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Leukemias

Battling the Hematological Malignancies: The 200 Years' War

University of Rochester Medical Center, Rochester, New York, USA

Key Words. Leukemia • Lymphoma • Myeloma • Cancer • Cancer therapy

Correspondence: Correspondence: Marshall A. Lichtman, M.D., University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14620, USA. Telephone: 585-275-2205; Fax: 585-271-1876; e-mail: mal{at}urmc.rochester.edu

Received November 20, 2007; accepted for publication December 14, 2007.

Disclosure: No potential conflicts of interest were reported by the author, planners, reviewers, or staff managers of this article.

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
After completing this course, the reader will be able to:

1. Discuss the advances that led to the current state of management of the hematological malignancies.
   
2. Describe the remaining major hurdles to curing these diseases in patients who do not respond to current therapy.
   
3. Identify the strategies needed to reach the goal of cure for most (all) patients.
   

	ABSTRACT

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
The delineation of the hematological malignancies began near the end of the first third of the 19th century with the recognition of the similarity among cases with lymph node tumors and an enlarged spleen (Hodgkin's disease). Descriptions of chronic and acute leukemia and myeloma followed thereafter. In the first years of the 20th century the discovery of x-radiation permitted palliative orthovoltage radiation therapy of Hodgkin's disease. Following World War II, legitimate drug therapy for the hematological malignancies was introduced: nitrogen mustard, adrenocorticotropic hormone and cortisone acetate, and anti–folic acid derivatives, initially aminopterin. Today, about 14 classes of drugs (different mechanisms of action) and >50 individual agents are being used, with others under study. Several examples of agents targeting specific transcription factors or oncoproteins have been introduced. Despite remarkable progress, including the ability to cure acute leukemia in about 70% of children, cure several genetic variants of acute myelogenous leukemia in younger adults, cure some cases of lymphoma in children and younger adults, and induce prolonged remission in many affected persons, the majority of patients face an uncertain outcome and shortened life. Thus, we have much to do in the next several decades. The significant hurdles we must overcome include: the apparent infrequency of an exogenous cause that can be avoided, the exponential increase in incidence rates with age and the dramatic negative effect of aging on the results of treatment, the challenge of one trillion or more disseminated cancer cells among which are a smaller population of cancer stem cells, the profound genetic diversity of the hematological malignancies (apparently hundreds of unique genetic primary lesions), the redundant growth and survival pathways defining the cancer phenotype, the decreasing market for pharmaceutical companies as therapy becomes more specific (fewer target patients) and drug development costs become more expensive, and the significant negative long-term effects of current therapy on both children and adults. These challenges will be gradually overcome, if we (a) develop new models of cooperation among academia, industry, and government, (b) continue the growth of international participation in cancer research (more keen minds to the task), and (c) convince the governments of the world, including that of the U.S., that an investment in minimizing the effects of cancer is as important as defending against other threats to the welfare and longevity of their citizens.

	PERSPECTIVE

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
The hematological malignancies include the various forms of leukemia, lymphoma, and myeloma. The incidence and prevalence of related blood cancers, such as the myeloproliferative diseases (thrombocythemia, polycythemia vera, and idiopathic myelofibrosis) and the myelodysplastic syndromes (clonal cytopenias and oligoblastic myelogenous leukemia) have not been tracked by the National Cancer Institute until recently. This oversight has resulted in an underestimation of the number of clonal (neoplastic) disorders of the lymphohematopoietic system in the U.S. The problem looms large nevertheless, with an incidence of about 135,000 new cases estimated to have occurred in 2007 and a prevalence of >800,000 affected persons in the U.S. in 2004 (Table 1).

The War Begins
The first shot in the 200 Years' War was fired by Thomas Hodgkin, who in 1832 described the first hematological malignancy in the medical literature. Thirty-three years later, the same disease of lymph nodes and spleen was described by Samuel Wilks, to which he designated the subtitle "Hodgkin's disease," in recognition of the initial description [1]. Although the descriptions were primitive by today's standards and some patients may have been misclassified, for the first time a focus was brought to bear on the hematological malignancies, in this case the lymphomas. Although incidental cases that probably represented leukemia were described earlier, the first cases of leukemia based on the clarity of the descriptions have been attributed to John Hughes Bennett (leukocythemia) and Rudolph Virchow (Weisses Blut) in 1845 [2]. Their contributions and the focus they brought to this newly appreciated disease, in which a principal feature was an accumulation of leukocytes in the blood, initiated our awareness of the leukemias.

The first description of myeloma is often dated to 1844: the report of the case of Mr. McBean based on the observational skills of Drs. William Macintyre, Thomas Watson, and John Dalrymple [3]. The latter was the pathologist in the group who described the marrow involvement and the characteristics of the prevalent cells, later identified as plasma cells. An additional noteworthy participant was Henry Bence Jones, the "chemical" pathologist, who was asked to examine the urine of Mr. McBean and in so doing described the characteristic precipitation reaction of urine, containing what we now recognize as monoclonal light chains (Bence Jones protein), on exposure to the appropriate temperature. The term "multiple myeloma" was assigned by the Russian pathologist von Rustizky in 1873 based on his observation of multiple tumors in marrow and bone. The case described by the German physician Otto Kahler in 1889 tied together anemia, bone disease, renal disease, and the type of proteinuria described by Bence Jones and rekindled an interest in the disease. Thereafter, it took about 20 years for Roentgen's discovery of x-rays to be implemented as a medical device for the identification of lytic bone lesions and about 50 years for the development of techniques to study plasma proteins and permit the association of serum protein spikes with myeloma [4].

Most of the 120 years between 1830 and 1950 were spent describing and classifying the myriad subtypes of disease that come under the rubric "the hematological malignancies," a process which, because of their complexity, continues to this day.

Incipient Treatment Approaches
Palliative orthovoltage radiation treatment for some blood cancers, notably Hodgkin lymphoma, was introduced just after the turn of the 20th century and advances in radiation technology and treatment concepts resulted in radiotherapy-induced cures in some patients with Hodgkin lymphoma by the late 1960s [5]. Meaningful anticancer drug development did not occur until after the second world war, in the late 1940s. Three landmark studies showed the potential of chemical therapy for the hematological malignancies. First was the introduction of alkylating agents for tumors of lymphocytes, derived from war-related research on mustard gas [6, 7]. Second was the efficacy of adrenocorticotropic hormone or cortisone acetate in the shrinkage of lymphomatous tumors [8]. Third was the introduction of folic acid antagonists for the treatment of childhood acute leukemia [9, 10]. The latter advance was a result of the collaboration of academia and industry, based on the misconception at the time that folic acid, required for DNA synthesis, caused progression of childhood leukemia ("acceleration phenomenon") [11]—a good example of how important findings may result from accidents of intellectual activity. The next 30 years were followed by the introduction of many new anticancer drugs in different drug classes [12].

In the last 30 years, many additional agents active against the blood cancers have been developed and approved for use, yet the diseases are of such a nature that the improbability that we will have curative therapy for most persons with hematological malignancies before the mid-21st century, 200 years from the clinical description of Hodgkin lymphoma, leads me to refer to the duration of the war in these dimensions. A near total solution will take time for the reasons outlined below, a period of time that no one can now foresee. Perhaps, this commentary should be titled the 200+ Years' War, but that lacks panache. Many improvements and advances will happen as research achievements enter the marketplace. Although my prophecy leans towards optimism, it is couched in realism.

Disease is inseparable from the human condition, but we should do all we can to minimize it for the betterment of mankind. Our task is to accelerate the happy day's arrival when we can advise all patients at the time of diagnosis that their blood cancer is curable. In the meanwhile, we will rescue as many patients as we can and attempt to prolong good health in those we cannot yet cure.

	REMARKABLE PROGRESS

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
In 1946, nitrogen mustard therapy was described in 67 patients with lymphoma, leukemia, and assorted other cancers, in what was the first cooperative cancer chemotherapy trial (University of Utah, Tufts University, University of Oregon, and the U.S. Army) [6]. There was, however, no possibility of cure for children or adults with a hematological malignancy. Many, including some physicians, thought a diagnosis of cancer sealed one's fate. There was nothing one could do to extend life; the situation was hopeless. Some thought experimental treatment was cruel and that the patients should be kept as comfortable as possible without adding disturbing "experiments," using newly designed drugs that were toxic and not curative. This attitude was especially so when the patient was a child or an older adult. "Let them die in peace" [13]. Fortunately, some physician–scientists did not listen to the fatalists.

One of the most important steps forward in the treatment of the hematological malignancies required the critical collaboration of industry and academia: Lederle Laboratories, Harvard Medical School, and the Boston Children's Hospital. Yellapragada SubbaRow, a chemist in the Research Division of Lederle Laboratories in Brian L. Hutchins' group, working on folic acid and related compounds, designed and synthesized the anti–folic acid agents requested by Farber and his colleagues to permit their classic study of aminopterin in childhood acute leukemia at the Boston Children's Hospital [9]. Several children so treated had a transient remission. This result established (a) that there was a background of presumptive normal hematopoietic cells (later validated) capable of re-emerging if the leukemia cells were sufficiently suppressed, (b) that there was variation among patients in the salutary effect of the drug, a harbinger of our learning of the heterogeneity of the genetic basis of this and other hematological malignancies, and (c) that further research might lead to prolonged remission or, perhaps, the cure of acute leukemia. Like the effect of Sputnik on American space science, the demonstration that the disease could be subdued at least for a time attracted and energized scientists to the challenge.

The development of many drug classes with additive or synergistic mechanisms of action (Table 2), their use in multidrug treatment programs, coupled with improved transfusion practices, especially the application of component transfusion, more effective treatment of infectious complications, and other technical advances have resulted in increased rates of remission, longer remission durations, and curative therapy for some. These advances roll off the "tongue" but they and others not mentioned were the results of the engagement of pioneering scientists in many fields working with financial support provided largely by the National Institutes of Health.

Today, about 70% of children with acute leukemia and 80% of children and adults with Hodgkin lymphoma are cured, thanks to carefully crafted multidrug therapy developed from sequential series of clinical trials. Cure is possible, indeed frequent, for children and younger adults with lymphoma. Remission is commonplace in adults with acute leukemia and cures occur in certain subtypes of the disease, especially in younger adults. New drugs, thalidomide congeners and proteasome inhibitors, introduced for patients with myeloma, a disease heretofore resistant to drug treatment, have increased the rate and duration of remissions of this disease.

The use of allogeneic hematopoietic stem cell transplantation has become widespread and can cure some patients with acute leukemia and lymphoma who escape drug therapy. Transplantation has been (a) improved to increase cure rates, (b) modified to extend the age of patients for whom it is available, and (c) made more accessible by the use of haploidentical or unrelated donors, if sibling donors are unavailable.

New drugs for the chronic leukemias have changed the life expectancy for such patients dramatically [16]. Very long-duration remissions, which are likely to be measured in decades, will be common, and hematopoietic stem cell transplantation can be used to cure eligible patients who escape the beneficial effects of drug therapy.

Monoclonal antibodies, either naked or with an attached cell toxin or radioisotope, designed to target surface proteins of myelogenous leukemia cells, lymphoma cells, and chronic lymphocytic leukemia (CLL) cells, have increased the frequency and duration of remissions; they have become standard additions to treatment programs [17].

Drugs that target epigenetic abnormalities of genes have begun to make a difference in the management of several blood cancers. Epigenetic modifications do not result from mutation in the base sequence of DNA but from attached molecular groups that modify gene action [18].

Although many of these beneficial effects will be incremental rather than decisive, with each passing year, new drugs or treatment programs are likely to extend life and make those years healthful and productive.

Another approach that has applicability in theory and is effective in animal models is immunotherapy, notably the use of cancer treatment vaccines, several of which are in clinical trials for use in patients with lymphoma, leukemia, and myeloma [19]. Striking evidence for the potential of immune cell therapy is evident in two diseases: chronic myelogenous leukemia (CML) and myeloma. In patients undergoing stem cell transplantation, the lymphocytes of stem cell donors can mount a potent immune response and induce a remission (graft versus CML and graft versus myeloma, respectively). Should these patients relapse, the infusion of lymphocytes from the transplant donor may induce remission, sometimes protracted, a dramatic immune cell effect. Immune cell approaches would be used in patients in remission with residual cancer cells by infusing immune cells (e.g., dendritic cells) exposed to relevant cancer cell antigens in the laboratory, which suppress the growth of residual blood cancer cells to which they have been sensitized, presumably for long periods or indefinitely. Other approaches to developing cancer vaccines are also being tested.

The net effect of these advances in therapy, the improvement in survival rates for the hematological malignancies over the last 30 years, is shown in Table 3, in which the 5-year survival rates from 1974–76 are compared with those from 1996–2003. The analysis requires a lag to assess the 5-year survival rate. This lag time is an important consideration because progress in certain areas in the last several years is not reflected here, notably, the introduction of imatinib mesylate (Gleevec® Novartis Pharmaceuticals Corporation, East Hanover, NJ) and its later congeners for CML, rituximab for the treatment of lymphomas, and thalidomide derivatives and proteasome inhibitors for myeloma, as examples. One would expect to see the CML and lymphoma 5-year survival rates increase significantly in the next several years.

It has been very difficult to make significant progress in the therapy of acute leukemia and myeloma in older persons. Note the single-digit 5-year survival rates in patients 65 years with acute myelogenous leukemia (AML) or ALL and low double-digit 5-year survival rate in myeloma. The results in the latter case are likely to improve, given the recent therapeutic advances in this disease.

A further increase in 5-year survival rates will be a contest of the more powerful scientific and drug development techniques available pitted against the more resistant diseases and subtypes of diseases that have been unresponsive to current therapy. The types of hematological malignancies with cells intrinsically more sensitive to therapy, for example, childhood ALL and Hodgkin lymphoma, are in the >80% cure range. Compare childhood ALL (>80% cure rate) with older adult AML or ALL (virtually incurable with current approaches).

Five-year survival rates do not indicate the cure of the subacute or chronic diseases: CML, CLL, lymphomas, and myeloma. In the acute leukemias, it is reasonable to estimate that the 5-year survival period, if "event-free," has a high probability of cure. The 5-year survival rates shown in Table 3 are not necessarily free from disease. Also, the survival data give no estimate of quality of life during that period.

The diagnosis of leukemia, lymphoma, or myeloma remains jarring, frightening, and threatening, but more options for longer remissions or cures are available to patients. Although dramatic therapeutic developments have occurred during my career in medicine, we still have very substantial challenges, indeed daunting challenges, and yet it is just those hurdles that spur us on. Why daunting?

	THE INFREQUENCY OF AN EXOGENOUS CAUSE

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
It is likely that most blood cancers are the result of cellular misadventures in blood-forming cells or lymphocytes, aberrations of normal cell processes, such as spontaneous mutations resulting in oncogene formation and inadequacies of DNA repair mechanisms.

Chemicals
Only a small proportion of the blood cancers have a cause related to exogenous or environmental factors. The only blood cancer for which there is convincing scientific evidence for an avoidable environmental cause is AML (and the closely related disease myelodysplasia), and only in a minority of cases. This major subtype of leukemia can be a result of long-standing cigarette smoking [20] or relatively high-level, prolonged exposure to benzene (>25–40 ppm-years) [21]. The use of the latter chemical is regulated by federal and state governments and about 0.1% of the population in the U.S. is potentially exposed to higher levels of it in an occupational setting, presumably in a regulated manner that would minimize risk. Cigarette smoking may account for about one sixth of cases of AML but this population-attributable risk is related to the number of heavy smokers in the population. There are major efforts by many agencies to try to educate people about the foolishness of smoking, because of the risk for heart and lung disease and several other major cancers for which the risk of development is much higher than that of leukemia, such as those of the oral cavity, larynx, bronchus, bladder, and others, tissues that are in direct contact with the carcinogens in tobacco smoke or carcinogenic metabolites.

AML also may occur as a result of intensive cytotoxic therapy (chemotherapy and/or radiation therapy) for another cancer, often a lymphoma or myeloma [22], but this is not "preventable" until such time as blood cancers can be approached in other ways, a solution that is not on the horizon, today.

Although there is a suspected association between lymphoma and certain chemicals such as organochlorines, organophosphates, and phenoxyacid herbicides, a causal relationship is unproven, and this is unlikely to account for a large proportion of lymphoma cases.

Microbes
Infection by five microbial agents, four viruses [hepatitis C virus, Epstein-Barr virus, T-cell lymphocytotropic virus, human immunodeficiency virus (HIV)] and one bacterium (Helicobacter pylori) is linked to a higher incidence of lymphoma. No vaccine exists for these agents today, and their contribution to lymphoma causation is relatively small.

Prevention of the overwhelming proportion of blood cancers is not a strategic option at this time, and where feasible, causal exposures are being managed by many agencies (e.g., benzene exposure, HIV transmission, and cigarette smoking).

	GENETIC PREDISPOSITION

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
A very small proportion of hematological malignancies are related to germline predisposition genes that are otherwise silent or that produce a phenotype (syndrome) known to be associated with a higher risk for a hematological malignancy (e.g., familial platelet syndrome) [23].

The human genome is replete with genetic variations, single nucleotide polymorphisms [24], minor structural variations in a gene, or variations in copy number [25], that may result in a protein product that behaves atypically. There are innumerable such variations and they give us our unique DNA fingerprint. They may account for an individual's predisposition to disease, responsiveness or lack thereof to specific drug therapy, and the development of short-term and long-term drug toxicity. Whole genome screens are superseding the study of individual polymorphic genes and should be a more comprehensive and powerful tool in assessing the impact of polymorphic gene distinctions on cancer predisposition and the effects of therapy [26]. We are in the infancy of our understanding of the relationship of polymorphisms to blood cancer onset or response to treatment. In the future, this type of information may provide a basis to develop a mechanism to intervene before disease onset or to design patient-specific therapy. These concepts are futuristic but worthy of continued research.

	THE IMPACT OF AGING AND AGE AT ONSET OF A BLOOD CANCER

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
A major obstacle to progress is the impact of age at onset on the pathobiology of the blood cancers [27]. The incidence rate of blood cancers increases exponentially with age. Note in Table 4, the 100-fold increase in the incidence rate of lymphoma between age 10 and 80 years and the 25-fold increase in the incidence rate of leukemia. The myeloma incidence rate increases 40-fold from age 40 to age 80 years. With lifespan increasing, the risk for developing a blood cancer increases as a larger proportion of an enlarging population is in the older age groups. In the first third of the 21st century, the members of the population of the U.S. who are >65 years old will double, as will the population >85 years old. Thereafter, the dramatic growth in the fraction of the population in these age groups will continue. The median age at onset of leukemia, lymphoma, and myeloma is 65–70 years. Most patients with blood cancers are >50 years of age. In the absence of preventive strategies, the number of individuals being stricken with a blood cancer will increase in proportion to the growth of the population in general and the older population in particular (Table 5).

We know that patients in the older age groups have blood cancer cells with chromosome changes and the expression of genes for drug resistance that predict poor outcome. This deleterious effect of age on cure rate is not a threshold effect—it increases with each decade of age from youth onward. The pathobiology of blood cancers with aging should be a paramount focus of research. One such investigative area is the development of compounds that reverse or ameliorate blood cancer cell drug resistance.

Tolerance to intensive therapy is reduced in older patients, and less noxious, targeted therapy may be critical to increasing the frequency and duration of remission and the rate of cure. The utility of oncoprotein-targeted therapy in the older adult is exemplified by imatinib mesylate, which has a similarly beneficial effect in patients with CML at all ages. Other agents that by happenstance are tolerable in older patients and have superior treatment outcomes include, for example, bortezomib, used in patients with myeloma. Although the fraction of older patients entering clinical drug trials has increased, as important is the discovery of drugs that have the potential of being effective in this age group. Drug discovery through basic and translational research is the horse, the clinical trial is the cart. The resistance to therapy of blood cancers in older patients is beginning to receive increased attention, and one can expect further progress in the near future.

	THE GENETIC HETEROGENEITY OF BLOOD CANCERS: THE COMPLEX TASK OF DEVELOPING THERAPY THAT CAN SILENCE ONCOGENES OR ONCOPROTEINS

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
In the mid-1950s, in parallel with a developing approach to the treatment of leukemia and lymphoma, the modern discipline of cancer cytogenetics and genetics was born [28, 29]. This provided the techniques to validate the seminal role of chromosome abnormalities in the etiology of the hematological malignancies and to initiate the genotyping of these tumors, a process that continues today, given the complexity of their genetic alterations. This complexity creates a large challenge confronting medical science: the number of distinct cancers that are represented when we refer to leukemia, lymphoma, and myeloma. These tumors are subclassified first by phenotype, which is determined by the type of cells involved, as examined by microscopy or by immunophenotyping using cell flow cytometers. AML, ALL, CML, CLL, and their numerous morphologic subtypes, and the subtypes of lymphoma are diseases as distinct in terms of their clinical manifestations and their responsivity to drug treatment as colon cancer, brain cancer, lung cancer, and breast cancer. Estimates of genetic variation in AML are a dramatic example. There are about 140 balanced structural chromosome abnormalities, about 700 unbalanced structural abnormalities, and about 23 numerical abnormalities of chromosomes that have been identified in cases of AML. There is no proof that each of the nearly 870 abnormalities is an initiating event, but a large proportion are likely to be seminal events. Thus, from a genetic standpoint, the 11 or so morphologic variants of AML represent hundreds of unique genetic lesions.

Table 6 lists the 27 phenotypes of lymphoma distinguished by their cellular appearance and clinical manifestations as designated by the World Health Organization. The genotypic variation of lymphoma, like AML, is far larger, ranging into the hundreds.

	DEALING WITH ONE TRILLION BLOOD CANCER CELLS

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
Drug-killing effects obey the mathematical principle of first-order kinetics. This principle contends that a drug kills a fixed proportion of the cell population, regardless of its size. It is a bit like the puzzle that asks, "If a person walks half way across a room, and then walks half of the remaining distance, and half of the remaining distance, and so on, how does the person ever cross the room?" The number of blood cancer cells in a child with acute leukemia has been estimated to be about one trillion cells [30]. This estimate is probably reasonable for most leukemias. The range of the body burden of myeloma cells is similar (1–3 x 10¹²), depending on stage of disease [31]. The number of lymphoma cells is probably in this range or higher depending on stage of disease. In the circumstance of one trillion blood cancer cells, if repeated treatment with a combination of drugs is successful in killing 99.999% of the cells, ten million blood cancer cells still remain.

Compounding that issue is the presence of cells in the leukemia (and lymphoma and myeloma) population that are cancer-initiating cells or cancer stem cells [32, 33]. They may represent one in several hundred thousand blood cancer cells in a given case. These cells are capable of replenishing and sustaining the growth of leukemia, lymphoma, and myeloma tumors indefinitely. Some argue that unless we can kill all the cancer-initiating cells, not just the mass of derivative cells that make up most of the tumor, cure for all patients will continue to elude us. Fortunately, these theoretical arguments prove to be oversimplified. We do cure patients, presumably without killing the last leukemia or lymphoma cell in most [34, 35]. What factors cause the growth potential of the residual leukemia cells to cease are unclear. In addition, one can induce remission for long periods, for example, 3, 5, or 7 years, before the residual leukemia or lymphoma cells accumulate again. Moreover, having followed patients with acute leukemia in remission for 5 years after induction therapy only to have them relapse and die, or patients with lymphoma for about 10 years, treating active sites from time to time, with long intervals of inactive disease, it is clear that patient longevity is in part related to the amazing variability observed in the growth potential of hematopoietic cancer stem cells. I do not understand what permits this "Rip Van Winkle" effect [36].

This unpredictable behavior of blood cancers in response to treatment is one reason why many hold out hope that a cancer vaccine might be useful in extending the period during which residual blood cancer cells do not accumulate. Other scientists are trying, with good success, to isolate blood cancer stem cells and to study their drug sensitivity. Normal or cancerous stem cells may be relatively drug resistant, a characteristic derived from an evolutionary process that selected for powerful processes to foil potentially lethal exogenous chemical exposures in critical germinating cells. Several drugs have been identified that, in the laboratory, appear to kill AML stem cells but not normal hematopoietic stem cells. Should they be found to do the same in patients, we may learn if focusing on hematopoietic cancer stem cells is a profitable path to follow. Presumably, the cancer stem cells exposed to drugs will be subject to first-order kinetics as well, and thus, we may have difficulty reaching a 100% cancer stem cell kill. On the other hand, practice often trumps theory in medicine, and improved outcome may be forthcoming with a kill rate that greatly lowers but does not eradicate residual leukemic stem cells.

	THE CHALLENGE OF SPECIFIC THERAPY FOR BLOOD CANCERS

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
Therapy for blood cancers in most cases is directed at processes and biochemical pathways shared by normal cells. Thus, normal tissues also bear the brunt of its effects. Fortunately, not by design, normal cells usually tolerate the onslaught. If we look at the categories of drugs used to treat the acute leukemias or the major categories of lymphoma, most date back about 35–60 years.

We now have more specific therapy for Philadelphia chromosome–positive CML, acute promyelocytic leukemia bearing a translocation between chromosomes 15 and 17, and hairy cell leukemia. In the first two cases, we understand the relationship of the drugs imatinib mesylate and its congeners and all-trans retinoic acid, a vitamin A derivative, to the genetic abnormalities that cause these two diseases. In the case of hairy cell leukemia, the specific beneficial effect of cladribine was discovered by trial and error. We do not have the molecular explanation for its singular effect on the form of B-cell CLL in which hairy cells are the cell type involved. Yet, a disease that once did not respond to any form of chemotherapy has been subdued in about 90% of patients by 1 week of treatment with cladribine. Unfortunately, these three examples of successful therapy directed at specific hematological malignancies represent only about 5% of the 135,000 cases of blood cancers that were estimated to have occurred in 2007. In addition, although a large majority of patients receive the benefits of these therapies, a subset do not—about 10%–30% of patients.

The introduction of antibodies engineered in the laboratory to attach to specific areas on the surface of blood cancer cells has been another very important advance in specific therapy. These antibodies may in themselves kill the leukemia or lymphoma cells with minimal side effects on other closely related tissues or may be attached to a cell toxin or a radioactive molecule that can be carried to the target leukemia or lymphoma cells, minimizing noxious effects on uninvolved tissues. Their effects can be quite dramatic.

New agents for the treatment of myeloma have resulted in an increase in the frequency and duration of remissions. Myeloma is a disease that has been very resistant to treatment in the past, and new categories of drugs, including proteasome inhibitors and thalidomide derivatives, are making the first significant inroads into improved drug therapy in a half century. These new approaches have increased the rates and durations of remission for patients with myeloma. Cure, however, is still not at hand.

The challenge to find specific therapy for hematological malignancies is enormous because of the genetic heterogeneity of these cancers. Techniques of gene silencing (oncogenes) or gene awakening (tumor suppressor genes) may be two of several approaches. Work continues on antisense molecules as therapeutic agents [37], and the increasing knowledge on the role of mutations in noncoding small RNA molecules in determining the malignant phenotype [38] provides a new approach to gene-silencing therapy. Because of the difficulties of using these approaches to develop practical and safe therapy, finding common secondary pathways, such as aberrant cell pathways that foster cell growth or aberrant pathways that regulate cell death, shared by a large proportion of genetically unique subtypes of leukemia, lymphoma, or myeloma will be important. The interruption of such pathways, which contribute to the malignant behavior of cells, may permit the physician to use fewer highly effective drugs to treat a large proportion of patients with different genetic lesions.

	THE IMPACT OF INCIDENCE RATES ON PHARMACEUTICAL COMPANIES

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
When one has stratified the blood cancers into phenotypes and genotypes, the number of patients amenable to a specific oncogene- or oncoprotein-targeted therapy becomes relatively small. This situation is unattractive for pharmaceutical companies that may need to invest hundreds of millions of dollars into the effort to develop a drug. For a pharmaceutical company, the greater the specificity of the drug, the fewer the number of future users. Today, most drugs can be used for several blood cancers and for cancers of other tissues. To move to more focused and, presumably, more effective and less toxic drugs, collaboration among governmental agencies, such as the National Institutes of Health, the pharmaceutical and biotechnology industries, and academic health centers (research-intensive medical schools, research institutes, research hospitals) needs to be further enhanced.

There are incentives for companies to pursue drugs with an apparently small market. For example, the development of imatinib mesylate may have done more than advance the treatment of CML; it may have caused pharmaceutical companies to have second thoughts about developing new drugs for uncommon cancers. The pharmaceutical company involved (Ciba-Geigy, later Novartis) was looking for a drug to block a tyrosine kinase (platelet-derived growth factor receptor) potentially involved in atherosclerosis, a very large market, but was forced to aggressively manufacture imatinib mesylate because of the demands of patients with CML, a very small market, and in the end did (very) well by doing good, because of pricing, because of the fact that the drug is required indefinitely, and because of the drug's ability to cause the remission of a gastrointestinal stromal tumor, which effectively doubled the target patient population. The latter event is another example of how drug development in the hematological malignancies continues to provide the path to therapy of other types of cancer.

	FINDING THE CURES, NOT THE CURE

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
Basic and translational research in leukemia, lymphoma, and myeloma have one overarching goal—to find cures for the innumerable genetic subtypes of these diseases. We are looking for many curative approaches. The common phrase "the cure for cancer," as understood by the public, requires re-education. This process requires the continuum from basic to clinical research. We have far too much to learn to forego basic research but we have enough basic information to support translating that information into better diagnosis and treatment. Thus, we must do both. Because we are looking for cures for many diseases, not a single cure, research programs have very diverse goals, encompassing finding better approaches to the many forms of leukemia, lymphoma, and myeloma. It is important that such efforts are part of an integrated whole, including government, industry, academia, foundations, and voluntary health agencies, trying where possible to develop partnerships. We should maintain an appropriate investment in basic research so that new discoveries can be used to develop new and better treatments and so that research grant support continues to bring young minds with new ideas, unencumbered by outdated concepts, and experienced in the most avant-garde technologies into the battle.

	LONG-TERM ILL EFFECTS OF THERAPY

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
All therapy for blood cancers has short-term noxious effects, most of which are tolerable or treatable and usually reversible. The increasing success of therapy, which results in cures or long-term remissions, has been complicated by an increasing frequency of late consequences of radiation therapy or intensive chemotherapy. Secondary AML, secondary cancers of other tissues, and organ failure, especially cardiac muscle insufficiency as a direct result of therapy or secondary to premature coronary artery disease, are examples of such effects. In children, additional consequences of treatment occur, when brain, endocrine gland, and bone development are in process [39]. These Pyrrhic victories are receiving increasing attention as therapists attempt, where reasonable and possible, to reduce the use of radiation therapy, reduce the intensity of chemotherapy, and avoid drugs known to be principal offenders without sacrificing the frequency of remission or cure.

	THE FUTURE

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 
A few things are apparent. We can expect to see blood cancers increase in incidence with their attendant consequences as a result of aging of the population and our inability to invoke prevention in most cases (Table 5). The counterforce will be new and better therapies leading to more frequent and longer remissions and more frequent cures: notably, a significant increase in the responsiveness of older patients and more therapies directed either at the specific gene abnormality in hematological cancer cells or at pathways that foster the malignant phenotype, such as apoptotic, angiogenic, or cell signaling pathways, or that are improved congeners of existing classes of drugs. An example of the evolution of specific therapy is the recent evidence that all-trans retinoic acid combined with arsenic trioxide in a therapeutic formulation can successfully treat acute promyelocytic leukemia without the use of chemotherapy. The combination works on a specific genetic abnormality in leukemic cells (oncoprotein-targeted therapy), resulting in their death and the re-emergence of normal blood cell development.

As we further dissect the complexities of the human genome and the mechanisms of gene regulation, we may learn more of the pathobiology of chromosome translocations, the role of mutated microRNA, and other aberrancies, and in so doing, perhaps, learn how to intervene to prevent or reverse the malignant phenotype.

Research institutes, foundations, and health agencies should provide unified, compelling arguments why a reinvigoration of the government's support for cancer research is in the public interest and should be a national priority.

	REFERENCES

Top Learning Objectives Abstract Perspective Remarkable Progress The Infrequency of an... Genetic Predisposition The Impact of Aging... The Genetic Heterogeneity of... Dealing with One Trillion... The Challenge of Specific... The Impact of Incidence... Finding the Cures, Not... Long-Term Ill Effects of... The Future References

 

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