40 - 110 Chronic Myeloid Leukemia

110 Chronic Myeloid Leukemia

alone frequently died from DIC induced by the release of gran­ ule components by the chemotherapy-treated leukemia cells. The prognosis of APL patients changed dramatically first with the introduction of tretinoin (all-trans-retinoic acid [ATRA]) and then with combined ATRA and arsenic trioxide (ATO). ATRA is an oral drug that induces the differentiation of leukemic cells bearing the t(15;17), which disrupts the RARA gene encoding retinoid acid receptor. ATRA decreases the frequency of DIC but often produces another complication called the APL (differentiation) syndrome. Occurring within the first 3 weeks of treatment, it is characterized by fever, fluid retention, dyspnea, chest pain, pulmonary infiltrates, pleural and pericardial effusions, and hypoxemia. The syndrome is related to adhesion of differentiated neoplastic cells to the pul­ monary vasculature endothelium. Glucocorticoids, chemotherapy for cytoreduction, and/or supportive measures can be effective for management of the APL syndrome. Temporary discontinuation of ATRA is necessary in cases of severe APL syndrome (i.e., patients developing renal failure or requiring admission to the intensive care unit due to respiratory distress). The mortality rate of this syndrome is ∼10% if unrecognized. APL syndrome may also occur, less commonly, with ATO.

In adults with low-risk APL (low leukocyte count at presenta­ tion), ATRA (45 mg/m2/d) plus ATO (0.15 mg/kg/d) was compared to ATRA plus concurrent idarubicin chemotherapy. ATRA/ATO was superior and is the new standard of care for such patients. CR rates in low-risk disease approach 100%, with excellent long-term survival. Notably, patients with high-risk APL (defined as leukocyte count >10,000/μL) must be uniquely treated, as they require imme­ diate cytoreduction with chemotherapy due to life-threatening APL syndrome and rapidly rising leukocyte count after initiation of ATRA. High-risk patients are at increased risk for induction death due to this syndrome as well as increased frequency of hemorrhagic complications (related to DIC). PART 4 Oncology and Hematology Assessment of residual disease by PCR amplification of the t(15;17) chimeric gene product PML-RARA following the final cycle of treatment is important. Disappearance of the signal is associated with long-term disease-free survival; its persistence or reemergence invariably predicts relapse. Sequential monitoring by PCR for PML-RARA is now considered standard for postremission monitoring of APL, at least in high-risk patients. ■ ■FURTHER READING Dinardo CD et al: Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 133:7, 2019. Döhner H et al: Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140:1345, 2020. Issa GC et al: The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature 615: 920, 2023. Jaiswal S, Ebert BL: Clonal hematopoiesis in human aging and dis­ ease. Science 366:eaan4673, 2019. Jongen-Lavrenic M et al: Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med 378:1189, 2018. Khoury JD et al: The 5th edition of the World Health Organization Clas­ sification of Haematolymphoid Tumours: Myeloid and histiocytic/

dendritic neoplasms. Leukemia. 36:1703, 2022. Perl AE et al: Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med 381:1728, 2019. Pollyea DA et al: Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia 33:2575, 2019. Roboz GJ et al: Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood 135:463, 2020. Stone RM et al: Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377:454, 2017.

Hagop Kantarjian, Elias Jabbour

Chronic Myeloid

Leukemia Chronic myeloid leukemia (CML) is a clonal hematopoietic myelopro­ liferative stem cell neoplasm. The disease is driven by the BCR::ABL1 chimeric gene that codes for a constitutively active tyrosine kinase, resulting from a reciprocal balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34.1;q11.2), known as the Philadelphia chromosome (Ph) (Fig. 110-1). Untreated, the course of CML is typically biphasic or triphasic, with an early indolent or chronic phase, followed often by an accelerated phase and a terminal blastic phase. Before the era of BCR::ABL1 tyrosine kinase inhibitors (TKIs), the median survival in CML was 3–7 years, and the 10-year survival rate was 30% or less. Introduced into standard CML therapy in 2000, TKIs have revolutionized the treatment, natural history, and progno­ sis of CML. Today, the estimated 10-year survival rate with imatinib mesylate, the first BCR::ABL1 TKI approved, is >85% and approaches that of a normal age-matched population. Allogeneic hematopoietic stem cell transplantation (HSCT), a curative approach but one that involves more risks, is now offered as later-line therapy after failure of TKIs. ■ ■INCIDENCE AND EPIDEMIOLOGY CML accounts for ∼15% of all cases of leukemia. There is a slight male predominance (male-to-female ratio 1.6:1). The median age at diag­ nosis is 55–65 years. It is uncommon in children; only 3% of patients with CML are younger than 20 years, although in recent years, a higher proportion of young patients have been diagnosed. The incidence of CML increases gradually with age, with a steeper increase after the age of 40–50 years. The annual incidence of CML is 2 cases per 100,000 individuals. In the United States, this translates into about 9000 new cases per year. The incidence of CML has not changed over several decades. By extrapolation, the worldwide annual incidence of CML is about 250,000 cases. With a median survival of 3–6 years before 2000, the disease prevalence in the United States was ~30,000 cases. With TKI therapy, the annual mortality has been reduced from 10–20% to about 1–2%. Therefore, the prevalence of CML is expected to continue to increase. Based on these estimates (incidence of 9000 cases, annual mortality of 2%), the plateau prevalence of CML is estimated to be reached at ~450,000 in the United Stated (9000 × 100/2) by about 2040, with full TKI optimal treatment penetration. The worldwide prevalence will depend on the treatment penetration of TKIs and their effect on reduction of worldwide annual mortality. Ideally, with full TKI treatment penetration, the worldwide prevalence should plateau at 35 times the incidence, or ~9–10 million patients. These estimates are based on extrapolations from the incidence and prevalence of CML in the United States, as well as an estimated annual mortality of 2% with modern TKI therapy; they could vary considerably if the estimates were to change. ■ ■ETIOLOGY There are no familial associations in CML. The risk of developing CML is not increased in monozygotic twins or in relatives of patients with CML. No etiologic agents are incriminated, and no associations exist with exposures to benzene or other toxins, fertilizers, insecticides, or viruses. CML is not a frequent secondary leukemia following therapy of other cancers with alkylating agents and/or radiation. Exposure to ionizing radiation (e.g., nuclear accidents, higher doses of radiation treatment) has increased the risk of CML, which peaks at 5–10 years after exposure and is dose-related. The median time to development of CML among atomic bomb survivors was 6.3 years. Following the Chernobyl accident, no increase in the incidence of CML was reported, suggesting that larger dose exposures of radiation are required to cause CML. Because of adequate protection, the risk of CML has not

q34 t(9;22)(q34.1;q11.2) A Chromosomes

Minor BCR BCR Major BCR ABL1 Micro BCR Normal ABL1 Breakpoint Translocation (9;22) B FIGURE 110-1  A. The Philadelphia (Ph) chromosome cytogenetic abnormality. B. Breakpoints in the long arms of chromosome 9 (ABL1 locus) and chromosome 22 (BCR regions) result in at least three different BCR::ABL1 oncoprotein messages, p210BCR::ABL1 (most common message in chronic myeloid leukemia [CML]), p190BCR::ABL1 (present in two-thirds of patients with Ph-positive acute lymphoblastic leukemia; rare in CML), and p230BCR::ABL1 (rare in CML and associated with an indolent course). Other rearrangements (e.g., e14a3, e14a3) are less common. (© 2013 The University of Texas MD Anderson Cancer Center.) increased among individuals working in the nuclear industry or among radiologists. ■ ■PATHOPHYSIOLOGY The t(9;22)(q34.1;q11.2) is present in >90% of classical CML cases. It results from a balanced reciprocal translocation between the long arms of chromosomes 9 and 22. It is present in hematopoietic cells (myeloid, erythroid, megakaryocytes, and monocytes; less often mature B lym­ phocytes; rarely mature T lymphocytes, but not stromal cells), but not in other cells in the human body. As a result of the genetic transloca­ tion, DNA sequences from the cellular ABL proto-oncogene 1 (ABL1) are juxtaposed to the major breakpoint cluster region (BCR) gene on chromosome 22, generating a hybrid BCR::ABL1 oncogene. Depending on the breakpoint site in the major BCR region on chromosome 22 (e13 or e14), two main messenger RNA transcripts occur, e13a2 (previously b2a2) and e14a2 (previously b3a2). Both transcripts encode for a novel oncoprotein of molecular weight 210 kDa, referred to as p210BCR::ABL1 (Fig. 110-1B). This oncoprotein exhibits constitutive kinase activity that leads to increased proliferation and reduced apoptosis of CML cells, endowing them with a growth advantage over their normal coun­ terparts. Over time, normal hematopoiesis is suppressed, but normal stem cells can persist and reemerge following effective anti-CML ther­ apy, for example with TKIs. In two-thirds of patients with Ph-positive

q11.2 5' e1 e1' e2' e12 e13 e14 e15 e16 CHAPTER 110 5' e19 1b Chronic Myeloid Leukemia 1a a2 a3 3' e1a2 e13a2 e14a2 e19a2 a11 p210BCR-ABL1 p230BCR-ABL1 p190BCR-ABL1 3' acute lymphoblastic leukemia (ALL) and in rare cases of CML, the breakpoint in BCR is more centromeric, in a region called the minor BCR region (mBCR). As a result, a shorter sequence of BCR is fused to ABL1, with a consequent e1a2 transcript and a smaller BCR::ABL1 oncoprotein, p190BCR::ABL1. When occurring in Ph-positive CML, this translocation is associated with a worse outcome. A rarer breakpoint in BCR occurs telomeric to the major BCR region in the micro-BCR (μ-BCR) region. It juxtaposes a larger fragment of the BCR gene to ABL1 and produces an e19a2 transcript and a larger p230BCR::ABL1 onco­ protein (associated with a more indolent CML course). Other rear­ rangements (based on different breakpoints in the ABL region), such as e13a3 or e14a3 (also resulting in a p210BCR::ABL1 oncoprotein), occur much less frequently. These are not readily identifiable nor quantifi­ able with the routine polymerase chain reaction (PCR) probes, thus producing falsely negative PCR levels on follow-up studies if not tested at diagnosis. The constitutive activation of BCR::ABL1 results in autophosphory­ lation and activation of multiple downstream pathways that affect gene transcription, apoptosis, stromal adherence, skeletal organization, and degradation of inhibitory proteins. These transduction pathways involve RAS, mitogen-activated protein (MAP) kinases, signal trans­ ducers and activators of transcription (STAT), phosphatidylinositol3-kinase (PI3k), MYC, and others. These interactions are mostly

mediated through tyrosine phosphorylation and require binding of BCR::ABL1 to adapter proteins such as GRB-2, CRK, CRK-like (CRK-L) protein, and Src homology containing proteins (SHC). Most BCR::ABL1 TKIs (imatinib, dasatinib, bosutinib, nilotinib, ponatinib) bind to the BCR::ABL1 ATP-binding domain, inhibiting its kinase activity, preventing the activation of transformation pathways, and inhibiting downstream signaling. As a result, proliferation of CML cells is inhibited and apoptosis induced, allowing the reemergence of nor­ mal hematopoiesis. An additional layer of complexity in CML is related to differences in signal transduction between CML-differentiated cells and early progenitors. Beta-catenin, Wnt1, Foxo3a, transforming growth factor β, interleukin 6, PP2A, SIRT1, and others have been implicated in CML stem cell survival. ABL1 also has a myristoyl site that functions as a negative regulator of its kinase activity. This site and its negative regulatory activity are lost upon fusion with BCR. Asciminib, a novel “third-generation” TKI (third generation refers to novel TKIs that inhibit the ABL1-T315I-mutated CML disease, such as ponatinib), is the first-in-class TKI that works through a novel mecha­ nism that specifically targets the ABL1 myristoyl pocket (STAMP is an acronym for specifically targets the ABL1 myristoyl pocket). Asciminib binds this myristoyl site and restores the lost inhibitory activity. Muta­ tions in other cancer-associated genes may also occur at diagnosis, most frequently in ASXL1, IKZF1, and RUNX1. Their significance is being clarified. Some reports suggest that their presence may be associated with worse response to TKI therapy and a higher risk of transforma­ tion to blastic phase. An ASXL1 mutation is often associated with a higher incidence of recurrent cytopenias on TKI therapy, resulting in frequent treatment interruptions, TKI dose reductions, failure to achieve optimal therapeutic milestones, and the need to proceed to allogeneic HSCT.

PART 4 Oncology and Hematology Experimental models have established the causal relationship between the BCR::ABL1 rearrangement and the development of CML. In animal models, expression of BCR::ABL1 in normal hema­ topoietic cells produced CML-like disorders or lymphoid leukemia, demonstrating the leukemogenic potential of BCR::ABL1 as a single oncogenic abnormality. Other models, however, suggest the need for a “second hit.” The cause of the BCR::ABL1 rearrangement is unknown. Molecular techniques that detect BCR::ABL1 at a level of 1 in 108 cells identify this molecular abnormality in the blood of up to 25% of normal adults and 5% of infants, but 0% of cord blood samples. This suggests that BCR::ABL1 is not sufficient to cause overt CML in the overwhelming majority of individuals in whom it occurs. Because CML develops in only 2 of 100,000 individuals annually, additional molecular events or poor immune recognition of the rearranged cells may contribute to overt CML. CML is defined by the presence of the BCR::ABL1 fusion gene in a patient with a myeloproliferative neoplasm. In some patients with a typical morphologic picture of CML, the Ph chromosome is not detectable by standard G-banding karyotype, but fluorescence in situ hybridization (FISH) and/or molecular studies (PCR) detect BCR::ABL1. These patients have a course similar to patients with Phpositive CML and respond to TKI therapy. Many of the remaining patients have atypical morphologic or clinical features and have other diseases, such as atypical CML, chronic myelomonocytic leukemia, and myelodysplastic syndrome/myeloproliferative neoplasms (MDS/ MPN). These individuals do not respond to TKI therapy and usually have a poor prognosis with a median survival of ~2–3 years. Detection of mutations in the granulocyte colony-stimulating factor receptor (CSF3R) in chronic neutrophilic leukemia (80% of cases) and in some cases of atypical CML (5–10% of cases), mutations in SETBP1 in atypi­ cal CML (25% of cases), and mutations in SF3B1 in MDS/MPN with ringed sideroblasts and marked thrombocytosis (MDS/MPN-RS-T; 50–70% of cases, associated with longer median survival of 7 years vs 3.3 years with wild-type SF3B1) supports the notion that these are distinct molecular and biologic entities. Patients with chronic neu­ trophilic leukemia or atypical CML whose disease is associated with CSF3R mutation may respond to ruxolitinib (a JAK2 inhibitor) therapy (complete response rate 50–60%).

The events associated with the transition of CML from a chronic to the accelerated-blastic phase are poorly understood. Characteristic chromosomal abnormalities such as a double Ph, trisomy 8, isochro­ mosome 17 or deletion of 17p (loss of TP53), 20q–, translocations involving 3q26, and others may be noted with disease acceleration. Molecular events associated with transformation include mutations in TP53, retinoblastoma 1 (RB1), myeloid transcriptions factors like RUNX1, and cell cycle regulators like p16. A plethora of other muta­ tions or functional abnormalities have been implicated in blastic trans­ formation, but no unifying theme has emerged other than the fact that BCR::ABL1 itself induces genetic instability that favors the acquisition of additional molecular defects and eventually results in blastic trans­ formation. One critical effect of TKIs is to stabilize the CML genome, leading to a reduced transformation rate. In particular, the previously observed sudden blastic transformations (i.e., abrupt transformation to blastic phase in a patient who had been in cytogenetic response) have become uncommon, occurring rarely in younger patients in the first 1–2 years of TKI therapy (usually sudden lymphoid blastic transfor­ mation). Sudden blastic transformations beyond the third year of TKI therapy are rare in patients who continue on TKI therapy. The inci­ dence of any CML blastic transformation is now reduced to 5–6% at 10 years. Moreover, the course of CML is now frequently more indolent in patients treated with TKI, even without cytogenetic response, com­ pared to previous experience with hydroxyurea/busulfan, suggesting a definite clinical benefit of continued inhibition of the kinase activity. Among patients developing resistance to TKIs, several resistance mechanisms have been observed. The most clinically relevant one is the development of ABL1 kinase domain mutations that may prevent the binding of TKIs to the catalytic site (ATP-binding site) of the kinase or maintain the kinase activity despite the presence of a TKI. More than 100 ABL1 kinase domain mutations have now been described, many of which confer relative or absolute resistance to imatinib. Consequently, secondgeneration (i.e., dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib, asciminib, olverembatinib [approved in China; ongoing trials worldwide since 2023]) were developed. All three third-generation TKIs demonstrate significant efficacy against T315I, a “gatekeeper” mutation that prevents binding of, and causes resistance to, imatinib and the second-generation TKIs (dasatinib, bosutinib, nilotinib). ■ ■CLINICAL PRESENTATION The presenting signs and symptoms in CML depend on the availabil­ ity of and access to health care, including physical examinations and screening tests. In developed countries, because of the wider access to health care screening and physical examinations, 50–60% of patients are diagnosed on routine blood tests and have minimal symptoms at presentation, such as fatigue. In geographic locations where access to health care is more limited, patients often present with high CML disease burden including splenomegaly, anemia, and related symptoms (abdominal pain, weight loss, fatigue), associated with a higher fre­ quency of high-risk CML. Presenting findings in patients diagnosed in the United States are shown in Table 110-1. Symptoms  Most patients with CML (90%) present in the indolent or chronic phase. Depending on the timing of diagnosis, patients are often asymptomatic (if the diagnosis is discovered during health care screening tests). Common symptoms, when present, are manifestations of anemia and splenomegaly. These include fatigue, malaise, weight loss (if high leukemia burden), or early satiety and left upper quadrant pain or masses (from splenomegaly). Less common presenting find­ ings include thrombotic or hyperviscosity-related events from severe leukocytosis or thrombocytosis. These include priapism, cardiovas­ cular complications, myocardial infarction, venous thrombosis, visual disturbances, dyspnea and pulmonary insufficiency, drowsiness, loss of coordination, confusion, or cerebrovascular accidents. Manifestations of bleeding diatheses include retinal hemorrhages, gastrointestinal bleeding, and others. Patients who present with, or progress to, the accelerated or blastic phases frequently have additional symptoms including unexplained fever, significant weight loss, severe fatigue, bone and joint pain, bleeding and thrombotic events, and infections.

TABLE 110-1  Presenting Signs and Symptoms of Newly Diagnosed Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase PARAMETER PERCENTAGE Age ≥60 years (median) 40–50 (55–65) Female gender 35–45 Splenomegaly

Hepatomegaly 5–10 Lymphadenopathy

Other extramedullary disease

Hemoglobin <10 g/dL 10–15 Platelets     >450 × 109 cells/L 30–35   <100 × 109 cells/L 3–5 White blood cells ≥50 × 109 cells/L 35–40 Marrow     ≥5% blasts

  ≥5% basophils 10–15 Peripheral blood     ≥3% blasts 8–10   ≥7% basophils

Additional chromosomal abnormalities (other than the Philadelphia chromosome) 4–5 Sokal risk     Low 60–65   Intermediate 25–30   High

Physical Findings  Splenomegaly is the most common physical finding, occurring in 20–70% of patients depending on health care screening frequency. Less common findings include hepatomegaly (5–10%), lymphadenopathy (5%), and extramedullary disease (skin or subcutaneous lesions). The latter indicates CML transformation if a biopsy confirms predominance of blasts. Other physical findings are manifestations of complications of high tumor burden described earlier (e.g., cardiovascular, cerebrovascular, bleeding). High basophil counts may be associated with histamine overproduction causing pru­ ritus, diarrhea, flushing, and even gastrointestinal ulcers. Hematologic and Marrow Findings  In untreated CML, leuko­ cytosis ranging from 10–500 × 109/L is common. The peripheral blood differential shows left-shifted hematopoiesis with predominance of neutrophils and the presence of bands, myelocytes, metamyelocytes, promyelocytes, and blasts (usually ≤5%). Basophils and/or eosinophils are frequently increased. Thrombocytosis is common, but thrombocy­ topenia is rare and, when present, suggests a worse prognosis, disease acceleration, or an unrelated etiology. Anemia is present in one-third of patients. Cyclic oscillations of counts are noted in 10–20% of patients without treatment. Biochemical abnormalities include a low leukocyte alkaline phosphatase score and high levels of vitamin B12, uric acid, lactic dehydrogenase, and lysozyme. The presence of unexplained and sustained leukocytosis, with or without splenomegaly, should lead to a marrow examination and cytogenetic analysis. The bone marrow is hypercellular with marked myeloid hyperpla­ sia and a high myeloid-to-erythroid ratio of 15–20:1. Marrow blasts are typically 5% or less; when higher, they carry a worse prognosis or represent transformation to accelerated phase (if they are ≥15%). Increased reticulin fibrosis (detected with silver stain) is common, with 30–40% of patients demonstrating grade 3–4 reticulin fibrosis. This was considered adverse in the pre-TKI era. With TKI therapy, reticulin fibrosis resolves in most patients and is not an indicator of poor prog­ nosis. Collagen fibrosis (Wright-Giemsa stain) is rare at diagnosis. Dis­ ease progression with a “spent phase” of myelofibrosis (myelophthisis,

or burnt-out marrow) was a common end-stage CML condition with busulfan therapy (20–30%); it is extremely rare now with TKI therapy.

Cytogenetic and Molecular Findings  The diagnosis of CML is straightforward and depends on documenting the translocation t(9;22) (q34.1;q11.2), which is identified by G-banding in 90% of cases. This is known as the Philadelphia chromosome (initially identified in Philadel­ phia as a minute chromosome; later identified to be chromosome 22) (Fig. 110-1). Some patients (~10%) may have complex translocations (complex variant Ph) involving three or more chromosomes including chromosomes 9 and 22 and one or more additional chromosomes. Others may have a “masked Ph,” involving translocations between chromosome 9 and a chromosome other than 22 (but molecularly showing the ABL1 rearrangement; known as simple variant Ph). The prognosis of these patients and their response to TKI therapy are like those in patients with Ph. Translocation (9;22)(q34;p13)/ETV6::ABL1 is now classified as a myeloproliferative neoplasm-eosinophilia and may respond better to second-generation TKIs. About 5–10% of patients may have additional chromosomal abnormalities (ACAs) in the Ph-positive cells at diagnosis. These usually involve trisomy 8, a double Ph, isochromosome 17 or 17p deletion, 20q–, or others. This was historically a sign of adverse prognosis, particularly when trisomy 8, double Ph, or chromosome 17 abnormalities were noted. A less com­ mon abnormality involving chromosome 3q26.2 occurs with disease progression and carries a poor prognosis. CHAPTER 110 Techniques such as FISH and PCR are now used to aid in the diag­ nosis of CML. They are more sensitive to estimate the CML burden in patients on TKI therapy. They can be done on peripheral blood and thus are more convenient to patients. Patients with CML at diagnosis should have a FISH analysis to quantify the percentage of Ph-positive cells, if FISH is used to replace marrow cytogenetic analysis in moni­ toring response to therapy. FISH will not detect additional chromo­ somal abnormalities; thus, a cytogenetic analysis is recommended at the time of diagnosis. In addition, 10–15% of patients may develop chromosomal abnormalities in Ph-negative metaphases after respond­ ing to TKIs. These abnormalities may carry a worse prognosis but are not detected by FISH unless already identified and FISH is used to follow them. Molecular studies at diagnosis are important to docu­ ment the type and presence of BCR::ABL1 transcripts to avoid spurious “undetectable” BCR::ABL1 transcripts on follow-up studies, with the false impression of a complete molecular response. The presence of the Philadelphia chromosome with “negative” PCR with standard method­ ology should prompt investigation of atypical transcripts (e13a3, e14a3, e19a2, others). Chronic Myeloid Leukemia Both FISH and PCR studies can be falsely positive at low levels or falsely negative because of technical issues. Therefore, a diagnosis of CML must always rely on a marrow analysis with routine cytogenetics. The diagnostic bone marrow confirms the presence of the Ph chromo­ some, detects additional chromosomal abnormalities, and quantifies the percentage of marrow blasts and basophils. In 10% of patients, the percentage of marrow blasts and basophils can be significantly higher than in the peripheral blood, conferring poorer prognosis or even rep­ resenting disease transformation. Monitoring patients on TKI therapy by cytogenetics, FISH, and PCR has become an important standard practice to assess response to therapy, emphasize compliance, evaluate possible treatment resistance, identify the need to change TKI therapy, and determine the need to assess for kinase domain mutations. Because of the decreasing reliance of bone marrow aspirations to monitor response, equivalence has been established to correlate cytogenetic results with PCR values. These are not absolute correlations but provide adequate guidance. A partial cytogenetic response is defined as the presence of 35% or less Ph-

positive metaphases by routine cytogenetic analysis. This is roughly equivalent to BCR::ABL1 transcripts on the International Scale (IS) of 10% or less. A complete cytogenetic response refers to the absence of Ph-positive metaphases (0% Ph positivity). This is approximately equiv­ alent to BCR::ABL1 transcripts (IS) ≤1% (MR2). A major molecular response (MMR or MR3) refers to BCR::ABL1 transcripts (IS) ≤0.1%, or roughly a 3-log or greater reduction of BCR::ABL1 transcripts from

a standardized baseline. MR4 (deep molecular response; DMR) refers to BCR::ABL1 transcripts (IS) ≤0.01%, and MR4.5 refers to BCR::ABL1 transcripts (IS) ≤0.0032%, roughly equivalent to a 4.5-log reduction or greater of transcripts.

Findings in CML Transformation  Progression of CML is usu­ ally associated with leukocytosis resistant to therapy, increasing anemia, fever and constitutional symptoms, and increased blasts and basophils in the peripheral blood or marrow. Criteria of acceleratedphase CML, historically associated with median survival of <2 years, include the presence of 15% or more peripheral blasts, 30% or more peripheral blasts plus promyelocytes, 20% or more peripheral baso­ phils, cytogenetic clonal evolution (presence of additional chromo­ somal abnormalities other than Ph), and thrombocytopenia <100 × 109/L (unrelated to therapy). About 5–10% of patients present with de novo accelerated phase or blastic phase. The prognosis of de novo accelerated phase with TKI therapy has improved, with an estimated 8-year survival rate of 60–70%. The median survival of accelerated phase evolving from chronic phase has also improved from a histori­ cal median survival of 18 months to an estimated 3-year survival rate of 50% on TKI therapy. Therefore, the criteria for accelerated-phase CML should be revisited because most clinical criteria defining accel­ erated phase have lost much of their prognostic significance. The newest World Health Organization (WHO) classification suggested eliminating accelerated-phase CML as an entity and classifying such patients as high-risk CML. However, the survival of patients with both de novo and evolved accelerated-phase CML is significantly worse than in high-risk CML. The accelerated-phase definition should be maintained in order to recognize such patients and treat them differ­ ently than chronic-phase CML, either with existing standards of care (combinations of TKIs with other agents, allogeneic HSCT) or on investigational trials of novel TKIs or other modalities. Blastic-phase CML is defined by the presence of 30% or more peripheral or mar­ row blasts or the presence of sheets of blasts in extramedullary disease (usually skin, soft tissues, or lytic bone lesions). Blastic-phase CML is commonly myeloid (60%) but can present uncommonly as erythroid, promyelocytic, monocytic, or megakaryocytic. Lymphoid blastic phase occurs in about 25% of patients. Lymphoblasts are terminal deoxy­ nucleotide transferase positive and peroxidase negative (although occasionally with low positivity up to 3–5%) and express lymphoid markers (CD10, CD19, CD20, CD22). They also often express myeloid markers (50–80%), resulting in diagnostic challenges. Proper immu­ nophenotypic diagnosis is important because lymphoid blastic-phase CML is responsive to anti-ALL-type chemotherapy (e.g., hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, and dexamethasone]) in combination with TKIs and immunotherapies (complete response rate 70%; median survival 3 years; high rates of bridging to allogeneic HSCT and possible cure). PART 4 Oncology and Hematology ■ ■PROGNOSIS AND CML COURSE Before the TKI era, the annual mortality in CML was 10% in the first 2 years and 15–20% thereafter. The median survival in CML was 3–7 years (with hydroxyurea-busulfan and interferon α). With­ out a curative option of allogeneic HSCT, the course of CML was toward transformation to, and death from, accelerated or blastic phases for most patients. Even disease stability was unpredictable, with some patients demonstrating sudden transformation to a blastic phase. With imatinib therapy, the annual mortality rate in CML has decreased to 1–2% in the first 20 years of observation. The 10-year survival rate is about 85%, the 10-year CML-specific survival rate is 90%, and CML-specific mortality rate is 10%; the 10-year incidence of blastic transformation is 5–6%. More than half of the deaths are from conditions other than CML, such as old age, comorbidities, accidents, suicides, other cancers, and other medical conditions (e.g., infections, surgical procedures) (Fig. 110-2). The course of CML has also become quite predictable. In the first 2 years of TKI therapy, rare sudden transformations are still reported (1–2%), usually lymphoid blastic transformations that respond to combinations of chemother­ apy and TKIs followed by allogeneic HSCT. These may be explained

by the intrinsic mechanisms of sudden transformation already exist­ ing in the CML clones before the start of therapy that were not ame­ nable to TKI inhibition, in particular imatinib. Second-generation TKIs (nilotinib, dasatinib, bosutinib) used as frontline therapy have reduced the incidence of transformation in the first 2–3 years from 4–6% with imatinib to 1–2% with second-generation TKIs. Disease transformation to accelerated or blastic phase is rare with continued TKI therapy, estimated at <1% annually in years 4–10 of follow-up. Patients usually develop resistance in the form of cytogenetic relapse, followed by hematologic relapse and subsequent transformation, rather than the previously feared sudden transformation without the warning signals of cytogenetic-hematologic relapse. Before the imatinib era, several pretreatment prognostic factors predicted for worse outcome in CML and have been incorporated into prognostic models and staging systems. These have included older age, significant splenomegaly, anemia, thrombocytopenia or thrombocyto­ sis, high percentages of blasts and basophils (and/or eosinophils), mar­ row fibrosis, additional chromosomal abnormalities, and others. The introduction of TKIs into CML therapy has decreased or eliminated the prognostic impact of these prognostic factors and the significance of the CML models (e.g., Sokal, Hasford, European Treatment and Outcome Study [EUTOS]). Treatment-related prognostic factors have emerged as the most important prognostic factors in the era of ima­ tinib therapy. Achievement of complete cytogenetic response (MR2) has become the major therapeutic endpoint and is the only endpoint associated with improvement in survival. Achievement of MMR (MR3) is associated with decreased risk of events (relapse) and CML transformation but not with survival prolongation among patients with complete cytogenetic response. This may be due to the efficacy of salvage TKI therapies, which are implemented at the first evidence of cytogenetic relapse. Achievement of durable DMR (MR4/MR4.5) may offer the possibility of treatment-free remission (TFR). A durable DMR for 2+ years is associated with a TFR rate of 50%; a durable DMR for 5+ years is associated with a TFR rate of 80%+. A TFR may allow a temporary TKI therapy interruption in women pursuing pregnancy. The lack of achievement of MMR or DMR should not be considered as “failure” of a particular TKI therapy and/or an indication to change the TKI or to consider allogeneic HSCT. Long-term updates of randomized trials suggest that second-

generation TKIs and imatinib are similarly effective in lower-risk CML; second-generation TKIs may offer a therapeutic advantage in high-risk CML and when TFR is an important treatment endpoint (younger patients). TREATMENT Chronic Phase Chronic Myeloid Leukemia Since 2001, six oral BCR::ABL1 TKIs have been approved by the U.S. Food and Drug Administration (FDA) for the treat­ ment of CML. These include imatinib (Gleevec, Glivec), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib (Bosulif), ponatinib (Iclu­ sig), and asciminib (Scemblix). Dasatinib, nilotinib, and bosutinib are referred to as second-generation TKIs; ponatinib and asciminib are referred to as third-generation TKIs, a term also used generally for the more recently developed TKIs that are active against T315Imutated CML (asciminib is also referred to as a STAMP inhibitor because of its different mechanism of action). Nilotinib is similar in structure to imatinib but 30 times more potent. Dasatinib and bosutinib inhibit the SRC family of kinases in addition to ABL1, with dasatinib reported to be 300 times more potent and bosuti­ nib 30–50 times more potent than imatinib (Table 110-2). Pona­ tinib inhibits vascular endothelial growth factor receptor (VEGFR), which may be partly responsible for the high incidence of hyperten­ sion observed with this agent (Table 110-2). ESTABLISHED AND EVOLVING THERAPEUTIC CONCEPTS IN CML In the early days of TKI development, the primary aim in CML therapy was to improve survival, as the therapeutic miracle of

1.0 0.8 Survival probability 0.6 0.4 Total Died TKI 2001-present Death-CML TKI 2001-present Death-CML or SCT TKI 2001-present 1996-2000 1991-1995 1983-1990 <1982

0.2

0.0

Years A CML Phase Referral Year Total Died Median (months) Accelerated Accelerated Blastic Blastic 1.0 0.8 Survival probability 0.6 0.4 0.2 0.0

B FIGURE 110-2  A. Survival in newly diagnosed chronic-phase chronic myeloid leukemia (CML) by era of therapy (MD Anderson Cancer Center experience from 1965 to present). Top blue curve is survival with tyrosine kinase inhibitors (TKIs), accounting for only CML-related deaths. The orange curve (second from top) accounts for deaths related to CML or CML treatment complications (e.g., deaths following allogeneic hematopoietic stem cell transplant [HSCT]). The red curve (third from top) is survival including all deaths regardless of causality (old age, car accidents, suicide, gun shots, second cancers, complications of unrelated surgeries, infections, others). The difference in the denominators, 613 minus 597 cases, is because 16 deaths were from unknown/undocumented causes (outside MD Anderson and no good tracking for cause of death). B. Survival in patients with accelerated- and blastic-phase CML referred to MD Anderson Cancer Center by era of therapy, demonstrating the significant survival benefit in the TKI era in accelerated-phase CML but the modest benefit in blastic-phase CML. Referred cases included de novo and post-chronic-phase transformations. TABLE 110-2  Medical Therapeutic Options in Chronic Myeloid Leukemia AGENT (BRAND NAME) APPROVED INDICATIONS DOSE SCHEDULE NOTABLE TOXICITIES Imatinib mesylate (Gleevec) All phases 400 mg daily See text Dasatinib (Sprycel) All phases First-line: 100 mg daily Salvage: 100 mg daily in chronic phase; 140 mg daily in transformation Nilotinib (Tasigna) All phases except blastic phase First-line: 300 mg twice daily Salvage: 400 mg twice daily Bosutinib (Bosulif) All phases First line: 400 mg daily Salvage: 500 mg daily Ponatinib (Iclusig) T315I mutation; failure of ≥2 tyrosine kinase inhibitors 45 mg daily (may consider lower starting doses, e.g.,

30 mg daily; lower the dose to 15 mg daily once a complete cytogenetic response is achieved) Asciminib (Scemblix) Third-line therapy; T315I mutation 40 mg twice daily or 80 mg daily; T315I: 200 mg twice daily Arterial occlusive events; hypertension; (others?) Omacetaxine mepesuccinate (Synribo) Failure ≥2 tyrosine kinase inhibitors 1.25 mg/m2 subcutaneously twice daily for 14 days of induction; 7 days of maintenance every month (consider shorter dose schedules, 7 days of induction, 2–5 days of maintenance)

95% 92% 86% 67% 44% 37% 8%

CHAPTER 110 1980–2000 2001–2013 1980–2000 2001–2013

p <0.001 Chronic Myeloid Leukemia 41% p <0.001 19% 5% 2% p = 0.015 Years Myelosuppression; pleural and pericardial effusions; pulmonary hypertension Diabetes; arterio-occlusive events; pancreatitis Diarrhea; liver toxicity; renal dysfunction Skin rashes (10–20%); pancreatitis (5%); arterio-occlusive events (10–20%); systemic hypertension (10–15%) Myelosuppression

near-normal survival with TKI therapy was never anticipated. It was thought that CML cells would develop resistance mechanisms after a period of TKI exposure. This happened, as CML was the first tumor demonstrating the development of mutations in the ABL1 kinase domain that prevented the binding of the TKIs. However, the true resistance rate was only 10% after 10 years of imatinib expo­ sure. The TKIs were developed at a dose level below the maximum tolerated dose (MTD; traditional development of chemotherapy agents in cancer), based on the toxicities noted in the first one to two courses or few months of therapy. As the success of therapy required treatment continuation for years, or even a patient’s life­ time, additional unanticipated toxicities were observed with longterm exposures. This shifted the concept to develop these targeted therapies in CML (and in other cancers) at an “optimal biologic dose” (OBD; a dose that presumably maintains the same efficacy but reduces toxicities). Such OBDs were derived initially from clini­ cal experience in CML, although ongoing trials are basing them on translational studies of the drug exposure and target modulation, compared with preclinical research findings. This led, in CML, to study dasatinib 50 mg daily as frontline therapy, which proved to be as effective and less toxic than 100 mg daily. Similar results were reported with other TKIs where dose adjustments after achiev­ ing a good molecular response maintained efficacy. Other early concepts included the following: (1) changing a TKI if evidence of toxicity (rather than lowering the TKI dose, with the concern being that lowering the TKI dose will compromise efficacy and cause resistance); (2) changing a TKI if the National Comprehensive Cancer Network (NCCN)/European Leukemia Network (ELN) landmark-defined milestones of “failure” or “warning” were noted; and (3) changing TKI therapy in a responding patient (MMR or even MR4), in order to achieve a complete molecular response and aim for a TFR status. As experience matured, it was noted that such strategies may be harmful, as they increased the cost of therapy and increased the risk of potential additional side effects, without ben­ efiting patients. At present, therapy of CML may consider lowerdose schedules of TKIs as frontline or later-line therapy; reducing the TKI dose once a good molecular response (≥MR2) is achieved; not changing TKI therapy in patients in good molecular response; and perhaps not changing TKI therapy based on the NCCN/ELN milestones (as the long-term follow-up data showed survival to be favorable even among patients who did not achieve these molecular milestones). These concepts will be discussed further.

PART 4 Oncology and Hematology At the beginning of the TKI experience, survival prolongation was the primary goal of therapy, but once near-normal survival was accomplished, investigators started addressing additional treatment endpoints. Thus, a second treatment goal was whether CML is cur­ able (defined, as in other cancers, as the ability to stop TKI therapy without disease recurrence after several years of observation). This led to studies aimed at stopping TKI therapy after 2–5 years of durable DMR and achieving a TFR status. The third treatment goal is to make TKI therapies available and affordable to all patients (rather than the few who can afford them), a problem addressed with the availability of generic TKIs. The fourth treatment goal is to minimize the early and long-term toxicities (currently addressed with studies investigating the OBDs of TKIs). Frontline Therapy of CML  Imatinib, dasatinib, bosutinib, and nilo­ tinib are all acceptable frontline therapies in CML. The long-term results of imatinib are very favorable. The 10-year cumulative rate of MMR is 90%, and of DMR 80%. The 10-year survival rate was 82%, and 10-year relative (compared with age-matched population) survival rate 92%. About 25% had to change to second-generation TKIs, 10% because of resistance to imatinib and 15% for other reasons (adverse events). The 10-year incidence of blastic-phase CML was 5.8%. In multiple randomized studies, (e.g., ENESTnd, DASISION, BFORE), the second-generation TKIs resulted in bet­ ter outcomes in early surrogate endpoints (higher rates of MMR and MR4.5; lower rates of blastic transformation). However, none

showed survival benefit. This may be because the rate of complete cytogenetic response (MR2) was ultimately similarly high with ima­ tinib versus second-generation TKIs and because later-line salvage TKI therapy (following close observation and treatment change at progression) provided highly effective therapy; this ensured adequate long-term outcome despite resistance or intolerance to initial imatinib therapy. The choice of TKI frontline CML therapy depends on several factors: (1) the treatment aims (survival, TFR), which are tightly linked to age; (2) the TKI cost and affordability (generic vs patented TKIs); and (3) the patient comorbidities (e.g., avoid dasatinib if his­ tory of lung injury or chronic lung disease; avoid nilotinib if history of pancreatitis, diabetes mellitus, or arterio-/veno-occlusive spastic events; avoid bosutinib if history of liver or renal dysfunction of gastrointestinal problems [colitis, diverticulitis]). In general, if survival is the treatment aim in CML, all four TKIs achieve similar outcomes. However, if TFR is the treatment aim, then secondgeneration TKIs may be preferred. Second-generation TKIs may also be preferred in high-risk chronic-phase CML. Two additional important aims include the comparative long-term toxicities and the TKI treatment value. The frontline TKI dose schedules are as follows: imatinib 400 mg orally daily; dasatinib 100 mg orally daily; bosutinib 400 mg orally daily (use dose escalation of 100–200 mg daily for 1–2 weeks, 300 mg daily for 2 weeks, then 400 mg daily to avoid the early self-limited gastrointestinal toxicity [diarrhea, nausea, and vomiting]); and nilotinib 300 mg orally twice a day (on an empty stomach). Dasat­ inib 50 mg orally daily is as effective in frontline therapy as 100 mg daily and significantly less toxic. A recent randomized trial compared asciminib to investigator’s TKI of choice in frontline CML therapy. The 12-month MMR was significantly higher with asciminib versus other TKIs (68% vs 49%; p<.001) and with asciminib versus imatinib (69% vs 40%); p<.001), but not with asciminib versus second-generation TKIs (66% vs 58%). Whether the higher MMR rate will translate into better longterm survival or TFR rates, lower long-term side-effects, or better treatment value is an open question. Management of TKI Toxicities  In the first 10–15 years of the TKI experience, it was common practice to change TKI therapy when toxicities occurred because of the erroneous assumption that reducing the TKI dose may reduce efficacy. This was not borne out in the long-term experience, particularly in patients who are in good molecular response. Among such patients, the TKI dose can be reduced for mild-moderate or even severe reversible toxicities. Imatinib can be reduced to 100–300 mg daily, dasatinib to 20–50 mg daily, nilotinib to 200 mg daily or 150 mg twice daily, bosutinib to 100–300 mg daily, and ponatinib to 15–30 mg daily, depending on the toxicities and molecular response. Side effects of TKIs are generally mild to moderate, although with long-term TKI therapy, they could affect the patient’s quality of life. Serious side effects occur in <5–10% of patients. With ima­ tinib therapy, common mild to moderate side effects include fluid retention, weight gain, nausea, diarrhea, skin rashes, periorbital edema, bone or muscle aches, fatigue, and others (rates of 10–20%). In general, second-generation TKIs are associated with lower rates of these bothersome adverse events. However, dasatinib 100 mg daily is associated with higher rates of myelosuppression (20–30%), particularly thrombocytopenia; pleural (10–25%) or pericardial effusions (≤5%); and pulmonary hypertension (<5%). A lower dose of dasatinib (50 mg daily instead of 100 mg daily) used in frontline CML therapy resulted in similar efficacy and a lower incidence of serious side effects (pleural effusions <5%, myelosuppression <10%). Nilotinib is associated with higher rates of hyperglycemia (10–20%), pruritus and skin rashes, hyperbilirubinemia (typically among patients with Gilbert’s syndrome and mostly of no clinical consequences), and headaches. Nilotinib is also associated with occasional instances of pancreatitis (<5%). Nilotinib 300–400 mg

twice daily is associated with a 10-year cumulative incidence of cardiovascular complications of 25–35%. Bosutinib is associated with higher rates of liver toxicity, renal dysfunction, and early and self-limited gastrointestinal adverse events, particularly diar­ rhea. Occasionally, the gastrointestinal symptoms mimic chronic severe enterocolitis, which reverses with treatment discontinuation. Ponatinib 45 mg daily is associated with higher rates of serious skin rashes (10–15%), pancreatitis (10%), elevations of amylase/ lipase (10%), and systemic hypertension (50–60%; severe in 20%).

Arterio-occlusive events (cardiovascular, cerebrovascular, and peripheral arterial) have been reported with most TKIs. The inci­ dence appears to be highest with ponatinib, but both nilotinib and dasatinib are associated with these events at an incidence significantly higher than imatinib or bosutinib. Among the TKIs, imatinib and bosutinib are associated with the lowest incidence of cardiovascular events. With long-term follow-up, rare but clinically relevant serious toxicities are emerging. Renal dysfunction and occasionally renal failure (creatinine elevations >2–3 mg/dL) are observed in 2–3% of patients, more frequently with imatinib and bosutinib than other TKIs, and usually reverse with TKI discontinuation and/or dose reduction. Rarely, patients may develop TKI-related peripheral neuropathy or even central neurotoxicities that are misdiagnosed as dementia or Alzheimer’s disease; these may reverse slowly after TKI discontinuation. Some toxicities are prohibitive and require a change of TKI therapy: recurrent pleural effusions (most commonly with dasat­ inib; least with imatinib and nilotinib; responsive to a short course of steroids); vasospastic or vaso-occlusive events (cerebrovascular accidents, myocardial infarction or unstable angina; more common with ponatinib and nilotinib; least with imatinib and bosutinib); pulmonary hypertension (1–2% with dasatinib, but can occur with other TKIs; slowly reversible with a short course of steroids and sildenafil citrate), pancreatitis (2% with nilotinib, 2–4% with ponatinib); neurologic problems (dementia-like, parkinsonism; rare and slowly reversible with TKI discontinuation); immunemediated events (pneumonitis, myocarditis, pericarditis, hepatitis, nephritis; usually reversible with TKI discontinuation and a short course of high-dose steroids [e.g., methylprednisolone 50 mg twice daily for 3–5 days]); and severe colitis (bosutinib; reversible with discontinuation). When switching TKI therapy for prohibitive toxicity, the dose of the new TKI does not have to be the dose recommended for “failure” (a term that historically encompassed resistance and intolerance). Many of these patients are already in good molecular response, and the dose of the new TKI used for previous TKI intolerance can be lower, particularly if the patient is already in ≥MR2: dasatinib 20–50 mg daily; bosutinib 100–300 mg daily; nilotinib 200 mg daily or 150 mg twice a day; ponatinib 15–30 mg daily. TKI cross-intolerance may be more common than previously thought. Because the TKIs have different chemical structures, cross-intolerance was thought to be uncommon. With experience, it appears that patients who have intolerance to one TKI may more often have intolerance to others, with the intolerance/side effect manifesting as the same or as a different one. Discontinuation of TKIs and TFR  Several studies have confirmed that TKI discontinuation among patients who achieve DMR (MR4) for longer than 2–3 years can result in TFR rates of 40–60%. Discon­ tinuation of TKI therapy after 5+ years of DMR is associated with TFR rates of 80%+. Since the incidence of durable MR4 is 60–80%, ~30–60% of all patients with CML on TKI therapy may potentially achieve TFR with optimization of the current TKI strategies. Sug­ gested conditions to attempt TFR include low or intermediate Sokal risk CML in first chronic phase (no evidence or history of transfor­ mation); quantifiable BCR::ABL1 transcripts (e13a2, e14a2); longterm TKI therapy (5+ years); and documented DMR for >2–5 years. Once TFR is attempted, patients should be monitored molecularly

every 1.5–2 months in the first 6–12 months, every 2–3 months in the second year, and then every 3–6 months in subsequent years (perhaps for up to 6–8 years of TFR status). TKIs should not be restarted unless the BCR::ABL1 transcripts (IS) increase to >0.1% (documented at least twice).

Management of TKI Resistance  Resistance to a TKI refers today to BCR::ABL1 transcripts (IS) >10% after 6 months of TKI frontline therapy or BCR::ABL1 transcripts (IS) >1% after 12+ months of frontline TKI therapy. The NCCN and ELN updates of the criteria for resistance and suboptimal response have evolved over time, settling on more conservative criteria to change TKI therapy. The long-term follow-up studies have shown that patients who previ­ ously met suboptimal or resistance criteria still had excellent longterm survival without changing TKI therapy. For example, older patients with persistent BCR::ABL1 transcripts (IS) 1–10% at 2 years of imatinib therapy still had 10-year survival rates similar to those with transcripts <1%. Before switching TKI therapy for resistance, it is important to check for BCR::ABL1 kinase domain mutations. About 50% of patients with TKI resistance have BCR::ABL1 mutations that may selectively respond to particular TKIs. For example, muta­ tions involving Y253H, E255K/V, and F359V/C/I respond better to dasatinib or bosutinib. Mutations involving V299L, T315A, and F317L/F/I/C respond better to nilotinib. T315I mutations require therapy with ponatinib or asciminib and serious consideration of allogeneic HSCT. CHAPTER 110 Dasatinib, bosutinib, nilotinib, ponatinib, and asciminib are approved for CML salvage therapy. The second-generation TKIs are excellent second-line therapies after imatinib frontline resistance. In patients with resistance to one second-generation TKI, switch­ ing to another second-generation TKI yields poor results (MR2 rate 10–20%; unless specific guiding mutations), and switching to ponatinib is indicated. Ponatinib is a very potent TKI with high activity in T315I-mutated CML and in CML after two TKI expo­ sures (particularly if there is resistance to a second-generation TKI). In third-line therapy, ponatinib produces high molecular response rates and improves survival compared with second-generation TKIs. Asciminib is approved as third-line therapy and for T315Imutated disease. Chronic Myeloid Leukemia The TKI dose schedule in later-line therapy for CML resistance is as follows: dasatinib 100 mg daily; nilotinib 400 mg twice daily; bosutinib 500 mg daily; ponatinib 45 mg daily; and asciminib 40 mg twice daily or 80 mg once daily or 200 mg twice daily in T315Imutated CML. Because ponatinib 45 mg daily may be associated with serious side effects, a response-directed dose-adjusted regi­ men (starting dose of 45 mg and reduction to 15 mg once MR2 is achieved) was investigated and resulted in a lower incidence of arterio-occlusive events. TKI later-line therapy in chronic-phase CML with dasatinib, nilotinib, bosutinib, ponatinib, or asciminib is associated with MR2 rates of 30–80%, depending on the line of therapy (second vs later), CML status (cytogenetic/molecular relapse vs hematologic relapse), prior response to other TKIs, number of prior TKIs used, and the mutations at the time of relapse. The estimated 6- to 8-year survival rates with second-generation TKIs as second-line therapy are 65–75% (compared with <30–40% before their availability). Ponatinib third-line therapy resulted in an MR2 rate of 50–60%, MMR rate of 40%, and a 5-year overall survival rate of 70–75%. Its results appear even surprisingly better in real-word data: MR2 rate 80%, MMR rate 70–75%, and MR4 rate 40%. ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT Allogeneic HSCT, a curative modality in CML, is associated with long-term survival rates of 50–70% when implemented in chronic phase. It carries the risk of complications related to myelosuppres­ sion, infections, and graft-versus-host disease (GVHD). Conse­ quently, the early (1-year) mortality rate is 5–30%, and 10–15% of

patients die in the subsequent 1–2 decades from long-term com­ plications of the transplant (rather than from CML relapse). These are related to GVHD, organ dysfunction, development of second cancers, occasional late relapses, and hazard ratios for mortality higher than in the normal population. Other significant morbidi­ ties include infertility, chronic immune-mediated complications, cataracts, hip necrosis, and other morbidities affecting quality of life. The cure and early mortality rates in chronic-phase CML are also associated with several factors: patient age, duration of chronic phase, whether the donor is related or unrelated, degree of match­ ing, preparative regimen, and others. In accelerated-phase CML, the cure rates with allogeneic HSCT are 30–50%, depending on the definition of accelerated disease. Patients with clonal evolution as the only criterion have cure rates of 40–50%. Patients undergo­ ing allogeneic HSCT in second chronic phase have cure rates of 40–50%. The cure rates with allogeneic HSCT in blastic-phase CML are ≤20%. Post–allogeneic HSCT strategies in the setting of molecu­ lar or cytogenetic relapse include the use of TKIs for prevention or treatment of relapse, donor lymphocyte infusions, and second allogeneic HSCTs, among others. TKIs are successful at reinducing cytogenetic/molecular remissions in the setting of cytogenetic or molecular relapse after allogeneic HSCT.

Choice and Timing of Allogeneic HSCT  Allogeneic HSCT was considered first-line CML therapy before 2000. The positive experi­ ence with TKIs has now relegated its use as a later-line approach. It should be considered in any patient in chronic-phase CML who develops resistance to a second-generation TKI or with a T315I-mutated disease. Relying on third-generation TKIs in these settings as long-term therapy can be very expensive ($250,000 to $1.5 million per year) and may be associated with serious toxici­ ties. Among patients who present with or evolve to blastic phase, combinations of chemotherapy and TKIs should be used to induce remission, followed by allogeneic HSCT as soon as possible. The same applies to patients who evolve from chronic to accelerated phase. Patients with de novo accelerated-phase CML may do well with long-term TKI therapy (estimated 8-year survival rate 75%). Older patients with CML (age 65–70 years or older) have a reason­ able CML-specific 10-year overall survival rate even with persistent molecular disease after 2 years of TKI therapy, with BCR::ABL1 transcripts (IS) 1–10%, or even > 10%. Such patients may opt to continue on daily TKI therapy alone or with the addition of other agents (hydroxyurea, decitabine, low-dose cytarabine). They can then remain in chronic-phase CML disease without MR2 and avoid the adverse events and poorer quality of life associated with allogeneic HSCT. MONITORING THERAPY IN CML Achievement of complete cytogenetic response by 12 months of imatinib therapy and its persistence later, the only consistent prog­ nostic factor associated with prolonged survival, is now the main therapeutic endpoint in CML. Failure to achieve a complete cyto­ genetic response by 12 months or occurrence of later cytogenetic or hematologic relapse is considered as treatment failure and an indication to change therapy. Because later-line TKI therapy may re-establish good outcome, it is important to ensure patient compliance to continued TKI therapy and change therapy when cytogenetic relapse is confirmed unless this is related to nonad­ herence. Patients on frontline imatinib therapy should be closely monitored until documentation of complete cytogenetic response, at which time they can be monitored every 6 months with periph­ eral blood PCR or more frequently (e.g., every 3 months) if there are concerns about changes in BCR::ABL1 transcripts. Cytogenetic relapse on imatinib is an indication of treatment failure and need to change TKI therapy. Mutational analysis in this instance helps in the selection of the next TKI and identifies mutations in 30–50% of patients. Mutational studies by standard Sanger sequencing (which is the technique currently available in most clinical laboratories) in patients in complete cytogenetic response (in whom there may be PART 4 Oncology and Hematology

concerns of increasing BCR::ABL1 transcripts) identify mutations in ≤5% and are therefore not indicated. Changes of TKI therapy for patients with “slow” molecular response have not been proven to be of long-term benefit compared to changes when more obvious signs of resistance appear. TREATMENT OF ACCELERATED AND BLASTIC PHASES Patients in accelerated or blastic phase may receive therapy with TKIs, preferably second- or third-generation TKIs (dasatinib, nilo­ tinib, bosutinib, ponatinib), alone or in combination with chemo­ therapy, to reduce the CML burden, before undergoing allogeneic HSCT. Response rates (major hematologic) with single-agent TKIs range from 30 to 50% in accelerated phase and from 20 to 30% in blastic phase. Cytogenetic responses, particularly complete cytoge­ netic responses, are uncommon (10–30%) and transient in blastic phase. Studies of TKIs in combination with chemotherapy show that combined TKI-chemotherapy strategies increase the response rates and their durability and improve survival. This is particularly true in CML lymphoid blastic phase, where the combination of anti-ALL chemotherapy with TKIs results in complete response rates of 70% and median survival times of 3 years (compared with historical response rates of 40–50% and median survival times of 12–18 months). This allows many patients to undergo allogeneic HSCT in a state of minimal CML burden or second chronic phase, which are associated with higher probability of long-term survival. In CML nonlymphoid blastic phase, anti–acute myeloid leukemia chemotherapy combined with TKIs results in complete remission rates of 30–50% and median survival times of 12 months (compared with historical response rates of 20–30% and median survival times of 3–5 months). In accelerated phase, response to single TKIs is significant in conditions where “softer” accelerated phase criteria are considered (e.g., clonal evolution alone, thrombocytosis alone, significant splenomegaly or resistance to hydroxyurea, but without evidence of high blast and basophil percentages). In accelerated phase, combinations frequently include TKIs with low-intensity chemotherapy such as low-dose cytarabine, decitabine, interferon α, hydroxyurea, or others. OTHER TREATMENTS AND SPECIAL THERAPEUTIC CONSIDERATIONS Interferon `  Interferon α is considered in combination with TKIs (an investigational approach) and occasionally in patients during pregnancy. Chemotherapeutic Agents  Hydroxyurea remains a safe and effec­ tive agent (at daily doses of 0.5–10 g) to reduce initial CML burden, as a temporary measure in between definitive therapies, or in com­ bination with TKIs to sustain complete hematologic or cytogenetic responses. Busulfan is often used in allogeneic HSCT preparative regimens. Because of its side effects (delayed myelosuppression, Addison-like disease, pulmonary and cardiac fibrosis, myelofi­ brosis), it is now rarely used in the chronic management of CML. Omacetaxine, low-dose cytarabine, decitabine, 6-mercaptopurine, 6-thioguanine, thiotepa, anagrelide, and other agents are sometimes useful in different CML settings to control the disease burden, usu­ ally in combination with a daily TKI. Others  Leukapheresis is occasionally used in patients presenting with extreme leukocytosis and leukostatic complications. Single doses of high-dose cytarabine or high doses of hydroxyurea, with tumor lysis management, may be as effective and less cumbersome. Pregnancy and CML  TKI therapy in the first trimester of preg­ nancy is associated with fetal malformations (2–10%). Women with CML who become pregnant should discontinue TKI therapy immediately. Among 125 babies delivered to women with CML who discontinued imatinib therapy as soon as the pregnancy was known, three babies were born with neurologic, skeletal, and renal malformations, suggesting the teratogenicity of imatinib known from animal studies. A similar experience has been reported with

dasatinib, where the incidence of malformations was reported to be higher, 10–12%. Data are scant with other TKIs. Control of CML during pregnancy can be managed with leukapheresis for severe symptomatic leukocytosis in the first trimester and with hydroxyurea subsequently until delivery. TKI therapy with ima­ tinib (but not dasatinib; scant data with nilotinib or bosutinib), if indicated, may be safe after 20 weeks of gestation and in the third trimester. There are reports of successful pregnancies and deliveries of normal babies with interferon α therapy and registry studies in essential thrombocytosis, but interferon α has side effects that may be troublesome during pregnancy, can be antiangiogenic, and may increase the risk of spontaneous abortions. Cytogenetic Abnormalities in Ph-Negative Cells; Mutations and CML  Approximately 5% of patients on TKI therapy and in

cytogenetic/molecular response may develop chromosomal abnormalities in the Ph-negative cells. These may involve loss of

chromosome Y, trisomy 8, 20q–, chromosome 5 or 7 abnormalities, and others. Most chromosomal abnormalities disappear spon­ taneously and may be indicative of the genetic instability of the hematopoietic stem cells that predisposes the patient to develop CML in the first place. Rarely (in <1% of instances), abnormalities involving chromosomes 5 or 7 may be truly clonal and evolve into myelodysplastic syndrome, acute myeloid leukemia, or myelo­ proliferative neoplasms. This is thought to be part of the natural course of patients in whom CML was suppressed and who live long enough to develop other hematologic malignancies. The presence of mutations (ASXL1, DNMT3A, RUNX1, TET2, EZH2, IDH1/2) at diagnosis or later during CML was discussed earlier. ■ ■GLOBAL ASPECTS OF CML Routine physical examinations and blood tests in the United States and advanced countries result in early detection of CML in most patients. About 50–70% of patients with CML are diagnosed incidentally, and high-risk CML as defined by prognostic models (e.g., Sokal risk groups) is found in only 10% of patients. This is different in emerging nations where most patients are diagnosed following evaluation for symptoms and many present with high tumor burden, such as massive splenomegaly, and advanced phases of CML (high-risk CML docu­ mented in 20–30%). Therefore, the prognosis of such patients on TKI therapy may be worse than the published experience. The high cost of TKI therapies (annual costs of $120,000–270,000 in the United States; lower but variable in the rest of the world) makes the general affordability of such treatments difficult. Fortunately, in 2024, some imatinib generic formulations cost about $500/year in the United States and worldwide. Generic dasatinib is also available in many geographies, and generic formulations of bosutinib, nilotinib, and ponatinib may become available by 2027. Therefore, in frontline CML therapy, if survival is the treatment endpoint, generic imatinib is a good choice. If TFR is the endpoint, generic dasatinib (50 or 100 mg daily) is a good choice. Although TKI treatment penetration is high in nations with universal health care and where cost of therapy is not an issue (e.g., Europe, Canada, Australia, United Kingdom), it may be less so in other nations, even in advanced ones like the United States, where out-of-pocket expenses may be prohibitive to a subset of patients. The estimated 10-year survival rate in CML is >85% in single-institution or national studies in countries with TKI affordability (Sweden) (Figs. 110-2 and 110-3), whereas the estimated 10-year survival rate worldwide is likely to be <50%. The Surveillance, Epidemiology, and End Results (SEER) data from the United States report an estimated 5-year survival rate of 70% in the era of TKIs. It appears that the treatment penetra­ tion of imatinib and other TKIs into CML therapy worldwide is still not optimal. The current high cost of TKI therapies, particularly in later-line therapy, encouraged considering allogeneic HSCT as third-line therapy (one-time cost of $20,000–500,000) despite the associated mortality and morbidities. Safe and effective generic TKIs should be preferred frontline and second-line therapies in CML, precluding the necessity

1.0 0.8 0.6 Overall survival 0.4 0.2 Chronic phase Accelerated phase Blast crisis 0.0

Years after diagnosis No. at risk CP AP BC

CHAPTER 110 FIGURE 110-3  Survival in chronic (CP), accelerated (AP), and blastic phase (BP) phases of chronic myeloid leukemia (CML) in the population-based Swedish national registry study. The accelerated- and blastic-phase cases are de novo presentations. The favorable outcome with de novo blastic phase may be due to use of 20% blasts or more to define blastic phase. (From Dr. Martin Hoglund, Swedish CML Registry, 2013.) Chronic Myeloid Leukemia of an allogeneic HSCT until evidence of resistance to generic secondgeneration TKIs. ■ ■FURTHER READING Cortes JE et al: Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: Results from the randomized BFORE Trial. J Clin Oncol 36:231, 2018. Cortes JE et al: Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: Final 5-year results of the phase 2 PACE trial. Blood 132:393, 2018. Gener-Ricos G et al: Low-dose dasatinib (50 mg daily) frontline therapy in newly diagnosed chronic phase chronic myeloid leukemia: 5-year follow-up results. Clin Lymphoma Myeloma Leuk 23:742, 2023. Haddad FG, Kantarjian H: Navigating the management of chronic phase CML in the era of generic BCR::ABL1 tyrosine kinase inhibi­ tors. J Natl Compr Canc Netw 22:e237116, 2024. Hochhaus A et al: Asciminib in newly diagnosed chronic myeloid leukemia. N Engl J Med 391:885, 2024. Kantarjian H et al: Long-term outcomes with frontline nilotinib ver­ sus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia 35:440, 2021. Kantarjian HM et al: Revising six established practices in the treat­ ment of chronic myeloid leukaemia. Lancet Haematol 10:e860, 2023. Kantarjian HM: What is the impact of failing to achieve TKI therapy milestones in chronic myeloid leukemia. Leukemia 37:2324, 2023. Mahon FX et al: European Stop Tyrosine Kinase Inhibitor Trial (EURO-SKI) in chronic myeloid leukemia: Final analysis and novel prognostic factors for treatment-free remission. J Clin Oncol 42:1875, 2024. Senapati J et al: Management of chronic myeloid leukemia in 2023: Common ground and common sense. Blood Cancer J 13:58, 2023. Shih YT et al: Treatment value of second-generation BCR-ABL1 tyro­ sine kinase inhibitors compared with imatinib to achieve treatment-free remission in patients with chronic myeloid leukaemia: A modelling study. Lancet Haematol 6:e398, 2019.