Incidence and Epidemiology

The annual incidence of CML has been estimated at approximately 10 cases per million. It accounts for approximately 15% of all patients with leukemia. ⁶ Although it is thus relatively infrequent, its importance relates to the cytogenetic and molecular understanding of the disease and effective therapy, which offers potential for cure.

Etilogy

In the great majority of patients, a causative factor cannot be identified. Nevertheless, it is well known that ionizing radiation is leukemogenic. Although CML has been observed, the most common type of leukemia following radiation has been acute myeloid leukemia, as demonstrated by studies following the atom bomb explosions in Japan in 1945 and by earlier studies in radiologists and in patients with ankylosing spondylitis treated with radiation therapy. ⁷

Clinical and Hematologic Characteristics

The median age of onset of CML is 50 years; the peak incidence occurs during the ages of 50 to 60 years. There is no sex preference. The first phase of the disease, the chronic phase, terminates in a second, more acute or abrupt course, called the blast phase. Sometimes, there is an intervening short-lived phase between the chronic and blast phases called the accelerated phase, characterized by a more gradual increase in blast cells in the peripheral blood, progressive anemia, thrombocytopennia, and increasing splenomegaly. The median survival approximates 3 to 5 years.

Symptoms and signs usually develop insidiously and include fatigue, anemia, progressive splenomegaly, and leukocytosis. In the chronic phase, the white blood cell count approximates 2,000,000/μl. The myeloid cells in the peripheral blood show all stages of differentiation, but the myelocyte predominates (Fig.125.1). Basophils and eosinophils are prominent. More than half of the patients have platelet counts above 1,000,000/μl but thrombotic phenomena are unusual. A slight degree of anemia is common. The striking biochemical abnormality in CML, still unexplained, is the reduction of leukocyte alkaline phosphatase activity, both in intensity and in the number of neutrophil band forms that stain positively for the enzyme. A high level of activity virtually excludes CML, but low values may also be seen in agnogenic myeloid metaplasia. Nevertheless, phagocytic function remains essentially normal. ⁸ The leukocyte alkaline phosphatase activity may increase with infection, clinical remission, or the onset of blast crisis.

Figure 125.1

Chronic myelocytic leukemia. Leukocytosis with myelocytes, metamyelocytes, band cells, and polymorphonuclear leukocytes are characteristic of the peripheral blood in the chronic phase of this disease.

Mature granulocytes synthesize and release an alpha globulin B₁₂ binding protein, transcobalamin 1, into the serum. The increase in the size of the white blood cell pool is reflected by marked elevation of serum B₁₂ and unsaturated B₁₂ binding capacity. An increase in circulating basophil level, histamine production, or both often occurs during blastic transformation, but the significance of this is not known. ⁹

The bone marrow is hypercellular and devoid of fat. ¹⁰ During the chronic phase, the myelocyte predominates; myeloblasts and promyelocytes usually account for less than 10% of the marrow cells. Early in the disease, megakaryocytes may be increased. Cells morphologically indistinguishable from true Gaucher cells can be seen in about 10% of cases. ¹¹ As in other myeloproliferative disorders, biopsy sections may show an increased number of reticulin fibers. As the disease evolves, varying degrees of fibrosis occur. ¹² The cause of this is unknown, but, presumably, the fibroblasts are not part of the malignant clone. Evidence suggests that the marrow fibrosis may be secondary phenomenon resulting from an abnormal interaction between the proliferative clone of megakaryocytes and elements regulating marrow fibrosis and collagen, including at least platelet-derived growth factor, transforming growth factor-beta basic fibroblastic growth factor, and other cytokines not completely described as yet.

Rare cases are similar to “typical” CML but lack the Ph chromosome and its molecular abnormality and have less characteristic clinical and hemotogolic features, including lower initial white cell and platelet counts and muramidasuria. ¹³ These Ph chromosome-negative patients, whose median survival is shortened to approximately 20 months, have less satisfactory responses to treatment than do Ph-positive patients. This type of leukemia will not be discussed in this chapter.

Terminal Chronic Myeloid Leukemia

At any time during the course of CML, but usually after a median interval of 36 months, there is a relatively abrupt change in the course of the disease. Owing to its morphologic and cytogenetic characteristics and its impaired response to chemotherapy, this phase has been called the accelerated, blast, or terminal phase. Clinically, the most reliable finding is the presence in the peripheral blood, bone marrow, or both of myeloblasts and promyelocytes exceeding 30% of the differential distribution ¹⁴ (Figs.125.2and 125.3). This occurs in about 70% of the cases. In the absence of frank blast crisis, other criteria include the development of fever of undetermined origin, increasing splenomegaly, a rising white blood cell count, basophilia, an increasing degree of anemia, and thrombocytopenia and refractoriness to previously effecive therapy such as busulfan (BUS) or hydroxyurea (HU). High blast cell counts may lead to pulmonary and/or cerebral leukostasis and hemorrhage. The median survival after blastic transformation is approximately 3 months. ¹⁴

Figure 125.2

Chronic myelocytic leukemia, blastic crisis. Marrow aspiration shows predominance of blastic forms, which may have myeloid or lymphoid appearance.

Figure 125.3

Chronic myelocytic leukemia, blastic crisis. This bone marrow biopsy shows that blasts with prominent nucleoli comprise about 75% of the marrow cells.

The blast crises are divided into two general types, myeloid and lymphoid. Biphenotypic or mixed lymphoblastic-myeloblastic crises have also been observed. ¹⁵ Lymphoid blast crisis occurs in 20 to 30% of patients. The cells often resemble those seen in acute lymphocytic leukemia and contain terminal deoxynucleotidyl transferase, an enzyme that catalyzes the polymerization of deoxynucleoside triphosphates. ¹⁶ Terminal deoxynucleotidyl transferase is found mainly in poorly differentiated normal and malignant lymphoid cells of T-cell and B-cell origin and is lost as these lymphocytes differentiate and mature. Although most lymphoblastoid crises are of B-cell origin because the cells stain with anti-CALLA (CD-10) and anti-B1 (CD-20) antigens, a few cases of T-cell blast crises have been described. ² Myeloid blast crisis may mimic acute myeloid leukemia. Rarely, patients present in myeloid blast crisis without a recognized antecedent chronic phase; the demonstration of the Ph chromosome and other phenotypic and molecular abnormalities distinguishes this condition from de novo AML.

Megakaryoblastic ¹⁷ and erythroblastic ¹⁸ transformations and blast crisis marked by basophilia and high blood histamine levels have been reported. Despite these observations, the basic mechanism by which the chronic phase transforms into the blast phase is not understood. Cytogenetic abnormalities per se may not necessarily be causally related to blast phase transformation. In addition to the cytogenetic abnormalities that will be discussed, alterations of the p53 and p16 genes have been reported to be associated with a clinical progression of the chronic phase to accelerated and acute blast phase disease. ¹⁹

Pathophysiology

The characteristic abnormality in CML is an increase in the myeloid component. ²⁰ The total granulocyte pool is from 10 to 150 times normal. This appears to be related to a shift in the number of self-renewal cells and differentiating cells toward the differentiating ones. For years, it has been known that the “malignant” cells in chronic phase CML are not completely autonomous and are still subject to some regulatory control. The exact reason, however, why the leukemic cells have a proliferative advantage is still unknown. It has been suggested that the primary biologic defect in CML is not unregulated proliferation of leukemic stem cells but rather discordant maturation, wherein a slight delay in cell maturation within the myeloid compartment results in increased myeloid mass. ²¹ In contrast to the normal state, in which the primitive progenitors have a large proliferative potential and produce the majority of cells, in CML, early progenitors have reduced proliferative capacity as the leukemic population expands. This occurs because an increased number of divisions takes place in the mature proliferative compartments (late blast, promyelocytes, and myelocytes), which are not under regulatory control, and because the mature cells have an increased lifespan. Leukocyte labeling techniques indicate that mature granulocytes equilibrate with the large total granulocyte pool and have a prolonged circulation. ²⁰

Defective adherence of immature CML cells to marrow stromal cells in vitro ²² facilitating early release in vivo into the circulation may also play a role in producing an increased WBC mass. Attempts have been made to correlate growth abnormalities with variations in hematopoietic factors, such as increased levels or sensitivity to granulocyte-macrophage colony-simulating factor (GM-CSF) or decreased levels of sensitivity to inhibitors of myelopoiesis, such as acid lactoferrin or prostaglandin E. ²³ The expression and subsequent loss of class II major histocompatibility determinants may also play a role. Whether these events are primary or secondary still remains to be determined. ²⁴

Cytogenetics

The Ph cromosome, the cytogenetic hallmark of CML, results from a reciprocal translocation of cytogenetic material following a break on chromosome 9 at band q34.1 that transposes the 3’ segment of the ABL gene to the 5’ segment of the bcr gene on chromosome 22 at band q11.21, resulting in the chimeric bcr-abl gene (Fig 125.4). In this chapter, bcr refers to the 5.8 kilobase (kb) segment that is the region of the breakpoint in CML on chromosome 22 and bcr-abl refers to the entire gene.

Figure 125.4

Diagrammatic schema of 9.22 Chromosome translocation.

The chromosome translocation is designated t(9;22)(q34.1;q11.21). ²⁵ It is found in approximately 95% of patients with CML. It is also observed in 5% of children and in 15 to 30% of adults with acute lymphocytic leukemia and in 2% of patients with newly diagnosed acute myelocytic leukemia. ^{26, 27} Despite the presumed specificity of the Ph chromosome and the bcr-abl gene, patients have now been found with typical clinical and hematologic characteristics of CML that lack the Ph chromosome but with the bcr-abl rearrangement. ²⁸ It has been estimated that approximately 5% of patients with the phenotype of typical CML are Ph negative but bcr-abl positive. The demonstration of the chimeric gene, therefore, now becomes the sine qua non for the diagnosis of CML. The response to treatment and the course of disease of CML patients who are Ph-negative bcr-abl positive is the same as that of Ph-positive bcr-abl patients. Excluded from this discussion are patients who may have some clinical and hematologic characteristics of CML but who are bcr-abl negative.

Some Ph-positive patients were initially described as having translocations involving chromosome 22 and chromosomes other than 9, but it is now believed that 9 is involved in all cases. ^{29– 32} This finding may be overlooked in complex translocations. Complex translocations involving three or more chromosomes may sometimes result in a “masked” Ph that is not smaller than the normal 22; such cases have been erroneously classified as Ph negative. ³³ There is no difference in survival in patients with standard compared to variant or complex translocations.

Progression of CML from the chronic to the accelerated or acute phase is accompanied by additional cytogenetic abnormalities that occur more commonly in the myeloid than in the lymphoid transformation. The exact pathogenic mechanism remains unknown; the most common abnormalities include a second Ph chromosome, isochromosome 17, +19, and trisomy 8 (+8), ²⁵ which results in a selective growth advantage of these cells. The molecular counterpart of these cytogenetic abnormalities may be mutations or deletions of tumor suppressor genes such as p16 and the p53, which may contribute to the malignant phenotype ¹⁹ ; hypermethethylation of DNA has also been suggested as a contributing cause. ³⁴ Sometimes aneuploid cells are found in routine cytogenetic studies that do not necessarily increase in number even with conventional therapy and may regress. Lymphoid blast crises do not have specific aneuploid markers. Hypodiploidy is common. Except for iso-17, the more common abnormalities have been reported in lymphoid and mixed lymphoid-myeloid transformations, but most patients with lymphoid blast crisis have no specific abnormalities. ³⁵

It is now evident that Ph mosaicism (i.e., the presence of residual normal cells without the Ph chromosome) is common in otherwise typical CML. This has been estimated at 20 to 25% of the cells, at least relatively early in the disease. ³³ In a comprehensive review, survival of patients exhibiting Ph mosaicism treated with chemotherapy did not differ significantly from that of more than 500 patients who were 100% Ph positive. ³³ However, the presence of Ph-negative cells could conceivably influence the response to rIFN-α and its duration.

Fluorescence In Situ Hybridization (FISH) Test

A number of other tests based upon molecular technology have been used in clinical practice to substitute for cytogenetic testing, ^{36, 37} which still remains the gold standard in most trials, but various modifications of the FISH technique have gained ascendancy.

The FISH test has expanded the sensitivity of the standard karyotype and permits the detection of submicroscopic abnormalities that may occur at low frequency. With this new method, targeted DNA sequences are visualized, which permits analysis and quantification of disease at the molecular level. It is more sensitive than standard cytogenetics since it can survey many more cells. This technique is also important because in situations where the marrow is packed with cells, making aspiration difficult, or when it is hypoplastic following chemotherapy, it is often impossible to obtain adequate marrow specimens for cytogenetic studies to quantify the disease status. Moreover, undergoing marrow aspiration is painful and costly. Variations of the standard FISH test include interphase FISH (i-FISH), hypermetaphase FISH (h-FISH), and the most recently reported D-FISH, which permits analysis of both peripheral blood and marrow specimens. ^{38, 39}

The D-FISH modification uses different colored bcr and abl DNA probes to detect a single bcr-abl fusion signal on the Ph chromosome spanning the common breakpoints of t(9;22)(q34;q11.2). Using D-FISH, the number of false-positive and false-negative cells approaches zero. Studies employing double bcr-abl fusion have detected the Ph chromosome and its varying translocations at diagnosis and at all times after treatment including cytogenetic remission. ^{38, 39} Moreover, recent studies of D-FISH indicate that the percentage of Ph cells in the peripheral blood over the course of therapy is a good predictor of corresponding changes in marrow.

Molecular Biology of CML

The recent increased understanding of the cytogenetics of CML has been accompanied by an equally spectacular appreciation of the molecular biology of the disease.

The reciprocal translocation of parts of chromosome 9 and 22 results in a fusion or chimeric gene with a protein product that has unique properties. The gene on chromosome 22 (bcr) involved in the translocation is of unknown function. The gene on chromosome 9, abl, has oncologic importance because it is the c-abl proto-oncogene, the normal cellular homologue of the transforming gene (v-abl) of the Abelson murine leukemia virus. ⁴⁰ Activation of the c-abl proto-oncogene to its oncogenic form is a result of the bcr-abl fusion (Fig 125.5). ^{40, 41}

Figure 125.5

Summary of the cytogenetic and molecular effects of the Ph Chromosome.

Although the breakpoints on both chromosomes 9 and 22 are usually restricted to quite specific regions, some heterogeneity does exist. On chromosome 9, breakage occurs in a region 200 kb or more in length, resulting in most of the c-abl genes being translocated. ⁴¹ Depending on the precise location of the breakpoint, c-abl exons 1a and 1b may be translocated to the Ph chromosome. However, post-transcriptional splicing of the transcript results in the coding sequence from these two exons being excluded from the bcr-abl mRNA. Variability in the chromosome 9 breakpoints usually has had no consequences since there are no differences in the biologic or clinical features of the disease in different patients. ⁴²

Depending on the site of the breakpoint in the bcr gene, the fusion protein can vary in size from 185 (190) kd to 230 kd. Thus, each fusion gene encodes the same portion of the abl gene but differs in the length of bcr sequence. Transcription of the fusion bcr-abl gene results in a chimeric bcr/abl mRNA that is translated into fusion proteins of varying sizes ranging from p190 ^bcr-abl, p210 ^bcr-abl, and p230 ^bcr-abl according to the breakpoint of the genes involved. These cytoplasmic proteins have unregulated constitutive tyrosine kinase activity, which is of major importance in CML since they activate a number of intracellular signaling pathways that affect cell proliferation and differentation, rendering the call independent of cytokine regulation. ^{42, 42} These include STAT, RAS, RAF, JUN kinase, MYC, AKT, and other signal transducers. ^{42, 43} bcr-abl may also be involved in cellular adhesion defects since CML cells adhere poorly to marrow stroma. ^{44, 45.}

Virtually all patients with typical chronic phase CML only express the 210 kd bcr-abl protein. Two types of bcr-abl mRNAs occur in this situation as a result of bcr breakpoint heterogeneity. These are known as either the b2a2 or b3a2 fusion. ^{42, 43} The clinical features, response to treatment, and prognosis are the same for both groups. Patients with Ph-positive acute lymphocytic leukemia express either a 210 kd or a 190 bcr-abl protein. (The latter is also referred to as a 185/190 kd; in this case, the RNA is 7.0 kd.) A larger 230 kd ^bcr-abl fusion protein has been reported in a subset of patients with chronic neutrophilic leukemia who run a more benign course and slower progression to blast phase disease. ⁴⁶ The fact that fusion proteins of different sizes can be correlated with different clinical outcomes suggests that the 190 kd ^bcr-abl protein has more tyrosine kinase activity than the 230 kd. Thus, the magnitude of the tyrosine kinase activity may affect the clinical manifestation of the illness. ^{42, 47} It should be emphasized that although the molecular abnormalities of CML have been elucidated in the last few years, the functions of bcr and abl in both normal cells and in CML are still not completely understood. The molecular test, reverse transcriptase-polymerase chain reaction (RT-PCR), detects RNA and is so sensitive that it can detect one Ph-positive cell expressing the bcr-abl transcript in 10⁵ nonleukemic cells. ⁴² In this regard, the finding of a RT-PCR for ^bcr-abl chimerism in low concentration in presumably normal adults is of significance. ^{48, 49} Whether a cohort of such patients will eventually develop CML will require long follow-up. Perhaps more than one oncogenic event may be required to produce the phenotype of the disease. Although there has been speculation whether the bcr-abl event is causally related to the clinical development of CML, abundant experimental evidence suggests that is is. The relation of c-abl to murine leukemia has already been discussed. Moreover, when murine bone marrow was infected with a retrovirus encoding p210 bcr-abl, and transplanted into irradiated syngeneic recipients, the recipients developed several hematologic malignancies including a syndrome closely resembling the chronic phase of human chronic myeloid leukemia. ^{50, 51}

The importance of p190 in the pathogenesis of leukemia has also been demonstrated. Mice were made transgenic for a p190 ^bcr-abl DNA construct. ⁵² The progeny were either moribund or died of acute leukemia (myeloid or lymphoid) 10 to 58 days after birth. Thus, these experiments suggest that p190 has a role in causing a very aggressive leukemia. A casual relationship between the Ph chromosome and human leukemia is suggested and fortifies the concept that elimination of the Ph chromosome may improve the prognosis of patients in CML.

Treatment

The most important recent advances in the treatment of CML have been the use of the recombinant interferons and marrow transplantation.

Treatment wtih Interferon and Other Drugs

Because interferons have a wide range of biologic activities, including antiviral, antiproliferative, immunomodulatory, antiangiogenic, and oncogene regulatory properties, ^{53– 55} their evaluation in CML was warranted. This decision was fortunate because until recently, the therapeutic notion existed that the natural course of CML could not be altered except for the use of bone marrow transplantation. There is now general agreement that recombinant interferon-α (rIFN-α) combined with chemotherapy with either HU or ara-C (and probably other chemotherapeutic agents) can prolong life in CML by causing durable suppression of the Ph-positive clone.

Initial clinical studies involved the use of human leukocyte interferon but rIFN-2a, -2b, and -2c have also been evaluated. Although recombinant IFN-gamma shares many of the functional properties of rIFN-α, significant differences exist. Early preclinical studies indicated that rIFN-gamma might be more potent with respect to the antiproliferative properties than rIFN-α. However, based on recent clinical experience, it is unlikely that rIFN-gamma will contribute to improved therapeutic response; it will not be discussed. ^{56– 58}

The bulk of the evidence for the effectiveness of interferon relates to the use of recombinant interferon alfa rIFN-α therapy and consists of at least 30 uncontrolled observational studies. ⁵⁹ In some cases, complete and durable cytogenetic remission after rIFN-α based therapy required months of treatment and has resulted in a few cases of sustained cytogenetic remission lasting many years, suggesting that a small percentage of patients may have been cured. The largest number of patients have been followed at the M.D. Anderson Cancer Center in observational studies where complete and partial hematologic remission rates with interferon therapy are reported between 70 to 80% and 6 to 10% respectively; remission rates reported by others are usually lower and range from 8 to 81% and 6 to 50% for complete and partial remissions respectively. ⁵⁹

More important than hematologic response after rIFN-α however, is the production of cytogenetic response, which unfortunately occurs significantly less often. Most investigators define cytogenetic response employing the M.D. Anderson criteria, using the percentage of Ph-positive metaphases reported on the most favorable karyotype. ⁶⁰ As previously mentioned, new methods are available not only for diagnosing CML but also for monitoring response to treatment. The FISH techniques obviate the need for cytogenetic analysis, although cytogenetic analysis still is the gold standard in most trials, and RT-PCR defines response on a molecular basis. Thus, treatment response of patients in the new millennium will be based on clinical, cytogenetic, and molecular responses.

Complete cytogenetic response is defined as 0% Ph-positive metaphases, partial cytogenetic response as 5 to 34% Ph positive, and minor response as 35 to 95%. At the M.D. Anderson Cancer Center, approximately 15 to 20% of the patients have had a complete cytogenetic response and another 15 to 20% a partial response. ⁶⁰ Cytogenetic responses reported by others approximate half of these values. The reasons for these differences have been reviewed in detail. ⁵⁹ Briefly, they are related to differences in case mix, age, stage of disease, elapsed time from diagnosis to treatment, and prognostic factors that differ among the various centers. In most cases, cytogenetic response occurs more frequently in patients who have low/normal platelet counts, a low percentage of blasts, and a nonpalpable spleen, (i.e., those defined as good risk or who have a favorable, low risk Sokal score).

The achievement of a cytogenetic remission is important because it is accompanied by a superior survival compared with those patients who have an intermediate response or none at all. ⁶⁰ In most studies in which a survival advantage has been shown, maximally tolerated doses of rIFN-α have been given leading to leukocyte counts of 2,000 to 4,000 μl. Usually, this dose is 5 million units (5 MU) per M²/day. Of considerable importance, except for one study ⁶¹ employing interferon only that did not show survival advantage, all others have, in fact, employed HU and or ara-C during induction and during some phase of the maintenance program.

The issue of whether interferon improves survival as compared to conventional therapy was finally established first by the Italian Study Group on Chronic Myeloid Leukemia. ⁶² Patients were randomized to receive rIFN-α or HU only and were stratified according to risk factors. Patients in the interferon arm were also allowed to receive HU if the response was considered “sluggish.” This occurred in one-third of the patients. After a median follow-up of 68 months, the frequency of clinical and hematologic remission was the same in both arms. However, in the interferon arm, a complete cytogenetic response was seen in 8% of the complete responders and a major response (67–99% Ph negative) in 11%. This compared with 0% and 1%, respectively, for the HU treated group. The time to progression from the chronic phase of leukemia to an accelerated or blastic phase was 72 months in the interferon group as compared with 45 months in the conventionally treated group (p < .001).Overall median survival was 72 months in the rIFN-α + HU arm compared with 52 months in the HU arm. Cytogenetic response (complete, major, or minor) could be correlated with survival. At a median of 112 months, in the interferon arm 30% of the patients were alive and 8% maintained a complete or major cytogenetic remission. In the chemotherapy arm, 18% of the patients were alive with a minor cytogenetic response in one case (Fig. 125.6). Of IFN-α patients who had cytogenetics, 16% were still in complete remission, but none of the chemotherapy patients (p < .001). ⁶³ Other randomized trials have essentially confirmed the superiority of interferon over HU in low risk patients. ⁵⁹ A number of single arm studies employing differing doses and schedules of rIFN-α and ara-C indicate that the combination is also effective. ^{59, 64, 65} Two prospective studies have demonstrated the superiority of ara-C rIFN-α over rIFN-α combined with varying doses of HU. ^{66, 67} The best results occurred in a French trial ⁶⁵ employing a combination of rIFN-α, MU/M² daily and ara-C, 20 mgm/M² sc for 10 days each month. ⁶⁵ In a randomized trial of 311 patients treated with rIFN-α and ara-C, a complete cytogenetic response (CCyr) was seen in 46 (15%) and a partial cytogenetic response (PCyR) in 80 (26%); in comparison, of 314 patients treated with rIFN-α HU, 28 patients (9%) had a CCyR and 47 (15%) a PCyR. ⁶⁶ An Italian randomized trial of 837 newly diagnosed CML confirmed the superiority of the rIFN-α + ara-C combination. ⁶⁷ Of 275 patients treated with ara-C, 40 mg/kg/10 days monthly and rIFN-α 9 MU/day, a CCyR was noted in 17 (7%) and a PCyR in 29 (10%), compared to the HU + rIFN-α arm, which yielded CCyR in 13 of 265 patients (1%) and PCyR in 22 (8%) (p = .01). ⁶⁶

Figure 125.6

Long-term survival of patients with chronic myeloid leukemia treated with interferon-α or conventional chemotherapy. Data of the Italian Cooperative Study group on Chronic Myeloid Leukemia. Blood 1998:92 1541–1548.

The side effects of r-IFN-α are not trivial. ⁵⁹ They include fever, chills, malaise, headache, anorexia, joint pain, vomiting, low backache, myalgia, various types of neuropathy, changes in mood and concentration, abnormalities of liver enzymes, retinal vein thrombosis, leukopenia, and thrombocytopenia. Long-term therapy can be associated with autoimmune effects, including immune-mediated thrombocytopenia, hypothyroidism, and hemolytic anemia. Varying degrees of impotence may occur in about one-quarter of men.

Treatment of Blast Crisis

No substantial progress has been made in the treatment of blast phase disease. In the past 15 years, we and others ^{74– 77} have tested a large series of drugs and drug regimens, particularly those useful in the treatment of the acute leukemias, and yet the treatment of blast-phase CML remains unsatisfactory. Using a combination of HU, 6-mercaptopurine, and prednisone, a hematologic response rate (complete and partial remission) of approximately 30% has been achieved. ⁷⁵ This modest improvement in response is characterized by a median remission duration of 7 months as compared with a survival time of 2 or 3 months for patients with no response.

Although a vincristine/prednisone combination is especially useful in other lymphatic malignancies, in our experience the survival in lymphoid blast crisis was not significantly increased over that of myeloid blast crisis, even with such tailored chemotherapy. A more recent study confirmed these results. ⁷⁴ To encompass both lymphoid and myeloid blast crisis, patients were given courses of vincristine, prednisone, and ara-C. Median survival for patients with response was 201 days, compared with 65 days for patients without response. ⁷⁸ Most of the patients with clinical responses had a remission after a single course of therapy. Detailed cytogenetic and molecular studies have not been reported in any of the trials. This suggests that therapeutic responsiveness in the blast crisis may depend on the inherent sensitivity of the blast cells regardless of type, rather than on the inherent effectiveness of the therapeutic regimen.

Bone Marrow Transplantation

The use of marrow transplantation in CML received its first impetus from the successful transplantation of marrow from the normal member of an identical twin pair to a sibling with CML. ⁷⁹ Such long-term disease-free survival encouraged the use of human leukocyte antigen (HLA) identical-sibling donors for patients in chronic-phase CML. Recently, either HLA-matched related or HLA-matched unrelated donors (MUD) have been used when no HLA sibling has been available. For allogeneic matches, it is best if the patient is relatively young, preferably under age 40, although some centers transplant patients until age 55. Unfortunately, the age and histocompatibility requirements eliminate the majority of CML patients. In a Cancer and Leukemia Group B (CALGB) study of 181 patients, only 10% were less than 30 years old, and only one-third were less than 50 years. ⁸⁰ Moreover, only one-third of patients have an HLA-matched sibling. The number of potential donors may be increased by using HLA-MUD. ⁸¹ Unfortunately, the survival rate of recipients receiving unrelated donors is much lower. This may be improved by careful molecular typing, especially HLA-A,-B and DRB1. ⁸¹ Unfortunately, the more careful the typing, the fewer donors available.

It is generally agreed that marrow transplantation in accelerated and/or blast-phase disease is relatively unsatisfactory; nonetheless, 15 to 20% of patients may become long-term survivors. Certainly, this exceeds the results observed in patients treated with chemotherapy in blast-phase disease, as all patients eventually fail drug treatment.

The true efficacy of allogeneic bone marrow transplant (BMT) in the treatment of chronic phase CML has not been evaluated in a strict fashion. Projected annual 3 to 5 year survival rates range from 38 to 80%, with the higher values reported from more experienced centers. In general, most studies report values around 50 to 60% and slightly lower probability for disease-free survival. Projected survival curves appear to plateau or taper more slowly after 3 to 7 years, suggesting that allogeneic BMT offers eligible patients, especially young adults with a genetic HLA identical sibling, a prospect for cure. Caveats exist, however, regarding the interpretation of BMT trials. ⁵⁹ Most studies are retrospective, lack complete documentation of the clinical characteristics of the patient population, provide few details of the methods of patient selection, and are not randomized with control, nontransplanted patients. In a recent analysis of 21 bone marrow reports, the status of the Ph chromosome was not reported in eight papers and the age in eight! ⁵⁹ Of the remaining 13 studies, the age ranged from 28 to 38 years; the mean was 32.4 years, Yet, frequently, the treatment algorithms recommended for allogeneic transplantation extend to age 50 years. Estimates of long-term survival in patients treated in BMT studies are either undocumented or less than 3 to 5 years. The larger studies rely on registry data collected from as many as 80 centers that have used heterogeneous transplant protocols and patients treated by multiple protocols and different treatment regimens. Thus, allogeneic BMT is not a specific treatment but rather a general approach that relates to the different preparative regimens, stem cell sources, prophylactic regimens against graft-versus-host disease and methods of supportive care. ⁵⁹ All of these, of course, have changed dramatically in recent years. In an attempt to determine whether to treat patients with either rIFN-α based regimens or BMT, the results of both treatment modalities have been compared. The many problems associated with this type of retrospective analysis have been discussed in detail elsewhere. ⁵⁹

Survival curves for BMT show that at least half of the patients remain alive 5% years after treatment, whereas similar occurrence for rIFN-α showed a continuous relapse rate over time with the curves crossing at about 7 to 8 years, yielding a survival advantage to BMT, This is frequently cited as evidence that BMT “cures” patients with CML. However, such inferences, which define the superiority of BMT when subjected to critical analysis, indicate that patients in BMT studies are, on average, at least 6 years younger than subjects in rIFN-α studies and are in a better prognostic group. ⁵⁹ An attempt to control for such differences was made by comparing 548 patients from the International Bone Marrow Transplant Registry (IBMTR) with 196 patients who had received rIFN-α or HU in a German randomized clinical trial (RCT). ⁸² Survival curves were less for BMT patients during the first 18 months of treatment, reflecting early transplant-related mortality, similar from 18 to 56 months but significantly better for BMT after 56 months. The 7 year probability of survival was 58% for BMT and 32% for rIFN-α plus HU with a survival advantage first becoming statistically significant after 5.5 years. However, in low-risk patients, there was no difference in survival rates in transplant patients and those who received interferon. The best strategy for overcoming these methodologic problems would be a randomized clinical trial that allocated patients to either receive BMT or a medical regimen. Considering worldwide practice, it is unlikely that such a trial would ever occur.

A recent multi-institutional randomized trial compared the use of bone marrow with peripheral blood stem cells (PBSC)*(from HLA identical siblings) for relatively favorable patients with a variety of hemotologic neoplasms, including CML, undergoing transplantation. Hematologic recovery was more rapid for PBSC and the 2 year actuarial survival significantly superior (BMT 45%, PBSC 70%, p = .02).

Cytogenetic and Molecular Follow-Up

Although rIFN-α can result in Ph-negative marrows, the more sensitive molecular test, RT-PCR, which, as previously mentioned, can detect less than one leukemic cell per 10,000 nonleukemic cells, may remain positive. However, RT-PCR negativity has indeed been reported in long-term cytogenetic remission after rIFN-α therapy, ⁸⁴ but it is more common after BMT. ^{84– 86} Negative RT-PCR results in patients treated with BMT predict a favorable outcome, but the evaluation of positive results is different owing to the sensitivity and possible false positivity of the test. ^{42, 46}

The issue of whether a positive PCR reaction always indicates eventual relapse is currently the subject of a keen debate. ^{88– 90} RT-PCR positivity per se is not always associated with immediate disease recurrence, especially in patients treated with rIFN-α although additional long-term follow-up and prospective studies are essential. The findings also suggests that interferon therapy suppresses the proliferation of Ph clones but does not completely eradicate all of the Ph stem cells in all cases. Current data suggest that rising values of quantitative RT-PCR precedes chromosome relapse, ⁸⁰ which precedes hematologic relapse. Late recurrences have been observed for post-transplant patients. ⁸⁹ This is of additional therapeutic importance since it appears that if disease reocurrence is detected early, donor lymphocyte infusions can produce another remission in the majority of patients. ⁹¹

Every option for the treatment of chronic phase CML involves trade-offs between benefits and harms. The choice that is selected may depend on objective clinical variables that influence probability such as patient age, stage of disease and comorbid conditions and on the subjective variables related to personal preferences. The issue of trading short-term risks for long-term benefits is never easy. The expert committee ⁵⁹ agreed that no treatment option should be pressed upon a patient without providing information about the potential benefits and harms involved. “Shared decision making” between patient and physician should always play an important role in any decision that is made. ⁹²

For physicians and patients who are comfortable accepting evidence from uncontrolled observational studies indicating that allogeneic BMT is more effective than nontransplant approaches, allogeneic BMT is a viable option for patients under the age of 40 who have an acceptable health status and a suitable HLA-matched donor. BMT should preferably be offered to patients with 1 or 2 years of diagnosis to achieve the greatest likelihood of success. For patients with adverse prognostic scores (reflected by a higher Sokol or Hasford score), the chances of success with rIFN-α are less compared to early BMT, which may thus be a more desirable option. Younger patients are also more likely to benefit from allogeneic BMT, especially if the donor is an HLA-matched sibling.

Future Directions

Notwithstanding our increased appreciation of the cytogenetic and molecular abnormalities in CML and the advances in therapy with interferon and transplantation in selected patients, it is obvious that a great deal more must be learned regarding the cause and pathogenesis of the disease before clinical application of presently conceived and potential therapies will lead to cure. The future, nevertheless, has never been brighter. Pursuing the nature of the molecular abnormalities in CML and targeting the specific tyrosine kinases involved have been translated into clinical application for compounds that specifically inhibit the bcr-abl kinase have been synthesized. Clinical trials are underway. ⁹³ Entirely new compounds, such as homoharringtonine, ⁹⁴ a novel plan alkaloid derived from an evergreen tree ubiquitous in China, has produced clinical and cytogenetic remissions. In vitro production of a large number of Ph-negative cells for autologous marrow transplantation is on the horizon, ⁹⁵ and, surely, improved techniques of allogeneic marrow will lead to greater therapeutic success.

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