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Leukaemia 

Leukaemia
Chapter:
Leukaemia
Author(s):

Shaun R. McCann

DOI:
10.1093/med/9780198717607.003.0007
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date: 25 November 2017

Introduction

The word leukaemia still is associated with foreboding and a fear of premature death. Steady advances have been made in the treatment of childhood leukaemia but, with notable exceptions, the same in not true in adults. The so-called genetic/molecular revolution has extended our understanding of the pathogenesis of many forms of leukaemia but, as yet, has rarely facilitated cure. Chronic myeloid leukaemia is the obvious exception but we wait eagerly to see if the cytogenetic/molecular revolution can provide cures for many elderly patients with leukaemia, as such patients respond poorly to chemotherapy.

Have we a cure?

Unlike many diseases, leukaemia was not really recognized as a distinct entity until early in the nineteenth century. The development of microscopy and subsequently of aniline dyes for staining blood and marrow films made a major contribution to diagnosis and classification of leukaemias. Cytogenetics, immunology, and latterly molecular biology have all contributed to our understanding and treatment of these diseases. However, the word ‘leukaemia’ still provokes a reaction of horror in the general population, including in some doctors. It is true that the treatment of childhood acute lymphoblastic leukaemia has been a major success story and that the use of tyrosine kinase inhibitors has radically altered the outcome for patients with chronic myeloid leukaemia. The use of all-trans retinoic acid (ATRA) and the old drug arsenic trioxide (As2O3) resulted in the cure of many patients with acute promyelocytic leukaemia and through stem cell transplantation, in spite of costs and complications; hope was given to many patients with an otherwise incurable disease. Notwithstanding advances in acute lymphoblastic leukaemia, leukaemia remains a disease of the young and, although mechanisms of the disease are being unravelled, we do not know its cause in most patients. None of the above approaches, except for tyrosine kinase inhibitors, would have been successful without the development of good supportive care with red cell and platelet transfusions, antibiotics, and antifungal therapy.

Who diagnosed leukaemia first?

The book Leukemia provides a thorough account of the doctors and scientists involved in the early diagnosis of this group of blood diseases (1). Alfred Armand Louis Marie Velpeau (1795–1867), Rudolf Ludwig Karl Virchow (1821–1902), Bennett, and David Cragie (1793–1866) are all mentioned but, to my mind, Alfred François Donné (1801–78) stands out as a major figure. Donné, who had graduated in Paris in 1831, provided the first description of leukaemia in the Cours de microscopie in 1844 when he reported the case of the patient Rayer in Hȏpital de la Charité:

[I found] no trace of purulent matter, neither in the vessels nor in the blood clot. Since I have frequently observed similar cases in the blood of individuals without purulent matter, I think that the excess of white blood cells is due to an arrest of differentiation (arrêt de l’évolution du sang). According to my theory about the origin and development of blood cells . . . [the] increase of white cells is the consequence of an arrest in differentiation of these intermediate cells (ne sont que le résultat d’un arrêt de développement de ces particules intermédiaires)’ (2).

As it turned out, Donné was spot on when he determined that leukaemia was the result of failure of differentiation, although it is easy for us now to understand the difficulties in separating infection and pus from malignancy (3). Bennett and Virchow had debated the issue of suppuration and leukaemia but, unfortunately, Donné was excluded from these discussions as he was not a professor (4). It’s amazing now silly and counterproductive academic jealousy can be. Donné was ignored by many in the medical profession, although his work with the daguerreotype, an early photographic process invented by Frenchman Louis Daguerre, led to the development of the first photomicroscope.

Neumann, who also had early and progressive ideas about stem cells, is credited with relating leukaemia to changes in the bone marrow; he also contributed the word ‘myelogenous’ to the lexicon (5). According to Leukemia, in 1876, Friedrich Mosler introduced bone marrow puncture (aspiration) as a means of diagnosing leukaemia (1). In the 1950s and 1960s, many people were involved in developing new drugs, with some degree of success. The seminal discovery of Peter Nowell and David Hungerford in 1960 (6, 7) of the first non-random chromosomal abnormality, the so-called Philadelphia chromosome, in patients with chronic myeloid leukaemia opened a new door to our understanding of leukaemia as an acquired chromosomal disorder. It also initiated the race among clinician/scientists that culminated in the use of tyrosine kinase inhibitors in the twenty-first century and changed the lives of thousands of people with chronic myeloid leukaemia.

The US NIH

Institutions which receive government support have played an important part in haematology. The NIH has an exalted reputation for most doctors, especially in the Western world, due to its role in public health. It owes its origin to the Marine Hospital Service (MHS), which was established in 1798 to provide medical care for sailors; for this service, the sailors paid 20 cents per month. By the early 1880s, the MHS began examining immigrants for signs of infectious diseases. The discoveries of Robert Heinrich Herman Koch (1843–1910) and others in Europe describing the microbiological causes of many infectious led to the establishment in 1887 of a one-room laboratory in the Marine Hospital at Stapleton, Staten Island, NY, under the direction of Joseph J. Kinyoun. His laboratory, called the ‘Laboratory of Hygiene’, was based on existing German facilities. He used a Zeiss microscope to demonstrate the cholera bacillus to colleagues. In 1891 the laboratory moved to Washington, DC, and in 1901 Congress made $35,000 available for a new building to investigate ‘infectious and contagious diseases and matters pertinent to public health’. In 1930 the Ransdell Act created the NIH to allow the application of fundamental chemistry to medical research.

The US National Cancer Institute was established in 1937 and became a designated arm of the NIH in 1944. During World War II, the NIH concentrated on the war effort, which include the development of vaccines and a synthetic form of quinine. The budget of the NIH went from $8 million in 1947 to $1 billion by 1966. In 1953 the Warren Grant Magnuson Clinical Center on the campus of the NIH in Bethesda, MD, opened to bring research laboratories closer to clinicians and to pursue clinical trials. Interestingly, the NIH website states that this development ‘did not represent a move toward “socialized medicine,” which was opposed by most American physicians in the 1950s’ (8). Judging by the hostility to attempts by President Barack Obama to introduce new health insurance legislation in 2008–10, it seems as if that position has not radically changed in the twenty-first century. Philanthropists Albert and Mary Lasker were supporters of the NIH, and Mary was particularly influential in expanding its role and budget.

The war on cancer

In 1971 President Richard Nixon signed the National Cancer Act. Although the word ‘war’ is not used in the legislation, many people associate the passage of the Act as the beginning of the ‘war on cancer’, at least in the United States. Whether the idea of a war on cancer is an appropriate one is a moot point, if one is to judge the outcomes of other wars waged by the United States since 1971, as these have been anything but successful. The idea of a war on cancer is borne out by the comments made in 2005 by Andrew von Eschenbach, the director of the National Cancer Institute, who said ‘we can make the dream —of a world free of pain and suffering and death due to cancer—a reality’ (9). However, since 1971, the terminology has become widespread, with The Financial Times in May/June 2014 writing about the pharma industries’ ‘new front in war on cancer’. Yet, the reality is that we do not know the causes of most common cancers, with exceptions such as lung cancer due to cigarette smoking, so that the cure for most cancers remains elusive. The Human Genome Project has increased our understanding of mechanisms involved in cancer but we have not yet reached the stage that Eschenbach predicted. It should be remembered that an ‘association’ and a ‘cause’ are two completely different concepts. Many associations have no biological significance, and the cause of most diseases, excluding infections, remains obscure.

Acute leukaemia in childhood: A success story

There is no doubt that the treatment of childhood leukaemia, acute lymphoblastic leukaemia, has been an outstanding success, with over 90% of children in Western countries becoming long-term disease-free survivors. The story began in the 1960s and has been well documented (1, 10, 11). However, a number of issues remain which need to be clarified. It is true that childhood acute lymphoblastic leukaemia was the first cancer to be brought into remission with chemotherapy, that the folic acid antagonist aminopterin was used successfully in 1948 (12), and that glucocorticoids were first used as a single agent in 1949 (13). The initial euphoria, well justified, was tempered when central nervous system (CNS) disease and testicular relapse became evident. CNS prophylaxis was undertaken with cranio/spinal irradiation and later with cranial irradiation and intrathecal methotrexate. Although these modalities were effective, they were also accompanied by significant toxicity. Testicular relapse was initially prevented by irradiation but later it became obvious that testicular leukaemia was a manifestation of generalized disease relapse. CNS leukaemia could be prevented with large doses of methotrexate and intrathecal therapy. Happily now, because of well-conducted clinical trials and research, we can offer a 90% chance of disease-free survival to children with acute lymphoblastic leukaemia without the use of radiotherapy and with minimal toxicity.

Less is more

The main question currently posed is, can some children with acute lymphoblastic leukaemia be cured with ‘less’ than the present approach and can we alter therapy to improve the prognosis? Undoubtedly, using molecular techniques to measure the degree of corticosteroid response has made it possible to adjust treatment in certain patients with persistent disease. As Ching-Hon Pui at St Jude Children’s Research Hospital said in a recent podcast, ‘Yes, for low-risk patients and those in whom the minimal residual disease assay reveals <0.01% leukaemia cells in the bone marrow, then treatment can be less intense and still achieve a >90% long-term cure rate. Whether duration of treatment can be reduced is not clear’ (14) (Figure 7.1).

Fig. 7.1 A photograph of Ching-Hon Pui. When I interviewed Pui in a recent podcast, he emphasized how important it was to treat the patient and his/her family and not just the disease.

Fig. 7.1
A photograph of Ching-Hon Pui. When I interviewed Pui in a recent podcast, he emphasized how important it was to treat the patient and his/her family and not just the disease.

Reproduced by kind permission of the European Hematology Association and Professor Ching-Hon Pui.

Acute myeloid leukaemia: A disease of the elderly

Acute myeloid leukaemia continues to be a huge problem for patients and doctors. Although great strides have been made in understanding the biology of the disease, the unfortunate fact is that most patients with acute myeloid leukaemia are over 60 years at the time of diagnosis (15). Apparently, age does make a difference and, apart from co-morbidity in the elderly, there may be inherent differences in the response of the leukaemic cells to chemotherapy (15). The recently introduced techniques of molecular biology, genomics, and whole genome sequencing have undoubtedly shed light on disease mechanisms but the cause of acute myeloid leukaemia and effective treatment for the majority of patients still elude us. Increasing doses of chemotherapy with the addition of antibody-directed drugs may improve outcome. The ability to dissect prognostic factors and decide which patients might benefit from allogeneic stem cell transplantation may be helpful (16) but the challenge of successfully treating elderly patients remains.

Genes and acute myeloid leukaemia

Some genetic aberrations, such as t(8;21)/AML1–ETO (RUNX1–RUNX1T1), inv(16)/CBFB–MYH2, or t(15;17)/PML–RARA, are associated with specific phenotypes, of which more later. Unravelling the genetics and epigenetics of leukaemogenesis has proven to be complicated. A number of different genetic abnormalities can lead to leukaemia, including mutations that interfere with transcription and thus block cell differentiation, activating mutations that lead to increased cell proliferation, and mutations that affect cell-cycle regulation and apoptosis. To make things even more complicated, different types of mutations may occur within the same leukaemia. Thus, mutations may both cause a block in differentiation and be associated with subsequent mutations resulting in increased cell proliferation. Epigenetic phenomena, such as hypermethylation of DNA, are frequently found in acute myeloid leukaemia; however, although hypomethylating agents and histone deacetylase inhibitors have offered some improvement in blood counts in patients with myelodysplasia, the results of such treatment have been disappointing. Recent techniques such as whole genome sequencing provide further insight into the biology of acute myeloid leukaemia, especially in large numbers of patients who have a normal karyotype (17, 18). However the heterogeneity of the genetic abnormalities in acute myeloid leukaemia has, so far, militated against so-called targeted therapy. Consequently, Gail J. Roboz, Director of the Weill Cornell Leukemia Program, has called for a change in clinical trials for acute myeloid leukaemia so that new agents can be tested on patients in remission, to see if the remission is prolonged, as well as for large cooperative trials for meaningful subgroup analysis based on molecular typing (19).

Personalized treatment/medicine for leukaemia: The story of acute promyelocytic leukaemia

Relevant genetic markers have increased our knowledge of disease mechanisms and ‘may’ provide guidance for an individualized approach to the treatment of some patients in the ideal setting of a sophisticated hospital environment. Although cytogenetic abnormalities have been identified in 55% of patients with acute myeloid leukaemia, new techniques have uncovered molecular markers in patients in whom the karyotype is reported as normal. The story of acute promyelocytic leukaemia, a variant of acute myeloid leukaemia, is a remarkable development in the treatment of leukaemia.

Acute promyelocytic leukaemia was first described in 1957, when Leif K. Hillested coined the term ‘acute promyelocytic leukaemia’ for an acute myeloid leukaemia variant that was associated with atypical promyelocytes, hypofibrinogenaemia, and a severe bleeding tendency (20). In 1976 a number of haematologists published a very important paper which outlined the morphological classification of acute leukaemia (21). This so-called FAB (French, British, American) classification recognized acute promyelocytic leukaemia as a distinct morphological entity and, in 1977, Janet D. Rowley and colleagues demonstrated presence of a consistent translocation between Chromosome 15 and 17 (termed t(15;17)) in acute promyelocytic leukaemia cells (22). Although the anthracycline daunorubicin had been used to induce remission in acute promyelocytic leukaemia, a high number of patients treated with this drug had died from uncontrolled bleeding, and overall survival at 5 years remained poor. However, acute promyelocytic leukaemia can now be cured without classic, cytotoxic chemotherapy, with the use of two differentiating agents: ATRA and arsenic trioxide.

ATRA

In 1981 Theodore R. Breitman induced differentiation of human acute promyelocytic leukaemia cells with retinoic acid (23). Christine Chomienne then demonstrated the differentiating effects of ATRA on acute promyelocytic leukaemia cells in vitro and the fact that ATRA was ten times more potent than 13-cis retinoic acid. Then, in 1987 Laurent Degos from the INSERM (Institute National de la Santé et de la Recherche Médicale), together with Zhen-Yi Wang of Shanghai Jiao Tong University, witnessed the first treatment of humans with acute promyelocytic leukaemia with ATRA in Shanghai (24). Subsequently, in 1988 a paper appeared in the journal Blood from investigators in Shanghai, claiming that remission in acute promyelocytic leukaemia could be induced using the differentiating agent ATRA (25). Wang, together with Zhu Chen, who had been a student of Wang and had worked with Degos at INSERM, explained that, in the days following the Cultural Revolution in China, a search was made for ways of treating malignant diseases other than with chemotherapy (26). This approach may have reflected the practical problems of obtaining chemotherapy and providing supportive care. Although in vitro data on the cellular differentiation potential of retinoic acid were available in China, Europe, and the United States, there appeared to be no reason to use retinoic acid outside China, as acute promyelocytic leukaemia responded fairly well to chemotherapy. The retinoid used by Western countries, 13-cis retinoic acid, produced by that the pharmaceutical company Roche, did not work in vivo (27), although its in vitro effect on acute promyelocytic leukaemia cells was similar to that of ATRA (28). Therefore, the patients in the first Western pilot study in 1988 were treated with ATRA produced in China. When diplomatic relations between France and China ceased because of the Tiananmen Square Massacre in June 1989, Roche France helped to produce the ATRA needed to allow patients to continue their treatment. Degos, then at the Memorial Sloan Kettering Cancer Center in New York, also persuaded Roche Nutley in New Jersey to manufacture ATRA (24). The results from the clinical trials led to approval by the FDA and the European Medicines Association (29). The t(15;17) translocation in acute promyelocytic leukaemia was subsequently shown to produce the PML–RAR alpha fusion protein, which inhibits the differentiation of myeloid precursors (30, 31). ATRA overcomes the dominant-negative effect of the PML–RAR alpha fusion protein and induces differentiation of the leukaemia cells, thus allowing patients with acute promyelocytic leukaemia to achieve complete remission (32). ATRA is, however, rapidly metabolized; therefore, complementary chemotherapy is required to sustain complete remission (33).

Arsenic

Traditional treatments may have a ‘scientific’ basis and should always be investigated. Although arsenic had been used in Manchuria 2000 years ago, it was only first reported as a treatment for leukaemia in the Western literature in 1878; it later became a popular treatment for chronic myeloid leukaemia in the 1930s (34). The compound arsenic trioxide has been under investigation in China as an anticancer treatment since the 1970s; Chinese investigators first reported responses to intravenous arsenic trioxide in patients with acute promyelocytic leukaemia in 1992 (35). Martin S. Tallman and Jessica K. Altman, both at the Robert H. Lurie Comprehensive Cancer Center in Chicago, IL, have stated that the addition of arsenic trioxide ‘may replace conventional therapy’ (36), and Francesco Lo-Coco at University of Rome, Tor Vergata and colleagues from Gruppo Italiano Malattie Ematologiche dell’Adulto, the German–Austrian Acute Myeloid Leukemia Study Group, and Study Alliance Leukemia have recently shown that a combination of ATRA and arsenic trioxide is at least as good as ATRA combined with chemotherapy at treating low-risk acute promyelocytic leukaemia (white blood cell count <10 × 109/l) (37). Thus, both agents now have a definite place in Western medicine in the treatment of acute promyelocytic leukaemia.

Myelodysplastic syndromes

In 2008 the WHO defined myelodysplastic syndromes as a group of clonal disorders occurring in adults of advanced age (median age at presentation is 70 years) and which are characterized by bone marrow hypercellularity and peripheral blood cytopenias (38). Until the late 1970s, these syndromes were simply known in purely descriptive term as ‘marrow hypercellularity with peripheral pancytopenia’. Progression of a myelodysplastic syndrome to acute myeloid leukaemia is the natural course in many patients but varies according to subtype. The majority of myelodysplastic syndromes occur without any known cause, although some may be caused by chemotherapy for other malignancies while others, such as Fanconi anaemia, are associated with congenital lesions. In the 1990s, there was an explosion of knowledge regarding genetic and molecular abnormalities associated with myelodysplastic syndromes, and epigenetic abnormalities associated with myelodysplastic syndromes have also been defined. A number of prognostic systems have been published; but, sadly, although low-dose chemotherapy, hypomethylating agents, and histone deacetylase inhibitors have all been tried, the cure for myelodysplastic syndromes remains elusive, and supportive care continues to be the cornerstone of management. Haematopoietic stem cell transplantation, however, may be appropriate for young patients with aggressive disease.

Chronic myeloid leukaemia

The diagnosis of chronic myeloid leukaemia was probably one of the most depressing therapeutic experiences for a haematologist until the early 1980s. Prior to the advent of treatment with tyrosine kinase inhibitors, the diagnosis of chronic myeloid leukaemia was a death sentence unless a suitable donor was available for haematopoietic stem cell transplantation. Symptomatic control was relatively easy but, as the disease progressed, premature death became inevitable. Disease progression was not always easy to predict but the knowledge of premature death hung over the patient like the sword of Damocles.

Patients presented with night sweats and fatigue, and the diagnosis was relatively easily made by the finding of an enlarged spleen and an elevated white cell count with premature white cell precursors in the peripheral blood. Finding the Philadelphia chromosome was a major breakthrough (6). The discovery by Rowley that the Philadelphia chromosome resulted from a reciprocal exchange between the long arms of Chromosomes 9 and 22 opened the door to understanding the biology of chronic myeloid leukaemia and culminated in effective treatment (39).

Imatinib: The magic bullet

The story of the development of imatinib brings together basic research into oncogenes, viral oncogenesis, and the observation that the fusion protein BCR–ABL was the cause of the malignant phenotype in chronic myeloid leukaemia. The important link between a determined scientist, Joerg Zimmerman at Ciba–Geigy (now Novartis) and a haematologist at the Oregon Health and Science University, Brian J. Druker, was at the heart of the development of tyrosine kinase inhibitors, and Druker’s name is now firmly linked to the use of tyrosine kinase inhibitors for this disease. Brian is a mild-mannered man; in a recent review of his work, he recalled how ‘at one time I was told I had no future’ (40). In that same review, he points out how seminal and sometimes apparently unconnected pieces of research eventually resulted in the clinical and very successful use of imatinib, the first tyrosine kinase inhibitor. The first presentation of the inhibition of chronic myeloid leukaemia colony formation and suppression of BCR–ABL-expressing cells in vitro at the annual meeting of the American Society of Hematology in 1998 was attended by about 50 people (in contrast, congress attendance comprised about 20,000 delegates). Following this presentation, Druker formed a team of investigators, including John Goldman, Charles Sawyers, and Moshe Talpaz. However, in spite of this formidable team, it took a lot of persuasion to get the pharmaceutical company Novartis to produce enough drug to conduct meaningful clinical trials on a relatively rare disease, particularly when a compound that the company thought would never work was being used. As Druker said in his review, it was also important to persuade Novartis that they could recoup their investment in the treatment of an uncommon disease. At €30,000 per year per patient for a drug that at present is taken for life, the investment was obviously rewarding. The so-called second-generation tyrosine kinase inhibitors are even more expensive; consequently, the widespread use of this class of drugs is problematical for many health services and patients. This problem was highlighted in a multi-authored paper (>100 experts in chronic myeloid leukaemia from North America, Europe, Russia, Latin America, Australia, Asia, the Middle East, and Africa) in Blood in 2013 (41).

After imatinib

There is no doubt that imatinib changed the world for patients with chronic myeloid leukaemia. Not only did it bring their spleen size and blood counts back to normal and make the abnormal Philadelphia chromosome disappear with relatively little toxicity, but the drug prevented the disease from progressing to the much-feared ‘blast crisis’. In practice, this means that the number of patients with so-called chronic-phase chronic myeloid leukaemia continues to grow; in India, which has a population of 1.2 billion, it is estimated that there will be 120,000 people taking imatinib, at a cost of $3.6 billion. In April 2013 the Supreme Court of India upheld the rejection of the patent application (1602/MAS/1998) filed by Novartis AG for Gleevec/Glivec (imatinib) in 1998 before the Indian Patent Office. A number of generic tyrosine kinase inhibitors are now available in India at a cost of $50–$100 per month, or $72 million for 120,000 patients. Novartis has since launched a drive to assist patients who could not afford Gleevec/Glivec and, at the time of publication, roughly 16,000 people receive Gleevec/Glivec free of charge.

Treating with, monitoring, and stopping tyrosine kinase inhibitors in patients with chronic myeloid leukaemia

The number of patients receiving haematopoietic stem cell transplantation has decreased markedly in most registries (Figure 7.2), owing to the success of treatment with tyrosine kinase inhibitors. Very few, if any, patients now require haematopoietic stem cell transplantation at the time of diagnosis of their chronic myeloid leukaemia. An editorial in Acta Haematologica in 2013 by Robert P. Gale and John M. Goldman suggested that stem cell transplants should only be offered to patients who don’t respond to tyrosine kinase inhibitors, have a problem with drug compliance, or show evidence of disease progression in spite of tyrosine kinase inhibitor therapy (42).

Fig. 7.2 The numbers of patients receiving haemopoietic stem cell transplantation for chronic myeloid leukaemia, from 1990 to 2012. Patients receiving allogeneic haematopoietic cell transplantation at an early stage of the disease are designated ‘CML early-allo’; patients receiving allogeneic haematopoietic cell transplantation at an advanced stage of the disease are designated ‘CML advanced-allo’; patients receiving autologous haematopoietic cell transplantation at an early stage of the disease are designated ‘CML early-auto’; and those receiving autologous haematopoietic cell transplantation at an early stage of the disease are designated ‘CML late-auto’; HSCT, haematopoietic stem cell transplantation.

Fig. 7.2
The numbers of patients receiving haemopoietic stem cell transplantation for chronic myeloid leukaemia, from 1990 to 2012. Patients receiving allogeneic haematopoietic cell transplantation at an early stage of the disease are designated ‘CML early-allo’; patients receiving allogeneic haematopoietic cell transplantation at an advanced stage of the disease are designated ‘CML advanced-allo’; patients receiving autologous haematopoietic cell transplantation at an early stage of the disease are designated ‘CML early-auto’; and those receiving autologous haematopoietic cell transplantation at an early stage of the disease are designated ‘CML late-auto’; HSCT, haematopoietic stem cell transplantation.

Reproduced by kind permission of the European Society for Blood and Marrow Transplantation. Copyright © 2015 European Society for Blood and Marrow Transplantation.

We can now monitor the patient’s response to tyrosine kinase inhibitors in a number of ways, including blood counts, spleen size, karyotyping, fluorescent in situ hybridization analysis, and measurement of BCR–ABL1 transcripts. Although the second-generation tyrosine kinase inhibitors lead to a more rapid and deeper molecular response than the first-generation ones, there is no evidence yet that they offer any survival advantage. In addition, they are more expensive and more toxic than imatinib.

There are a number of reasons why a patient might lose his/her response to imatinib. One of these came as a surprise to many physicians: poor compliance (43). Measurement of plasma imatinib levels was suggested as a way of detecting compliance failures (44); however, it was found that patients may take the drug a few days before the clinic visit and in order to have plasma levels within the therapeutic range for the duration of the test (44). The issue persists, and the reasons for non-compliance are in urgent need of additional study.

When to stop tyrosine kinase inhibitors?

In a beautifully written editorial in 2013, Gale and Goldman make the point that, although a complete cytogenetic response is desirable, molecular responses are still awaiting prospective clinical trials to validate their importance in outcome (42). Most investigators believe that a reduction in BCR–ABL1 transcript levels of <10% at 3 months may be the best predictor of survival. Patterns of rise in BCR–ABL1 transcript levels may indicate the evolution of a resistant clone or a compliance problem (45).

The most vexed question for patients, doctors, and health services is, when can tyrosine kinase inhibitors safely be stopped? Some investigators suggest that observation of a deep molecular response for 2 years may be sufficient to consider stopping tyrosine kinase inhibitors. Yet the problem is, what is a deep molecular response? As François X. Mahon points out, discontinuation of treatment should only be contemplated within the confines of a clinical study (46).

BCR–ABL1 kinase domain mutations in chronic myeloid leukaemia

Loss of response to tyrosine kinase inhibitors can be due to a number of mechanisms, including poor compliance, as mentioned above, or mutations in the ABL1 kinase domain. Many mutations have been documented and the most dreaded is the T315I, which renders the patient resistant to all tyrosine kinase inhibitors except ponatinib, which unfortunately is a toxic agent. The choice of stem cell transplantation or ponatinib for patients with the T315I mutation will depend on the patient’s age and the existence of a suitable donor. Recommendations for the management of chronic myeloid leukaemia have evolved since the introduction of tyrosine kinase inhibitors and were refined in 2013: the ABL1 kinase domain mutations E255K/V, F359C/V, and Y253H are more sensitive to dasatinib than to nilotinib, and F317L and V299L are more sensitive to nilotinib than to dasatinib (47).

Thus, chronic myeloid leukaemia, a disease that was universally fatal 15 years ago, is now eminently, albeit very expensively, treatable, and current clinical issues include compliance and discontinuation of treatment. There is also another question: is chronic myeloid leukaemia a paradigm for cancer, or just a strange disease?

Minimal residual disease in leukaemia

The term coined to describe the concept that disease relapse was due to the re-emergence of small numbers of malignant cells not killed by the initial therapy was ‘minimal residual disease’, which was first investigated in non-Hodgkin lymphoma and in acute lymphoblastic leukaemia.

In the mid-1980s, interest was generated in the possible use of autologous bone marrow transplantation to cure adult intermediate-grade or high-grade non-Hodgkin lymphoma (48). Subsequently, PCR-based assays indicated that were fewer relapses following autologous transplantation if the bone marrow or mobilized peripheral blood stem cells were free of ‘molecular’ disease (49).

Acute lymphoblastic leukaemia of childhood has provided a vehicle to explore different methods of identifying residual leukaemia cells after or during treatment (50, 51). Such methods include immunophenotyping or molecular analysis, which may enable clinicians to adjust therapy. As Pui observed in a recent podcast, ‘The white blood cell count at diagnosis is no longer of prognostic significance, as treatment can be intensified in this group. The absence of leukaemic cells in the bone marrow by flow cytometry at Day 14 strongly influences treatment schedules’ (14).

The cytogenetic abnormality in chronic myeloid leukaemia provided a method for detection of residual disease but measurement proved difficult to standardize and results were very dependent on the number of metaphases counted (52). The identification of the BCR–ABL1 fusion gene facilitated the establishment of a PCR test to detect low levels of the fusion gene transcripts (53, 54). Thus, monitoring of patients with chronic myeloid leukaemia receiving tyrosine kinase inhibitors is now done by molecular analysis of BCR–ABL1 transcripts (55, 56) although, as Goldman and Gale point out, analysis of the results should take into consideration the methodology and sensitivity of the assay (42).

Chronic lymphocytic leukaemia: The one that got left behind

Although chronic lymphocytic leukaemia, a B-cell disease, is the most common form of leukaemia in the Western world, with a relevant clinical staging defined in the mid-1970s (57, 58), it is only relatively recently that it has entered the ‘molecular’ age. We now have a number of molecular parameters in addition to clinical signs and symptoms, although the latter are still important for diagnosis. In a recent review, Nicholas Chiorazzi focused on three prognostic indicators: genetic abnormalities, expression of specific proteins, and the immunoglobulin heavy chain variable region (IGHV) mutation status (59). Genetic abnormalities include del(13q), Trisomy 12, del(11q), and del(17p). Specific proteins in or on the chronic lymphocytic leukaemia cell surface including CD38 and Zap-70, and the mutational status of IGHV are all important. Sometimes, these different abnormalities occur together. For example, del(13q) is usually found in patients with mutated IGHV, and these patients appear to have a more favourable outcome compared to those with del(17p) and who have aggressive disease.

For many years, treatment for chronic lymphocytic leukaemia consisted of chlorambucil, fludarabine, or combinations of both, together with mitoxantrone and with or without the monoclonal antibody rituximab. Since 2010, no doubt spurred on by the success of tyrosine kinase inhibitors in chronic myeloid leukaemia, a number of new agents have been investigated, including antibodies, ‘engineered’ T-cells, tyrosine kinase inhibitors, and mTOR inhibitors. However, as Michael Hallek pointed out in 2013, chronic lymphocytic leukaemia is a biologically complex disease, unlike chronic myeloid leukaemia, which is initiated by a single oncogene (BCR–ABL1). He also believes that these ‘new’ agents will still have to be combined with chemotherapy (60). Interestingly, a number of the new agents are associated with a rise in peripheral blood lymphocyte counts, as occurs with corticosteroids, and this finding may be disturbing to both patients and their doctors. Rather than pursuing a cure at present, it may be that disease control allied to a good quality of life should be the goal.

Conclusion

In summary, there has undoubtedly been great progress in the treatment of leukaemia since the 1940s. Some forms of leukaemia are curable without chemotherapy, and the introduction of so-called targeted therapy with tyrosine kinase inhibitors for chronic myeloid leukaemia has completely changed the prognosis for that disease. Haemopoietic stem cell transplantation, although toxic, expensive, and difficult, still provides a cure for many patients. In spite of all these advances, however, most adults with acute leukaemia or myelodysplastic syndrome are destined to die from their disease, and the causes of these fatal illnesses continue to elude us.

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