Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

112. Chronic Leukemias

Christopher A. Fausel and Patrick J. Kiel


KEY CONCEPTS

 Images Chronic myelogenous leukemia (CML) is defined by the presence of the Philadelphia chromosome (Ph), a translocation between chromosomes 9 and 22. The resulting abnormal fusion protein, p210 BCR-ABL, phosphorylates tyrosine kinase residues and is constitutively active, resulting in uncontrolled hematopoietic cell proliferation.

 Images The disease course of CML is characterized by a progressive increase in white blood cells over a period of years that ultimately transforms to an acute leukemia.

 Images The four commercially available tyrosine kinase inhibitors, imatinib, dasatinib, nilotinib, and bosutinib, have demonstrated efficacy in treatment of newly diagnosed CML patients and in patients with either accelerated phase or blast crisis.

 Images CML monitoring requires assessment of milestone throughout therapy such as hematologic, cytogenetic, and molecular responses, the ideal of which is a molecular response.

 Images Allogeneic hematopoietic stem cell transplant (HSCT) is the only known curative treatment option for CML and is reserved for patients with a suitable donor and progression after treatment with tyrosine kinase-based therapy.

 Images The management of CLL is highly individualized and includes observation in patients with early-stage disease and treatment with chemotherapy, biologic therapy, or both in patients with more advanced disease.

 Images Alemtuzumab, ofatumumab, and rituximab monoclonal antibody therapy are all indicated for the treatment of CLL. Ofatumumab is reserved for patients that have progressed following fludarabine-based and alemtuzumab-based regimens.

 Images Regimens such as fludarabine, cyclophosphamide, and rituximab are considered as first-line therapy for patients with CLL who are younger or have more aggressive disease, such as the presence of chromosome 17 deletion.

 Images Allogeneic HSCT in patients with CLL appears to achieve long-term disease-free survival in some patients, but the older patient population diagnosed with the disease and donor availability preclude widespread use.


The chronic leukemias include chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, and prolymphocytic leukemia. The typical clinical presentation of the chronic leukemias is an indolent course in contrast to patients with acute leukemia who will die of their disease within weeks to months if not treated. This chapter focuses on the two most common types of chronic leukemia, CML and CLL.

CHRONIC MYELOGENOUS LEUKEMIA

Chronic myeloid leukemia is a myeloproliferative disease that results from malignant transformation of a subpopulation of pluripotent hematopoietic stem cells. Bone marrow hyperplasia and accumulation of differentiated myeloid cells in the peripheral blood are the initial presenting features of the disease. The terminal stage of CML is characterized by rapid accumulation of blast cells in the bone marrow and suppression of normal hematopoiesis that ultimately leads to death. CML was the first malignant disease identified with a consistent cytogenetic abnormality, namely the Philadelphia chromosome (Ph) that code for the BCR-ABL oncogene. This dominant cytogenetic abnormality has allowed CML to become the template for development of molecular targeted drug therapies.

Epidemiology and Etiology

It is estimated that 5,920 new cases of CML will be diagnosed in the United States in 2013, with 610 deaths.1 The median age of diagnosis is 64 and are no currently known associations between the development of CML and hereditary, familial, geographic, ethnic, or economic status. An increased risk of CML has been noted with ionizing radiation exposure and in atomic bomb survivors from Hiroshima and Nagasaki.2,3

Pathophysiology

Chronic myeloid leukemia was first described in 1845, but extensive research into the genetic and molecular characteristics of the disease began with the discovery of the Ph in 1960 by Nowell and Hungerford.4 Research in the 1980s identified the molecular changes that occur as a result of the Ph when an oncogenic protein was identified and implicated in the pathophysiology of CML.4,5

Ph is the first karyotypic abnormality specifically implicated in the pathogenesis of cancer, and its discovery has resulted in extensive research into the molecular biology of CML.6 This chromosomal abnormality is characteristic of CML and is present in about 95% of patients with the disease.7,8

Images Ph, identified as a shortened long arm of chromosome 22, is found in granulocyte and erythrocyte progenitors, macrophages, megakaryocytes, and lymphocytes. The Ph is the consequence of breaks in chromosomes 9 and 22 resulting in a transposition that relocates the 3′ end of ABL (Abelson proto-oncogene) from its normal site on chromosome 9 at band 34 to the 5′ end of BCR (breakpoint cluster region) on chromosome 22 at band 11 [symbolized as t(9;22)(q34;q11)].8,9 This results in the formation of the hybrid BCR-ABL fusion gene (Fig. 112-1). Through this chromosomal translocation, the ABLprotooncogene is able to escape the normal genetic controls on its senescence and is activated into a functional oncogene, directing the transcription of an 8.5-kilobase messenger ribonucleic acid (mRNA) molecule. The mRNA is translated into a 210-kDa protein—p210 BCR-ABL—that is constitutively (constantly) activated compared to the 145-kDa protein translated by the normal ABL gene.7,8 Although p210 BCR-ABL is the most common tyrosine kinase found in CML, variations in the breakpoints in the ABL gene encode different size proteins. For example, a smaller protein, p190 BCR-ABL, is involved in two-thirds of adults with Ph-positive acute lymphoblastic leukemia, but is rarely found in patients with CML.8

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FIGURE 112-1 Diagram of the chromosomal translocation that results in the Philadelphia chromosome. (Reprinted with permission from Fishleder AJ. Oncogenes and cancer: Clinical applications. Cleve Clin J Med 1990;57:721–726. Copyright © 1990 Cleveland Clinic. All rights reserved.)

Because CML begins with the malignant transformation of a single cell, it is considered a clonal disease. The progeny from this transformed primitive hematopoietic stem cell results in a proliferative advantage over normal hematopoietic cells that displaces normal hematopoiesis. The Ph is found in both myeloid and lymphoid cells, which suggests that the transformed cell of CML is a pluripotent stem cell.9 This alteration gives the transformed progenitor cell an inheritable growth advantage, leading to the proliferation of a neoplastic, monoclonal population of cells.8 Disrupted maturation leads to additional divisions by CML progenitor cells before reaching a nonproliferative stage; the resulting number of circulating granulocytes may be many times higher than normal. In the advanced stages of CML, cytopenias may occur in association with fibrotic changes in the bone marrow.8

The BCR-ABL fusion gene encodes for a constitutively active tyrosine kinase that is involved in both the increased proliferation of the CML clone and the reduction in Fas-mediated apoptosis. Characterization of the adenosine triphosphate binding site on the BCR-ABL tyrosine kinase has provided a target for inhibition of tyrosine kinase activity. The first FDA-approved tyrosine kinase inhibitor (TKI), imatinib mesylate (Gleevec®), was indicated for patients in chronic phase who had failed interferon alpha (IFN-α) or for those with advanced disease. Imatinib received additional FDA approval in 2002 for first-line treatment in newly diagnosed CML. Second-generation TKIs with a higher binding affinity and selectivity for ABL kinase are approved as both frontline agents and salvage for patients with resistance or intolerance to imatinib.

Clinical Presentation

Images The three clinical phases of CML are: chronic phase (CP), accelerated phase (AP), and blast crisis (BC) (Table 112-1). Nearly 90% of patients present with CP at the time of diagnosis. Often the diagnosis of CML is found incidentally during routine examination or if a complete blood count is obtained for unrelated reasons because patients are often asymptomatic upon presentation. Signs and symptoms include fatigue, sweating, bone pain, weight loss, abdominal discomfort, and early satiety secondary to splenomegaly. Leukocytosis is the hallmark of CP, which can be as high as 1,000,000 cells/mm3 (1,000 × 109/L) placing patients at risk for complications of leukostasis. Symptoms secondary to leukostasis include acute abdominal pain resulting from splenic infarctions, priapism, retinal hemorrhage, cerebrovascular accidents, confusion, hyperuricemia, and gouty arthritis.8 Patients can survive several years in CP without treatment.

TABLE 112-1 Criteria for Different Phases of Chronic Myelogenous Leukemia

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Initial laboratory workup includes complete blood count with differential, complete metabolic panel, and serum uric acid. A bone marrow aspiration and biopsy is required to confirm the diagnosis of CML. The differential diagnosis of CML includes infection, myeloproliferative disorders (i.e., polycythemia vera, essential thrombocythemia, myelofibrosis), and chronic myelomonocytic leukemia. Bone marrow is markedly hypercellular (75% to 90%) with increased granulocyte/erythroid ratio increased (10 to 30: 1), erythropoiesis increased megakaryocytes normal. Karyotyping (cytogenetic analysis) is required for a diagnosis. The bone marrow aspiration is analyzed with fluorescence in situ hybridization (FISH) to determine the presence of the Ph chromosome. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) is also performed to assess the baseline BCR-ABL transcript levels.


CLINICAL PRESENTATION Chronic Myelogenous Leukemia1

General

    • 90% of patients are diagnosed in chronic phase

    • 50% are asymptomatic in chronic phase and often diagnosed following abnormal complete blood count

Signs and Symptoms

    • Fatigue

    • Left upper quadrant pain

    • Abdominal pain or distension

    • Weight loss

    • Night sweats

Physical Examination

    • Splenomegaly

    • Hepatomegaly

Laboratory Tests

    • Peripheral blood

      • Leukocytosis

      • Thrombocytosis

      • Basophilia

      • Low or undetectable leukocyte alkaline phosphatase

      • Elevated uric acid and lactate dehydrogenase

    • Molecular testing

      • Presence of BCR-ABL by reverse-transcription polymerase chain reaction

    • Bone marrow

      • Hypercellular

      • Fully mature myeloid cells

      • Increased megakaryocytes

      • <10% blasts in chronic phase

    • Cytogenetics

      • Presence of the Philadelphia chromosome

      • Additional abnormalities

AP is characterized by progressive myeloid maturation arrest and loss of efficacy of drug therapy directed to attenuate the increase in white blood cells. Clinical findings of AP include anemia, increasing peripheral blood and bone marrow blasts and basophils, clonal cytogenetic evolution, extramedullary disease sites (bone, breast, CNS, mucosal tissue, lymph nodes, and skin), exacerbation of splenomegaly, and either thrombocytosis or thrombocytopenia. Nonspecific findings such as bone pain, fever, night sweats, and weight loss may occur. The most commonly observed cytogenetic changes with disease progression are an additional Ph chromosome, trisomy 8, and isochromosome 17q. Survival typically will not exceed several months. The World Health Organization (WHO) classification defines AP CML as one or more of the following changes: 10% to 19% of blasts in the peripheral blood or bone marrow, persistent thrombocytopenia less than 100,000 cells/mm3 (100 × 109/L) (not related to drug therapy), thrombocytosis greater than 1,000,000 cells/mm3 (1,000 × 109/L) despite drug therapy, peripheral basophilia >20%, increasing spleen size and white blood cell count despite drug therapy, bone marrow evidence of progression of the leukemic clone or new cytogenetic abnormalities.10

BC is the terminal stage of disease and clinically resembles acute leukemia where the leukemic clone overwhelmingly dominates the bone marrow at the expense of normal hematopoiesis. The WHO classification defines BC CML as the presence of one or more of the following: >20% blasts in the peripheral blood or bone marrow, extramedullary disease, or large clusters of blasts in the bone marrow.10Patients can present occasionally with BC without an apparent AP. One-third of patients present with BC of lymphoid lineage, while two-thirds present with BC of myeloid lineage or undifferentiated like phenotype. The increased proliferative rate in BC CML is the consequence of a number of factors in addition to BCR-ABL, such as the activation of the oncogene signaling pathways and loss of tumor suppressors such as p53. Duration of BC is typically days to weeks before death.

Prognosis

Several models have been proposed for estimating prognosis in patients with CML, but the one proposed by Sokal et al. has become the most widely used.13 The Sokal algorithm uses spleen size, percentage of circulating blasts, platelet count, and age as prognostic factors for patients in CP. However, this scoring system was developed prior to the advent of TKI therapy and may have limited predictive value in the era of imatinib. The median overall survival for patients diagnosed with CP, AP, and BC CML was reported to be 47 months, 12 to 24 months, and 3 to 6 months respectively in the era prior to the introduction of TKIs.11,12

TREATMENT

Chronic Myelogenous Leukemi

Desired Outcomes

Without effective treatment, CML disease progression leads inexorably to a fatal outcome within 5 years. The overriding treatment goals for CML include the eradication of the leukemic clone from the bone marrow and maintenance of CP with minimal toxicity from treatment. The only proven therapy to eradicate the malignant clone from the bone marrow is an allogeneic hematopoietic stem cell transplantation (HSCT). Both immunotherapy with IFN-α and TKI-based therapies have demonstrated the ability to extend CP beyond the expected period of several years, but data to confirm the curative ability of these agents are lacking. The introduction of TKI therapy has dramatically changed the clinical course of CML where patients can now expect to maintain disease control for many years.13 The current standard of practice is to initiate TKI therapy for newly diagnosed CML patients. Long-term follow-up from phase III trials have documented a response in excess of 85% of patients that receive imatinib as primary treatment.14,15 Table 112-2 shows the effect of various treatment modalities on survival in CP CML.

TABLE 112-2 Effect of Therapy on Survival in Patients with Early Chronic-Phase Chronic Myelogenous Leukemia

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Clinical response in CML is measured by hematologic, cytogenetic, and molecular indices, all of which have standardized criteria.16 Hematologic response is defined as the normalization of peripheral blood counts and is the earliest type of response observed in CML patients. Cytogenetic responses are based on the percentage of cells positive for Ph in a bone marrow biopsy. Complete cytogenetic response is defined as the elimination of Ph from all cells in the marrow sample whereas major cytogenetic response is defined as fewer than 35% Ph-positive cells. Patients who have a major or complete cytogenetic response have an improved survival compared to those who fail to achieve a cytogenetic response.17

Because most patients on imatinib achieve a complete cytogenetic response, more sensitive tests to monitor disease status have become more prominently used. Molecular responses are determined by RT-PCR, which are several logs more sensitive than methods used to measure cytogenetic responses. A complete molecular response is the absence of BCR-ABL transcripts by RT-PCR. RT-PCR assays should be interpreted carefully because they have varying sensitivities and may show a complete molecular remission even when low levels of BCR-ABL transcripts are present.17 A major molecular response is a ≥3-log reduction in BCR-ABL transcripts by RT-PCR assay. Quantitative RT-PCR should be performed on every patient prior to initiating therapy and throughout therapy to monitor residual disease. Because bone marrow and peripheral blood BCR-ABL mRNA levels are correlated, peripheral blood can often be used for this analysis.16,17

Conventional Chemotherapy

Conventional cytotoxic chemotherapy is used in CP CML to reduce and temporarily control high peripheral white blood cell (WBC) counts. Historically, the two agents used for leukoreduction are busulfan (Myleran) and hydroxyurea (Hydrea). Busulfan is no longer used because randomized trials have shown that hydroxyurea treatment provides a modest survival advantage, and busulfan has a risk of potentially life-threatening pulmonary fibrosis.18

Hydroxyurea rapidly lowers high circulating WBCs in CP CML by inhibiting ribonucleotide reductase, which inhibits DNA synthesis, eliminating cells in the S phase of the cell cycle, and synchronizing cells in the G1 or pre-DNA synthesis phase. Hydroxyurea is initiated at 40 to 50 mg/kg/day in divided doses until the WBC count falls to about 10,000 cells/mm3 (10 × 109/L). Hydroxyurea may be discontinued once adequate control of the WBC count is achieved and a TKI has been initiated. Hydroxyurea is not specifically active against Ph and will not change the natural progression of the disease to BC.

Interferon Alfa

The interferons are a family of glycoproteins involved in many of the functional aspects of the hematopoietic system. Prior to the introduction of imatinib, IFN-α was the preferred agent in the treatment of CML. The role of IFN-αhas since been relegated to patients who fail TKIs and are not candidates for allogeneic HSCT.

Images Use of IFN-α in the treatment of CP CML was based on reports that 20% to 50% of patients achieve a major cytogenetic response, which led to prolonged survival.6 In the 10% to 15% of patients achieving a complete cytogenetic response, the median survival was more than 10 years. Patients enrolled on the IFN-α arm in the International Randomized Interferon vs. STI571 (IRIS) trial had a complete cytogenetic response of 14%, as compared with 76% of patients treated with imatinib.14 The 2013 National Comprehensive Cancer Network (NCCN) guidelines recommend IFN-α only for posttransplant relapse.15

IFN-α use is also limited by its toxicity profile because it is associated with both short-term constitutional toxicities and potentially dose-limiting long-term toxicities. In the IRIS trial, 26% of patients discontinued IFN-α as a result of intolerable side effects.14 The most predictable early toxicity is a flu-like syndrome characterized by fever, chills, myalgia, headache, and anorexia. These dose-dependent effects may be a result of IFN-α–induced leukocytosis and release of inflammatory cytokines. Cardiovascular toxicities (tachycardia, hypotension) are seen in approximately 15% of patients in the first few weeks. Long-term adverse effects include weight loss, alopecia, neurologic effects (paresthesia, cognitive impairment, depression), and immune-mediated complications (hemolysis, thrombocytopenia, nephrotic syndrome, systemic lupus erythematosus, hypothyroidism) occur in approximately 5% to 20% of patients.

Despite falling out of clinical favor, IFN-α still remains a disease-modifying agent and ongoing clinical trials are investigating the use of imatinib and IFN-α in combination for the treatment of CML. Imatinib has been combined with pegylated interferon-α2a in newly diagnosed CP CML yielding improved major molecular response rate at 12 months compared with imatinib 400 mg daily alone (57% vs. 38%), but the 12-month complete cytogenetic response rate was similar (66% vs. 58%).19

Imatinib Mesylate (Gleevec®)

A transformative discovery in cancer therapeutics was the characterization of the adenosine triphosphate binding site on the BCR-ABL tyrosine kinase. This specific receptor established a novel drug discovery platform for molecular targeted therapy in CML. Numerous TKIs were in development in the 1990s and STI571 (STI stands for signal transduction inhibitor), subsequently named imatinib (Gleevec®), emerged as the drug with the best oral bioavailability and high binding affinity for the BCR-ABL tyrosine kinase.20,21 In 2001, imatinib mesylate received FDA approval for patients in CP CML who had failed IFN-α treatment and in patients with AP or BC CML based on phase II studies. In 2002, it received FDA approval for first-line treatment in newly diagnosed CML on the basis of the 2-year follow-up in the IRIS phase III trial.22

Imatinib inhibits several other tyrosine kinases including BCR-ABL, C-Kit, and platelet-derived growth factor receptor (PDGFR). Imatinib competitively binds to the adenosine triphosphate (ATP)-binding site on BCR-ABL, which inhibits the phosphorylation of proteins involved with CML clone proliferation.23 Table 112-3 summarizes the clinical results of imatinib in CML patients in CP, AP, and BC CML. Table 112-4 summarizes the dosing, food–drug interactions, and drug–drug interactions of TKIs. Early phase I and phase II studies of imatinib, designed to determine maximum tolerated dose and safety, showed higher than expected response rates in all stages of CML.24

TABLE 112-3 Cytogenetic and Molecular Response Associated with Tyrosine Kinase Inhibitor Therapy in Chronic Myelogenous Leukemia

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TABLE 112-4 Dosing of Tyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia

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Chronic Phase

The IRIS study compared imatinib 400 mg orally daily to IFN-α plus low-dose subcutaneous cytarabine in 1,106 patients with newly diagnosed CP CML.22 After a median follow-up of 19 months, patients who received imatinib achieved a complete hematologic response of 96%, major cytogenetic response of 85%, and complete cytogenetic response of 69%. Six percent of patients had progressed to AP or BC and only 4% discontinued imatinib because of an adverse event. The study was designed to allow crossover to the opposite treatment arm for lack of response or intolerance. After 5 years of follow-up, only 3% of patients randomized initially to receive IFN-α remained on their initial regimen compared with 69% of patients in the imatinib arm. The 5-year follow-up data from the IRIS trial was published in December 2006 and 8-year follow-up data presented in December 2009.14,25 Estimated 5-year and 8-year overall survival of the 553 patients who were originally randomized to receive imatinib is 89% and 85%, respectively. At 8 years, estimated event-free survival (EFS) was 81% and freedom-from-progression to AP or BC was 92% and annual rates of progression to AP or BC in years 4 through 8 were 0.9%, 0.5%, 0%, 0%, and 0.4%. Only 55% of patients remained on imatinib therapy at the 8-year time point.25

Cytogenetic and molecular responses secondary to imatinib are associated with EFS and risk of progression to AP or BC. Patients that do not achieve a hematologic response by 3 months, cytogenetic response by 6 months, or a major cytogenetic response by 12 months fare significantly worse compared to responders. In addition, patients with a complete cytogenetic response and at least a 3-log reduction in BCR-ABL levels via RT-PCR correlated with a 100% survival without disease progression at 18 months. The risk of disease progression according to the Sokal scoring system estimated the rates of disease progression to be 3%, 8%, and 17% in low-risk, intermediate-risk, and high-risk patients, respectively. However, the Sokal score was not associated with disease progression in patients who achieved a complete cytogenetic response.14

Images Although most patients attain a complete cytogenetic response on imatinib, very few patients achieve a complete molecular response. In a study of patients enrolled in the IRIS study, Hughes et al. reported that less than 5% of patients on imatinib have undetectable levels of BCR-ABL when analyzed by RT-PCR.26 Recent data suggest that the level of residual disease is predictive of progression-free survival. A 3-log decline in BCL-ABL mRNA within 3 months after achieving a complete cytogenetic response is reported to be a predictor of longer progression-free survival.27 Careful monitoring of BCR-ABL levels by RT-PCR is necessary to guide clinician decision making for therapy modification. The 2013 NCCN guidelines recommend imatinib 400 mg orally daily as one of several options for patients in CP CML (see Table 112-3).15

Higher imatinib doses have been evaluated in clinical trials. The European Leukemia Net conducted a randomized phase II trial in high-risk patients defined by the Sokal scoring system to imatinib 400 mg versus 800 mg daily and evaluated the proportion of patients achieving a complete cytogenetic response at 12 months.28 Patients receiving the higher dose of imatinib achieved a 64% complete cytogenetic response compared to 58% of patients receiving standard dose with a median follow-up period of 12 months (P = 0.435). These study results do not justify the routine use of imatinib 800 mg daily as frontline therapy in high-risk patients with CP CML. A phase II trial evaluated imatinib 400 mg daily for 2 weeks, then titrated to 400 mg twice daily in patients with an intermediate-risk Sokal score appeared to have benefit with 88% and 91% of patients achieving a complete cytogenetic response at 12 and 24 months.29 These data require validation with a phase III clinical trial before a widespread use of a higher dose can become standard of care in CP CML.

Accelerated Phase/Blast Crisis

Response rates for patients with AP or BC CML are reduced compared with those in CP CML. A phase II study evaluating imatinib 600 mg daily in patients with AP CML yielded complete hematologic and complete cytogenetic response rates of 71% and 19%, respectively.30 Prior to protocol amendments, patients were able to receive imatinib 400 mg daily, but the rates of hematologic response, cytogenetic response, disease progression, and overall survival were inferior to imatinib 600 mg. The toxicity profile between imatinib 400 mg and 600 mg daily was similar.

Traditional therapy for BC CML has focused on administering cytotoxic chemotherapy in treatment programs similar to acute leukemia induction. Etoposide (VP-16) cytarabine (Ara-C), and carboplatin (VAC-regimen) has demonstrated efficacy in patients with BC CML with a median overall survival of 7 months.31 Imatinib has demonstrated modest benefit in BC CML. An open-label, nonrandomized trial evaluated imatinib 400 mg daily with dose escalation to 600 mg daily and 400 mg twice daily (for patients not achieving a hematologic response after one month).32 The primary objectives were to assess hematologic response, complete cytogenetic response, and the return to CP CML. Fifteen percent developed a complete hematologic response, 7.4% achieved a complete cytogenetic response, and 18% achieved a second CP. Imatinib 600 mg was associated with sustained hematologic response. The median overall survival was 6.9 months.

Imatinib Resistance

Despite having high cytogenetic response rates, some patients treated with imatinib will not respond to therapy or will relapse after an initial response.33 The most prominent mechanism of imatinib resistance is the presence of point mutations in one or more areas on the ABL kinase. More than 100 different mutations have been discovered thus far. Many of these mutations can cause a conformational change in the ATP binding site, which greatly decreases the ability of imatinib to bind and inhibit kinase activity.34 Imatinib binds to BCR-ABL by establishing a series of hydrogen bonds with side changes of amino acids within the kinase domain. Mutations which alter this surface can decrease the affinity of imatinib for BCR-ABL, potentially preventing binding entirely. The kinase domain of BCR-ABL, which encompasses amino acids 225 to 400, can be subdivided into ATP and imatinib binding site (P loop), the catalytic site where the phosphate from ATP is transferred to the substrate protein, and the activation domain that determines the state of the kinase (open or closed). The imatinib binding site is located in the region of amino acids 300 to 325. Resistance is caused by point mutations in one or more of several areas on the ABL kinase. The T315I mutation occurs directly within the imatinib binding site and completely disrupts imatinib binding.35 This mutation has gained notoriety by conferring resistance not only to imatinib but also to second-generation BCR-ABL kinase inhibitors.

The other known clinically relevant mechanism of resistance is BCR-ABL gene amplification. The BCR-ABL gene is overexpressed to such an extent that the typical 400 mg daily dose of imatinib is insufficient to inhibit the activity of the kinase. Reports of clinically significant resistance have been published owing to BCR-ABL gene amplification, multiple copies of Ph, or both. The largest series published this far included 66 patients, in whom only 2 had confirmed BCR-ABL genomic amplification.35 Other proposed mechanisms of resistance to imatinib include differential binding to α1-acid glycoprotein in serum, overexpression of P-glycoprotein-induced drug efflux, and clonal evolution to acquisition of additional cytogenetic abnormalities.36

Imatinib Monitoring

Imatinib therapy should be frequently monitored to assess response or disease progression. Recommendations for monitoring include baseline molecular and cytogenetic assessment. Patients with CP CML who have an optimal response have a complete hematologic response within 3 months, partial cytogenetic response within 6 months, complete cytogenetic response within 12 months and major molecular response within 18 months of starting imatinib. BCR-ABL transcripts should be evaluated by RT-PCR every 3 months and bone marrow cytogenetics performed at 3 months if RT-PCR is unavailable or 12 months if neither complete cytogenetic response nor major molecular response is achieved. Bone marrow cytogenetics are repeated at 18 months if the patient is not in major molecular response or did not have a complete cytogenetic response at 12 months.1517 The loss of hematologic or cytogenetic responses or clonal evolution at any time should be considered a treatment failure warranting a change in therapy. BCR-ABL kinase domain mutation analysis is performed for patients who have an inadequate initial response at 3, 12, or 18 months, have any sign of loss of response, or demonstrate disease progression to AP or BC.15

Adverse Effects and Drug Interactions

Tables 112-4 and 112-5 summarize drug–drug interactions, adverse drug reactions, and monitoring of imatinib. Imatinib-induced myelosuppression is one of the most common adverse events. Moderate-to-severe myelosuppression occurs in about 5% to 10% of patients with CP CML and in 50% to 60% of patients in AP or BC.14 The myelosuppression typically occurs within the first 4 weeks of therapy and is more common in patients with advanced disease (i.e., high blastic involvement of the bone marrow) and those with a low hemoglobin. Hematopoiesis in patients with CML depends on the amount of Ph-positive progenitors, although some degree of myelosuppression should be expected when the malignant clone is suppressed. However, imatinib also suppresses normal hematopoiesis, which suggests that myelosuppression associated with imatinib is probably related to effects on the Ph clone and normal hematopoietic cells.3 Patients should have complete blood counts drawn every 1 to 2 weeks to assess for myelosuppression while receiving imatinib. Appropriate initial management of myelosuppression is to interrupt imatinib treatment, not dose reduce, as dose reductions below 300 mg daily do not fully inhibit BCR-ABL and may lead to the emergence of imatinib resistance.15

TABLE 112-5 Monitoring of Tyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia

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Nonhematologic toxicities associated with imatinib include gastrointestinal complications, fluid retention, myalgias and arthralgias, rash, and hepatotoxicity. Drug rash frequently occurs but is usually mild and can be managed with antihistamines or topical steroids. Severe rash, while uncommon, has been reported as an important cause for discontinuation of therapy. Algorithms for desensitization for patients that have experienced serious imatinib-associated rash have been published.37 Hepatotoxicity can occur with imatinib, and the drug should be withheld if liver function tests exceed five times the upper limits of normal. After the liver function tests normalize, imatinib can be restarted at a reduced dose of not less than 300 mg per day. Imatinib is then dose escalated to the initial dose if liver function tests do not rise during 6 to 12 weeks of treatment. Death as a consequence of liver failure has been reported in a patient receiving large doses of acetaminophen concomitantly with imatinib. It is recommended that patients on imatinib limit their use of acetaminophen to 1,300 mg daily.15 Other medications that are known to be hepatotoxic should be used with caution while patients are treated with imatinib.

Advanced-Generation Tyrosine Kinase Inhibitors

Dasatinib (Sprycel®) and nilotinib (Tasigna®) are approved second-generation TKIs used for the treatment of CML in patients who are resistant or intolerant to imatinib therapy; both drugs are also approved for first-line treatment of CP CML. Dasatinib is an oral BCR-ABL TKI that was FDA approved in 2006 for the treatment of imatinib-resistant CML. Dasatinib is an oral TKI of BCR-ABL, the SRC family, C-KIT, EPHA2, and PDGFR. Preclinical data show that dasatinib is 300 times more potent than imatinib and inhibits the growth of imatinib-resistant clones, with the exception of the T315I.38 Dasatinib received accelerated approval based on hematologic and cytogenetic responses seen in imatinib-resistant or imatinib-intolerant patients.

Dasatinib has been evaluated in patients with imatinib-resistant or -intolerant CP, AP, and BC CML. In a phase II trial of 186 patients in CP CML receiving dasatinib 70 mg orally twice daily a hematologic response and major cytogenetic response were noted in 90% and 52% of patients, respectively.39 Kantarjian et al. evaluated imatinib 400 mg twice daily compared to dasatinib 70 mg twice daily in patients who developed resistance or were intolerant to imatinib 400 mg daily dosing. At 2 years follow-up, patients receiving dasatinib were more likely to achieve a complete hematologic response (93% vs. 82%; P= 0.034), major cytogenetic response (53% vs. 33%; P = 0.023), and an increased estimated progression-free survival at 2 years, which suggests that dasatinib is superior to imatinib dose escalation in disease progression.40 A trial evaluating different dosing strategies of dasatinib showed that 100 mg once daily was as efficacious as dasatinib 70 mg twice daily, 50 mg twice daily or 140 mg once daily but with decreased adverse events such as pleural effusions.41 The standard dose of dasatinib for patients with CP CML is now accepted to be 100 mg daily.

Dasatinib induces responses in patients who are resistant or intolerant to imatinib with advanced disease CML. Patients with AP CML were administered dasatinib 70 mg twice daily with 45% achieving a complete hematologic response, 39% achieved a complete cytogenetic response, 66% had progression-free survival, and 82% were alive at 2 years.42 A phase III trial comparing dasatinib 70 mg twice daily to 140 mg once daily reported similar efficacy at 15 months follow-up, but an improved safety profile that established dasatinib 140 mg once daily as the preferred dosing in AP CML.43 Dasatinib induced a hematologic response in 35% and a major cytogenetic response in 33% of patients with BC CML. Median overall survival for patients receiving dasatinib in BC CML is 11.8 months.44

Dasatinib has been evaluated as first-line therapy in a phase III trial of 519 patients with CP CML.45 Patients were randomized to dasatinib 100 mg once daily or imatinib 400 mg once daily. The rate of complete cytogenetic response at 2 years was higher with dasatinib as compared with imatinib (86% vs. 82%, P = 0.007). The rate of major molecular response was also significantly higher in the dasatinib group (64% vs. 46%, P <0.0001). At the time of analysis, 77% of dasatinib and 75% of imatinib patients remained on study with transformation to AP/BC occurring in 2.3% of dasatinib versus 5% of imatinib patients. Progression-free survival at 2 years was similar in the two groups. Adverse effects were similar between the two treatment groups, with the exception that 14% of dasatinib-treated patients developed grade 1 or 2 pleural effusions.

Nilotinib has 20 to 30 times the inhibitory activity of the BCR-ABL tyrosine kinase with activity against C-KIT and PDGFR (but not SRC kinases) due to a modification of the methylpiperazinyl structure of imatinib. Nilotinib has inhibitory activity against imatinib-resistant mutants with the exception of T315I. In a phase II trial of 280 patients with imatinib-resistant or -intolerant CP CML, 59% of patients treated with nilotinib 400 mg twice daily achieved a major cytogenetic response, with an estimated 4-year progression-free and overall survival of 57% and 78%, respectively.46 In patients with AP CML treated with nilotinib 400 or 600 mg twice daily, 26% achieved a complete hematologic response and 29% achieve a major cytogenetic response.47 For first-line treatment of CML, results of a randomized trial in 846 patients comparing nilotinib at two doses (300 or 400 mg twice daily) to imatinib 400 mg once daily have been published.48 The primary end point of the trial was major molecular response. At 3 years, both nilotinib arms had a significantly higher major molecular response rate at 12 months (73% and 70% for nilotinib 300 and 400 mg twice daily, respectively) as compared to imatinib (53%, P <0.001 for both comparisons). The nilotinib arms also had a significant improvement in the time-to-progression to the AP or BC, as compared to the imatinib arm. The number of patients discontinued from treatment was similar in all three treatment arms. Nilotinib provides an alternative to dasatinib in patients with imatinib-resistant or -intolerant CP or AP CML and is one of several options in frontline treatment of CP CML.15 The phase III trial results for both dasatinib and nilotinib have made them viable alternatives to imatinib for first-line treatment for newly diagnosed CP CML.

Two other TKIs were approved for treatment of CML in 2012, bosutinib and ponatinib. Bosutinib has 15 to 100 times the inhibitory activity of the BCR-ABL tyrosine kinase as imatinib with activity against SRC kinases with minimal activity against C-KIT and PDGFR. In a phase I/II dose escalation study, bosutinib was evaluated in patients with CP CML with resistance or intolerance to imatinib.49 Among the 288 patients previously treated with imatinib, 34% achieved a major cytogenetic response at 24 weeks. Among patients previously treated with imatinib followed by dasatinib or nilotinib, 27% achieved a major cytogenetic response at 24 weeks. Grade 3 or 4 nonhematologic adverse events included diarrhea (9%), rash (9%), and vomiting (3%). Based on this study, the bosutinib dose that was recommended for phase II trials was 500 mg daily. A major cytogenetic response was observed in 32% of patients and a complete cytogenetic response was observed in 24% of patients in the phase II trials.50

Bosutinib 500 mg daily was compared to imatinib 400 mg daily in a phase III randomized trial of 502 patients in newly diagnosed CP CML.51 Although the primary end point of complete cytogenetic response rate at 12 months (70% with bosutinib vs. 68% with imatinib) was not significantly different observed, the rate of major molecular response was significantly higher in the bosutinib group (41% vs. 27%, P<0.001). The incidence of adverse events was similar between the groups with the exception that bosutinib had a higher incidence of diarrhea (68% vs. 21%) and imatinib had a higher incidence of edema (38% vs. 11%).

Ponatinib is considered a third-generation TKI that contains a novel triple-bond linkage in its chemical structure that avoids the steric hindrance caused by the bulky isoleucine residue at position 315 in T315I BCR-ABL binding site cleft, providing clinical activity against this resistance phenotype. In a phase I trial, 65 patients had refractory CML in either CP, AP, BC or Ph positive ALL, the maximum tolerated dose of ponatinib was 45 mg with dose-limiting toxicities identified as pancreatitis and myelosuppression.52 Of the 43 patients with CP CML, 63% achieved a complete cytogenetic response and 44% a major molecular response. The 22 patients with AP/BC CML or Ph positive acute lymphocytic leukemia (ALL), 14% achieved complete cytogenetic response and 9% major molecular response. In the 12 patients who harbored a T315I mutation, 92% attained a complete cytogenetic response and 67% a major molecular response. These data led to the design of a phase II study of 449 CML patients who were resistant or intolerant to dasatinib or nilotinib or had documented T315I mutation on study entry.53 Patients were assigned to six cohorts: CP CML, AP CML or BC CML with each disease group further stratified by TKI resistance/intolerance or presence of T315I mutation. The patient population was heavily pretreated with 53% having received imatinib, dasatinib and nilotinib prior to enrollment. The primary end point was major cytogenetic response at 12 months. For patients with TKI resistant/intolerant disease, the primary end point was achieved in 50%, 58%, and 35% of patients with CP, AP, and BC CML, respectively. For patients with T315I mutations, major cytogenetic responses reported were 70% for CP CML, 50% for AP CML and 33% for BC CML. About one-third of patients experienced myelosuppression and/or cutaneous reaction and pancreatitis was reported in 5% of patients. The drug label contains a black box warning for arterial thrombosis including fatal myocardial infarction and stroke in 8% of patients in clinical trials.54 Hepatotoxicity including reports of liver failure and death are also included in the black box warning, several of which occurred within 1 week of starting therapy. The manufacturer recommends specific dose modifications for myelosuppression, hepatotoxicity and elevated lipase.

Tables 112-4 and 112-5 summarize dosing, drug interactions, adverse drug reactions, and monitoring of advanced-generation TKIs. Edema and plural effusions can be managed by dasatinib drug holiday, diuretics, or short courses of steroids. Nilotinib can be associated with indirect bilirubin elevations in 10% to 15% of patients.46,47 Nilotinib may prolong the QTc interval (block box warning) and patients should have an electrocardiogram at baseline, at 7 days following initiation of therapy, and periodically thereafter. Based on early clinical trial data, bosutinib appears to have similar adverse events of diarrhea, nausea and vomiting, rash, and abdominal discomfort.49 Like imatinib, advanced-generation TKIs are metabolized by cytochrome P450 (CYP)3A4. Clinicians need to be aware of possible drug interactions with inducers and inhibitors of the CYP3A4 pathway such as phenytoin, azole antifungals, or macrolide antibiotics.

Omacetaxine

Omacetaxine was approved by the FDA in October 2012 for treatment of CP or AP CML with resistance or intolerance to two or more TKIs. Omacetaxine is a first-in-class cephalotaxine ester that inhibits protein synthesis independent of direct BCR-ABL binding. The putative mechanism is the reduction of BCR-ABL oncoproteins and Mcl-1, an anti-apoptotic Bcl-2 family member, via binding to A-site cleft in the peptidyl-transferase center of the large ribosomal subunits. Efficacy with omacetaxine has been demonstrated in two patients groups: CP or AP CML resistant to two or more TKIs and patients previously treated with imatinib harboring the T315I mutation. The former group was presented in a combined analysis of two phase II studies for CP and AP CML. Omacetaxine was administered at 1.25 mg/m2subcutaneously twice daily for 14 consecutive days every 28 days then for 7 days every 28 days as maintenance.55 Of the 122 patients enrolled, 81 had CP CML of which 20% achieved a major cytogenetic response with a median duration of 18 months and a median overall survival of 34 months. In the AP CML group, no patients achieved a major cytogenetic response and 27% of patients had a major hematologic response with a median overall survival of 16 months.

A phase II trial of omacetaxine was conducted in 62 CP CML patients with a history of the T315I mutation.56 Patients were treated with the induction regimen as above and transitioned to maintenance when the patient achieved a hematologic response. Hematologic response was attained in 77%, complete cytogenetic response in 16%, and major cytogenetic response in 23% of patients. The median number of cycles to gain a hematologic response was one, and for major cytogenetic response was 2.5 months. The median duration of complete hematologic response was 9.1 months, and major cytogenetic response was 6.6 months. Grade 3/4 toxicities reported in these trials was myelosuppression with occasional reports of myalgias and arthralgias and gastrointestinal toxicity.

Hematopoietic Stem Cell Transplantation

Images Allogeneic HSCT remains the only therapy proven to cure patients with CML, with many patients alive and disease-free decades after transplant. Patients undergoing allogeneic HSCT from a human leukocyte antigen (HLA)-matched sibling donor have 5-year survival rates ranging from 60% to 80% and long-term survival of approximately 50%.54,55 In most long-term survivors, the BCR-ABLtranslocation is absent in all diagnostic tests including RT-PCR. Prognostic risk factors associated with survival outcomes include age, phase of disease, and disease duration. Increasing age is associated with poorer prognosis, with higher transplant-related mortality in patients older than age 50 years. Patients with CP who receive allogeneic HSCT have better outcomes than those in AP or BC. The time from diagnosis to transplantation also affects outcomes. Patients who undergo matched-sibling allogeneic HSCT within the first year of diagnosis have a better 5-year survival rate than those who undergo transplantation more than 1 year after their diagnosis (70% to 80% vs. 50% to 60%).57,58 These data were reported prior to the use of imatinib as first-line therapy for CML.

The major limitation for broad application of HSCT is that fewer than 30% of patients who are transplant-eligible will have an HLA-matched sibling donor. The most practical approach is to use an HLA-matched unrelated donor, if available. Matched unrelated donor HSCT has an overall 5-year survival reported to be 40% to 70%, which approaches overall survival data results reported for matched-sibling donor HSCT.9,57,58 The advent of TKI therapy has resulted in fewer transplants for CML. Data collected to date appear to show that imatinib use prior to transplantation does not negatively affect transplant-related mortality.59


Clinical Controversy…

The controversy of whether to use allogeneic hematopoietic stem cell transplantation (HSCT) or second-generation tyrosine kinase inhibitor (TKI) therapy as second-line treatment for patients that have progression or are intolerant to imatinib is ongoing. Dasatinib keeps 90% of chronic phase (CP) patients treated first-line with imatinib free from disease progression with a median follow-up of 15 months. For patients that have progressed to accelerated phase (AP), dasatinib and nilotinib can produce hematologic response in about one-half of patients and major cytogenetic responses in close to one-third of patients. At 1 year, about 75% of patients will still be alive. It is unknown what efficacy of second-generation TKIs will confer as a long-term treatment option. Allogeneic HSCT remains an option for patients with a suitable donor, younger age, and good performance status.

Treatment options in patients who relapse after transplantation are limited. Graft-versus-leukemia (GVL) effect, TKIs, omacetaxine, IFN-α, or a clinical trial are reasonable options. The infusion of donor lymphocytes function as a form of adoptive immunotherapy can induce a GVL effect. In relapsed CML, donor lymphocytes induce durable responses and these responses strongly correlate with the development of graft-versus-host disease (GVHD).60Tumor burden also predicts the likelihood of response to donor lymphocyte infusion in relapsed CML. The optimal method of administering donor lymphocytes remains unclear, but these data suggest it may be possible to partially separate the GVL effect from GVHD.

Imatinib has been used in patients who have residual disease after allogeneic HSCT. Most patients respond to imatinib with complete molecular response of 70%.61 Use of imatinib or other TKI therapies require further study to determine the magnitude of benefit when applied in the post-HSCT setting.62 The role of nonmyeloablative transplants in CML is evolving, but preliminary results suggest comparable outcomes to myeloablative transplants. The experience of German registry data suggests that 17% of all transplants for CML use a reduced-intensity conditioning regimen.63

Personalized Pharmacotherapy

Personalized treatment of CML is mostly directed following initiation of second-line therapy. Mutational analysis of binding sites that confer resistance to TKIs should be evaluated if initial response is inadequate, or the milestones of complete cytogenetic response or major molecular response are lost, or if any signs of disease progression in the form of AP or BC are noted.64 The results of this analysis will guide selection of the appropriate TKI as second-line therapy.65 In addition, with the advent of omacetaxine and ponatinib, two agents are now available that are active against the T315I mutation that confers resistance to the rest of the TKIs.

Preliminary data support the role of therapeutic drug monitoring of TKIs in CML. Trough imatinib levels of ≥1 mcmol/L have been associated in patients with a higher response than those with >1 mcmol/L.66Data on nilotinib and dasatinib are more limited. The clinical applicability of therapeutic drug monitoring is still to be determined because the drug assays are not yet commercially available

Evaluation of Therapeutic Outcomes

Current standard of care is for patients with newly diagnosed CP CML to receive imatinib or one of the second-generation TKI. The goal of disease monitoring in CML is to differentiate patients who have optimally responded to an initial course of TKI therapy from those at high risk for treatment failure. With imatinib, nilotinib, and dasatinib as appropriate options for frontline therapy for newly diagnosed CP CML, and bosutinib, ponatinib, and omacetaxine approved for salvage therapy, clinicians have a large number of treatment options to consider before allogeneic HSCT. Future research opportunities will focus on how to select second-, third-, and fourth-line therapies and whether combination therapy provides additional long-term benefit.

CHRONIC LYMPHOCYTIC LEUKEMIA

Epidemiology and Etiology

CLL is a lymphoproliferative disorder characterized by accumulation of functionally incompetent clonal B lymphocytes.67 CLL is the most common form of leukemia in the United States, but is rare in other countries, such as Japan and China. It is estimated that 15,680 new cases of CLL will be diagnosed in the United States in 2013 with 4,580 deaths.1 Occasional family clusters have been recognized, and first-degree relatives of patients with CLL are at three times the risk of developing a lymphoid malignancy as compared with the general population. CLL is a disease of the elderly, with a median age of 72 years, although 20% to 30% of CLL occurs in patients who are younger than 55 years of age. Male sex, white race, family history, and advanced age are known risk factors for the disease.

Pathophysiology

CLL cells are comprised of a neoplastic clone of CD5+ cells, which express low levels of surface-membrane immunoglobulin M (IgM) and immunoglobulin D (IgD) compared to normal peripheral blood B cells. Normal CD5+ B lymphocytes are present in the lymph nodes and in the blood. Neoplastic CD5+ cells accumulate in the lymph nodes and spleen because of the loss of apoptosis by either the over-expression of an oncogene, such as bcl-1 or -2, or loss of a tumor suppressor gene, such as RB1.67 The bcl-2 protein is a major regulator of apoptosis or programmed cell death. Evidence is emerging that antigenic stimulation and cytokines drive the proliferation of the CLL cells.

A monoclonal population of B cells with a similar surface antigen phenotype as CLL cells has been recently identified in patients up to several years prior to diagnosis of the disease.68 This phenomenon, termed monoclonal B-cell lymphocytosis (MBL) appears to be predictive as to whether a patient is at risk for developing CLL over time. In a cohort of 77,000 patients enrolled in a cancer screening trial, 45 patients were diagnosed with CLL throughout the duration of the study. Baseline blood samples collected on enrollment of the screening trial were analyzed for the patients who developed CLL. MBL was present in 44 of 45 of the patients by either flow cytometric or molecular analysis (i.e., RT-PCR assay) and confirmed in 41 of 45 of these patients by both methods. Samples predated the diagnosis of CLL in a time period ranging from 6 months to 6.4 years. This finding could lead to potentially earlier diagnosis and intervention for CLL.

Cytogenetic abnormalities correlate with disease progression in CLL. About 80% of patients with CLL have a karyotypic abnormality. The chromosomes that are most frequently involved include chromosomes 13, 12, 11, and 17.69 Additional cytogenetic abnormalities may be acquired during therapy, particularly with deletions of chromosome 17, which have an adverse effect on survival.70 Somatic point mutations have been identified in a cohort of 91 patients yielding nine mutated genes: TP53ATMMYD88NOTCH1SF3B1ZMYM3MAPK1FBXW7, and DDX3X.71 These mutations were associated with cell-cycle and DNA repair pathways, intracellular signaling, inflammatory pathways, and RNA splicing and processing. A correlation was identified with SF3B1 and chromosome 11 deletions providing insight into how these mutations may impact clinical outcomes.

About 4% of patients with CLL will undergo transformation of their disease to an aggressive non-Hodgkin lymphoma (diffuse large B cell), which is termed Richter’s syndrome. Richter’s syndrome may be triggered by accumulation of additional cytogenetic abnormalities in the malignant clone of lymphocytes or by viral infections, such as Epstein-Barr’s virus.72


CLINICAL PRESENTATION Chronic Lymphocytic Leukemia

Constitutional Symptoms

    • Fever, fatigue, weight loss

Physical Examination

    • Lymphadenopathy (87%)

    • Splenomegaly (54%)

    • Hepatomegaly (14%)

Laboratory Tests

    • Peripheral blood

      • Lymphocytosis

      • Coombs-positive autoimmune hemolytic anemia

      • Hyper- or hypogammaglobulinemia

      • Monoclonal gammopathy

      • Anemia

      • Thrombocytopenia

    • Bone marrow

      • Hypercellular

      • Increased mature lymphocytes

      • Increased megakaryocytes

    • Molecular markers

      • Cytogenetics (17p-)

      • ZAP-70 mutations

Staging and Prognosis

Survival times for patients with CLL are widely variable, with some patients succumbing to disease within 3 years and others living into a second decade from the time of diagnosis. The Rai and the Binet staging systems are commonly used in CLL with the Rai being favored in the United States and the Binet in Europe. The Rai staging system has been combined into a risk classification scheme: low risk (stage 0), intermediate risk (stages I and II), and high risk (stages III and IV) with median survivals of greater than 10 years, 7 years, and 2 to 4 years, respectively.73

The disease course for CLL varies within each stage such that one patient may have an indolent course with long survival time, while another patient may have more aggressive disease and a relatively short survival time. The Rai and Binet staging systems incompletely predict for individual patients who may experience more rapid disease progression. Patients with Richter’s syndrome will have a rapidly advancing disease course that mimics diffuse large B-cell non-Hodgkin lymphoma. However, successful treatment of the diffuse large B-cell non-Hodgkin lymphoma with combination chemotherapy will not eradicate the underlying clone of CLL cells and patients will ultimately relapse.72

Biomarkers such as CD38 expression and ζ-associated protein 70 (ZAP-70) expression have been explored as prognostic factors for CLL. CD38 is a cell-surface antigen that is associated with early progression, significantly shorter overall survival, and a poor response to fludarabine.7476 ZAP-70 is an intracellular protein with tyrosine kinase activity. Once considered as simply a surrogate marker for the unmutated variable region of the immunoglobulin heavy chain gene (IGHV), elevated ZAP-70 expression appears to predict for rapid CLL disease progression and independently correlates with prognosis.73,76,77

Cytogenetic changes such as deletion of the short arm of chromosome 17 (17p-), which corresponds to p53 silencing, can be biomarkers of poor response to therapy. A prospective study showed that newly diagnosed patients with 17p- had a median time-to-progression following first-line therapy with either fludarabine or fludarabine and cyclophosphamide of 10 to 12 months.70 Patients with chromosomal abnormalities of 13, 12, 11, and 17 have reported median survivals of 133 months, 114 months, 79 months, and 32 months, respectively.69


Clinical Controversy…

Certain molecular and cellular markers have been identified that may predict chronic lymphocytic leukemia (CLL) disease progression. ZAP-70 expression, CD38 expression, IGHV mutations, and 17p- are associated with a more aggressive clinical course of CLL. Controversy surrounds whether or not treatment should be based on these biologic markers alone. 17p- is the most consistent poor prognostic marker and results in a loss of the tumor suppressor gene, p53. Consensus guidelines now delineate treatment options for patients based on the presence of 17p-. If a patient has 17p- more aggressive regimens that contain immunotherapy and purine analogs (e.g., fludarabine, cyclophosphamide, and rituximab) are recommended as first-line treatments. For second-line therapy, regimens with multiagent chemotherapy combined with immunotherapy (e.g., oxaliplatin, fludarabine, cytarabine, and rituximab) are considered standard therapy.

TREATMENT

Chronic Lymphocytic Leukemia

Desired Outcomes

Images The primary goals of treatment for CLL are to achieve and maintain remission duration with minimize treatment-related toxicity. The management of patients with CLL is highly individualized with some patients receiving therapy on diagnosis, while other patients with early-stage disease are managed expectantly. Indications for starting treatment include disease-related symptoms (fatigue, night sweats, weight loss, fever), threatened end-organ function, bulky disease, doubling of lymphocyte doubling time in less than 6 months, progressive anemia, and platelet count less than 100,000/mm3 (100 × 109/L).7981Consideration of initial treatment options is based on several factors including age of the patient, disease stage, and high-risk prognostic factors, such as deletion 17p or 11q.

Most stage 0 patients do not require treatment and can be managed with observation. In patients with stage I disease, treatment is controversial. A consistent survival benefit from early therapy has not been reported in asymptomatic patients.79,81 Cytotoxic chemotherapy in early stage CLL is usually reserved for patients who have disease characteristics consistent with a more aggressive course, such as short lymphocyte doubling times and presence of biologic markers such as ZAP-70 or high-risk cytogenetics. In stages II through IV disease, treatment is required, with the goal of achieving a partial or complete remission. Table 112-6 shows the regimens used to treat newly diagnosed and previously treated CLL.73,74,76,77

TABLE 112-6 Treatment for Newly Diagnosed and Previously Treated Chronic Lymphocytic Leukemia

Images

Cytotoxic Chemotherapy

Orally administered alkylating agents such as chlorambucil and cyclophosphamide, given either alone or with corticosteroids, historically have been used as primary treatment for CLL. Results from a meta-analysis involving 2,048 patients from six randomized controlled studies evaluated low-dose alkylating agents in CLL.82 That analysis showed that delayed treatment with alkylating agents in asymptomatic patients did not adversely affect 10-year survival. More importantly, if only deaths caused by CLL were considered, significantly longer survival was observed when treatment was deferred. Chlorambucil continues to be widely used in elderly, symptomatic patients as initial treatment for CLL, but its use is based on a small number of studies with no demonstrable survival advantage.73 Commonly used dosing schedules for chlorambucil are intermittent pulse dosing of 15 to 40 mg/m2 orally every 28 days or daily doses of 4 to 8 mg/m2/day.83 The dose of chlorambucil is often titrated to circumvent myelosuppression.

Cyclophosphamide produces a similar response rate as chlorambucil (overall response rate: 40% to 60%; complete response: 4%) and can be used in patients who cannot tolerate chlorambucil or in whom response is not optimal. Some patients who do not respond to chlorambucil will respond to single-agent cyclophosphamide. Cyclophosphamide is typically given orally at a daily dose of 1 to 3 mg/kg. Oral cyclophosphamide is less commonly used compared to chlorambucil because of the risk of hemorrhagic cystitis and bladder cancer with prolonged treatment.

Fludarabine-based therapy is a common initial treatment in CLL. It is particularly useful in younger patients and in those patients who can tolerate immunosuppressive chemotherapy. Fludarabine, along with the other purine analogs, 2-chlorodeoxyadenosine (cladribine) and 2-deoxycoformycin (pentostatin), are highly active in CLL, with fludarabine being the most widely studied agent in the class in the treatment of CLL.83,84 Most patients receive fludarabine 25 to 30 mg/m2 IV daily for 5 days when used as a single agent. Cladribine and pentostatin have similar activity, although head-to-head trials comparing these three nucleosides have not been conducted.83,85,86

Fludarabine was initially studied in CLL patients who were refractory to chlorambucil. Several trials reported overall response rates to fludarabine in previously treated patients ranging from 13% to 59% and complete response rates of 3% to 37%.87 Fludarabine has higher overall response and complete remission rates than alkylating-based therapies in the frontline setting. In one of the randomized studies that compared fludarabine to chlorambucil in chemotherapy-naïve patients, fludarabine-treated patients had a higher complete remission rate as compared with chlorambucil (20% vs. 5%).88 However, the higher complete remission rate did not translate into a significant difference in overall survival and patients treated with fludarabine had a higher rate of severe neutropenia and infection. The study allowed chlorambucil failures to cross over to fludarabine, which may have hampered the ability to show a survival advantage in the fludarabine arm. A recent review of younger patients enrolled in a large phase III trial showed that 33% of patients receiving fludarabine or fludarabine-based therapy had infectious complications.89An increase in Pneumocystis infections was not observed, but a 6% increase in herpes and varicella zoster infection was documented. Dose reductions occurred frequently as a result of the infectious episodes. Based on the increased risk of infectious complications, some practitioners recommend antiviral and antibacterial prophylaxis be given with treatment.81

Bendamustine is an alkylating agent that contains a purine-derivative benzimidazole ring in its chemical structure that yields a compound that is non–cross-resistant with other alkylating agents. Bendamustine induces cell death via single and double-stranded cross-links.89 Efficacy of bendamustine was established as first-line agent in Binet stage B or C CLL in a phase III trial that randomized 319 patients to bendamustine or chlorambucil.90 Complete response rates of 31% versus 2% and an overall response rate for 68% versus 31% were observed for bendamustine and chlorambucil respectively. The median progression-free survival was 21.6 versus 8.3 months favoring bendamustine. Adverse events reported for bendamustine includes hematologic toxicity in about 25% of patients, and gastrointestinal and cutaneous toxicity.

Biologic Therapy

Monoclonal antibodies, such as rituximab and alemtuzumab, are increasingly being used in the treatment of CLL. Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen expressed on B lymphocytes. Rituximab was initially approved for patients with indolent non-Hodgkin lymphoma and later for aggressive non-Hodgkin lymphoma. Rituximab received FDA approval for the treatment of CD20-positive CLL in 2010. CLL cells have less prominent CD20 expression on their surface as compared to non-Hodgkin lymphoma, which may translate into lower clinical response. Efficacy with rituximab as a single agent in CLL is moderate with a 58% overall response rate reported with 9% complete responses.91 Subsequent studies have used higher rituximab doses (up to 500 mg/m2 per cycle) when given in combination with other agents.

Images Alemtuzumab is a monoclonal antibody that targets the CD52 antigen found on both B and T lymphocytes. This agent was initially FDA approved in 2001 for the treatment of patients with CLL who had been treated with alkylating agents and had failed fludarabine therapy and is now approved as a single agent for both frontline and salvage treatment of CLL. Alemtuzumab is titrated to a maintenance dose of 30 mg IV or subcutaneously given 3 times a week for 12 weeks. As a single agent, alemtuzumab has produced response rates from 33% to 53% in patients with refractory disease, but complete responses are infrequent.92

Results from a randomized phase III trial comparing alemtuzumab to chlorambucil in chemotherapy-naïve patients with symptomatic CLL showed higher complete response rates with alemtuzumab than with chlorambucil, 24% versus 2%, respectively.93 These differences in response rate translated into a significant difference in progression-free survival (hazard ratio, 0.58; 95% confidence interval, 0.43 to 0.77, P<0.0001).

Infusion-related reactions are one of the most frequently reported toxicities with alemtuzumab. The reactions experienced with IV administration include fever, rigors, and hypotension.94 Alemtuzumab is associated with serious, potentially life-threatening toxicities, including pancytopenia, infusion reactions, and opportunistic infections. Because of alemtuzumab’s profound immunosuppression, the 2013 NCCN guidelines recommend antibacterial and antiviral prophylaxis to prevent Cytomegalovirus reactivation and Pneumocystis infections.80 Prophylaxis with trimethoprim-sulfamethoxazole and famciclovir or valacyclovir is recommended with the use of alemtuzumab.91Alemtuzumab is FDA-approved for IV administration, although the use of subcutaneous alemtuzumab has been evaluated to reduce the frequency of these reactions. In a study by Lundin et al., 41 patients received 30 mg of subcutaneous alemtuzumab three times a week for 12 weeks, which yielded a response rate of 87%.95 Major adverse event were grades 1 and 2 skin reactions in 90% of patients; fever, rigors, and hypotension were infrequent. About 10% of patients had reactivation of Cytomegalovirus and required ganciclovir treatment. Similar to IV administration, antiviral and antibacterial prophylaxis is warranted when alemtuzumab is given via the subcutaneous route.95

Ofatumumab is a fully human monoclonal antibody to CD20 that was approved as single-agent therapy in 2009 for patients with CLL that is refractory to fludarabine and alemtuzumab. Ofatumumab is administered as an IV infusion with an initial dose of 300 mg then four weekly doses followed by four monthly doses of 2,000 mg. An overall response rate was reported of 58% in patients with fludarabine and alemtuzumab refractory disease and 47% in bulky fludarabine refractory disease.96 Median time-to-progression was 5.7 and 5.9 months and median overall survival 13.7 and 15.4 months in the fludarabine, alemtuzumab refractory patients and bulky fludarabine refractory disease patients, respectively. Adverse events reported in greater than 10% of patients included infection and neutropenia. Infusion-related events were reported in approximately 60% of patients with the 40% during the first infusion and 25% with the second infusion. Serious toxicities such as fatal infections, progressive multifocal leukoencephalopathy, and hepatitis B reactivation have been reported.

Combination Therapy

The single-agent activity of fludarabine has led to incorporation of fludarabine in combination regimens in patients with CLL. The most widely studied combination is fludarabine with cyclophosphamide, which produces complete response rates between 25% and 40% in treatment-naïve patients as compared with 20% to 30% for single-agent fludarabine.78,84 Although improved response rates and progression-free survival have been reported with fludarabine and cyclophosphamide combinations compared with fludarabine alone, no benefit in overall survival has yet been observed.

Images The combination of fludarabine and rituximab has promising activity. In vitro studies suggest that rituximab is synergistic with fludarabine and cyclophosphamide and has led investigators to evaluate this combination in clinical trials. Results from an uncontrolled trial of fludarabine, cyclophosphamide, and rituximab (FCR) reported a complete remission rate of 70% in previously untreated CLL patients.97FCR has documented a complete remission rate of 25% in previous treated patients. Results of two phase III trials comparing FCR with fludarabine and cyclophosphamide documented a progression-free survival benefit (30 vs. 20 months) in patients treated with FCR in patients with refractory disease and an overall survival benefit (87.2% vs. 82.5%) in patients with newly diagnosed disease.98,99 The results of these phase III trials led to FDA approval of rituximab with fludarabine and cyclophosphamide in CLL.

Bendamustine and rituximab have been combined in two phase II studies in patients with CLL, in frontline and the relapsed setting. In the frontline setting, 117 patients were treated with bendamustine 90 mg/m2 days 1 and 2 and rituximab 375 mg/m2 IV on day 0 for cycle 1 and then 500 mg/m2 IV on day 1 for subsequent cycles.100 Overall, 88% of patients had a clinical response with 23% being complete responses. The median EFS was 34 months with 90% of patients reported being alive at the median follow-up time point of 27 months. Patients with 17p- responded less well, with a 37.5% overall response rate. Grade 3/4 myelosuppression was experienced in about 20% of patients. In the relapsed setting, a similar regimen as above was administered with the exception of a lower bendamustine dose of 70 mg/m2in 78 patients who had received a median of two prior treatments.101 The overall response rate was 59%, with 9% of patients having a complete response. With a median follow-up of 24 months, the EFS was 14.7 months with a median overall survival of 34 months. About 25% of patients experienced grade 3/4 myelosuppression with three treatment-related deaths related to infection.

Hematopoietic Stem Cell Transplantation

Images There is limited experience with the use of HSCT in CLL. Patients treated with allogeneic HSCT achieve higher remission rates and appear to have a longer disease-free survival, but is associated with high treatment-related mortality, which approaches 40%. Contrary to the high mortality reported in most studies, a randomized phase II study of high-risk CLL patients comparing allogeneic and autologous HSCT reported 100-day mortality of 4% in both arms. After 6 years of follow-up, no difference in overall survival (58% autologous and 55% allogeneic) was observed.102 This low early mortality must be interpreted carefully, given that only 25 carefully selected patients received allogeneic HSCT as compared with 137 who received autologous HSCT. T-cell depletion was performed on the allogeneic grafts, which may reduce 100-day mortality at the cost of increased relapse, infectious complications, or posttransplant lymphoproliferative disorders as a consequence of reduced GVL effect.102

Although allogeneic HSCT may offer the potential of cure in CLL, the advanced age of most patients, limited donor availability, and the high treatment-related mortality precludes the routine application in the management of this disease. Allogeneic HSCT is a more viable option for younger patients with aggressive disease. Older patients who are not candidates for full-intensity allogeneic HSCT may be candidates for nonmyeloablative allogeneic HSCT.

Gene Therapy

The use of gene therapy in CLL had been considered as a potential treatment strategy because of the presence of tumor specific antigens such as CD19. A preliminary report described the modification of autologous T cells expressing an anti-CD19 chimeric antigen receptor (CART19) in a single patient who had advanced CLL.103 The patient’s autologous T cells were collected via leukapheresis and treated with a self-inactivating lentiviral vector to express the CD19 specific chimeric antigen receptor concurrently with the costimulatory CD137 signaling domain. The patient received a preparative regimen of pentostatin 4 mg/m2 and cyclophosphamide 600 mg/m2 IV followed by reinfusion of 3 × 108 autologous T cells of which 5% were transduced over three separate daily infusions 96 hours following completion of chemotherapy.

The patient’s clinical course was marked by low-grade fevers and chills 2 weeks following the first infusion. In the succeeding 5-day period, the patient experienced fevers, rigors, diaphoresis, anorexia, nausea, and diarrhea. The patient was diagnosed with tumor lysis syndrome on day 22 following the first infusion and was treated with rasburicase and supportively. By day 28, the patient had neither resolution of his adenopathy nor evidence of CLL from a bone marrow aspirate. At 3 and 6 months following infusion, the patient remained free of adenopathy and bone marrow studies continued to show no evidence of CLL by morphologic karyotypic or flow cytometric analysis. This clinical report represents the first sustained remission published in the medical literature with transduced autologous T cells in treatment of CLL.

Personalized Pharmacotherapy

Molecular biomarkers are important as predictors for disease time to progression, decision making for initiation of treatment, and prognosis. The most important are cytogenetic abnormalities such as deletion 17p and 11q, which are associated with more aggressive disease that is less responsive to treatment. Unmutated status of the immunoglobulin heavy chain variable gene locus and overexpression of ZAP-70 and CD38 expression are also predictive of poor prognosis.

The 2013 NCCN guidelines segregate treatment options based on the presence of deletion 17p- or 11q, age older or younger than 70 years, and first- and second-line regimens.80 Preferred first-line therapy options for patients younger than 70 years without poor-risk cytogenetics or significant comorbidities are aggressive chemoimmunotherapy regimens such as fludarabine, cyclophosphamide, rituximab; and pentostatin, cyclophosphamide, and rituximab. Patients who are older than 70 years without poor-risk cytogenetics may be treated with chemotherapy (bendamustine, chlorambucil, and cyclophosphamide/prednisone), immunotherapy (rituximab), or milder chemoimmunotherapy (fludarabine and rituximab). Second-line therapeutic options for patients without poor-risk cytogenetics are again divided by the duration of response with first-line treatment, which is loosely defined as a long response greater than 36 months for fludarabine/cyclophosphamide and rituximab or greater than 18 months for chlorambucil. Regimens recommended for short responses consist of chemoimmunotherapy (fludarabine, cyclophosphamide, and rituximab; pentostatin, cyclophosphamide, and rituximab; and oxaliplatin, fludarabine, cytarabine, and rituximab) or traditional regimens used for aggressive non-Hodgkin lymphoma (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone [CHOP]) with rituximab. For patients who have poor-risk cytogenetics, first-line therapy options consist primarily of more aggressive chemoimmunotherapy treatment options (fludarabine, cyclophosphamide, and rituximab; fludarabine and rituximab; high-dose methylprednisolone and rituximab; bendamustine and rituximab; pentostatin, cyclophosphamide, and rituximab). Second-line regimens are similar to those outlined above for patients younger than as described above for short responses.

The next generation of prognostic data to incorporate into drug therapy decision making will likely come from the study of somatic gene mutations and whole genome sequencing from individual patients. A report identified specific somatic gene mutations that were associated with resistance to chemotherapy such as TP53 and others newly associated with CLL, such as SF3B1.104 Tracking subclonal heterogeneity was performed in patients receiving therapy revealed that certain tumor subclones evolved over time in a heterogeneous fashion for each individual patient. These data may ultimately predict which patients will achieve a suboptimal response to therapy and guide the selection of salvage therapies.105

Evaluation of Therapeutic Outcomes

CLL is an incurable disease and the goal of therapy is to optimize remission duration while minimizing the burden of treatment-related adverse effects.

Supportive care for patients undergoing active treatment for CLL is crucial for ensuring a successful outcome. Patients may become hypogammaglobinemic as a consequence of disease progression or treatment will need routine monitoring of serum IgG. If the serum IgG falls below 500 mg/dL (5 g/L), then monthly replacement doses of 300 to 500 mg/kg of IV immune globulin is warranted. Antibiotic prophylaxis for patients receiving fludarabine-based regimens or chemoimmunotherapy should be considered for herpes virus and Pneumocystis. Patients who are treated with alemtuzumab will require monitoring for cytomegalovirus (CMV) antigen every 1 to 2 weeks while on therapy and for 2 months after or be given prophylaxis with valganciclovir.

ABBREVIATIONS

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