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Chapter6

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Chronic myelogenous leukemia

Hagop Kantarjian1, Elias Jabbour1 and Susan O’Brien

Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

University of California at Irvine, Irvine, CA, USA

Introduction, 83 Epidemiology, 83 Clinical presentation and natural history, 83 Prognostic models, 84 Molecular biology, 85 Therapy, 86

Introduction

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm that arises from a pluripotent stem cell. The Philadelphia (Ph) chromosome results from a reciprocal translocation between chromosomes 9 and 22, and constitutes the cytogenetic hallmark of CML. It can be detected in myeloid, erythroid, megakaryocytic, B, and sometimes T, lymphoid cells, but not in marrow fibroblasts. A critical milestone in CML research was the demonstration that this translocation involves the ABL1 (v- abl Abelson murine leukemia viral oncogene homolog 1) gene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromo- some 22, and results in the formation of the chimeric BCR::ABL1 fusion transcript that encodes the constitutively active BCR::ABL1 tyrosine kinase. The discovery that BCR::ABL1 plays a pivotal role in the pathogenesis of CML set the stage for the development of therapeutic strategies aimed specifically at inhibiting this kinase and its downstream signals. The BCR::ABL1 molecular events define CML as a unique cancer from both the diagnostic and the therapeutic standpoint. Herein, we summarize the current knowledge regarding the molecular biology of CML and the treatment modalities, including novel BCR::ABL1 kinase inhibitors (TKIs).

Epidemiology

CML has an annual incidence of 1.6 per 100 000 adults and isslightly more frequent in men (male- to- female ratio 1.4:1). It represents approximately 15% of leukemias. The annual

Allogeneic hematopoietic stem cell transplantation, 94 Therapy of CML- AP and CML- BP, 95 Philadelphia chromosome- negative CML, 95 Summary, 96 Further reading, 96

incidence is about 9500 cases; with patients living a nearnormal life span on BCR::ABL1 TKI therapy, the prevalence continues to increase and is estimated to have reached about130 000–170 000 cases in the United States in 2023. The median age of onset is 60–65 years, and the incidence increases with age. There are no known causal etiologies, and CML is neither preventable nor inherited. However, ionizing radiation is leukemogenic, and CML has been observed in individuals exposed to the radiation from atomic bomb explosions in Japan in 1945. There, the incidence of CML was 50- fold higher than in non- exposed subjects and peaked approximately 10 years after the explosion, although patients younger than 15 years of age developed CML earlier than those 30 years of age or older. In most cases of CML, no antecedent radiation exposure is discernible.

Clinical presentation andnatural history

CML evolves typically in three phases. Approximately 90% of patients are diagnosed in chronic phase (CML- CP), characterized by high numbers of immature myeloid cells and mature granulocytes in the bone marrow and peripheral blood. Patients diagnosed in CMLmatic. If symptoms are present, they usually relate to the presence of splenomegaly (e.g. abdominal fullness, early satiety, pain). Other signs and symptoms include anorexia, weight loss, fever, fatigue, or anemia. Leukocytosis with white blood cell count exceeding 100 × 109/L is noted less frequently in the United States today due to surveillance from annual physical examinations and screening tests, but is

CP are often asympto-

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frequently seen in emerging nations. Severe leukocytosis can result in signs and symptoms of hyper- viscosity (priapism, cerebrovascular accidents, dizziness, confusion) or retinal hemorrhage. In CML- CP, CML cells retain the ability to differentiate and produce morphologically normal blood elements capable of carrying out the physiologic functions of normal counterparts. In about 50% of cases, CML- CP is diagnosed after a routine blood test for unrelated reasons. The peripheral blood smear in CML- CP is characterized by a left shift (i.e. increasing numbers of younger progenitors), although blasts typically comprise less than 5% of white blood cells. At times, a higher percent of circulating blasts is noted compared with marrow blasts. Basophilia is often present. The leukocyte alkaline phosphatase activity is reduced both in intensity and in the number of neutrophil band forms that stain positively for this enzyme. The bone marrow aspirate and biopsy are hypercellular and demonstrate granulocytic and megakaryocytic hyperplasia, basophilia, and a blast percentage of 5% or less. Historically, the median survival of patients in CML- CP was three to five years. Untreated, most patients progressed to a blastic phase (CML- BP), characterized by a peripheral blood or bone marrow blasts percentage of 30% or more, and frequently preceded by an accelerated phase (CML- AP). Before the introduction of TKI therapy, the estimated annual risk of transformation from CML- CP to CML- BP was approximately 10% in the first two years after diagnosis and 15–20% thereafter. With TKI therapy, this annual incidence was reduced to 2% in the first two years, and to 1% or less thereafter (estimated at about 6% at 10 years in the German trials). Both CML- AP and CML- BP are characterized by increasing arrest of maturation of blood cells.

The diagnostic criteria of CML- AP include the presence of 15–29% blasts, 30% or more blasts plus promyelocytes, 20% or more basophils, platelets less than 100 × 109/L unrelated to therapy, or cytogenetic clonal evolution. These criteria are less adverse if present at diagnosis, but serious if they develop on therapy. The average survival of patients in CML-

AP was one to two years before the TKI era, but with TKI therapy, the estimated four- year survival has increased to 60–70%. In contrast to CML- AP following CML- CP, de novo CML- AP has a better prognosis with frontline TKI therapy, with an estimated eight- year survival rate of 80%. Patients in CML- AP may present with fever, night sweats, weight loss, or bleeding associated with thrombocytopenia. However, the transition from CML- CP to CML- AP is usually subclinical, and laboratory monitoring is necessary to detect disease progression.

CML- BP is defined by the presence of 30% or more blasts in the marrow or blood, or the presence of extramedullary blastic foci. Because of the early pluripotent stem cell involvement in CML, the blastic phase can present morphologically and immunophenotypically as myeloid, lymphoid, erythroid,

megakaryocytic or undifferentiated. The CML- BP is lymphoid in 20–30% of patients, myeloid in 50%, and undifferentiated in 20% (megakaryocytic [M7] or erythroblastic [M6] in <5%). In lymphoid CML- BP, blast cells often express both lymphoid and myeloid cell surface markers (40–50%). Cells from patients with lymphoid CML- BP exhibit high levels of the enzyme terminal deoxynucleotidyl transferase (TdT). Most cases of lymphoid CML- BP arise from progenitors ofthe B- cell lineage, and express CD10, CD19, and CD22. T- cell CML- BP rarely has been described. The phenotype of myeloid CML- BP cells resembles that of acute myeloid leukemia, with blasts staining with myeloperoxidase (MPO)and expressing CD13, CD33, and CD117. Clinically, CML- BP is characterized by prominent hypercatabolic symptoms, related to increasing tumor burden, and resistance to conventional chemotherapeutic agents. The median survival of patients in CML- BP prior to the introduction of TKI therapy was 2–6months. With TKI- based therapy, it improved to a median of 1–3+ years (3+ years with lymphoid BP; 1+ year with non- lymphoid BP), particularly when TKIs are combined with chemotherapy and followed by allogeneic (hematopoietic) stem cell transplantation (HCT).

Prognostic models

Different prognostic models have been developed to predict outcome in CML- CP in the pre- TKI era. These risk models usually incorporated as adverse factors older age, larger spleen size, thrombocytopenia or thrombocytosis, higher percent of blasts and basophils, and cytogenetic clonal evolution. The risk models commonly referred to are the Sokal and Hasford scores. They historically categorized patients into low- , intermediate- , and high- risk groups with median survivals of 4.5, 3.5, and 2.5 years, respectively.

These risk models are less important in the TKI era, where response to TKI therapy in the first year (achievement of complete cytogenetic response [CCyR]; Phphases 0%; roughly equivalent to BCR::ABL1 transcripts on the International Scale [IS] < 1%) is the single determining factor of long- term outcome and survival. Several modern risk models address outcomes on TKI therapy and include the EUTOS Score and EUTOS long- term survival (ETLS) Score. Risk models still may have value in deciding on frontline therapy with imatinib versus second- generation TKIs.

Risk factors that maintain prognostic significance in the era of TKIs include high blast (≥10–15%) and basophil (≥20%) percentages, massive splenomegaly, and chromosome abnormalities involving 17p- /isochromosome 17, chromosome 7, or 3q26.2. Molecular abnormalities, particularly ASXL1 mutations, predict for risk of cytopenias on TKI therapy, poor response to TKIs, and perhaps worse outcome. In a study of DNA microarrays analyzing gene expression in CML,

positive meta-

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Chromosome 22 Chromosome 9

M-bcr

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significant differences in gene expression were observed in CML- CP versus CML- AP. Gene- expression profiling may facilitate a more comprehensive stratification of CML that segregates genetically defined risk subgroups.

Molecular biology

BCR::ABL1 oncogene

The fusion of the ABL1 and the BCR genes resulting from the reciprocal translocation t(9;22)(q34;q11.2) gives rise tothe BCR::ABL1 oncogene that encodes for the constitutively active BCR::ABL1 tyrosine kinase. Several experimental models have established a causal relationship between BCR::ABL1 and human leukemia, which led to the development of the BCR::ABL1 TKIs. BCR::ABL1 can transform hematopoietic stem cells, but not committed progenitors lacking self- renewal capacity.

The breakpoint within ABL1 at 9q34 occurs in nearly all patients upstream of exon 2, with some variability in the specific site either upstream of exon Ib, downstream of exon Ia, or more frequently between the two (Figure6.1). Breakpoints within BCR localize to three main breakpoint cluster regions (bcr). In most patients with CML and in one- third of those with Ph- positive acute lymphoblastic leukemia (ALL), the breakpoint maps to the major breakpoint cluster region (M-bcr), which spans BCR exons 12–16 (formerly called b1– b5), giving rise to a fusion transcript with either e13a2 (b2a2)

or e14a2 (b3a2) junctions; these translate into a 210- kDa protein (p210

BCR::ABL1

). In patients with Ph- positive ALL, and rarely in CML, the breakpoints within BCR localize to an area of 54.4 kb between exons e2′ and e2, termed the minor breakpoint cluster region (m- bcr), which gives rise to an e1a2/a3 fusion transcript and translates to a 190- kDa protein (p190

BCR::ABL1

). More than 95% of CML cases have p210

BCR::ABL1

molecular abnormality. In contrast, in Ph- positive ALL, twothirds of patients have the p190

BCR::ABL1

molecular abnormality. The P190 CML- CP may have a worse outcome than P210 CML- CP. A third breakpoint cluster region (μ- bcr) hasbeen identified, which gives rise to an e19- a2/a3fusion transcript and a 230- kDa fusion protein (p230

BCR::ABL1

). P230CML- CP is associated with a more indolent course and with a phenotype more akin to chronic neutrophilic leukemia (Figure6.1).

BCR::ABL1 kinase signaling pathways

BCR::ABL1 signals through an intricate network of molecular pathways that promote diminished growth- factor/adhesion dependence, decrease apoptosis, and enhance proliferation. Phosphorylation of BCR Tyr177 provides a high- affinity docking site for the SH2 domain of growth factor receptorbound protein 2 (GRB2), which in turn recruits SOS (a guanine- nucleotide exchanger of RAS), thus activating RAS and the adapter GRB2- associated binding protein 2 (GAB2). BCR::ABL1- induced GAB2 phosphorylation activates the phosphatidylinositol 3- kinase (PI3K)/AKT and the

m-bcr

Figure6.1 The Philadelphia chromosome and associated BCR::ABL1 molecular abnormalities.

μ-bcr

e1ʹ e2ʹ

e12

e16

e19

e23

5ʹ 3ʹ

BCR

ABL1

e1a2

e13a2

e14a2

e19a2

5ʹ 3ʹ

BCR::ABL1

p190

BCR::ABL1

p210

BCR::ABL1

p230

a11

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RAS/ERK pathways. BCR::ABL1 also phosphorylates the SRC family of kinases (SFKs) HCK, LYN, and FGR, which leads to activation of STAT5 (signal transducer and activation of transcription 5). Upon dimerization, STAT5 translocates to the nucleus and binds to cognate DNA sequences to modulate gene transcription. STAT5 also upregulates theanti- apoptotic protein BCLXL, which is repressed by the tumor suppressor and negative regulator of granulocyte differentiation ICSBP (transcription factor interferon consensus sequence binding protein). The RAC subfamily of guanosine triphosphatases (GTPases) RAC1, RAC2, and RAC3 as well as the enzyme 12/15lipoxygenase (12/15- LO) have also been identified as important elements in BCR::ABL1 downstream signaling. Although BCR::ABL1 signals through a multitude of downstream components, the kinase activity of this oncogenic enzyme is central to the pathogenesis of CML. This provided the rationale to develop therapeutic strategies that inhibit the kinase activity of BCR::ABL1.

Therapy

General

Since 2000, the treatment of CML has changed dramatically. Conventional chemotherapeutic agents such as busulfan or hydroxycarbamide (hydroxyurea) are no longer used, except to achieve initial or transient cytoreduction (hydroxyurea) or as a component of the allogeneic SCT preparative regimens (busulfan). The maturing experience of imatinib mesylate and other TKIs has brought about a change in the therapeutic algorithm for CML. Today, six TKIs are approved by the Food and Drug Administration (FDA) to treat CML: imatinib (first- generation TKI); dasatinib, nilotinib, bosutinib (second- generation TKIs); ponatinib and asciminib (third- generation TKIs). Imatinib and the second- generation TKIs (dasatinib, bosutinib, nilotinib) are approved as frontline therapy for CML- CP. All TKIs can be used as subsequentline therapies depending on several factors: prior TKIs and response; BCR::ABL1 kinase domain (KD) mutations; failure due to resistance or intolerance; co- morbidities; whether therapy is for second- line or later- line salvage; and cost of TKIs. Third- generation TKIs are active against the T315I gatekeeper mutation. The choice of TKIs in frontline and later- line settings will be detailed later.

Imatinib mesylate (Gleevec) is an orally bioavailable 2- phenylaminopyrimidine relatively selective for the constitutively active tyrosine kinase of the BCR::ABL1 fusion protein. It also inhibits other kinases such as KIT, platelet- derived growth factor receptor (PDGFR)α and PDGFRβ, and ABLrelated gene (ARG). Dasatinib (Sprycel) is a subnanomolar inhibitor of BCR::ABL1 and SFKs, with potent activity against KIT (IC50 13 nmol/L), PDGFRβ (IC50 28 nmol/L), and ephrin receptor EPHA2 (IC50 17 nmol/L) tyrosine kinases.

Itis 350 times more potent than imatinib invitro. Dasatinib inhibits multiple imatinib- resistant BCR::ABL1 mutant isoforms, except for T315I. Bosutinib (Bosulif) is a potent SFK and ABL1 kinase inhibitor with negligible activity against KIT and PDGFR, which may result in an improved toxicity profile (less myelosuppression [no inhibition of KIT], and fewer pleural effusions [no inhibition of PDGFR]). Nilotinib (Tasigna) is a phenylaminopyrimidine derived from the crystal structure of imatinib in complex with ABL1kinase. Itis 30–50 times more potent than imatinib against unmutated BCR::ABL1 and inhibits the tyrosine kinase activity of 32 of 33 BCR::ABL1 mutants tested, the exception being T315I. Ponatinib (Iclusig) is a pan BCR::ABL1inhibitor and likely the most potent TKI so far. It is more toxic when used at 45 mg daily. It is effective against the T315I mutation and also inhibits fms- like tyrosine kinase 3 (FLT3), FGFR, vascular endothelial growth factor receptor (VEGFR), PDGFR, and c- KIT. Asciminib (Scemblix; FDA approval in 2022 as third- line therapy, and for T315I- mutated CML) is another third- generation TKI active against T315I- mutated CML. It works through a different mechanism of action, by bindingto the myristoyl pocket of ABL1 and allosterically inhibiting the overactive kinase activity. It is referred to as a Specific Targeting of the ABL Myristoyl Pocket (STAMP) inhibitor. Omacetaxine mepsuccinate (Synribo) is a nonTKI protein synthesis inhibitor approved by the FDA for thetreatment of CML post failure of two TKIs. Allogeneic SCT remains a curative modality in patients with CML post failure of 2+ TKIs.

Several general principles are emerging in CML TKI therapy. The first general principle is adherence to treatment, which is critical for the success of therapy. Patients who are less than 90% adherent to TKI therapy have a significantly lower probability of achieving the deepest molecular responses compared with more compliant patients.

A second general principle is the importance of daily, uninterrupted TKI therapy in both CML- CP (single- agent TKI; possible addition of other agents if hematologic resistance and lack of better treatment alternatives), or in transformation (CMLstandard therapies, e.g. hydroxyurea, cytarabine, hypomethylating agents; CML- BP using TKI combinations with acute leukemia chemotherapies). TKI therapy is superior to nonTKIs (e.g. hydroxyurea), even when responses less than CCyR are achieved. In CML- BP, the use of TKI in combination with chemotherapy is superior to single- agent TKI or chemotherapy alone, even after failure of TKI or chemotherapy. The only exceptions to not using TKIs in CML- CP or advanced CML phases are: low- risk CML as maintenance after allogeneic SCT; CML with sustained durable deep molecular responses (DMR; BCR::ABL1 transcript levels [IS] <0.01%) beyond two to five years where TKI treatment discontinuation is considered in order to achieve a treatment- free

AP using TKI alone or in combination with other

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remission status (TFR; equivalent to molecular cures; discussed later); or persistent and intractable cytopenias related to TKIs (often with the presence of ASXL1 mutations) not alleviated by optimization of the TKI dose schedules.

A third general principle is not to discard or change a TKI unless there is consistent evidence of loss of CCyR (BCR::ABL1 transcripts [IS] >1%), or unless there is a TKIassociated severe toxicity or a chronic moderate toxicity affecting the quality of life and not alleviated with optimization of the TKI dose schedule (dose reduction) and symptom management. Because of the availability of six TKIs and the ease of changing therapy, there is a tendency to change TKIs in situations of perceived suboptimal response (e.g. increased BCR::ABL1 transcripts [IS] >0.1%; termed loss of major molecular response [MMR]) or because of toxicities that could be minimized or eliminated with TKI dose reductions and proper medical management. This could result in discarding TKIs that could still offer clinical benefit.

Frontline CML therapy

Frontline CML therapy today is with any of the four approved TKIs: imatinib, dasatinib, bosutinib or nilotinib. The FDAapproved doses were based on the phase 2–3 studies that developed TKIs at one dose below the Maximum Tolerated Dose (MTD), a tradition borrowed from the development of cancer cytotoxic drugs (usually given for a year or less), and where the chosen dose is expected to produce serious side effects in less than 25% of patients. As targeted therapies were developed, the BCR::ABL1 TKIs being among the first, patients lived longer, in some cases to near- normal life spans, and treatment was required for several years, or even a lifetime. These dose schedules uncovered unanticipated longerterm side effects and inspired the concept of using targeted therapies at an Optimal Biologic Dose (OBD). The OBD presumably would be as effective and less toxic than the dose below the MTD. This concept and the clinical experience encouraged the use of the BCR::ABL1 TKIs at lower dose schedules in frontline therapy (e.g. using dasatinib 50

mg daily; or even 20 mg daily in patients 70 years and older) and in later- line therapy (e.g. using ponatinib at 30–15 mg daily instead of 45 mg daily).

Frontline TKI dose schedules are as follows: imatinib

400 mg daily; dasatinib 100 mg daily (50 mg appears as

effective and significantly less toxic); bosutinib 400 mg daily (a dose- escalation starting with 200 mg daily × 7,300 mg daily × 2–3 weeks, then 400 mg daily reduces significantly thedropout rate caused by the early self- limited gastrointestinal side effects); nilotinib 300 mg twice daily on an empty stomach.

The aim of frontline TKI therapy is normalization of survival. For this purpose, any of the four TKIs are effective, provided that patients are compliant with therapy, are moni-

tored optimally for response, and therapy changed if there is evidence of CML resistance (loss of CCyR; BCR::ABL1 transcripts [IS]

> 1%) after 1+ year of TKI therapy). Imatinib generic formulations are available in the United States and the world at a cost of <$500/year. Dasatinib generic formulations are currently available outside the United States and will be available in the United States by 2024. Thus, for a good “treatment value” (benefit: cost), these two generic TKIs are preferred. Bosutinib and nilotinib generic formulations may become available by 2027. In patients with highrisk CML, the second- generation TKIs may be better.

A secondary aim is achievement of a durable DMR (MR4; equal 4- log reduction of BCR::ABL1 transcripts; BCR::ABL1 transcripts [IS] <0.01%) for 2–5+ years in order to attempt a TFR. A durable DMR of 2+ years is associated, upon TKI discontinuation, with a TFR rate of 40–60%. A durable DMR for 5+ year is associated with a TFR rate of 80+%. Secondgeneration TKIs may result in faster achievement of a DMR status. Imatinib is associated with a five- year DMR rate of 60–65% and a 10- year DMR rate of 80%. Dasatinib is associated with a five- year DMR rate of 80+%.

The DASISION phase 3 randomized trial compared dasatinib 100 mg daily to imatinib 400 mg daily in 519 patients with newly diagnosed CML- CP. The cumulative five- year rate of MMR was 76% with dasatinib and 64% with imatinib (P= 0.002); the cumulative rate of MR4.5 (4.5log reduction of BCR::ABL1 transcripts from baseline; BCR- ABL1 transcripts [IS] < 0.0032%) was 42% versus 33% (P = 0.025). The estimated five- year survival rate was 91% with dasatinib versus 90% with imatinib. Two other randomized trials of frontline dasatinib versus imatinib (North American Cooperative Groups; SPIRIT 2) showed similar results of better early surrogate endpoints for dasatinib and equivalent survivals.

The ENEST- nd phase 3 international randomized study compared two doses of nilotinib (300 mg twice daily and 400 mg twice daily) to imatinib 400 mg daily. The cumulative five- year incidence of MMR was 77% with both nilotinib schedules and 60% with imatinib (P=

<0.0001%). The estimated five- year survival rates were 94% with nilotinib 300 mg twice daily, 96% with nilotinib 400 mg twice daily, and 92% with imatinib. The survival rates in the low- risk Sokal group were 97%, 99%, and 100%, respectively. In the intermediate- risk group, they were 94%, 97%, and 89%, respectively. In the high- risk group, they were 89%, 91% and 84%, respectively.

While nilotinib therapy was generally well- tolerated, the longer- term follow- up identified a cumulative increased risk of cardiovascular events. In the ENEST- nd trial, the 10- year cumulative risk of cardiovascular events was 24.8% with nilotinib 300 mg twice daily, 33.4% with nilotinib 400 mg twice daily, and 6.3% with imatinib 400 mg daily. Therefore, any potential added benefit of using nilotinib as initial therapy in the intermediate- and high- risk Sokal groups

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should be weighed against the cumulative risk of cardiovascular complications.

At MD Anderson Cancer Center (MDACC), several frontline studies evaluated the outcomes of patients with newly diagnosed CML treated with imatinib 400 mg daily (n= 73), imatinib 800 mg daily (n= 210), dasatinib 50 mg twice daily or 100 mg daily (n= 144), and nilotinib 300 mg twice daily (n= 130). An analysis of the total experience of 557 patients showed a 10- year relative survival of 91%. Among patients achieving CCyR, the 10- year survival was 94% overall, and 96–97% whether patients were in MMR, MR4 or MR4.5. The cumulative incidence of MR4 at fiveyears was 71% with second- generation TKIs and 57% with imatinib 400 mg daily. By multivariate analysis, older age, smoking, co- morbidities, and increased peripheral blasts were independent adverse risk factors for survival. The TKI therapy was not associated with differences in survival.

Selection of frontline TKI therapy

The choice of frontline TKI therapy depends on several factors: (i) the aim of therapy and patient age; (ii) comorbidities; (iii) CML risk; and (iv) cost of the TKI.

The patient age and aim of therapy are closely linked. In older patients, survival is the primary goal, and the achievement of TFR is a secondary consideration. Therefore, imatinib may be preferred. In younger patients, achievement of TFR may be important; thus, second- generation TKIs such as dasatinib may be preferred.

When choosing a TKI, some caution should be exercised based on prior medical history. Dasatinib should be avoided in patients with pre- existing pulmonary conditions such chronic obstructive lung disease or pleural effusions, since this would increase the risk of pleural effusions, and in patients with pulmonary hypertension. Bosutinib should be avoided in patients with preor renal dysfunction, since it may exacerbate these conditions. Nilotinib should be avoided in patients with diabetes (may be worsened), history of pancreatitis, or history or cardiovascular events, whether arterio- occlusive (AOE) or veno- occlusive (VOE).

In patients with high- risk CML, second- generation TKIs may be preferred since they reduce the risk of transformation and may improve survival.

Now that out- of- pocket expenses for prescription drugs sometimes reach 25%, generic imatinib and dasatinib (thelatter available outside the United States) may be preferred frontline therapies due to their good treatment value. Also, dasatinib 50 mg daily has been shown to be as effective, less toxic, and half the price of the approved 100 mg daily dose.

existing enterocolitis, or hepatic

Discontinuation of TKI therapy and TFR

Several studies have shown that TKI discontinuation in patients with CML- CP who have durable DMR for at least two years results in a TFR rate of 40–60%. TKI discontinuation after a durable DMR for 5+ years results in TFR in 80+%. Adaptation of TFR in practice should adhere to strict criteria. Patients must have low- or intermediate- risk disease (not high- risk), have quantifiable BCR::ABL1 transcripts (e13a2 or e14a2), have a documented history of chronic phase disease (with no evidence of transformation), and have an optimal response to frontline TKI therapy. The combined duration of TKI treatments should be atleast 5+ years, with undetectable BCR::ABL1 transcripts documented for at least two to five years by assessments every six months. Patients must be willing to comply with monitoring by PCR every two months in the first two years after TKI discontinuation, and every three to six months thereafter.

Which treatment endpoints/milestones areclinically relevant in CML?

The achievement of CCyR or BCR::ABL1 transcripts (IS) ≤1% at 12months and later on TKI therapy is associated with a significant survival benefit compared with lesser degrees of response. Therefore, achieving CCyR is the primary endpoint of TKI therapy. Achievement of MMR (BCR::ABL1 ≤ 0.1% IS) is associated with modest improve- ments in event- free survival (EFS), but not with a survival benefit. Achievement of durable DMR offers the possibility of treatment discontinuation and TFR. Lack of achievement of MMR or of MR4.5 should not be interpreted as a need to change TKI therapy or to consider allogeneic SCT. Other measurements of outcome include EFS, transformation- free survival (TFS) and progression- free survival (PFS). Event is defined differently in various studies and could include instances of treatment discontinuation that have no relevance to survival outcome (e.g. discontinuation for toxicity, noncauses unrelated to CML, etc.). Transformation encompasses CML- AP, and many of the AP criteria have lost their prognostic relevance on TKI therapy.

All key randomized trials of imatinib compared with second- generation TKIs as initial therapy for CML- CP have shown significant benefits of surrogate endpoints, but similar survivals. While some studies and reviews may propose using the more expensive (patented) secondgeneration TKIs, the generic TKI formulations (generic imatinib anywhere; generic dasatinib outside the United States) provide a significantly better treatment value and should be considered in most patients. Patented second- and third- generation TKIs still cost $200 000+/year and have a poor treatment value.

compliance; death from

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There has been an emphasis in the literature on treatment endpoints/milestones other than survival. The three key ones are: (i) achievement of early molecular response (EMR; BCR::ABL1 transcripts [IS] <10% by three to six months of TKI therapy); (ii) achievement of MMR; and (iii) achievement of durable DMR for at least two years, as a condition for TFR. This has resulted in excessive rotations of second- and third- generation TKIs, increasing drug- associated financial toxicities, without objective evidence of improved outcome.

The initial emphasis on EMR at three months was based on a study from the United Kingdom that reported that patients with newly diagnosed CML on imatinib therapy who achieved BCR::ABL1 transcripts (IS) levels >10% at three months had an eight- year survival rate of 54% compared with 93% for those with lower levels. However, patients did not have the option of early change to secondgeneration TKIs. At MDACC, a similar analysis showed 10- year survival rates of 94% versus 98%; these patients accessed second- generation TKIs at first evidence of loss of CCyR. Analyses from Australia and MDACC showed that an evaluation at six months might be more appropriate. In these analyses, patients with BCR::ABL1 transcripts (IS) >10% at six months had worse long- term outcome regardless of the BCR::ABL1 transcript levels at three months. This requires a change of therapy in only 8% of patients, the ones who really need it. A similar situation in a patient on a second- generation TKI (dasatinib, bosutinib, nilotinib) does not necessarily demand consideration of a change of TKI (no better one available) or of consideration of allogeneic HCT (five- year survival better with continuation of TKI versus allogeneic HCT).

Several long- term follow- up studies have shown that, among patients achieving CCyR, survival was similar whether they achieved MMR or lesser degrees of molecular response.

Pursuing TFR via aggressive TKI rotations in patients with persistent molecular disease after 3+ years of imatinibor dasatinib has never been shown to increase the TFR rate.

At MDACC, the major treatment milestones are 6 and 12months. Patients with BCR::ABL1 transcripts [IS] >10% at six months, or not achieving CCyR (BCR::ABL1 transcripts [IS] ≤1%) at one year, or with loss of response at any later time, are offered a change of TKI therapy if possible. Patients on second TKIs with BCR::ABL1 transcripts (IS) >10% at six months should be observed closely for signs of progression, but cannot be changed to “better” TKIs in general, and have a better survival with continued TKI therapy compared with proceeding to allogeneic SCT (five-

year survival rates 85–90% versus 65–70%). Among such patients, a change to a third- generation TKI can be considered. TKI therapy should not be changed in patients in CCyR who have not achieved MMR.

Monitoring response andresistance

At baseline, a bone marrow examination is needed to establish the diagnosis, determine the percentage of blasts and basophils (10% of patients may have higher percentages in the marrow than blood that could change the CML phase), and perform cytogenetic analysis (confirm the presence ofthe Philadelphia chromosome and assess for additional abnormalities, or clonal evolution). A pre- treatment fluorescence in situ hybridization (FISH) analysis (assess Ph- positivity) and PCR (measure BCR::ABL1 transcripts) help avoid later false- negative tests if alternative transcripts are present initially (2–3% of cases).

The current recommendation that follow- up marrow studies be done at 3, 6, and 12months after starting therapy may not be necessary. An alternative is to evaluate response by FISH and PCR on peripheral blood. If a patient is responding optimally, and the FISH study is negative at 6 or 12 months and/or BCR::ABL1 transcripts [IS] are <1%, it may be reasonable to omit marrow examinations. Repeat marrow examination may be indicated in patients on TKI therapy with persistent cytopenias (to detect clonal evolution, additional cytogenetic abnormalities in the Ph- negative cells, or other molecular abnormalities such as ASXL1 mutations). It is also indicated anytime CML resistance is observed (loss of CCyR; BCR::ABL1 transcripts [IS] >1–10%) to restage CML (still CP or transformed), and to assess for ABL1 mutations that may guide the choice of the next TKI.

For patients in CCyR or MMR receiving TKI therapy, molecular monitoring every six months for BCR::ABL1 transcripts every is acceptable. More frequent monitoring that detects minor variations (the result can vary by almost

0.5log in the same sample) may confuse the physician and patient, and lead to unnecessary changes in TKIs. For patients with rising BCR::ABL1 transcripts between 0.1% and 1%, monitoring every three months may be of value.

Distinguishing CML failure due to toxicities/ intolerance versus true resistance

The CML literature has often considered “treatment failure” to include both (i) failure due to CML resistance (usually defined as loss of CCyR or persistent BCR::ABL1 transcripts [IS] >1%), and (ii) failure due to TKI intolerance/side effects. The latter was considered as failure because, in the early days of TKIs development, there was a trend to switch TKIs whenever side effects were observed, even if they were mildmoderate, or severe but reversible with dose reduction. The assumption was that reducing the TKI dose might induce CML resistance. As experience indicated that an OBD might be as effective and less toxic, and that most of the TKI side effects were reversible and alleviated with dose reductions that maintained efficacy once patients were in good molecular

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response, practitioners are learning to distinguish these two forms of failure in relation to their optimal management.

Management of TKI “Failure” due to side effects/intolerance

Imatinib is associated with mostly mild- to- moderate toxicities, including fatigue, nausea, vomiting, diarrhea, skin rashes, muscle cramps and bone aches, periorbital or leg edema, and weight gain. Serious but uncommon toxicities (<2%) include decreased glomerular filtration rate that is reversible with treatment discontinuation or interruption and resumption at lower doses. Hepatic or cardiopulmonary adverse events are rare, as are peripheral neuropathies and neurologic toxicities (including Parkinsonism, dementialike presentations and other conditions). These reverse slowly over months after TKI discontinuation. Drug- related myelosuppression occurs in 10%–30% of patients and is managed with brief treatment interruptions and/or dose modifications, or with growth factors (e.g. erythropoietin for anemia, filgrastim for neutropenia).

On average, the chronic mild- to- moderate toxicities affecting quality of life are less frequent with secondgeneration TKIs compared with imatinib.

Dasatinib is associated with pleural effusions in up to 20% of patients, of which 2–3% may be severe enough to require thoracentesis. Most resolve with dasatinib treatment interruption, diuretics, and short courses of corticosteroids. Patients can then be restarted on lower doses of dasatinib (20–50 mg daily. Myelosuppression (particularly thrombocytopenia) is more common with dasatinib than with imatinib. Pulmonary hypertension can occur occasionally and manifests clinically as shortness of breath, normal chest radiograph and right- sided heart failure. It is reversible with dasatinib discontinuation.

The most significant toxicities of bosutinib include myelosuppression (30%); liver function abnormalities (17%, mostly mild15%; severe in <5%); and gastrointestinal problems (nausea 45%; diarrhea 70–80%- early and self- limited, but requiring dose reductions to 300–400 mg daily, severe in 8%).

Notable side- effects with nilotinib include headache and skin rashes (common, 20–30%; but mild to moderate; alleviated by dose reduction), self- limited elevation of indirect bilirubin (10%), elevations of blood sugar (10–20%), and, rarely, pancreatitis (1–2%). The 10- year cumulative incidence of vasospastic/vasoocclusive disease is 24% with nilotinib 300 mg twice daily and 33% with nilotinib 400 mg twice daily.

Significant ponatinib toxicities include pancreatitis in 10–15%, severe thrombocytopenia in 35%, severe skin rashes in 5–10%, vasospastic and vasoocclusive disease in 15–20%, and hypertension in 35% (severe in 10–15%).

moderate; severe in 7%); renal dysfunction (10–

Common toxicities observed with asciminib include thrombocytopenia (30%), neutropenia (23%), headache (20%), and hypertension (13%; Grade quency of arterial- occlusive events is around 5%, although compared to other TKIs, the follow- up is shorter.

A common scenario in CML is a patient on TKI therapy and in good molecular response who experiences mildmoderate side effects that affect quality of life, or severe but reversible side effects (if TKI is dose reduced). In such situations, the best approach is to reduce the TKI dose and observe for reversibility of the side effects and maintenance of the response (measuring BCR::ABL1 transcripts every three months). Changing the TKI prematurely in such instances might eliminate still- effective TKIs for a particular patient.

Less often, the TKI side effects are serious or recurrent, with concern for irreversible organ damage. Examples of such worrisome toxicities are recurrent pleural effusions with lower doses dasatinib (20–50 mg daily) or another TKI; pulmonary hypertension; vasoocclusive events (arterial or venous; usually with ponatinib or nilotinib; imatinib or bosutinib would be safer); renal dysfunction even after lowering the TKI dose (usually with bosutinib or imatinib; nilotinib or dasatinib would be safer); recurrent clinical pancreatitis (more than once) on the same TKI even after dose reduction; neurologic deterioration (dementia- like findings, Parkinsonism; serious but rare; may improve several months after TKI discontinuation); severe immune- mediated pneumonitis, myo- pericarditis, hepatitis, or nephritis. In these situations, a change to a different TKI is a safer option. Occasionally, in a patient with a borderline molecular response and side effects, a TKI dose reduction may result in an increase of the BCR::ABL1 transcripts, which, if consistent, would require a change to a different TKI at an effective dose that does not cause intolerance.

The following are some suggested TKI dose reductions, which should be undertaken after consideration of the degree and duration of the molecular response, the kind and severity of the side effect, and the patient age and co-

morbidities: (i) imatinib from 400 mg daily to 100–300 mg daily; (ii) dasatinib from 50 to 100daily to 20–50 mg daily; (iii) bosutinib from 400 mg daily to 100–300 mg daily; (iv) nilotinib from 300 mg BID to 150 mg BID or 200 mg daily (Table6.2).

≥ 3, 6.4%). The fre-

Management of CML post- TKI resistance (trueCML failure)

Frontline TKI resistance can be categorized as primary ( failure to respond to TKI from the onset of therapy) and secondary (after initial achievement of response). While the incidence of CML resistance was thought to be high (40–60% after five years; primary in 10%, secondary in 20–30%), the

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quoted higher rates were due to the inclusion of patients withsub- optimal response or with TKI intolerance. In the German experience, the 10- year incidence of imatinib resistance was only 10%. In the MDACC experience, the five- year incidence of CML resistance on dasatinib was 5%. Thus, most patients with CML on frontline imatinib or dasatinib therapy would achieve the goal of near- normal survival, and about 20–40% will achieve the goal of TFR.

The choice of TKI post frontline CML resistance depends on the frontline and later TKIs used, patient co- morbidities, presence of an ABL1 KD mutation, and the cost of the TKI relative to other options.

If resistance is to frontline imatinib therapy, changing to a second- generation TKI is the most appropriate course. The choice of dasatinib, bosutinib or nilotinib depends again on co- morbidities and the ABL1 mutations (guiding in 50% of resistant cases). Patients who develop CML resistance on frontline or later- line second- generation TKI therapy (dasatinib, bosutinib, nilotinib) should not rotate to other secondgeneration TKIs unless there is a guiding mutation. In such patients, changing to a third- generation TKI (ponatinib, asciminib) is appropriate. If a T315I mutation is detected, therapy with a third- generation TKI is required. Ponatinib is preferred because of the longer- term experience in a large number of patients and lower cost. The asciminib dose in T315I- mutated CML is 200 mg BID, at a cost that exceeds $1.2million annually in the US.

Allogeneic HCT is an option in patients who develop CML resistance to a second- or third- generation TKI; it is highly curative as a one- time procedure. With the choices of stem cell donor increasing (matched sibling, matched unrelated, haplo- identical, and umbilical cord), SCT is now an option for most patients if needed.

In older patients (65–70+ years), we recommend forgoing allogeneic HCT in favor of strategies that maintain disease control in CP for 10+ years (even if a patient is not in CCyR). These include an optimal TKI combined with other antiCML drugs (hypomethylating agent, low- dose cytarabine, hydroxyurea, or omacetaxine [two to five days per month rather than the approved schedule of two weeks per month]). In these situations, maintaining disease control with or without a cytogenetic response might be acceptable. Maintaining a daily TKI dose schedule is important to control CML optimally. In the MDACC experience, the 10- year CML- specific survival was 90% with BCR::ABL1 transcripts (IS) 1–10%, and 75% with transcripts >10%.

Mutations within the kinase domain of BCR::ABL1 are a frequent mechanism of resistance to TKIs. The frequency of BCR::ABL1 mutations in CML- CP after cytogenetic relapse on imatinib is 30% and after hematologic relapse, 50%. Detection of mutations is rare in patients responding to frontline therapy (less than 5%). Mutation rates are higher (50–90%) in patients experiencing CML transformation.

More than 100 BCR::ABL1 mutations encoding for single amino acid substitutions have been reported, conferring different degrees of imatinib resistance (Table 6.1). The most frequently reported mutations map to the P-

loop region of the kinase domain, which serves as a docking site for phosphate moieties of ATP. Mutations also frequently map to the activation loop, which impairs the achievement of the inactive conformation of the kinase to which imatinib binds, the catalytic domain, and the gatekeeper T315 residue. The T315I mutation causes steric hindrance to TKI binding and confers resistance to imatinib and second- generation TKIs but is sensitive to ponatinib and asciminib. Some patients with CML failing sequential TKI therapies carry more than one mutation within the same BCR::ABL1 molecule (“compound” mutations or “polymutants”), which is associated with increased oncogenic potency compared with every single mutation.

Table6.1 helps guide the choice of the TKI in cases of

mutant- resistant CML.

BCR::ABL1 mutations do not explain all cases of clinical resistance to TKI therapy. Other possible explanations include BCR::ABL1- independent mechanisms (most common in patients with primary resistance); sub- therapeutic imatinib/TKI plasma levels; excessive binding of imatinib to the plasma protein α1- acid glycoprotein 1 (AGP1); overexpression of ABCB1 (MDR- 1) transmembrane protein, which regulates imatinib efflux from the cell; polymorphisms of the human organic cation transporter (hOCT1), which regulates imatinib influx; clonal evolution; SFK or BCR- ABL1 overexpression; and intrinsic low TKI sensitivity of quiescent CML stem cells (Lin−CD34+BCRABL1- positive cells). Each of the mechanisms of resistance suggests a different possible therapeutic intervention.

The long- term updates of TKIs in CML salvage are showing continued favorable results.

In a phase 3 study of different dose schedules of dasatinib in 670 patients with CML- CP post- imatinib resistance or intolerance, the cumulative CCyR rate was 50%, the MMR rate 42% and the estimated seven-

year survival rate 65%.

In a phase 2 trial of bosutinib 500 mg orally daily in 288 patients with CML post imatinib resistance or intolerance, the CCyR was 50%, and the eight- year survival rate was 79%.

In a study of 321 patients with CML- CP post imatinib resistance or intolerance treated with nilotinib 400 mg BID, the CCyR rate was 45% and the four- year survival rate was 78%. In the phase 2 trial of ponatinib 45 mg orally daily in 270 patients with heavily pretreated CML- CP (failure to 2+ TKI or T315I- mutated), the CCyR rate was 54%, the MMR rate was 40%, and the five- year survival rate was 73%. Among the subset of 64 patients with a T315I mutation, the CCyR rate was 70%, MMR rate 58%, and five- year survival rate 70%. In a real- life experience in 515 patients treated with ponatinib in CML- CP (90% exposed to at least 2 other TKIs;

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92 Molecular Hematology

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Table6.1 Relative activity profile of BCR::ABL1 tyrosine kinase inhibitors in imatinib- resistant mutants

IC50- fold increase relative to WT (W=1)

Mutation Imatinib Bosutinib Dasatinib Nilotinib Ponatinib

M244V 0.9 0.9 2 1.2 3.2

L248R 14.6 22.9 12.5 30.2 6.2

L248V 3.5 3.5 5.1 2.8 3.4

G250E 6.9 4.3 4.4 4.6 6

Q252H 1.4 0.8 3.1 2.6 6.1

Y253F 3.6 1 1.6 3.2 3.7

Y253H 8.7 0.6 2.6 36.8 2.6

E255K 6 9.5 5.6 6.7 8.7

E255V 17 5.5 3.4 10.3 12.9

V299L 1.5 26.1 8.7 1.3 0.6

T315A 1.7 6 58.9 2.7 0.4

T315I 17.5 45.4 75 39.4 3

T315V 12.2 29.3 738.8 57 2.1

F317L 2.6 2.4 4.5 2.2 0.7

F317R 2.3 33.5 114.8 2.3 4.9

F317V 0.4 11.5 21.3 0.5 2.3

M351T 1.8 0.7 0.9 0.4 1.2

F359I 6 2.9 3 16.3 2.9

F359V 2.9 0.9 1.5 5.2 4.4

H396R 3.9 0.8 1.6 3.1 5.9

F486S 8.1 2.3 3 1.9 2.1

White=very sensitive (IC50resistant (IC50 > 10). Source: Adapted from Redaelli, S etal. Am J Hematol. 2012; 87: E125–E128.

fold increase <2); yellow=moderately sensitive (IC50 2.1–4); orange=resistant (IC50 4.1–10); red=highly

52% exposed to at least 3 other TKIs), the CCyR rate was 78%, the MMR rate was 74%, and the MR4 rate was 43%. With a median follow-

up time of 14 months, only 9% of

patients had died.

Asciminib was recently approved by the FDA as third- line therapy for CML- CP and for the treatment of T315I- mutated CML. The dose schedule is 40 mg BID or 80 mg daily in nonT315I CML and 200 mg BID in T315I- mutated CML. The latter dose schedule costs more than $1.2million annually and is not a good treatment value; ponatinib or alternative combination strategies/allogeneic HCT are favored. In an update of the ASCEMBL phase 3 trial randomizing patients in third- line therapy to asciminib 40 mg BID (n =157) or bosutinib 500 mg daily (n=76) (primary endpoint of MMR at six months met, resulting in the FDA approval), asciminib still resulted in a higher rate of MMR. However, the two- year PFS rates were 94% with asciminib and 91% with bosutinib.

The twoappears that the early surrogate endpoint of 6-

year survival rates were 97% versus 99%. Thus, it

month MMR may not be a good predictor of long- term outcome. Also, with a median follow- up of 2.3 years, 8/157 (5%) of patients on asciminib developed AOEs. Of note, the experience with bosutinib as third- line therapy in other trials showed it to be significantly less toxic and more effective that what was reported in the ASCEMBL trial. Longer follow- up of more patients on asciminib therapy and direct comparison of the safety and efficacy of dose- adjusted ponatinib versus asciminib in CML- CP are warranted.

In a pivotal study of omacetaxine, 122 patients with CML- CP (n=81) or CML- AP (n=41) who had received two or more prior TKIs were treated. In chronic phase, the major cytogenetic response rate was 20% (complete 10%), the median duration of response was 17.7 months, and the median survival was 34months.

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