymphomas Case 1
++
Authors: Neha Mehta; Alison Moskowitz; Steven Horwitz
++
A 70-year-old woman was admitted to her local hospital with a 3-week history of increasing general malaise, fluctuating fevers associated with drenching sweats, and a 10% weight loss. On the day of presentation, her husband had noticed that the "whites of her eyes" had become yellow. There was no other relevant history, and apart from vitamin supplements, she was on no medications. On physical examination, she was pale and jaundiced, and there was a macular rash over her trunk and upper extremities. There was generalized lymphadenopathy with the largest nodes measuring 3 cm in diameter. The liver and spleen were each palpable 3 cm below the costal margin. A complete blood count (CBC) revealed a hemoglobin of 82 g/L with an MCV of 104 fl (reference range, 80–99 fl). The white cell count was 10.2 × 109/L with a neutrophil count of 4.9 × 109/L, a lymphocyte count of 2.9 × 109/L, a monocyte count of 0.5 × 109/L, and an eosinophil count of 1.8 × 109/L. The blood film showed polychromasia and spherocytosis and confirmed the eosinophilia. The absolute reticulocyte count was 360 × 109/L (reference range, 25–80 × 109/L in women). The bilirubin was raised at 42 μmol/L with only 10% conjugated. Transaminase and alkaline phosphatase levels were at the upper limits of normal. The immunoglobulin (Ig) levels were IgG, 21.9 g/L (reference range, 6.0–16.0 g/L), IgA, 2.9 g/L (reference range, 0.8–3.0g/L); and IgM, 3.1 g/L (reference range, 0.4–2.5 g/L), and immunoelectrophoresis revealed polyclonal hypergammaglobulinemia with a small IgGκ paraprotein quantified as 3.9 g/L. A presumptive diagnosis of autoimmune hemolytic anemia (AIHA) was made, and a direct antiglobulin test (DAT) result was positive. An underlying lymphoma was also suspected.
++
If this patient has a lymphoma, which type do you think is most likely?
++
A. Lymphocytic lymphoma
B. Diffuse large B-cell lymphoma (DLBCL)
C. Nodal marginal zone lymphoma (NMZL)
D. Peripheral T-cell lymphoma–not otherwise specified (PTCL-NOS)
E. Angioimmunoblastic T-cell lymphoma (AITL)
++
++
++
Seven hours after admission, a further CBC was taken, and the hemoglobin level was now only 71 g/L. The patient reported that she was becoming short of breath on minimal exercise, and a decision was made to start her on high-dose oral glucocorticoids. Within 2 days, the rate of hemolysis had decreased with an increase in the hemoglobin level, and the lymphadenopathy and the hepatosplenomegaly had regressed significantly. A computerized tomography/positron emission tomography (CT/PET) scan was normal. A marrow aspirate and biopsy revealed erythroid hyperplasia but no abnormal cell infiltrates.
++
++
A. Reassure the patient that she did not have a lymphoma.
B. Tell the patient that the hemolysis was probably related to an acute infection.
C. Tell the patient that she did have a lymphoma.
D. Start chemotherapy on the assumption that she did have a lymphoma.
E. Watch and wait.
++
++
++
Five months later, the patient reported the return of B symptoms but not yet as severe as at presentation. There was no evidence of AIHA. On examination, disseminated lymphadenopathy was found, and the spleen tip was just palpable.
++
A 2-cm axillary node was removed, and this revealed effacement of the normal lymphoid architecture with loss of germinal centers, a pleomorphic cellular infiltrate, and proliferation of small arborizing blood vessels. Immunocytochemistry revealed that the infiltrating lymphocytes were CD3+, CD4+, CD10+, CD30+.Fluorescence in situ hybridization showed scattered EBV+ B cells. A definitive diagnosis of AITL was made.
++
Which of the following is incorrect?
++
A. AITL is the commonest type of mature T-cell lymphoma.
B. There is frequent expression of the follicular T helper markers such as ICOS and CXCL13.
C. The gene expression profile in AITL is very similar to a subset of PTCL-NOS referred to as T follicular helper (TFH) lymphomas.
D. The presence of EBV+ B cells is not uncommon in AITL.
++
++
++
Although it is not possible to make a diagnosis without histology, the pronounced B symptoms, disseminated lymphadenopathy and hepatosplenomegaly, skin rash, eosinophilia, concomitant autoimmune hemolysis, hypergammaglobulinemia, and presence of a paraprotein are characteristic of AITL.
++
++
Although there is a strong possibility that the patient has AITL, it is not possible, without histology, to say that she definitely has a lymphoma. Careful follow-up is the only option. This illustrates the problem of administering glucocorticoids to a patient with suspected lymphoma before a biopsy has been taken. Mature T-cell lymphomas, especially AITL, are often highly responsive to glucocorticoids, although the remissions so obtained are usually short-lived. Sometimes remissions arise spontaneously in AITL but again are usually short-lived.
++
++
AITL is the second commonest type of mature T-cell lymphoma, accounting for about 18% of such cases. PTCL-NOS accounts for about 26% of cases. There is major overlap of AITL and TFH lymphomas, which are still included in the PTCL-NOS category. Future changes to the classification are to be expected. The presence of scattered EBV+ B-cells is frequent in AITL and is thought to reflect an element of underlying immunodeficiency. Some patients present with a concomitant EBV+ B-cell lymphoma or relapse with this disease.
++
++
The patient was treated with brentuximab vedotin in view of the CD30 positivity, together with cyclophosphamide, hydroxydaunorubicin, and prednisone (BV-CHP), although it should be noted that there is not good evidence that this is preferable to standard cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin), and prednisone (CHOP) in AITL. The patient achieved a complete remission which is seen in 50% to 60% of cases. Consolidation high-dose therapy and autologous transplantation was not performed as it would have been in many centers; there is no randomized controlled trial data addressing this issue. The patient has now been in remission for 1 year.
+++
Mature T-Cell and Natural Killer Cell Lymphomas Case 2
++
Authors: Neha Mehta; Alison Moskowitz; Steven Horwitz
++
A 37-year-old woman presented to her family physician with enlargement of her left breast that had become apparent about 1 month earlier and had increased in size since that time. Eight years earlier, she had bilateral breast implants for cosmetic purposes, and no problems had occurred since they were inserted until this time. On examination, the enlarged left breast was firm and slightly tender, but her family doctor detected no discrete mass. He found no other abnormalities on physical examination. She was referred back to the cosmetic surgeon who had inserted the implants, and an ultrasound showed an effusion adjacent to the implant. There was also a suggestion of irregular thickening of the capsule surrounding the implant, so she was referred to a surgical oncologist. Magnetic resonance imaging was performed, and this confirmed the thickening of the capsule, raising the possibility that this was an implant-associated lymphoma.
++
What is the most common type of lymphoma affecting the breast in women without an implant?
++
A. Follicular lymphoma
B. Marginal zone lymphoma
C. Mantle cell lymphoma
D. DLBCL
E. Anaplastic large cell lymphoma expressing the anaplastic lymphoma kinase.
F. Anaplastic large cell lymphoma not expressing the anaplastic lymphoma kinase.
++
++
In women with breast implants, what is the most common type of lymphoma affecting the breast?
++
A. Follicular lymphoma
B. Marginal zone lymphoma
C. Mantle cell lymphoma
D. DLBCL
E. Anaplastic large cell lymphoma expressing the anaplastic lymphoma kinase
F. Anaplastic large cell lymphoma not expressing the anaplastic lymphoma kinase
++
++
++
The effusion was aspirated, and a needle biopsy was taken of the thickened capsule. The biopsy was of poor quality and considered nondiagnostic, but the aspirated fluid contained large atypical lymphocytes expressing CD2, CD7, CD4, and CD30. The Ki67 staining was positive in about 75% of cells. Staining for anaplastic large cell lymphoma kinase (ALK) was negative. A diagnosis of anaplastic large cell lymphoma–ALK negative was made, and the tissue biopsy was not repeated. This type of lymphoma is found in association with breast implants, particularly those with a textured surface. Widely differing estimates of the frequency of such lymphomas arising in women with breast implants have been made. A life-time risk between 1 in 2000 and 1 in a 100,000 has been quoted, so it is certainly very uncommon. The patient had a CT/PET scan, and no disease was found outside of the breast. This was in accord with the fact that more than 80% of breast implant associated lymphomas are staged as IE.
++
Which of the following statements are correct?
++
A. Treatment is removal of the implant and complete resection of the capsule and scar tissue.
B. A sentinel node biopsy should be performed.
C. Treatment is removal of the implant and complete resection of the capsule and scar tissue followed by a course of cyclophosphamide, hydroxydaunorubicin (Adriamycin), vincristine (Oncovin), and prednisone (CHOP).
D. The implant in the other breast must be removed.
E. Under no circumstances should breast implants be reinserted.
++
++
++
DLBCL accounts for about 85% of all breast non-Hodgkin lymphomas.
++
++
++
Removal of the implant with resection of the capsule is curative in more than 95% of cases, providing the surgical margins are clear of lymphoma. A sentinel node biopsy is not recommended because the capsule drains into several different effluent lymph tracts. There is no need to give chemotherapy unless there is more advanced disease than in this patient. It is often advised that the implant in the other breast should be removed because bilateral breast lymphomas are found in about 5% of cases. It is not, however, mandatory. Whether or not to have an implant(s) reinserted is a complex decision requiring detailed discussion with the patient. Breast associated lymphomas usually arise when textured implants have been used, and it can be argued that replacement with smooth implants is reasonable.
++
++
The patient had both implants removed with full clearance of the capsule and scar tissue on the left. She elected not to have her implants replaced. She is fit and well 5 years after surgery.
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Mature T-Cell and Natural Killer Cell Lymphomas Case 3
++
Authors: Neha Mehta; Alison Moskowitz; Steven Horwitz
++
A 50-year-old businessman, born and raised in Mexico but living in the United States for the past 6 years, reported that the right side of his nose had been blocked for about 2 months. There was no discharge. Over the past 2 weeks, visible swelling had developed on the right side of the nose. There was no other relevant family or previous medical history. He was on no medications. On physical examination, a tumor was apparent in the right nostril, and there was an area of erythema, without perforation, on the hard palate. There was no lymphadenopathy in Waldeyer ring or elsewhere. There was no hepatosplenomegaly. A biopsy of the nasal tumor revealed an infiltrate of medium-sized atypical lymphocytes with vascular invasion and necrosis. The initial immunocytochemistry found the tumor cells to be CD19-, CD20- surface CD3-, CD2+, and CD7+. This indicated a diagnosis of extranodal natural killer/T-cell (ENK/T) lymphoma, nasal type.
++
In which countries are ENK/T-cell lymphomas not more common than in the United States?
++
A. Mexico
B. Argentina
C. Taiwan
D. South Korea
E. Sweden
++
++
Which of the following findings are not typical of this type of lymphoma?
++
A. Presence of cytoplasmic CD3 despite surface CD3 negativity
B. Strong expression of CD56
C. Expression of CD10
D. TCR-γ chain rearrangement may be present.
E. Fluorescent in situ hybridization reveals the presence of Epstein Barr virus (EBV)–related RNAs (EBERs) in virtually all cases.
++
++
++
ENK/T-cell lymphomas are most often seen in Central and South America and in Southeast Asia. The incidence is broadly similar in Sweden to the US.
++
++
The immunophenotype is variable and often considered to be "aberrant" compared with reactive NK cells, but the presence of cytoplasmic CD3 without surface expression is usual, and CD56 is usually strongly expressed. CD10 is a germinal center B-cell marker but is also expressed in angioimmunoblastic T-cell lymphoma. Clonal rearrangement of both the TCR γ chain and β chain may be present. There is a very strong association with EBV, and the presence of EBERs is usually considered to be a diagnostic requirement.
++
The patient was treated with a combination of gemcitabine, L-asparaginase, and oxaliplatin and local radiotherapy. L-asparaginase is infrequently used in the treatment of lymphomas, but major single agent activity has been demonstrated in ENK/T-cell lymphomas.
++
For a more detailed discussion, see Chapter 103 in Williams Hematology, 10th edition.
++
Authors: Elizabeth K. O'Donnell; Giada Bianchi; Kenneth Anderson
++
A 61-year-old woman presented to her family physician with a 1-year history of midthoracic back pain that had become progressively more severe. She also noticed that she had lost more than 1 inch in height. In the past 2 weeks, she had become constipated, which she attributed to her use of codeine tablets. She had developed thirst that was hard to satisfy and had little energy. She gave no other relevant previous history, and there was no significant family history. On examination, the physician noted a kyphosis but found no other abnormalities. A complete blood count revealed a hemoglobin of 89 g/L, a WBC of 7.5 × 109/L with a neutrophil count of 3.9 × 109/L, and a lymphocyte count of 3.0 × 109/L. A blood film was reported as normal. The sodium and potassium levels were normal, but the urea and creatinine were raised with an estimated creatinine clearance of 32 mL/min. The serum albumin level was 42 g/L, and liver function tests were normal. The serum calcium level was 2.89 mmol/L (reference range, 2.1–2.6 mmol/L), and the phosphate level was 1.4 mmol/L (reference range, 1.1–1.5 mmol/L). The lactate dehydrogenase (LDH) level was 201 IU/L (reference range, <214 IU/L), and the β2M level was 2.9 mg/L (reference range, 0.8–2.2 mg/L).
++
She was urgently referred to a hematologist, and further investigations were carried out. The immunoglobulin (Ig) levels were IgG, 26.1 g/L (reference range 6.0 – 16.0 g/L); IgA, 0.7 g/L (reference range 0.8 – 3.0g/L); and IgM, 0.4 g/L. and IgM 0.1 g/L (reference range 0.4 -2.5 g/L). Immunoelectrophoresis identified an IgG paraprotein quantified at 21 g/L. A marrow aspirate and biopsy revealed infiltration of approximately 40% by κ light chain–restricted plasma cells. A skeletal survey showed diffuse osteoporosis and multiple lytic lesions in the spine, skull, and long bones.
++
A diagnosis of myeloma was made with hypercalcemia, renal failure, and hypogammaglobulinemia.
++
Which of the following statements is incorrect?
++
A. IgG is the most frequent type of paraprotein found in myeloma.
B. Ig A paraprotein occurs in about 20% of cases.
C. Light chain only myeloma accounts for about 20% of cases of myeloma.
D. Nonsecretory myeloma is caused by a failure of light chain synthesis by the myeloma cells.
++
++
Which of the following are unusual (<10%) in the cytogenetic analysis of myeloma marrow at diagnosis?
++
A. Hyperdiploidy
B. t(11;14)(q13;q23)
C. del (13)
D. del (17)
++
++
What of the following are independent prognostic factors in myeloma?
++
++
++
++
The patient was immediately admitted to the hospital and treated with vigorous rehydration, a loop diuretic, and a slow infusion of a single dose of a bisphosphonate. The hypercalcemia rapidly resolved, and over the next week, the creatinine returned to the normal range.
++
As soon as she was rehydrated, chemotherapy was also started.
++
Which of the following chemotherapy regimens would you choose?
++
++
++
++
The patient tolerated chemotherapy well and had a very good partial response. This was consolidated with high-dose melphalan and an autologous hemopoietic stem cell transplant. There were no serious complications and restaging showed no evidence of minimal residual disease (MRD) as determined by polymerase chain reaction analysis of blood and marrow samples. Maintenance with lenalidomide was started, and she also continued with monthly zoledronic acid in view of her lytic bone lesions and osteoporosis. Eighteen months later, she was still in remission and MRD negative, but on routine follow-up, she reported some painful swelling of the lower right gums, which was making eating difficult and was associated with "bad breath" and a "nasty taste" in the mouth. On examination, the gums were erythematous, and naked bone was visible with a slight discharge emanating from this area. The nearby teeth were loose. A diagnosis of osteonecrosis of the jaw (ONJ) was made and confirmed by radiography.
++
Which of the following statements is incorrect?
++
A. ONJ occurs in about 10% of patients with myeloma treated long term with zoledronic acid therapy.
B. ONJ is predisposed by invasive dental procedures.
C. If ONJ occurs, bisphosphonate therapy should be stopped.
D. Complete healing occurs in about half of patients with conservative therapy.
++
++
++
IgG myeloma accounts for about 60% of cases with about 20% being Ig A and a similar proportion light chain only. The rare nonsecretory myeloma is caused by a failure of light chain secretion rather than synthesis with intracytoplasmic light chains being demonstrable by immunohistochemistry.
++
++
Hyperdiploidy defined as more than 46 chromosomes but fewer than 76 chromosomes occurs in nearly half of patients with myeloma. The t(11;14) (q13;23) translocation is the most frequent translocation found in myeloma, leading to upregulation of cyclin D1. A del(13) occurs in at least half of patients with myeloma and is more common in nonhyperdiploid cases. A del (17) or TP53 abnormality occurs in fewer than 10% of patients at diagnosis but is more common at later stages of the disease. Trisomies are frequent in myeloma, but, strangely, they mainly involve odd numbered chromosomes (chromosomes 3, 5, 7, 9, 11, 15, 19, and 21). This patient was found to be hyperdiploid and have a trisomy 15, which is associated with a favorable prognosis.
++
++
The International Staging System (ISS) used just the β2M level (favorable is <3.5mg/L) and the albumin level (favorable is >35 g/L) to define 3 prognostic groups with 0, 1, or 2 adverse factors. The revised ISS also includes the serum LDH level and cytogenetics. A number of studies have also shown that the GEP provides additional independent prognostic information, but it is not yet used routinely. This patient had a raised β2m, but it was less than the prognostic cut-off level. The albumin was not low, but dehydration secondary to the hypercalcemia could have caused an elevation of the albumin level. The serum LDH was normal, and the cytogenetic profile was favorable. GEP was not performed.
++