CHRONIC Myeloid Leukemia

Definition

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease caused by the reciprocal translocation of gene sequences from the breakpoint cluster region ( BCR ) gene on chromosome 22 with the tyrosine kinase sequences of the Abelson ( ABL ) gene on chromosome 9. On a cytogenetic level, this results in an elongated chromosome 9 and a shortened chromosome 22, the latter known as the Philadelphia (Ph) chromosome. The unique chimeric fusion protein, BCR-ABL , is a constitutively active tyrosine kinase that drives the pathogenesis of the disease. Thus, BCR-ABL represents the target for tyrosine kinase inhibitor therapy as well as a direct measure of disease burden. As described further below, there can be cases of “Ph-” CML, where the Ph chromosome is not detected, but other methods (fluorescence in situ hybridization [FISH], polymerase chain reaction [PCR]) can detect the chimeric BCR-ABL . There is no BCR-ABL -negative CML, and such diseases as “atypical” CML and chronic neutrophilic leukemia have distinct genetic features that identify them as unique disease entities (discussed briefly later).

CML is categorized in different phases (chronic, accelerated, and blast phases) based on bone marrow and peripheral blood blast counts, additional cytogenetic abnormalities besides the Ph chromosome, and clinical features such as fever. There are several classification schemes, including those proposed by the European Leukemia Network and the World Health Organization (WHO). The main difference between the European Leukemia Network and WHO classifications is the definition of accelerated phase and blast phase: the European Leukemia Network defines accelerated phase as peripheral or bone marrow blast counts of at least 15% to less than 30%, and blast phase as blasts counts greater than or equal to 30%, whereas in the WHO classification, these values are at least 10 to 20% and greater or equal to 20%, respectively. Of note, the WHO criteria are rarely used in clinical practice or clinical trials. More than 75% of CML cases in the developed world are diagnosed in the chronic phase, whereas the proportion of cases of advanced (accelerated and blast) phase disease is higher in the developing world. Untreated chronic phase CML will eventually progress to advanced phase within a mean period of approximately 3 to 5 years, and when disease reaches blast crisis, the natural history is survival of less than 1 year.

Epidemiology

The incidence of CML is fairly uniform throughout the world, affecting about 1 to 1.5 per 100,000 of the adult population each year. In the Western industrialized world, CML represents approximately 15% of all adult and less than 5% of all childhood leukemias, with a median age of onset of about 65 years. The median age appears to be earlier in the developing world. As a result of the spectacular success of tyrosine kinase inhibitor therapy (see later), the prevalence of CML is increasing steadily because the average duration of the disease has lengthened appreciably.

There are no described “CML families.” The greatest risk factor for CML is radiation exposure, particularly in Japanese atomic bomb blast survivors. Although ABL sequences are found in the Abelson murine leukemia retrovirus, no infectious agent for human CML has been described.

Pathobiology

The Ph chromosome is an acquired cytogenetic abnormality present in all leukemic cells of the myeloid lineage and in some B cells and T cells in CML patients. It is formed as a result of a reciprocal translocation of genetic material of chromosomes 9 and 22 expressed as t(9;22)(q34;q11) ( Fig. 170-1 ). The Ph chromosome is found in more than 90% of CML patients, whereas approximately 5% of cases have translocations that involve chromosomes 9, 22, and others as well. The remaining 5% of patients with clinical and hematologic features consistent with CML have undetectable Ph chromosome, but BCR-ABL can be detected by FISH (which detects the DNA fusion) or reverse transcription–polymerase chain reaction (RT-PCR), which detects the chimeric mRNA.

Three possible breakpoints in the BCR gene exist, including breaks in the major breakpoint cluster region (M-BCR) in the intron between exons e13 and e14 or in the intron between exons e14 and e15. These breakpoints account for more than 95% of CML cases. The breakpoint in the ABL gene is varied and can occur broadly upstream of exon a2. Thus, the two possible common BCR breakpoints, merging with the ABL breakpoint, can yield two slightly different chimeric BCR-ABL genes, which yields a longer e13a2 or slightly smaller e14a2 transcript. Both transcripts are translated into a 210-kD BCR-ABL tyrosine kinase (p210 ^BCR-ABL ) that has greatly enhanced tyrosine kinase activity compared with the normal ABL protein. Rarely in CML, the breakpoint BCR occurs 5′ to the common breakpoint between exons e1 and e2 in an area designated the minor breakpoint cluster region (m-bcr). This produces the e1a2 mRNA, yielding a smaller BCR-ABL fusion gene (p190 ^BCR-ABL ). Curiously, although this genetic alteration is uncommon in CML, it accounts for roughly half of the cases of Ph chromosome–positive acute lymphoblastic leukemia (ALL).

Very rarely, a breakpoint in the so-called micro breakpoint cluster region (µ-bcr) results in e19a2 chimeric mRNA and a larger 230-kD BCR-ABL protein (p230 ^BCR-ABL ). This molecular lesion appears to be associated with the rare Ph chromosome–positive chronic neutrophilic leukemia.

The normal ABL protein is a nonreceptor tyrosine kinase with important roles in signal transduction and the regulation of cell growth. Normal ABL protein migrates between the cytoplasm and nucleus. The chimeric BCR-ABL protein, however, associates with the cytoplasmic membrane and is constitutively active with increased kinase activity, causing activation of numerous signal transduction pathways, including MYC, RAS, STAT, JUN, and phosphatidylinositol-3 kinase. Unlike many multihit models of carcinogenesis, the single BCR-ABL lesion thus appears to influence cell cycling, differentiation, and apoptosis, causing DNA genetic instability and attenuation of the DNA damage response. In murine models, BCR-ABL can cause myeloproliferative diseases similar to human CML, although chronic phase has been difficult to simulate until recent sophisticated genetically engineered murine models coupled inducible BCR-ABL with the genetic scrambling of the Sleeping Beauty transposon. In vitro studies suggest that BCR-ABL expression allows cells to become cytokine independent, protects cells from apoptotic responses to DNA damage, and increases adhesion of hematopoietic cells to extracellular matrix proteins.

The progression to advanced phase disease will eventually occur in all cases not treated with a tyrosine kinase inhibitor or allogeneic transplantation, and advanced phase disease is not curable without transplant (even in the age of tyrosine kinase inhibitors). Progression is associated with a further block in differentiation, with death coming from the eventual absence of normal platelets (bleeding) or white blood cells (infection). Blast counts increase and new cytogenetic abnormalities accumulate. The most common cytogenetic changes in progression are an additional Ph chromosome, trisomy 8, isochrome i(17q), and trisomy 19. Gene expression profiling suggests that the bulk of the genetic changes triggering progression occur from the transition of chronic to accelerated phase, with relatively minor genetic changes occurring from accelerated to blast phase. In keeping with the stem cell origin nature of CML, in about 25% of blast phase cases, the predominant blast expansion is in the lymphoid, not myeloid, lineage.

Clinical Manifestations

Most CML patients (>90%) present in chronic phase, often diagnosed incidentally during routine examination and blood cell counts. Symptoms, when present, usually include fatigue and abdominal discomfort from splenomegaly. More extreme constitutional symptoms of weight loss, bone pain, fever, and night sweats are more commonly associated with advancing disease. This has practical clinical relevance because although the tyrosine kinase inhibitors used to treat CML (discussed later) are generally well tolerated, compliance early in the treatment course can be challenging because the medications can make patients feel worse than they felt before they were diagnosed.

Diagnosis

Patients generally present with leukocytosis, often accompanied by thrombocytosis and anemia ( Fig. 170-2 ). Basophilia and eosinophilia are common. Without any other obvious explanation for a high white blood cell (WBC) count, the diagnosis of CML can be entertained.

In CML, the diagnostic and monitoring target is the chimeric BCR-ABL gene, whether this is at the chromosome level (metaphase cytogenetics), at the DNA level (FISH), or by chimeric mRNA transcript (RT-PCR).

Treatment

Tyrosine kinase inhibitors are the cornerstone of treatment for CML ( Fig. 170-3 ). ^,

Frontline Tyrosine Kinase Inhibitors for CML

There are four FDA-approved tyrosine kinase inhibitors for newly diagnosed chronic phase CML, the “first-generation” tyrosine kinase inhibitor imatinib and three “second-generation” agents, dasatinib, nilotinib, and bosutinib ( Table 170-1 ). All work by competitively binding to the adenosine triphosphate (ATP)-binding pocket of BCR-ABL, thus blocking phosphate passage to other downstream signaling effector proteins. In addition, each tyrosine kinase inhibitor has a unique pattern of “off-target” kinase inhibition, which likely explains how the different toxicities of the agents can provide a 67% complete cytogenetic response compared with 7% in the control arm. After more than a decade of follow-up, the cumulative rate of complete cytogenetic response with imatinib is 80 to 85%, with an estimated freedom from progression to progressive disease and overall survival of 92% and 83%, respectively. Moreover, roughly half all patients with a complete cytogenetic response obtain a major molecular response.

TABLE 170-1

THERAPY OF CHRONIC MYELOID LEUKEMIA WITH OUTCOMES AND MOST FREQUENT SIDE EFFECTS

SETTING	DRUGS	CCyR (%)	SURVIVAL (%)	NOTABLE SIDE EFFECTS (top three)
Frontline	Imatinib	65% at 5 years	83% at 11 years	Muscle spasms (41%), edema (37%), hypophosphatemia (28%)
	Dasatinib	86% at 2 years	91% at 5 years	Neutropenia (29%), pleural effusion (28%), diarrhea (21%)
	Nilotinib	85% at 4 years	94% at 54 months	Rash (38%), headache (32%), fatigue (23%)
	Bosutinib	77% at 1 year	N/A	Diarrhea (70%), increased ALT (23%), thrombocytopenia (14%)
Second/third line	Dasatinib	50% at 5 years	71% at 6 years
	Nilotinib		85% at 3 years	For all TKIs given as third-line agents, same side effects occur with higher frequency
	Bosutinib	40% at 2 years	92% at 2 years
	Ponatinib	45% at 2 years	90% at 2 years
	Omacetaxine	10% at 2 years	85% at 2 years	Cytopenias

ALT = alanine aminotransferase; TKI = tyrosine kinase inhibitor.

However, the long-term follow-up studies showed that more than 40% of patients discontinue imatinib therapy. These failures of imatinib are roughly divided into thirds: primary resistance to tyrosine kinase inhibitors, intolerance, and resistance/progression after an initial response. Second-generation TKIs (nilotinib, dasatinib, and bosutinib; Table 170-2 ) produce superior short-term responses, as measured by rate of complete cytogenetic response and major molecular response by 12 months of therapy. In addition, the second-generation tyrosine kinase inhibitors produce a higher proportion of “deep” molecular responses (which may influence the potential for tyrosine kinase inhibitor discontinuation, discussed later). Transformation to advanced phase disease is less frequent. However, long-term survival has not been significantly different between imatinib and the second-generation tyrosine kinase inhibitors.

TABLE 170-2

TWELVE-MONTH RESPONSES IN THE ENESTnd, DASISION, AND BOSUTINIB TRIALS

	ENESTND Trial			DASISION Trial		BFORE Trial
RESPONSE	NIL300 bid	NIL400 bid	IM 400	DAS 100	IM 400	BOS 400	IM 400
CCyR	80%	78%	65%	83%	72%	77%	66%
MMR	44%	43%	22%	46%	28%	47%	37%
AP/BC	0.7%	0.4%	4.2%	1.9%	3.5%	2%	3%

AP/BC = patients progressing to accelerated phase and blast crisis; bid = twice daily; CCyR = complete cytogenetic remission; DAS = dasatinib; IM = imatinib; MMR = major molecular response; NIL = nilotinib.

Several trials have also compared standard (400 mg/day) to high-dose (600 to 800 mg/day) imatinib. These studies consistently show that high-dose imatinib can yield similar short- and long-term outcomes as the second-generation tyrosine kinase inhibitors. However, these higher doses are less well tolerated and are discouraged as initial therapy in newly diagnosed chronic phase cases.

Toxicities of Tyrosine Kinase Inhibitors

The common side effect of tyrosine kinase inhibitors is myelosuppression, which is less problematic in imatinib than the second-generation tyrosine kinase inhibitors (with grade 3 or 4 cytopenias occurring in roughly 10% vs. more than 20% for imatinib and the second-generation tyrosine kinase inhibitors, respectively). In addition, each tyrosine kinase inhibitor has a unique side-effect profile (see Table 170-1 ). The tyrosine kinase inhibitors tend to be “cross-tolerant” in that if a patient must change the tyrosine kinase inhibitor because of a particular side effect, it is unlikely that the same complication would be found with another tyrosine kinase inhibitor. Chronic fatigue (mostly correlated with musculoskeletal pain and muscular cramps) is especially problematic for imatinib users and is the side effect that most affects quality of life, although fluid retention is also a problem. Pleural effusion is an adverse event for dasatinib and can be found in about 20% of patients (as opposed to 1% with imatinib). In addition, reversible pulmonary arterial hypertension is a rare (about 5%) but serious side effect with dasatinib. Nilotinib can cause a prolongation of the QT interval and is associated with an increased risk for peripheral arterial occlusive disease. Bosutinib’s primary toxicity is diarrhea, which can occur in up to 70% of patients. Ponatinib has a strong association with hypertension and carries a black box warning regarding hepatotoxicity and vascular occlusion. Indeed, arterial and venous thrombosis and occlusions occurred in approximately 30% of CML patients receiving the drug who had highly resistant disease, and these events happened in cases with and without cardiovascular risk factors. Peripheral and coronary occlusion are seen to a lesser degree with bosutinib and are least likely in patients treated with imatinib.

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