Chronic Leukemias

One of the most prognostically significant landmarks is achieving CCyR at 12 months and many other parameters are based on the likelihood of obtaining this response. For example, for patients who do not achieve a MCyR by 6 months, the probability of obtaining a CCyR at 12 months is 50% or lower.

Question 30.3 The correct answer is A.

Peripheral blood RQ-PCR is a sensitive test that can be used in monitoring for minimal residual disease (MRD) in CML. It is usually expressed as an absolute ratio of BCR-ABL1 transcripts to a control gene such as ABL1 or as log reductions from the 100% value. This value is adjusted to a standardized reference IS. It is generally accepted that CCyR corresponds to an approximately 2-log reduction in transcript levels (MR2) or 1% IS. Major molecular response (MR3) is defined as a 3-log reduction in transcript levels or 0.1% IS. A complete molecular response (CMR) is generally defined as the absence of detectable BCR-ABL transcripts, a status that depends on the technology and criteria for negativity employed, with the limits of technology being somewhere between MR4 and MR5.

Question 30.4 The correct answer is A.

Currently, imatinib, dasatinib, and nilotinib are the FDA-approved TKIs for frontline use. The choice of therapy depends on patient comorbidities and the individual TKI side-effect profile. Nilotinib associated with hyperglycemia is peripheral vascular disease and is probably not the best choice for this patient. The newer, more potent TKIs induce faster cytogenetic and molecular responses, but in only the imatinib versus nilotinib study this has translated into a significant difference in progression-free survival (PFS) at 3 years. Dasatinib is associated with pleural effusions, pulmonary hypertension and can be associated with significant morbidity in patients with pre-existing pulmonary disease. Imatinib does not have specific contraindications. Until a solid body of evidence that newer TKIs carry a superior survival benefit, imatinib remains a solid first-line choice. The approved doses in the frontline setting are imatinib 400 mg QD, nilotinib 300 mg BID, and dasatinib 100 mg QD. Second-line approved doses are nilotinib 400 mg BID, dasatinib 100 mg QD, bosutinib 500 mg QD, and ponatinib at 30 mg Po QD.

Question 30.5 The correct answer is B.

A loss of disease control in the first 5 years of therapy occurs in approximately 15% of chronic-phase patients treated with imatinib. The majority (40%) of the patients who relapse have point mutations in the ABL kinase domain that render the kinase less sensitive to imatinib. Substitution of threonine by isoleucine in position 315 of the kinase domain (T315I) is the most common mutation that emerges in patients with resistance to newer TKIs. Ponatinib is the only TKI that has activity against T315I mutation. The optimal dose is not defined in this setting although 45 mg daily was used in the PACE clinical trial. When this dose was used in the frontline setting, it led to several cardiac, cerebral, and peripheral vascular thrombotic events in up to 27% of patients and have included fatal myocardial infarction and stroke that led to the early termination of phase III study and further led to a recommended initial dose of 30 mg daily.

Question 30.6 The correct answer is E.

Pleural effusions are one of the common side effects of dasatinib and reported at an incidence of 14% to 54%. They can occur at any time during the therapy and can recur even after a dose reduction. Routine surveillance chest radiographs and diagnostic thoracentesis are not required and temporary discontinuation of the drug is often enough for spontaneous resolution. In a symptomatic patient such as the current woman, this process can be hastened through diuresis, corticosteroids (often as 0.5 mg/kg of prednisone for 1 or 2 weeks). Pulmonary hypertension is also a rare side effect of dasatinib.

Question 30.7 The correct answer is A.

The optimal monitoring for the achievement of landmarks for someone being treated with imatinib is as follows: Bone marrow biopsy every 6 months until CCyR is achieved, RQ-PCR every 3 months for first 2 years, then every 4 to 6 months. With the advent of RQ-PCR standardized to international scale (IS), peripheral blood can be used for molecular surveillance and the bone marrow biopsies may be avoided in the future.

Question 30.8 The correct answers are B and C.

Relapse on therapy in CML is defined as a loss of a previously obtained response, such as a loss of CHR, loss of CCyR, or increase in RQ-PCR transcript level. Minor changes in RQ-PCR are common and a 2–3 factor increase on international scale is considered normal as accuracy of the test varies substantially depending on the depth of response. It is important to confirm the rise through a repeat testing before changing the therapy. Decrease in the previously normal platelet count, constitute a loss of CHR and the rise of Ph-positive metaphase levels from 0% to 20% represents loss of CCyR. Both are considered relapse and warrant for change in therapy.

Question 30.9 The correct answer is E.

Important landmarks that are considered to be associated with good prognosis are CHR at 3 months, MCyR at 6 months, CCyR at 12 months, and 3-log reduction in BCR-ABL transcripts (MR3) measured by RQ-PCR at 12 months. Of all these parameters, CCyR at 12 months is considered the most important prognostic landmark and the other parameters predict the likelihood of achieving this response. Of note, patients who achieve a CCyR at 12 months but did not achieve MR3 tend to achieve this eventually without any further intervention. Patients who do not achieve these landmarks on first-line therapy constitute primary cytogenetic resistance, an event that occurs rarely, is associated with persistent cytopenias and considered to be a poor risk category.

Question 30.10 The correct answers are A and B.

With the advent of imatinib and newer TKIs, hematopoietic cell transplantation (HCT) for chronic-phase CML has decreased significantly. But HCT still remains an effective therapy for patients who are resistant to TKIs and remain in chronic phase and for patients with advanced phase disease whose leukemia can be restored to the chronic phase. Reduced-intensity conditioning regimens (AKA nonmyeloablative regimens) have shown to be superior to myeloablative HCT in patients >60 years of age with disease-free survival ranging from 40% to 85% at 3 to 5 years. However, infections and acute and chronic graft versus host disease remain significant problems.

Question 30.11 The correct answer is E.

The current accepted criteria for the diagnosis of accelerated phase include (1) progressive splenomegaly and myelofibrosis; (2) bone marrow or peripheral blood blasts ≥15% but <30%; (3) bone marrow or peripheral blood blasts plus promyelocytes ≥30%; (4) bone marrow or peripheral blood basophils ≥20%; (5) platelet count <100 × 10⁹/L unrelated to therapy; and (6) clonal evolution in a Ph-chromosome–positive clone. The blastic phase is defined as bone marrow or peripheral blood blast ≥30% or the presence of extramedullary blast infiltrates.

Question 30.12 The correct answer is B.

Breakpoints within BCR localize to one of three breakpoint cluster regions that lead to three different sized BCR-ABL1 transcripts in CML. More than 90% of CML patients and one-third of Ph-positive ALL patients express the 210 kDa due to a breakpoint in major breakpoint cluster region (M-bcr), which spans exons e12–e16 (formerly exons b1–b5). The remainder of Ph-positive ALL patients and rare CML cases harbor breakpoints in minor breakpoint cluster region (m-bcr), generating an e1a2 transcript that is translated into p190BCR-ABL1. A third breakpoint down-stream of exon 19 (e19a2) in the micro breakpoint cluster region (μ-bcr) gives rise to p230BCR-ABL1 and is associated with neutrophilia.

Question 30.13 The correct answers are A, C, and E.

Disease progression is believed to be due to the accumulation of molecular abnormalities that lead to a loss of terminal differentiation capacity of the leukemic clone, which continues to depend on BCR-ABL1 activity. The molecular basis is poorly defined, but point mutations or deletions in the p53 tumor suppressor gene have been observed in up to 25% of patients with myeloid blast crisis, and as many as 50% of patients with lymphoid transformation show a homozygous deletion in the p16 tumor suppressor gene. Studies have demonstrated that telomere length decreases with disease progression from chronic to blast phase. Clonal evolution in a Ph-chromosome–positive clone is one of the causative and accepted criteria for progression of CML into advanced phase.

Question 30.14 The correct answer is E.

CD38 positivity, IGHV-unmutated status, ZAP-70 expression, and Short lymphocyte doubling time (<6 months) are associated with shorter survival. ZAP-70 is normally expressed on T-cells. Its expression on CLL cells (B cells) is associated with activation of these malignant cells. Zap-70 expression is associated with IGHV-unmutated state, increased disease progression, and worse overall survival. Other factors associated with shortened survival in CLL are diffuse pattern of bone marrow infiltration, advanced age and male gender, abnormal karyotype, high serum levels of β2-microglobulin and soluble CD23, and a CLL-PLL category (11% to 54% prolymphocytes in the blood).

Question 30.15 The correct answer is C.

This patient developed relapsed disease based on the loss of MCyR and that he did not attain CCyR at 12 months probably secondary to noncompliance. Before considering the change of therapy, patient compliance and development of resistance to TKIs need to be addressed. Noncompliance is one of the important reasons for loss of therapy and adherence to therapy needs to be addressed in every visit. In a compliant patient, resistance to therapy should be considered and investigated by testing for ABL kinase domain mutations (particularly for T315I mutation).

Question 30.16 The correct answer is D.

Autoantibodies in CLL are often polyclonal and are Ig G, indicating that they are not produced by the leukemic clone. They are usually targeted against hematopoietic cells and can lead to cytopenias of any of the three lineages (RBC, WBC, and platelets) or can lead to hemolytic anemia. The severity of the autoimmune phenomenon does not necessarily correlate with the severity of CLL, and such events may develop in patients whose disease is responding to therapy.

Question 30.17 The correct answers are A and B.

This patient has hairy cell leukemia (HCL), a rare B-cell lymphoproliferative disorder that comprises 2% of all leukemias. Classic “hairy cells” are seen on the peripheral smear albeit less frequently. These cells are positive for B-cell markers CD19, CD20, CD22, and CD25. CD103 positivity obviated the need for tartrate-resistant acid phosphatase (TRAP) testing. Pentostatin and cladribine are the major treatment options for HCL. Cladribine at 0.1 mg/kg/d given either as continuous infusion for 7 days or at 0.14 mg/kg/d as 2-hour infusion for 5 days is the preferred frontline therapy. Interferon-α is reserved for relapsed HCL. Prolymphocytic leukemia (PLL), an important differential diagnosis for HCL, is often associated with lymphocytosis, the prolymphocytes have prominent nucleoli and are negative for CD25 and CD103. Nucleoside analogues and alemtuzumab are treatment options for PLL.

Question 30.18 The correct answer is D.

The IWCLL revised criteria for active disease, an indication to initiate treatment include constitutional symptoms attributable to CLL: weight loss (>10% of baseline weight within the preceding 6 months), extreme fatigue (ECOG performance status ≥2), fever (temperature higher than 38°C or 100.5°F for at least 2 weeks) or night sweats without evidence of infection; evidence of progressive bone marrow failure characterized by the development of or worsening of anemia and/or thrombocytopenia; autoimmune hemolytic anemia and/or autoimmune thrombocytopenia, poorly responsive to corticosteroid therapy; massive (>6 cm below the left costal margin) or progressive splenomegaly; bulky (>10 cm in longest diameter) or progressive lymphadenopathy; and progressive lymphocytosis defined as an increase in the absolute lymphocyte count by >50% over a 2-month period, or a doubling time predicted to be <6 months. Hypogammaglobulinemia or monoclonal gammopathy alone is not a sufficient criterion to initiate therapy. Disease course in low- or intermediate-risk groups is not uniform and can be indolent or rapidly progressive. Of note, approximately one-third of patients with early-stage never require therapy. It is known that early treatment of low-grade patients does not translate into better survival. Newer better therapies such as ibrutinib, idelalisib, chimeric antigen receptor–bearing T-cell (CAR-T cells), BCL-2 inhibitors, and lenalidomide have been shown to be effective in relapsed and refractory CLL. However, it is unknown whether treating the low-risk patients with these novel agents improves survival.

Question 30.19 The correct answer is D.

Rituximab is a chimeric immunoglobulin IgG1 CD20 monoclonal antibody (mAb) that became an important adjunct in the treatment of CLL. It does not have significant activities in CLL when used as monotherapy but when used in combination with fludarabine and cyclophosphamide it demonstrated superior remission rates (95% in FCR arm vs. 88% with FC), improved PFS (52 months vs. 33 months with FC) and OS (84% vs. 79% at 38 months with FC). Maintenance rituximab has not been routinely used in patients with CLL. Although rituximab targets normal B cells, studies have shown that there is no significant effect on immunoglobulin levels.

Question 30.20 The correct answer is A.

Del(17p) is associated with poor prognosis and shortened survival in patients with CLL. Ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor that has shown promising overall response rate in the relapsed and fludarabine-refractory setting. Similar responses were noted across risk categories, including for high-risk del(17p), heavily pretreated, and advanced stage disease. The 2-year PFS rate was 75% and OS rate was 83% with durable responses. Ibrutinib is approved at a dose of 420 mg PO once daily in the relapsed/refractory setting and as such is the preferred choice of treatment for this patient population. While allo-SCT was associated with long-term remissions and possible cure, with the availability of newer therapies, it may be reserved for patients with high-risk and relapsed CLL.

Question 30.21 The correct answer is C.

BRAF V600E mutation is present in almost all cases of hairy cell leukemia (HCL). It is currently being explored as a potential therapeutic target using vemurafenib in relapsed HCL patients.

Question 30.22 The correct answer is A and B.

Monoclonal B lymphocytosis (MBL) is an often incidental diagnosis of defined as a population of clonal CD5+/19+/23+ B cells in up to 3.5% of otherwise normal individuals over the age of 40. These individuals are often asymptomatic with no adenopathy or splenomegaly. Furthermore, as many as 13% of family members of patients with familial CLL harbor a population of cells with an immunophenotype consistent with CLL, but do not fulfill CLL diagnostic criteria. It is estimated that the rate of progression from MBL to CLL is 1% to 2% per year. Currently, there is no indication to perform screening for MBL.

Corresponding chapters in Cancer: Principles & Practice of Oncology, Tenth Edition: 108 (Molecular Biology of Chronic Leukemias), 109 (Chronic Myelogenous Leukemia), and 110 (Chronic Lymphocytic Leukemias).

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