InternalMed_Harrison

InternalMed_Harrison. In addition to cytogenetics and/or molecular aberrations, several other factors are associated with outcome in AML. Age at diagnosis is one of the most important risk factors. Advancing age is associated with a poorer prognosis not only because of its influence on the ability to survive induction therapy due to coexisting comorbidities, but also because with each successive decade of age, a greater proportion of patients have an intrinsically more resistant disease. A prolonged symptomatic interval with cytopenias preceding diagnosis or a history of antecedent hematologic disorders including myeloproliferative neoplasms is often found in older patients and is a clinical feature associated with a lower complete remission (CR) rate and shorter survival time. The CR rate is lower in patients who have had anemia, leukopenia, and/or thrombocytopenia for >3 months before the diagnosis of AML when compared to those without such a history. Responsiveness to chemotherapy declines as the


InternalMed_Harrison

InternalMed_Harrison. who have had anemia, leukopenia, and/or thrombocytopenia for >3 months before the diagnosis of AML when compared to those without such a history. Responsiveness to chemotherapy declines as the duration of the antecedent disorder(s) increases. AML developing after treatment with cytotoxic agents for other malignancies is usually difficult to treat successfully. Finally, it is likely that AML in older patients is also associated with poor outcome because of the presence of distinct biologic features that may increase the aggressiveness of the disease and reduce the likelihood of treatment response. The leukemic cells in older patients more commonly express the multidrug resistance 1 (MDR1) efflux pump that conveys resistance to natural product–derived agents such as the anthracyclines that are frequently incorporated into the initial treatment. In addition, older patients less frequently harbor favorable cytogenetic abnormalities [i.e., t(8;21), inv(16), and t(16;16)] and more


InternalMed_Harrison

InternalMed_Harrison. that are frequently incorporated into the initial treatment. In addition, older patients less frequently harbor favorable cytogenetic abnormalities [i.e., t(8;21), inv(16), and t(16;16)] and more frequently harbor adverse cytogenetic (e.g., complex and monosomal karyotypes) and/or molecular (e.g., ASXL1, IDH2, RUNX1, TET2) abnormalities.


InternalMed_Harrison

InternalMed_Harrison. Other factors independently associated with worse outcome are a low performance status that influences ability to survive induction therapy and thus respond to treatment and a high presenting leukocyte count that in some series is an adverse prognostic factor for attaining a CR. Among patients with hyperleukocytosis (>100,000/μL), early central nervous system bleeding and pulmonary leukostasis contribute to poor outcome with initial therapy.


InternalMed_Harrison

InternalMed_Harrison. Achievement of CR is associated with better outcome and longer survival. CR is defined after examination of both blood and bone marrow. The blood neutrophil count must be ≥1000/μL and the platelet count ≥100,000/μL. Hemoglobin concentration is not considered in determining CR. Circulating blasts should be absent. Although rare blasts may be detected in the blood during marrow regeneration, they should disappear on successive studies. The bone marrow should contain <5% blasts, and Auer rods should be absent. Extramedullary leukemia should not be present. Patients who achieve CR after one induction cycle have longer CR durations than those requiring multiple cycles. CLINICAL PRESENTATION Symptoms Patients with AML most often present with nonspecific symptoms that begin gradually or abruptly and are the consequence of anemia, leukocytosis, leukopenia or leukocyte dysfunction, or thrombocytopenia. Nearly half have had symptoms for ≤3 months before the leukemia was diagnosed.


InternalMed_Harrison

InternalMed_Harrison. Half of patients mention fatigue as the first symptom, but most complain of fatigue or weakness at the time of diagnosis. Anorexia and weight loss are common. Fever with or without an identifiable infection is the initial symptom in approximately 10% of patients. 681 Signs of abnormal hemostasis (bleeding, easy bruising) are noted first in 5% of patients. On occasion, bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis is the presenting symptom. Rarely patients may present with symptoms from a myeloid sarcoma that is a tumor mass consisting of myeloid blasts occurring at anatomic sites other than bone marrow. Sites involved are most commonly the skin, lymph node, gastrointestinal tract, soft tissue, and testis. This rare presentation, often characterized by chromosome aberrations [e.g., monosomy 7, trisomy 8, MLL rearrangement, inv(16), trisomy 4, t(8;21)], may precede or coincide with AML.


InternalMed_Harrison

InternalMed_Harrison. Physical Findings Fever, splenomegaly, hepatomegaly, lymphadenopathy, sternal tenderness, and evidence of infection and hemorrhage are often found at diagnosis. Significant gastrointestinal bleeding, intrapulmonary hemorrhage, or intracranial hemorrhage occurs most often in APL. Bleeding associated with coagulopathy may also occur in monocytic AML and with extreme degrees of leukocytosis or thrombocytopenia in other morphologic subtypes. Retinal hemorrhages are detected in 15% of patients. Infiltration of the gingivae, skin, soft tissues, or meninges with leukemic blasts at diagnosis is characteristic of the monocytic subtypes and those with 11q23 chromosomal abnormalities.


InternalMed_Harrison

InternalMed_Harrison. Hematologic Findings Anemia is usually present at diagnosis and can be severe. The degree varies considerably, irrespective of other hematologic findings, splenomegaly, or duration of symptoms. The anemia is usually normocytic normochromic. Decreased erythropoiesis often results in a reduced reticulocyte count, and red blood cell (RBC) sur vival is decreased by accelerated destruction. Active blood loss also contributes to the anemia.


InternalMed_Harrison

InternalMed_Harrison. The median presenting leukocyte count is about 15,000/μL. Between 25 and 40% of patients have counts <5000/μL, and 20% have counts >100,000/μL. Fewer than 5% have no detectable leukemic cells in the blood. The morphology of the malignant cell varies in different subsets. In AML, the cytoplasm often contains primary (nonspecific) granules, and the nucleus shows fine, lacy chromatin with one or more nucleoli characteristic of immature cells. Abnormal rod-shaped granules called Auer rods are not uniformly present, but when they are, myeloid lineage is virtually certain (Fig. 132-1). Poor neutrophil function may be noted functionally by impaired phagocytosis and migration and morphologically by abnormal lobulation and deficient granulation.


InternalMed_Harrison

InternalMed_Harrison. Platelet counts <100,000/μL are found at diagnosis in ~75% of patients, and about 25% have counts <25,000/μL. Both morphologic and functional platelet abnormalities can be observed, including large and bizarre shapes with abnormal granulation and inability of platelets to aggregate or adhere normally to one another.


InternalMed_Harrison

InternalMed_Harrison. Pretreatment Evaluation Once the diagnosis of AML is suspected, a rapid evaluation and initiation of appropriate therapy should follow. In addition to clarifying the subtype of leukemia, initial studies should evaluate the overall functional integrity of the major organ systems, including the cardiovascular, pulmonary, hepatic, and renal systems (Table 132-4). Factors that have prognostic significance, either for achieving CR or for predicting the duration of CR, should also be assessed before initiating treatment, including cytogenetics and molecular markers (see above). Leukemic cells should be obtained from all patients and cryopreserved for future use as new tests and therapeutics become available. All patients should be evaluated for infection.


InternalMed_Harrison

InternalMed_Harrison. Most patients are anemic and thrombocytopenic at presentation. Replacement of the appropriate blood components, if necessary, should begin promptly. Because qualitative platelet dysfunction or the presence of an infection may increase the likelihood of bleeding, evidence of hemorrhage justifies the immediate use of platelet transfusion, even if the platelet count is only moderately decreased. About 50% of patients have a mild to moderate elevation of serum uric acid at presentation. Only 10% have marked elevations, but renal precipitation of uric acid and the nephropathy that may result is a serious but uncommon complication. The initiation of chemotherapy may aggravate hyperuricemia, and patients are usually started immediately on allopurinol and hydration at diagnosis. Rasburicase (recombinant


InternalMed_Harrison

InternalMed_Harrison. FIGURE 132-1 Morphology of acute myeloid leukemia (AML) cells. A. Uniform population of primitive myeloblasts with immature chromatin, nucleoli in some cells, and primary cytoplasmic granules. B. Leukemic myeloblast containing an Auer rod. C. Promyelocytic leukemia cells with prominent cytoplasmic primary granules. D. Peroxidase stain shows dark blue color characteristic of peroxidase in granules in AML. uric oxidase) is also useful for treating uric acid nephropathy and often can normalize the serum uric acid level within hours with a single dose of treatment. The presence of high concentrations of lysozyme, a marker for monocytic differentiation, may be etiologic in renal tubular dysfunction, which could worsen other renal problems that arise during the initial phases of therapy.


InternalMed_Harrison

InternalMed_Harrison. Treatment of the newly diagnosed patient with AML is usually divided into two phases, induction and postremission management (Fig. 132-2). The initial goal is to induce CR. Once CR is obtained, further therapy must be used to prolong survival and achieve cure. The initial induction treatment and subsequent postremission therapy are often chosen based on the patient’s age. Intensifying therapy with traditional chemotherapy agents such as cytarabine and anthracyclines in younger patients (<60 years) appears to increase the cure rate of AML. In older patients, the benefit of intensive therapy is controversial; novel approaches for selecting patients predicted to be responsive to treatment and new therapies are being pursued.


InternalMed_Harrison

InternalMed_Harrison. The most commonly used CR induction regimens (for patients other than those with APL) consist of combination chemotherapy with cytarabine and an anthracycline (e.g., daunorubicin, idarubicin, mitoxantrone). Cytarabine is a cell cycle S-phase–specific antimetabolite that becomes phosphorylated intracellularly to an active triphosphate form that interferes with DNA synthesis. Anthracyclines are DNA intercalators. Their primary mode of action is thought to be inhibition of topoisomerase II, leading to DNA breaks.


InternalMed_Harrison

InternalMed_Harrison. In younger adults (age <60 years), cytarabine is used either at standard dose (100–200 mg/m2) administered as a continuous intravenous infusion for 7 days or higher dose (2 g/m2) administered intravenously every 12 h for 6 days. With standard-dose cytarabine, anthracycline therapy generally consists of daunorubicin (60–90 mg/m2) or idarubicin (12 mg/m2) intravenously on days 1, 2, and 3 (the 7 and 3 regimen). Other agents can be added (i.e., cladribine) when 60 mg/m2 of daunorubicin is used.


InternalMed_Harrison

InternalMed_Harrison. High-dose cytarabine-based regimens have also been shown to induce high CR rates. When given in high doses, higher intracellular levels of cytarabine may be achieved, thereby saturating the cytarabine-inactivating enzymes and increasing the intracellular levels of 1-β-D-arabinofuranylcytosine-triphosphate, the active metabolite incorporated into DNA. Thus, higher doses of cytarabine may increase the inhibition of DNA synthesis and thereby overcome resistance to standard-dose cytarabine. With high-dose cytarabine, daunorubicin 60 mg/m2 or idarubicin 12 mg/m2 is generally used. The hematologic toxicity of high-dose cytarabine-based induction regimens has typically been greater than that associated with 7 and 3 regimens. Toxicity with high-dose cytarabine also includes pulmonary toxicity and significant and occasionally irreversible


InternalMed_Harrison

InternalMed_Harrison. Increasing fatigue or decreased exercise tolerance (anemia) Excess bleeding or bleeding from unusual sites (DIC, thrombocytopenia) Fevers or recurrent infections (neutropenia) Headache, vision changes, nonfocal neurologic abnormalities (CNS leukemia or bleed) Early satiety (splenomegaly) Family history of AML (Fanconi, Bloom, or Kostmann syndromes or ataxia-telangiectasia) History of cancer (exposure to alkylating agents, radiation, topoisomerase II inhibitors) Occupational exposures (radiation, benzene, petroleum products, paint, smoking, pesticides)


InternalMed_Harrison

InternalMed_Harrison. Performance status (prognostic factor) Ecchymosis and oozing from IV sites (DIC, possible acute promyelocytic leukemia) Fever and tachycardia (signs of infection) Papilledema, retinal infiltrates, cranial nerve abnormalities (CNS leukemia) Poor dentition, dental abscesses Gum hypertrophy (leukemic infiltration, most common in monocytic leukemia) Skin infiltration or nodules (leukemia infiltration, most common in monocytic leukemia) Lymphadenopathy, splenomegaly, hepatomegaly Back pain, lower extremity weakness [spinal granulocytic sarcoma, most likely in t(8;21) patients]


InternalMed_Harrison

InternalMed_Harrison. CBC with manual differential cell count Chemistry tests (electrolytes, creatinine, BUN, calcium, phosphorus, uric acid, hepatic enzymes, bilirubin, LDH, amylase, lipase) Clotting studies (prothrombin time, partial thromboplastin time, fibrinogen, D-dimer) Viral serologies (CMV, HSV-1, varicella-zoster) RBC type and screen HLA typing for potential allogeneic HSCT Bone marrow aspirate and biopsy (morphology, cytogenetics, flow cytometry, molecular studies for NPM1 and CEBPA mutations and FLT3-ITD) Cryopreservation of viable leukemia cells Myocardial function (echocardiogram or MUGA scan) PA and lateral chest radiograph Placement of central venous access device Dental evaluation (for those with poor dentition) Lumbar puncture (for those with symptoms of CNS involvement) Screening spine MRI (for patients with back pain, lower extremity weakness, paresthesias) Social work referral for patient and family psychosocial support


InternalMed_Harrison

InternalMed_Harrison. Provide patients with information regarding their disease, financial counseling, and support group contacts Abbreviations: AML, acute myeloid leukemia; BUN, blood urea nitrogen; CBC, complete blood count; CMV, cytomegalovirus; CNS, central nervous system; DIC, disseminated intravascular coagulation; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplantation; HSV, herpes simplex virus; IV, intravenous; LDH, lactate dehydrogenase; MRI, magnetic reso nance imaging; MUGA, multigated acquisition; PA, posteroanterior; RBC, red blood (cell) count.


InternalMed_Harrison

InternalMed_Harrison. cerebellar toxicity. All patients treated with high-dose cytarabine must be closely monitored for cerebellar toxicity. Full cerebellar testing should be performed before each dose, and further high-dose cytarabine should be withheld if evidence of cerebellar toxicity develops. This toxicity occurs more commonly in patients with renal impairment and in those older than age 60 years. The increased toxicity observed with high-dose cytarabine has limited the use of this therapy in older AML patients.


InternalMed_Harrison

InternalMed_Harrison. Incorporation of novel and molecular targeting agents into these regimens is currently under investigation. For patients with FLT3ITD AML, trials with tyrosine kinase inhibitors are ongoing. Patients with CBF AML may benefit from the combination of gemtuzumab ozogamicin, a monoclonal CD33 antibody linked to the cytotoxic agent calicheamicin, with induction and consolidation chemotherapies. This agent, initially approved for older patients with relapsed disease, has been withdrawn from the U.S. market at the request of the U.S. Food and Drug Administration due to concerns about the product’s toxicity, including myelosuppression, infusion toxicity, and venoocclusive disease and the clinical benefit of the initially recommended higher doses. However, the aforementioned recent results are encouraging and support the reintroduction of this agent into the therapeutic armamentarium for AML.


InternalMed_Harrison

InternalMed_Harrison. In older patients (age ≥60 years), the outcome is generally poor likely due to a higher induction treatment–related mortality rate and frequency of resistant disease, especially in patients with prior hematologic disorders (MDS or myeloproliferative syndromes) or who have received chemotherapy treatment for another malignancy or harbor cytogenetic and genetic abnormalities that adversely impact on clinical outcome. These patients should be considered for clinical trials. Alternatively, older patients can be also treated with the 7 and 3 regimen with standard-dose cytarabine and idarubicin (12 mg/m2), daunorubicin (45–90 mg/m2), or mitoxantrone (12 mg/ m2). For patients older than 65 years, higher dose daunorubicin (90 mg/m2) has not shown benefit due to the increased toxicity and is not recommended. The combination of gemtuzumab ozogamicin with chemotherapy reduces the risk of relapse for patients age 50–70 years with previously untreated AML. Finally, older patients may be considered


InternalMed_Harrison

InternalMed_Harrison. The combination of gemtuzumab ozogamicin with chemotherapy reduces the risk of relapse for patients age 50–70 years with previously untreated AML. Finally, older patients may be considered for single-agent therapies with clofarabine or hypomethylating agents (i.e., 5-azacitidine or decitabine). The latter are often used for patients unfit for more intensive therapies.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis AML Previously untreated CBF AML: t(8;21) or inv(16) or t(16;16) Low risk normal cytogenetics (CEBPA double mutations or NPM1 mutations without FLT3-ITD) High risk normal cytogenetics (FLT3-ITD and/or NPM1 wild type) and High risk abnormal cytogenetics Salvage treatment Patient candidate for allogeneic HSCT and has suitable donor Yes: Allogeneic HSCT No: Investigational therapy If CR: investigational therapy If CR, consolidation therapy: Allogeneic HSCT If CR: Investigational molecular targeted therapy If CR, consolidation therapy: High-dose cytarabine or autologous HSCT If CR: Investigational molecular targeted therapy If CR, consolidation therapy: High-dose cytarabine Investigational therapy Induction therapy: Daunorubicin+ cytarabine-based regimen Induction therapy: Daunorubicin+ cytarabine-based regimen Induction therapy: Daunorubicin+ cytarabine-based regimen Investigational molecular targeted therapy Investigational molecular targeted therapy Either option acceptable


InternalMed_Harrison

InternalMed_Harrison. cytarabine-based regimen Induction therapy: Daunorubicin+ cytarabine-based regimen Investigational molecular targeted therapy Investigational molecular targeted therapy Either option acceptable Either option acceptable Either option acceptable Refractory or relapsed Refractory or relapsed


InternalMed_Harrison

InternalMed_Harrison. FIGURE 132-2 Flow chart for the therapy of newly diagnosed acute myeloid leukemia (AML). For all forms of AML except acute promyelocytic leukemia (APL), standard therapy includes a regimen based on a 7-day continuous infusion of cytarabine (100–200 mg/m2 per day) and a 3-day course of daunorubicin (60–90 mg/m2 per day) with or without additional drugs. Idarubicin (12–13 mg/m2 per day) could be used in place of daunorubicin (not shown). Patients who achieve complete remission (CR) undergo postremission consolidation therapy, including sequential courses of high-dose cytarabine, autologous hematopoietic stem cell transplantation (HSCT), allogeneic HSCT, or novel therapies, based on their predicted risk of relapse (i.e., risk-stratified therapy). Patients with APL (see text for treatment) usually receive tretinoin and arsenic trioxide–based regimens with or without anthracycline-based chemotherapy and possibly maintenance with tretinoin. CBF, core binding factor; ITD, internal tandem


InternalMed_Harrison

InternalMed_Harrison. usually receive tretinoin and arsenic trioxide–based regimens with or without anthracycline-based chemotherapy and possibly maintenance with tretinoin. CBF, core binding factor; ITD, internal tandem duplication.


InternalMed_Harrison

InternalMed_Harrison. After one cycle of the 7 and 3 chemotherapy induction regimen, if persistence of leukemia is documented, the patient is usually retreated with the same agents (cytarabine and the anthracycline) for 5 and 2 days, respectively. Our recommendation, however, is to consider changing therapy in this setting. Induction of a durable first CR is critical to long-term disease-free survival in AML. However, without further therapy, virtually all patients experience relapse. Thus, postremission therapy is designed to eradicate residual leukemic cells to prevent relapse and prolong survival. The type of postremission therapy in AML is often based on age and cytogenetic and molecular risk.


InternalMed_Harrison

InternalMed_Harrison. For younger patients, most studies include intensive chemotherapy and allogeneic or autologous hematopoietic stem cell transplantation (HSCT). In the postremission setting, high-dose cytarabine for three to four cycles is more effective than standard-dose cytarabine. The Cancer and Leukemia Group B (CALGB), for example, compared the duration of CR in patients randomly assigned after remission to four cycles of high (3 g/m2, every 12 h on days 1, 3, and 5), intermediate (400 mg/m2 for 5 days by continuous infusion), or standard (100 mg/m2 per day for 5 days by continuous infusion) doses of cytarabine. A dose-response effect for cytarabine in patients with AML who were age ≤60 years was demonstrated. High-dose cytarabine significantly prolonged CR and increased the fraction cured in patients with favorable [t(8;21) and inv(16)] and normal cytogenetics, but it had no significant effect on patients with other abnormal karyotypes. As discussed, high-dose cytarabine has increased toxicity


InternalMed_Harrison

InternalMed_Harrison. with favorable [t(8;21) and inv(16)] and normal cytogenetics, but it had no significant effect on patients with other abnormal karyotypes. As discussed, high-dose cytarabine has increased toxicity in older patients. Therefore, in this age group, for patients without CBF AML, exploration of attenuated chemotherapy regimens has been pursued. However, because the outcome of older patients is poor, allogeneic HSCT, when feasible, should be strongly considered. Postremission therapy is also a setting for introduction of new agents (Table 132-5).


InternalMed_Harrison

InternalMed_Harrison. Autologous HSCT preceded by one to two cycles of high-dose cytarabine is also an option for intensive consolidation therapy. Autologous HSCT has been generally applied to AML patients in the context of a clinical trial or when the risk of repetitive intensive chemotherapy represents a higher risk than the autologous HSCT (e.g., in patients with severe platelet alloimmunization) or when other factors including patient age, comorbid conditions, and fertility are considered.


InternalMed_Harrison

InternalMed_Harrison. Allogeneic HSCT is used in patients age <70–75 years with a human leukocyte antigen (HLA)-compatible donor who have high-risk cytogenetics. Selected high-risk patients are also considered for alternative donor transplants (e.g., mismatched unrelated, haploidentical related, and unrelated umbilical cord donors). In patients with CN-AML and high-risk molecular features such as FLT3-ITD, allogeneic HSCT is best applied in the context of clinical trials because the impact of aggressive therapy on outcome is unknown. For older patients, exploration of reduced-intensity allogeneic HSCT has been pursued.


InternalMed_Harrison

InternalMed_Harrison. Trials comparing intensive chemotherapy and autologous and allogeneic HSCT have shown improved duration of remission with allogeneic HSCT compared to autologous HSCT or chemotherapy alone. However, overall survival is generally not different; the improved disease control with allogeneic HSCT is erased by the increase in fatal toxicity. In fact, relapse following allogeneic HSCT occurs in only a small fraction of patients, but treatment-related toxicity is relatively high; complications include venoocclusive disease, graft-versus-host disease (GVHD), and infections. Autologous HSCT can be administered in young and older patients and uses the same preparative regimens. Patients subsequently receive their own stem cells collected while in remission. The toxicity is relatively low with Class of Drugs Examples of Agents in Class Inhibitors of Mutant proteins Tyrosine kinase inhibitors Dasatinib, midostaurin, quizartinib, sorafenib IDH2 mutation inhibitor AG-221


InternalMed_Harrison

InternalMed_Harrison. Class of Drugs Examples of Agents in Class Inhibitors of Mutant proteins Tyrosine kinase inhibitors Dasatinib, midostaurin, quizartinib, sorafenib IDH2 mutation inhibitor AG-221 Inhibitors of Cell Proliferation Inhibitors of Protein Synthesis and Degradation HSP-90 antagonists 17-Allylaminogeldanamycin (17-AAG), DMAG, or derivatives Nucleoside analogues Clofarabine, troxacitabine, elacytarabine, sapacitabine Compounds with Immuno-Mediated Mechanisms Antibodies CSL362 (anti-CD123), anti-CD33 (SGN33), anti-KIR Immunomodulatory Lenalidomide, interleukin 2, histamine dihydrochloride autologous HSCT (5% mortality rate), but the relapse rate is higher than with allogeneic HSCT, due to the absence of the graft-versusleukemia (GVL) effect seen with allogeneic HSCT and possible contamination of the autologous stem cells with residual tumor cells.


InternalMed_Harrison

InternalMed_Harrison. Prognostic factors may ultimately help to select the appropriate postremission therapy in patients in first CR. Our approach includes allogeneic HSCT in first CR for patients without favorable cytogenetics or genotype (e.g., patients who do not have CEBPA biallelic mutations or NPM1 mutations without FLT3-ITD) and/or with other poor risk factors (e.g., an antecedent hematologic disorder or failure to attain remission with a single induction course). If a suitable HLA donor does not exist, investigational therapeutic approaches are considered. Indeed, postremission therapy is also a setting for introduction of new agents (Table 132-5). Because FLT3-ITD can be targeted with emerging novel inhibitors, patients with this molecular abnormality should be considered for clinical trials with these agents whenever possible.


InternalMed_Harrison

InternalMed_Harrison. Patients with the favorable CBF AML [i.e., t(8;21), inv(16), or t(16;16)] are treated with repetitive doses of high-dose cytarabine, which offers a high frequency of cure without the morbidity of transplant. Among AML patients with t(8;21) and inv(16), those with KIT mutations, who have a worse prognosis, may be considered for novel investigational studies, including tyrosine kinase inhibitors. The inclusion of gemtuzumab ozogamicin in induction and consolidation chemotherapy-based treatment has been reported to be beneficial in this subset of patients.


InternalMed_Harrison

InternalMed_Harrison. For patients in morphologic CR, immunophenotyping to detect minute populations of blasts or sensitive molecular assays (e.g., reverse transcriptase polymerase chain reaction [RT-PCR]) to detect AML-associated molecular abnormalities (e.g., NPM1 mutation, the CBF AML RUNX1/RUNX1T1 and CBFB/MYH11 transcripts, the APL PML/RARA transcript), and the less sensitive metaphase cytogenetics or interphase cytogenetics by fluorescence in situ hybridization (FISH) to detect AML-associated cytogenetic aberrations, can be performed to assess whether clinically meaningful minimal residual disease (MRD) is present at sequential time points during 685 or after treatment. Detection of MRD may be a reliable discriminator between patients who will continue in CR and those who are destined to experience disease recurrence and therefore require early therapeutic intervention before clinical relapse occurs. Although assessment of MRD in bone marrow and/or blood during CR is routinely used in the clinic to


InternalMed_Harrison

InternalMed_Harrison. recurrence and therefore require early therapeutic intervention before clinical relapse occurs. Although assessment of MRD in bone marrow and/or blood during CR is routinely used in the clinic to anticipate clinical relapse and initiate timely salvage treatment for APL patients, for other cytogenetic and molecular subtypes of AML, this is an area of current investigation.


InternalMed_Harrison

InternalMed_Harrison. Measures geared to supporting patients through several weeks of neutropenia and thrombocytopenia are critical to the success of AML therapy. Patients with AML should be treated in centers expert in providing supportive measures. Multilumen right atrial catheters should be inserted as soon as patients with newly diagnosed AML have been stabilized. They should be used thereafter for administration of intravenous medications and transfusions, as well as for blood drawing.


InternalMed_Harrison

InternalMed_Harrison. Adequate and prompt blood bank support is critical to therapy of AML. Platelet transfusions should be given as needed to maintain a platelet count ≥10,000/μL. The platelet count should be kept at higher levels in febrile patients and during episodes of active bleeding or DIC. Patients with poor posttransfusion platelet count increments may benefit from administration of platelets from HLA-matched donors. RBC transfusions should be administered to keep the hemoglobin level >80 g/L (8 g/dL) in the absence of active bleed ing, DIC, or congestive heart failure, which require higher hemoglobin levels. Blood products leukodepleted by filtration should be used to avert or delay alloimmunization as well as febrile reactions. Blood products should also be irradiated to prevent transfusion-associated GVHD. Cytomegalovirus (CMV)-negative blood products should be used for CMV-seronegative patients who are potential candidates for allogeneic HSCT. Leukodepleted products are also effective for


InternalMed_Harrison

InternalMed_Harrison. GVHD. Cytomegalovirus (CMV)-negative blood products should be used for CMV-seronegative patients who are potential candidates for allogeneic HSCT. Leukodepleted products are also effective for these patients if CMV-negative products are not available.


InternalMed_Harrison

InternalMed_Harrison. Neutropenia (neutrophils <500/μL or <1000/μL and predicted to decline to <500/μL over the next 48 h) can be part of the initial presentation and/or a side effect of the chemotherapy treatment in AML patients. Thus, infectious complications remain the major cause of morbidity and death during induction and postremission chemotherapy for AML. Antibacterial (i.e., quinolones) and antifungal (i.e., posaconazole) prophylaxis in the absence of fever is likely to be beneficial. For patients who are herpes simplex virus or varicellazoster seropositive, antiviral prophylaxis should be initiated (e.g., acyclovir, valacyclovir).


InternalMed_Harrison

InternalMed_Harrison. Fever develops in most patients with AML, but infections are documented in only half of febrile patients. Early initiation of empirical broad-spectrum antibacterial and antifungal antibiotics has significantly reduced the number of patients dying of infectious complications (Chap. 104). An antibiotic regimen adequate to treat gram-negative organisms should be instituted at the onset of fever in a neutropenic patient after clinical evaluation, including a detailed physical examination with inspection of the indwelling catheter exit site and a perirectal examination, as well as procurement of cultures and radiographs aimed at documenting the source of fever. Specific antibiotic regimens should be based on antibiotic sensitivity data obtained from the institution at which the patient is being treated. Acceptable regimens for empiric antibiotic therapy include monotherapy with imipenem-cilastatin, meropenem, piperacillin/ tazobactam, or an extended-spectrum antipseudomonal cephalosporin


InternalMed_Harrison

InternalMed_Harrison. treated. Acceptable regimens for empiric antibiotic therapy include monotherapy with imipenem-cilastatin, meropenem, piperacillin/ tazobactam, or an extended-spectrum antipseudomonal cephalosporin (cefepime or ceftazidime). The combination of an aminoglycoside with an antipseudomonal penicillin (e.g., piperacillin) or an aminoglycoside in combination with an extended-spectrum antipseudomonal cephalosporin should be considered in complicated or resistant cases. Aminoglycosides should be avoided if possible in patients with renal insufficiency. Empirical vancomycin should be added in neutropenic patients with catheter-related infections, blood cultures positive for gram-positive bacteria before final identification and susceptibility testing, hypotension or shock, 686 or known colonization with penicillin/cephalosporin-resistant pneumococci or methicillin-resistant Staphylococcus aureus. In special situations where decreased susceptibility to vancomycin, vancomycin-resistant organisms,


InternalMed_Harrison

InternalMed_Harrison. with penicillin/cephalosporin-resistant pneumococci or methicillin-resistant Staphylococcus aureus. In special situations where decreased susceptibility to vancomycin, vancomycin-resistant organisms, or vancomycin toxicity is documented, other options including linezolid, daptomycin, and quinupristin/ dalfopristin need to be considered. Caspofungin (or a similar echinocandin), voriconazole, or liposomal amphotericin B should be considered for antifungal treatment if fever persists for 4–7 days following initiation of empiric antibiotic therapy. Amphotericin B has long been used for antifungal therapy. Although liposomal formulations have improved the toxicity profile of this agent, its use has been limited to situations with high risk of or documented mold infections. Caspofungin has been approved for empiric antifungal treatment. Voriconazole has also been shown to be equivalent in efficacy and less toxic than amphotericin B. Antibacterial and antifungal antibiotics should be


InternalMed_Harrison

InternalMed_Harrison. been approved for empiric antifungal treatment. Voriconazole has also been shown to be equivalent in efficacy and less toxic than amphotericin B. Antibacterial and antifungal antibiotics should be continued until patients are no longer neutropenic, regardless of whether a specific source has been found for the fever. Recombinant hematopoietic growth factors have been incorporated into clinical trials in AML. These trials have been designed to lower the infection rate after chemotherapy. Both G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) have reduced the median time to neutrophil recovery. This accelerated rate of neutrophil recovery, however, has not generally translated into significant reductions in infection rates or shortened hospitalizations. In most randomized studies, both G-CSF and GM-CSF have failed to improve the CR rate, disease-free survival, or overall survival. Although receptors for both G-CSF and GM-CSF are present on AML blasts, therapeutic


InternalMed_Harrison

InternalMed_Harrison. studies, both G-CSF and GM-CSF have failed to improve the CR rate, disease-free survival, or overall survival. Although receptors for both G-CSF and GM-CSF are present on AML blasts, therapeutic efficacy is neither enhanced nor inhibited by these agents. The use of growth factors as supportive care for AML patients is controversial. We favor their use in elderly patients with complicated courses, those receiving intensive postremission regimens, patients with uncontrolled infections, or those participating in clinical trials.


InternalMed_Harrison

InternalMed_Harrison. With the 7 and 3 regimen, 65–75% of younger and 50–60% of older patients with primary AML achieve CR. Two-thirds achieve CR after a single course of therapy, and one-third require two courses. Of patients who do not achieve CR, approximately 50% have a drug-resistant leukemia, and 50% do not achieve CR because of fatal complications of bone marrow aplasia or impaired recovery of normal stem cells. Patients with refractory disease after induction should be considered for salvage treatments, preferentially on clinical trials, before receiving allogeneic HSCT usually administered in patients who achieve a disease-free status. Because these patients are usually not cured even if they achieve second CR with salvage chemotherapy, allogeneic HSCT is a necessary therapeutic step.


InternalMed_Harrison

InternalMed_Harrison. In patients who relapse after achieving CR, the length of first CR is predictive of response to salvage chemotherapy treatment; patients with longer first CR (>12 months) generally relapse with drug-sensitive disease and have a higher chance of attaining a CR, even with the same chemotherapeutic agents used for first remission induction. Whether initial CR was achieved with one or two courses of chemotherapy and the type of postremission therapy may also predict achievement of second CR. Similar to patients with refractory disease, patients with relapsed disease are rarely cured by the salvage chemotherapy treatments. Therefore, patients who eventually achieve a second CR and are eligible for allogeneic HSCT should be transplanted.


InternalMed_Harrison

InternalMed_Harrison. Because achievement of a second CR with routine salvage therapies is relatively uncommon, especially in patients who relapse rapidly after achievement of first CR (<12 months), these patients and those lacking HLA-compatible donors or who are not candidates for allogeneic HSCT should be considered for innovative approaches on clinical trials (Table 132-5). The discovery of novel gene mutations and mechanisms of leukemogenesis that might represent actionable therapeutic targets has prompted the development of new targeting agents. In addition to kinase inhibitors for FLT3and KIT-mutated AML, other compounds targeting the aberrant activity of mutant proteins (e.g., IDH2 inhibitors) or biologic mechanisms deregulating epigenetics (e.g., histone deacetylase and DNA methyltransferase inhibitors), cell proliferation (e.g., farnesyl transferase inhibitors), protein synthesis (e.g., aminopeptide inhibitors) and folding (e.g., heat shock protein inhibitors), and ubiquitination, or with novel


InternalMed_Harrison

InternalMed_Harrison. cell proliferation (e.g., farnesyl transferase inhibitors), protein synthesis (e.g., aminopeptide inhibitors) and folding (e.g., heat shock protein inhibitors), and ubiquitination, or with novel cytotoxic mechanisms (e.g., clofarabine, sapacitabine), are being tested in clinical trials. Furthermore, approaches with antibodies targeting commonly expressed leukemia blasts (e.g., CD33) or leukemia initiating cells (e.g., CD123) and immunomodulatory agents (e.g., lenalidomide) are also under investigation. Once these compounds have demonstrated safety and activity as single agents, investigation of combinations with other molecular targeting compounds and/or chemotherapy should be pursued.


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InternalMed_Harrison. APL is a highly curable subtype of AML, and approximately 85% of these patients achieve long-term survival with current approaches. APL has long been shown to be responsive to cytarabine and daunorubicin, but previously patients treated with these drugs alone frequently died from DIC induced by the release of granule components by the chemotherapy-treated leukemia cells. However, the prognosis of APL patients has changed dramatically from adverse to favorable with the introduction of tretinoin, an oral drug that induces the differentiation of leukemic cells bearing the t(15;17), where disruption of the RARA gene encoding a retinoid acid receptor occurs. Tretinoin decreases the frequency of DIC but produces another complication called the APL differentiation syndrome. Occurring within the first 3 weeks of treatment, it is characterized by fever, fluid retention, dyspnea, chest pain, pulmonary infiltrates, pleural and pericardial effusions, and hypoxemia. The syndrome is related to


InternalMed_Harrison

InternalMed_Harrison. the first 3 weeks of treatment, it is characterized by fever, fluid retention, dyspnea, chest pain, pulmonary infiltrates, pleural and pericardial effusions, and hypoxemia. The syndrome is related to adhesion of differentiated neoplastic cells to the pulmonary vasculature endothelium. Glucocorticoids, chemotherapy, and/ or supportive measures can be effective for management of the APL differentiation syndrome. Temporary discontinuation of tretinoin is necessary in cases of severe APL differentiation syndrome (i.e., patients developing renal failure or requiring admission to the intensive care unit due to respiratory distress). The mortality rate of this syndrome is about 10%.


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InternalMed_Harrison. Tretinoin (45 mg/m2 per day orally until remission is documented) plus concurrent anthracycline-based (i.e., idarubicin or daunorubicin) chemotherapy appears to be among the most effective treatment for APL, leading to CR rates of 90–95%. The role of cytarabine in APL induction and consolidation is controversial. The addition of cytarabine, although not demonstrated to increase the CR rate, seemingly decreases the risk for relapse. Following achievement of CR, patients should receive at least two cycles of anthracyclinebased chemotherapy.


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InternalMed_Harrison. Arsenic trioxide has significant antileukemic activity and is being explored as part of initial treatment in clinical trials of APL. In a randomized trial, arsenic trioxide improved outcome if used after achievement of CR and before consolidation therapy with anthracycline-based chemotherapy. Patients receiving arsenic trioxide are at risk of APL differentiation syndrome, especially when it is administered during induction or salvage treatment after disease relapse. In addition, arsenic trioxide may prolong the QT interval, increasing the risk of cardiac arrhythmias.


InternalMed_Harrison

InternalMed_Harrison. Given the progress made in APL resulting in high cure rates, in recent years the goal has been to identify patients with low risk of relapse (i.e., those presenting with a leukocyte count ≤10,000/μL) where attempts are being made to decrease the amount of therapy administered and to identify patients at greatest risk of relapse (i.e., those presenting with a leukocyte count ≥10,000/μL) where new approaches can be developed to increase cure. A study compared the gold standard (tretinoin plus chemotherapy) in newly diagnosed non-high-risk APL with a chemotherapy-free combination of tretinoin and arsenic trioxide. An equivalent outcome was demonstrated between the two arms, and the chemotherapy-free regimen will likely become a new standard for non-high-risk APL patients. Combinations of tretinoin, arsenic trioxide, and/or chemotherapy and/or gemtuzumab ozogamicin have shown favorable responses in high-risk APL patients at diagnosis.


InternalMed_Harrison

InternalMed_Harrison. Combinations of tretinoin, arsenic trioxide, and/or chemotherapy and/or gemtuzumab ozogamicin have shown favorable responses in high-risk APL patients at diagnosis. Assessment of residual disease by RT-PCR amplification of the t(15;17) chimeric gene product PML-RARA following the final cycle of chemotherapy is an important step in the management of APL patients. Disappearance of the signal is associated with long-term disease-free survival; its persistence documented by two consecutive tests performed 2 weeks apart invariably predicts relapse. Sequential monitoring of RT-PCR for PML-RARA is now considered standard for postremission monitoring of APL, especially in high-risk patients.


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InternalMed_Harrison. The benefit from maintenance therapy with tretinoin has been documented in some studies and not in others. Thus, the use of tretinoin depends on which regimen has been used for induction and consolidation treatment and the risk category of the patients, with those with high-risk disease seemingly benefiting the most from maintenance therapy. Patients in molecular, cytogenetic, or clinical relapse should be salvaged with arsenic trioxide with or without tretinoin; it produces meaningful responses in up to 85% of patients and can be followed by autologous or, less frequently, especially if RT-PCR positive for PML-RARA, allogeneic HSCT.


InternalMed_Harrison

InternalMed_Harrison. Chronic Myeloid Leukemia Hagop Kantarjian, Jorge Cortes Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder. The disease is driven by the BCR-ABL1 chimeric gene prod-uct, a constitutively active tyrosine kinase, resulting from a reciprocal balanced translocation between the long arms of chromosomes 9 and 133 22, t(9;22) (q34;q11.2), cytogenetically detected as the Philadelphia chromosome (Ph) (Fig. 133-1). Untreated, the course of CML may be biphasic or triphasic, with an early indolent or chronic phase, followed often by an accelerated phase and a terminal blastic phase. Before the era of selective BCR-ABL1 tyrosine kinase inhibitors (TKIs), the median survival in CML was 3–7 years, and the 10-year survival rate was 30% or less. Introduced into CML therapy in 2000, TKIs have revolutionized the treatment, natural history, and prognosis of CML. Today, the estimated 10-year survival rate with imatinib mesylate, the first BCR-ABL1 TKI approved, is 85%. Allogeneic


InternalMed_Harrison

InternalMed_Harrison. TKIs have revolutionized the treatment, natural history, and prognosis of CML. Today, the estimated 10-year survival rate with imatinib mesylate, the first BCR-ABL1 TKI approved, is 85%. Allogeneic stem cell transplantation (SCT), a curative but risky treatment approach, is now offered as secondor third-line therapy after failure of TKIs.


InternalMed_Harrison

InternalMed_Harrison. CML accounts for 15% of all cases of leukemia. There is a slight male preponderance (male:female ratio 1.6:1). The median age at diagnosis is 55–65 years. It is uncommon in children; only 3% of patients with CML are younger than 20 years. CML incidence increases slowly with age, with a steeper increase after the age of 40–50 years. The annual incidence of CML is 1.5 cases per 100,000 individuals. In the United States, this translates into 4500–5000 new cases per year. The incidence of CML has not changed over several decades. By extrapolation, the worldwide annual incidence of CML is about 100,000 cases. With a median survival of 6 years before 2000, the disease prevalence in the United States was 20,000–30,000 cases. With TKI therapy, the annual mortality has been reduced from 10–20% to about 2%. Therefore, the prevalence of CML in the United States is expected to continue to increase (about 80,000 in 2013) and reach a plateau of approximately 180,000 cases around 2030. The worldwide


InternalMed_Harrison

InternalMed_Harrison. 2%. Therefore, the prevalence of CML in the United States is expected to continue to increase (about 80,000 in 2013) and reach a plateau of approximately 180,000 cases around 2030. The worldwide prevalence will depend on the treatment penetration of TKIs and their effect on reduction of worldwide annual mortality. Ideally, with full TKI treatment penetration, the worldwide prevalence should plateau at 35 times the incidence, or around 3 million patients.


InternalMed_Harrison

InternalMed_Harrison. There are no familial associations in CML. The risk of developing CML is not increased in monozygotic twins or in relatives of patients. No etiologic agents are incriminated, and no associations exist with exposures to benzene or other toxins, fertilizers, insecticides, or viruses. CML is not a frequent secondary leukemia following therapy of other cancers with alkylating agents and/or radiation. Exposure to ionizing radiation (e.g., nuclear accidents, radiation treatment for ankylosing spondylitis or cervical cancer) has increased the risk of CML, which peaks at 5–10 years after exposure and is dose-related. The median time to development of CML among atomic bomb survivors was 6.3 years. Following the Chernobyl accident, the incidence of CML did not increase, suggesting that only large doses of radiation can cause CML. Because of adequate protection, the risk of CML is not increased in individuals working in the nuclear industry or among radiologists in recent times.


InternalMed_Harrison

InternalMed_Harrison. The t(9;22) (q34;q11.2) is present in more than 90% of classical CML cases. It results from a balanced reciprocal translocation between the long arms of chromosomes 9 and 22. It is present in hematopoietic cells (myeloid, erythroid, megakaryocytes, and monocytes; less often mature B lymphocytes; rarely mature T lymphocytes, but not stromal cells), but not in other cells in the human body. As a result of the translocation, DNA sequences from the cellular oncogene ABL1 are translocated next to the major breakpoint cluster region (BCR) gene on chromosome 22, generating a hybrid oncogene, BCR-ABL1. This fusion gene codes for a novel oncoprotein of molecular weight 210 kDa, referred to as p210BCR-ABL1 (Fig. 133-1B). This BCR-ABL1 oncoprotein exhibits constitutive kinase activity that leads to excessive proliferation and reduced apoptosis of CML cells, endowing them with a growth advantage over their normal counterparts. Over time, normal hematopoiesis is suppressed, but normal stem cells


InternalMed_Harrison

InternalMed_Harrison. excessive proliferation and reduced apoptosis of CML cells, endowing them with a growth advantage over their normal counterparts. Over time, normal hematopoiesis is suppressed, but normal stem cells can persist and may reemerge following effective therapy, for example with TKIs. In Ph-positive acute lymphocytic leukemia (ALL) and in rare cases of CML, the breakpoint in BCR is more centromeric, in a region called the minor BCR region (mBCR). As a result, a shorter sequence of BCR is fused to ABL1, with a consequent smaller BCR-ABL1 oncoprotein, p190BCR-ABL1. When occurring in Ph-positive CML, this translocation may predict for a worse outcome. A third rare breakpoint in BCR occurs telomeric to the major BCR region and is called micro-BCR (μ-BCR). It juxtaposes a larger fragment of the BCR gene to ABL1 and produces a larger p230BCR-ABL1 oncoprotein, which is associated with a more indolent CML course.


InternalMed_Harrison

InternalMed_Harrison. The constitutive activation of BCR-ABL1 results in autophosphorylation and activation of multiple downstream pathways that modify gene transcription, apoptosis, skeletal organization, and degradation of inhibitory proteins. These transduction pathways may involve RAS, mitogenactivated protein (MAP) kinases, signal transducers and activators of transcription (STAT), phosphatidylinositol-3-kinase (PI3k), MYC, and others. These interactions are mostly mediated through tyrosine phosphorylation and require binding of BCR-ABL1 to adapter proteins such as GRB-2, CRK, CRK-like (CRK-L) protein, and Src homology containing proteins (SHC). BCR-ABL1 TKIs bind to the BCR-ABL1 kinase domain (KD), preventing the activation of transformation pathways and inhibiting downstream signaling. As a result, proliferation of CML cells is inhibited and apoptosis induced, leading to the reemergence of normal hematopoiesis. A plethora of signaling pathways have been implicated in BCR-ABL1-mediated cellular


InternalMed_Harrison

InternalMed_Harrison. proliferation of CML cells is inhibited and apoptosis induced, leading to the reemergence of normal hematopoiesis. A plethora of signaling pathways have been implicated in BCR-ABL1-mediated cellular transformation. The emerging picture is a complex and redundant transformation network. An additional layer of complexity is related to differences in signal transduction between CML differentiated cells and early progenitors. Beta-catenin, Wnt1, Foxo3a, transforming growth factor β, interleukin-6, PP2A, SIRT1, and others have been implicated in CML stem cell survival.


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InternalMed_Harrison. Experimental models have established the causal relationship between the Ph-related BCR-ABL1 molecular events and the development of CML. In animal models, expression of BCR-ABL1 in normal hematopoietic cells produced CML-like disorders or lymphoid leukemia, demonstrating the leukemogenic potential of BCR-ABL1 as a single oncogenic abnormality. q34q11.2 t(9;22)(q34;q11.2) FIGURE 133-1 A. The Philadelphia (Ph) chromosome cytogenetic abnormality. B. Breakpoints in the long arms of chromosome 9 (ABL locus) and chromosome 22 (BCR regions) result in three different BCR-ABL oncoprotein messages, p210BCR-ABL1 (most common message in chronic myeloid leukemia [CML]), p190BCR-ABL1 (present in two-thirds of patients with Ph-positive acute lymphocytic leukemia; rare in CML), and p230BCR-ABL1 (rare in CML and associated with an indolent course). (© 2013 The University of Texas MD Anderson Cancer Center.)


InternalMed_Harrison

InternalMed_Harrison. The cause of the BCR-ABL1 molecular rearrangement is unknown. Molecular techniques that detect BCR-ABL1 at a level of 1 in 108 identify this molecular abnormality in the blood of up to 25% of normal adults and 5% of infants, but 0% of cord blood samples. This suggests that BCR-ABL1 is not sufficient to cause overt CML in the overwhelming majority of individuals in whom it occurs. Because CML develops in only 1.5 of 100,000 individuals annually, it is evident that additional molecular events or poor immune recognition of the rearranged cells are needed to cause overt CML.


InternalMed_Harrison

InternalMed_Harrison. CML is defined by the presence of BCR-ABL1 abnormality in a patient with a myeloproliferative neoplasm. In some patients with a typical morphologic picture of CML, the Ph abnormality is not detectable by standard cytogenetic analysis, but fluorescence in situ hybridization (FISH) and molecular studies (polymerase chain reaction [PCR]) detect BCR-ABL1. These patients have a course similar to Ph-positive CML and respond to TKI therapy. Many of the remaining patients have atypical morphologic or clinical features and belong to other diagnostic groups, such as atypical CML or chronic myelomonocytic leukemia. These individuals do not respond to TKI therapy and have a poor prognosis with a median survival of about 2–3 years. Detection of mutations in the granulocyte colony-stimulating factor receptor (CSF3R) in chronic neutrophilic leukemia and in some cases of atypical CML and of mutations in SETBP1 in atypical CML confirmed that they are distinct entities.


InternalMed_Harrison

InternalMed_Harrison. The mechanisms associated with the transition of CML from a chronic to accelerated-blastic phase are poorly understood. They are often associated with characteristic chromosomal abnormalities such as a double Ph, trisomy 8, isochromosome 17 or deletion of 17p (loss of TP53), 20q–, and others. Molecular events associated with transformation include mutations in TP53, retinoblastoma 1 (RB1), myeloid transcriptions factors like Runx1, and cell cycle regulators like p16. A plethora of other mutations or functional abnormalities have been implicated in blastic transformation, but no unifying theme has emerged other than that BCR-ABL1 itself induces genetic instability that leads to the acquisition of additional mutations and eventually to blastic transformation. In this frame of thinking, one critical effect of TKIs is their ability to stabilize the CML genome, leading to a much reduced transformation rate. In particular, the previously observed sudden blastic transformations (i.e., abrupt


InternalMed_Harrison

InternalMed_Harrison. effect of TKIs is their ability to stabilize the CML genome, leading to a much reduced transformation rate. In particular, the previously observed sudden blastic transformations (i.e., abrupt transformation to blastic phase in a patient who had been in cytogenetic response) have become uncommon, occurring rarely in younger patients in the first 1–2 years of TKI therapy (usually sudden lymphoid blastic transformations). Sudden transformations beyond the third year of TKI therapy are rare in patients who continue on TKI therapy. Moreover, initial experience suggests that the course of CML has become significantly more indolent, even without cytogenetic responses, in patients on TKI-based therapy compared to previous experience with hydroxyurea/busulfan.


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InternalMed_Harrison. Among patients developing resistance to TKIs, several resistance mechanisms have been observed. The most clinically relevant one is the development of different ABL1 kinase domain mutations that prevent the binding of TKIs to the catalytic site (ATP binding site) of the kinase. More than 100 BCR-ABL1 mutations have now been described, many of which confer relative or absolute resistance to imatinib. This has resulted in the development of second-generation TKIs (i.e., dasatinib, nilotinib, bosutinib) and of a third-generation TKI (ponatinib) with selective efficacy against T315I, a mutation of the gatekeeper residue of the kinase that causes resistance to all other TKIs.


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InternalMed_Harrison. The presenting signs and symptoms in CML depend on the availability of and access to health care procedures, including physical exams and screening tests. In the United States, because of the easy access to health care screening and physical exams, 50–60% of patients are diagnosed on routine blood tests and have minimal symptoms at presentation, such as fatigue. In geographic locations where access to health care is more limited, patients often present with high CML burden including splenomegaly, anemia, and related symptoms (abdominal pain, weight loss, fatigue), as well as a higher frequency of high-risk CML. Presenting findings in patients diagnosed in the United States are shown in Table 133-1.


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InternalMed_Harrison. Symptoms Most patients with CML (90%) present in the indolent or chronic phase. Depending on the timing of diagnosis, patients are often asymptomatic (if the diagnosis is discovered during health care screening tests). Common symptoms, when present, are manifestations of anemia and splenomegaly. These may include fatigue, malaise, weight loss (if high leukemia burden), or early satiety and left upper quadrant pain or masses (from splenomegaly). Less common presenting findings include thrombotic or vasoocclusive events (from severe leukocytosis or thrombocytosis). These include priapism, cardiovascular complications, myocardial infarction, venous thrombosis, visual disturbances, dyspnea and pulmonary insufficiency, drowsiness, loss of coordination, confusion, or cerebrovascular accidents. Bleeding diatheses findings include retinal hemorrhages, gastrointestinal bleeding,


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InternalMed_Harrison. Cytogenetic clonal evolution other than the Philadelphia chromosome Sokal risk Low Intermediate High and others. Patients who present with, or progress to, the accelerated 689 or blastic phases have additional symptoms including unexplained fever, significant weight loss, severe fatigue, bone and joint aches, bleeding and thrombotic events, and infections.


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InternalMed_Harrison. Physical Findings Splenomegaly is the most common physical finding, occurring in 20–70% of patients depending on health care screening frequency. Other less common findings include hepatomegaly (10–20%), lymphadenopathy (5–10%), and extramedullary disease (skin or subcutaneous lesions). The latter indicates CML transformation if a biopsy confirms the presence of sheets of blasts. Other physical findings are manifestations of complications of high tumor burden described earlier (e.g., cardiovascular, cerebrovascular, bleeding). High basophil counts may be associated with histamine overproduction causing pruritus, diarrhea, flushing, and even gastrointestinal ulcers.


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InternalMed_Harrison. Hematologic and Marrow Findings In untreated CML, leukocytosis ranging from 10–500 × 109/L is common. The peripheral blood differential shows left-shifted hematopoiesis with predominance of neutrophils and the presence of bands, myelocytes, metamyelocytes, promyelocytes, and blasts (usually ≤5%). Basophils and/or eosinophils are frequently increased. Thrombocytosis is common, but thrombocytopenia is rare and, when present, suggests a worse prognosis, disease acceleration, or an unrelated etiology. Anemia is present in one-third of patients. Cyclic oscillations of counts are noted in 25% of patients without treatment. Biochemical abnormalities include a low leukocyte alkaline phosphatase score and high levels of vitamin B12, uric acid, lactic dehydrogenase, and lysozyme. The presence of unexplained and sustained leukocytosis, with or without splenomegaly, should lead to a marrow examination and cytogenetic analysis.


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InternalMed_Harrison. The bone marrow is hypercellular with marked myeloid hyperplasia and a high myeloid-to-erythroid ratio of 15–20:1. Marrow blasts are 5% or less; when higher, they carry a worse prognosis or represent acceleration (if they are ≥15%). Increased reticulin fibrosis (by Snook’s silver stain) is common, with 30–40% of patients demonstrating grade 3–4 reticulin fibrosis. This was considered adverse in the pre-TKI era. With TKI therapy, reticulin fibrosis resolves in most patients and is not an indicator of poor prognosis. Collagen fibrosis (Wright-Giemsa stain) is rare at diagnosis. Disease progression with a “spent phase” of myelofibrosis (myelophthisis, or burnt-out marrow) was common with busulfan therapy (20–30%) but is rare with TKI therapy.


InternalMed_Harrison

InternalMed_Harrison. Cytogenetic and Molecular Findings The diagnosis of CML is straightforward and depends on documenting t(9;22)(q34;q11.2), which is found in 90% of cases. This is known as the Philadelphia-chromosome abnormality (discovered in Philadelphia) and was initially identified as a shortened chromosome, later identified to be chromosome 22 (22q–) (Fig. 133-1). Some patients may have complex translocations (variant Ph) involving three or more translocations that include chromosomes 9 and 22 and one or more other chromosomes. Others may have a “masked Ph,” involving translocations between chromosome 9 and a chromosome other than 22. The prognosis of these patients and their response to TKI therapy are similar to those in patients with Ph. About 5–10% of patients may have additional chromosomal abnormalities in the Ph-positive cells. These usually involve trisomy 8, a double Ph, isochromosome 17 or 17p deletion, 20q–, or others. This is referred to as clonal evolution and was historically a sign


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InternalMed_Harrison. in the Ph-positive cells. These usually involve trisomy 8, a double Ph, isochromosome 17 or 17p deletion, 20q–, or others. This is referred to as clonal evolution and was historically a sign of adverse prognosis, particularly when trisomy 8, double Ph, or chromosome 17 abnormalities were noted.


InternalMed_Harrison

InternalMed_Harrison. Techniques such as FISH and PCR are now used to aid in the diagnosis of CML. They are more sensitive approaches to estimate the CML burden in patients on TKI therapy. They can be done on peripheral samples, and thus are less painful and more convenient. Patients with CML at diagnosis should have a FISH analysis to quantify the percentage of Ph-positive cells, if FISH is used to replace marrow cytogenetic analysis in monitoring response to therapy. FISH may not detect additional chromosomal abnormalities (clonal evolution); thus, a cytogenetic analysis is usually recommended at the time of diagnosis. The BCR-ABL1 RNA message is usually one of two variants: e13a2 (formerly b2a2) and e14a2 (formerly b3a2). About 2–5% of patients 690 may have other RNA fusion types (e.g., e1a2, e13a3, or e14a3). In these patients, the routine PCR primers may not amplify the BCR-ABL1 transcripts, thus leading to false-negative results. Therefore, molecular studies at diagnosis are important to document the


InternalMed_Harrison

InternalMed_Harrison. In these patients, the routine PCR primers may not amplify the BCR-ABL1 transcripts, thus leading to false-negative results. Therefore, molecular studies at diagnosis are important to document the type and presence of BCR-ABL1 transcripts to avoid erroneously “undetectable” BCRABL1 transcripts on follow-up studies, with the misconception of a complete molecular response. Both FISH and PCR studies can be falsely positive at low levels or falsely negative because of technical issues. Therefore, a diagnosis of CML must always rely on a marrow analysis with routine cytogenetics. The diagnostic bone marrow confirms the presence of the Ph chromosome, detects clonal evolution, i.e., chromosomal abnormalities in the Ph-positive cells (which may be prognostic), and also quantifies the percentage of marrow blasts and basophils. In 10% of patients, the percentage of marrow blasts and basophils can be significantly higher than in the peripheral blood, suggesting poorer prognosis or even disease


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InternalMed_Harrison. of marrow blasts and basophils. In 10% of patients, the percentage of marrow blasts and basophils can be significantly higher than in the peripheral blood, suggesting poorer prognosis or even disease transformation. Monitoring patients on TKI therapy by cytogenetics, FISH, and molecular studies has become an important standard practice to assess response to therapy, emphasize compliance, evaluate possible treatment resistance, change TKI therapy, and order mutational analysis studies. It is thus important to recognize the comparability of these measures in monitoring response. A partial cytogenetic response is defined as the presence of 35% less Ph-positive metaphases by routine cytogenetic analysis. This is roughly equivalent to BCR-ABL1 transcripts by the International Scale (IS) of 10% or less. A complete cytogenetic response refers to the absence of Ph-positive metaphases (0% Ph positivity). This is approximately equivalent to BCR-ABL1 transcripts (IS) of 1% or less. A major


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InternalMed_Harrison. 10% or less. A complete cytogenetic response refers to the absence of Ph-positive metaphases (0% Ph positivity). This is approximately equivalent to BCR-ABL1 transcripts (IS) of 1% or less. A major molecular response refers to BCR-ABL1 transcripts (IS) ≤0.1%, or roughly a 3-log or greater reduction of CML burden from baseline. A complete molecular response usually refers to BCR-ABL1 transcripts (IS) <0.0032% (undetectable by current techniques), roughly equivalent to a more than 4.5-log reduction of CML burden from baseline.


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InternalMed_Harrison. Findings in CML Transformation Progression of CML is usually associated with leukocytosis resistant to therapy, increasing anemia, fever and constitutional symptoms, and increased blasts and basophils in the peripheral blood or marrow. Criteria of accelerated-phase CML, historically associated with median survival of less than 1.5 years, include the presence of 15% or more peripheral blasts, 30% or more peripheral blasts plus promyelocytes, 20% or more peripheral basophils, cytogenetic clonal evolution (presence of chromosomal abnormalities in addition to Ph), and thrombocytopenia <100 × 109/L (unrelated to 1.0 therapy). About 5–10% of patients present with de novo accelerated phase or blastic phase. The prognosis of de novo accelerated phase with TKI therapy has improved significantly, with an estimated 8-year survival rate of 75%. The median survival of accelerated phase evolving from chronic phase has also improved from a historical median survival of 18 months to an estimated


InternalMed_Harrison

InternalMed_Harrison. with an estimated 8-year survival rate of 75%. The median survival of accelerated phase evolving from chronic phase has also improved from a historical median survival of 18 months to an estimated 4-year survival rate of 70% on TKI therapy. Therefore, the criteria for accelerated-phase CML should be revisited because most have lost much of their prognostic significance. Blastic-phase CML is defined by the presence of 30% or more peripheral or marrow blasts or the presence of sheets of blasts in extramedullary disease (usually skin, soft tissues, or lytic bone lesions). Blasticphase CML is commonly myeloid (60%) but can present uncommonly as erythroid, promyelocytic, monocytic, or megakaryocytic. Lymphoid blastic phase occurs in about 25% of patients. Lymphoblasts are terminal deoxynucleotide transferase positive and peroxidase negative (although occasionally with low positivity up to 3–5%) and express lymphoid markers (CD10, CD19, CD20, CD22). However, they also often express myeloid


InternalMed_Harrison

InternalMed_Harrison. transferase positive and peroxidase negative (although occasionally with low positivity up to 3–5%) and express lymphoid markers (CD10, CD19, CD20, CD22). However, they also often express myeloid markers (50–80%), resulting in diagnostic confusion. This is important because, unlike other morphologic blastic phases, lymphoid blastic-phase CML is quite responsive to antiALL-type chemotherapy (e.g., hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, and dexamethasone]) in combination with TKIs.


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InternalMed_Harrison. Before the imatinib era, the annual mortality in CML was 10% in the first 2 years and 15–20% thereafter. The median survival time in CML was 3–7 years (with hydroxyurea-busulfan and interferon α). Without a curative option of allogeneic SCT, the course of CML was inexorable toward transformation to, and death from, accelerated or blastic phases. The disease stability was unpredictable, with some patients demonstrating sudden transformation to a blastic phase. With imatinib therapy, the annual mortality in CML has decreased to 2% in the first 12 years of observation. Half of the deaths are from factors other than CML, such as old age, accidents, suicides, other cancers, and other medical conditions (e.g., infections, surgical procedures). The estimated 8to 10-year survival rate is now 85%, or 93% if only CML-related deaths are considered (Fig. 133-2). The course of CML has also become quite predictable. In the first 2 years of TKI therapy, rare sudden transformations are still noted


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InternalMed_Harrison. or 93% if only CML-related deaths are considered (Fig. 133-2). The course of CML has also become quite predictable. In the first 2 years of TKI therapy, rare sudden transformations are still noted (1–2%), usually lymphoid blastic transformations that respond to combinations of chemotherapy and TKIs followed by allogeneic SCT. These may be explained by the intrinsic mechanisms of sudden transformation already existing in the CML clones before the start of therapy that were not amenable to TKI inhibition, in particular imatinib. Second-generation TKIs (nilotinib, 1.0 0.0 0.0 100 1 2 3 4 5 6 7 8 9 Years 41% 19% 5% 2% Accelerated 1980–2000 398 325 28 p = 0.015 Accelerated 2001–2013 258 86 88 Blastic 1980–2000 196 189 5 Blastic 2001–2013 175 133 7 p < 0.001 p < 0.001


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InternalMed_Harrison. FIGURE 133-2 A. Survival in newly diagnosed chronic-phase chronic myeloid leukemia (CML) by era of therapy (M.D. Anderson Cancer Center experience from 1965 to present). Causes of non-CML deaths in 22 patients were other cancers (n = 7), postsurgical complications (n = 3), car accident (n = 2), suicide (n = 1), neurologic events (n = 3), cardiac (n = 3), pneumonia (n = 1), and unknown (n = 2). B. Survival in patients with acceleratedand blastic-phase CML referred to M.D. Anderson Cancer Center by era of therapy, demonstrating the significant survival benefit in the tyrosine kinase inhibitor (TKI) era in accelerated-phase CML but the modest benefit in blastic-phase CML. Referred cases included de novo and post-chronic-phase transformations.


InternalMed_Harrison

InternalMed_Harrison. 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 dasatinib) used as frontline therapy have reduced the incidence of transformation in the first 2–3 years from 6–8% with imatinib to 2–4% with nilotinib or dasatinib. Disease transformation to accelerated or blastic phase is rare on continued TKI therapy, estimated at <1% annually in years 4–8 of follow-up on the original imatinib trials. Patients usually develop resistance in the form of cytogenetic relapse, followed by hematologic relapse and subsequent transformation, rather than the previously feared sudden transformations without the warning signals of cytogenetic-hematologic relapse.


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InternalMed_Harrison. Before the imatinib era, several pretreatment prognostic factors predicted for worse outcome in CML and have been incorporated into prognostic models and staging systems. These have included older age, significant splenomegaly, anemia, thrombocytopenia or thrombocytosis, high percentages of blasts and basophils (and/or eosinophils), marrow fibrosis, deletions in the long arm of chromosome 9, clonal evolution, and others. Different risk models and staging systems, derived from multivariate analyses, were proposed to define different risk groups. As with the introduction of cisplatin into testicular cancer therapy, the introduction of TKIs into CML therapy has nullified or lessened the prognostic impact of most of these prognostic factors and the significance of the CML models (e.g., Sokal, Hasford, European Treatment and Outcome Study [EUTOS]). Treatment-related prognostic factors have emerged as the most important prognostic factors in the era of imatinib therapy. Achievement of


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InternalMed_Harrison. Hasford, European Treatment and Outcome Study [EUTOS]). Treatment-related prognostic factors have emerged as the most important prognostic factors in the era of imatinib therapy. Achievement of complete cytogenetic response has become the major therapeutic endpoint and is the only endpoint associated with improvement in survival. Achievement of a major molecular response is associated with decreased risk of events (relapse) and CML progression, may predict for differences in event-free survival (depending on the definition of an event) and for small differences in transformation rates, but has not been associated with survival prolongation. Among patients in complete cytogenetic response, survival is similar independent of whether they achieve a major molecular response or not. This may be due to the efficacy of salvage TKI therapies, which are and should be implemented at the first evidence of cytogenetic relapse. Achievement of complete molecular response (undetectable BCR-ABL1


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InternalMed_Harrison. be due to the efficacy of salvage TKI therapies, which are and should be implemented at the first evidence of cytogenetic relapse. Achievement of complete molecular response (undetectable BCR-ABL1 transcripts), particularly when durable (>2 years), may offer the possibility of durable molecular response (molecular cure rather than functional cure) in the context of investigational trials and may allow temporary therapy interruption in women eager to have babies. The lack of achievement of major or complete molecular responses should not be considered as “failure” of a particular TKI therapy and/or an indication to change the TKI or to consider allogeneic SCT.


InternalMed_Harrison

InternalMed_Harrison. Pretreatment prognostic factors and prognostic models have lost much of their clinical relevance to define prognosis and to select different therapies. However TKI-associated therapeutic responses have gained major clinical relevance and dictate appropriate and careful monitoring of patients to optimize their treatment.


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InternalMed_Harrison. The introduction of TKI therapy, first in the form of imatinib mesylate in 2001, has revolutionized the treatment and prognosis in CML. Before 2000, allogeneic SCT was frontline therapy, when available, because of its potentially curative capacity. Otherwise, patients 691 were offered interferon α therapy (approved for the treatment of CML in 1986), which had modest benefits (improving survival from a median of 3–4 years with hydroxyurea-busulfan to a median of 6–7 years), but also significant side effects. Other alternatives included hydroxyurea, busulfan, and other nonspecific chemotherapies. With TKI therapy, the estimated 10-year survival in CML is 85%. Since 2001, six agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of CML. These include five oral BCR-ABL1-selective TKIs: imatinib (Gleevec), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib (Bosulif), and ponatinib (Iclusig). Imatinib 400 mg orally daily, nilotinib 300 mg orally twice a


InternalMed_Harrison

InternalMed_Harrison. oral BCR-ABL1-selective TKIs: imatinib (Gleevec), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib (Bosulif), and ponatinib (Iclusig). Imatinib 400 mg orally daily, nilotinib 300 mg orally twice a day (on an empty stomach), and dasatinib 100 mg orally daily are approved for frontline therapy of CML. All three are also approved for salvage therapy (nilotinib 400 mg twice daily), in addition to bosutinib (500 mg daily) and ponatinib (45 mg daily). Imatinib, dasatinib (140 mg daily), bosutinib, and ponatinib are also approved for the treatment of CML transformation (accelerated and blastic phase), whereas nilotinib is only approved for chronic and accelerated phase. Dasatinib, nilotinib, and bosutinib are referred to as sec-ond-generation TKIs; ponatinib is referred to as a third-generation TKI. The sixth approved agent is omacetaxine (Synribo), a protein synthesis inhibitor with presumed more selective inhibition of the synthesis of the BCR-ABL1 oncoprotein. It is approved for the


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InternalMed_Harrison. TKI. The sixth approved agent is omacetaxine (Synribo), a protein synthesis inhibitor with presumed more selective inhibition of the synthesis of the BCR-ABL1 oncoprotein. It is approved for the treatment of chronicand accelerated-phase CML after failure of two or more TKIs, at 1.25 mg/m2 subcutaneously twice a day for 14 days for induction and for 7 days for consolidation-maintenance. Nilotinib is similar in structure to imatinib but 30 times more potent. Dasatinib and bosutinib are dual SRC-ABL1 TKIs (dasatinib is reported to be 300 times more potent and bosutinib 30–50 times more potent than imatinib). Ponatinib is effective against wild-type and mutant BCRABL1 clones. It is unique in being the only currently available BCRABL1 TKI that is active against T315I, a gatekeeper mutant resistant to the other four TKIs (Table 133-2).


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InternalMed_Harrison. Imatinib, nilotinib, and dasatinib are all acceptable frontline therapies in CML. The long-term results of imatinib are very favorable. The 8-year follow-up results show a cumulative complete cytogenetic response rate (occurring at least once) of 83%, with 60–65% of patients being in complete cytogenetic response at 5-year follow-up. The estimated 8-year event-free survival rate is 81%, and the overall survival rate is 85%. Among patients continuing on imatinib, the annual rate of transformation to accelerated-blastic phase in years 4–8 is <1%. In two randomized studies, one comparing nilotinib 300 mg twice daily or 400 mg twice daily with imatinib (ENEST-nd) and the other comparing dasatinib 100 mg daily with imatinib (DASISION), the second-generation TKIs were associated with better outcomes in early surrogate endpoints, including higher rates of complete cytogenetic responses (85–87% vs 77–82%), major molecular responses (65–76% vs 46–63%), and undetectable BCR-ABL1 transcripts


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InternalMed_Harrison. outcomes in early surrogate endpoints, including higher rates of complete cytogenetic responses (85–87% vs 77–82%), major molecular responses (65–76% vs 46–63%), and undetectable BCR-ABL1 transcripts (IS) (32–37% vs 15–30%), and lower rates of transformation to accelerated-blastic phase (2–4% vs 6%). However, neither study showed a survival benefit with second-generation TKIs (median follow-up times of 4–5 years). This may be because salvage 692 therapy with other TKIs (following close observation and treatment change at progression) provides highly effective salvage therapy that rebalances the negative effect of the relapse. Salvage therapy in chronic phase with dasatinib, nilotinib, bosutinib, or ponatinib is associated with complete cytogenetic response rates of 30–60% of patients, depending on the salvage status (cytogenetic vs hematologic relapse), prior response to other TKIs, and the mutations at the time of relapse. Complete cytogenetic responses are generally durable,


InternalMed_Harrison

InternalMed_Harrison. depending on the salvage status (cytogenetic vs hematologic relapse), prior response to other TKIs, and the mutations at the time of relapse. Complete cytogenetic responses are generally durable, particularly in the absence of clonal evolution and mutations. Ponatinib is the only TKI active in the setting of T315I mutation, with complete cytogenetic response rates of 50–70%. The estimated 3to 5-year survival rates with new TKIs as salvage are 70–80% (compared with <50% before their availability). For example, with dasatinib salvage after imatinib failure in chronic-phase CML, the major molecular response rates were 40–43%, the estimated 6-year survival rates were 74–83%, and progression-free survival rates were 40–51%. Thus, TKIs in the salvage setting have already reduced the annual mortality from the historical rate of 10–15% to ≤5%. The goal of CML therapy is viewed differently in the context of research versus standard practice. In current practice, functional cure, defined as


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InternalMed_Harrison. from the historical rate of 10–15% to ≤5%. The goal of CML therapy is viewed differently in the context of research versus standard practice. In current practice, functional cure, defined as survival with CML similar to survival among normal individuals, is the current goal of therapy. CML is now considered an indolent disease, which, with appropriate TKI therapy, treatment compliance, careful monitoring, and early change to other TKIs as indicated, can be associated with close to normal survival. Therefore, in standard practice, achievement and maintenance of a complete cytogenetic response are the aims of therapy, because complete cytogenetic response is the only treatment-related factor associated with survival prolongation. Lack of achievement of a major molecular response (protects against events; associated with longer event-free survival) or of negative BCR-ABL1 transcripts (offers the potential of TKI interruption on investigational studies) should not be considered


InternalMed_Harrison

InternalMed_Harrison. against events; associated with longer event-free survival) or of negative BCR-ABL1 transcripts (offers the potential of TKI interruption on investigational studies) should not be considered indications to change TKI therapy or to consider allogeneic SCT. A general practice rule is to continue the particular TKI chosen at the most tolerable dose schedule not associated with grade 3–4 side effects or with bothersome chronic side effects, for as long as possible, until either cytogenetic relapse or the persistence of unacceptable side effects. These two factors (i.e., cytogenetic relapse and intolerable side effects as judged by the patient and treating physician) are the indicators of “failure” of a particular TKI therapy. Because of the increasing prevalence of CML (cost of TKI therapy) and the emerging long-term low rates of significant organ toxicities, the ultimate goal of CML therapy in the research setting is to achieve eradication of the disease (molecular cure) that is


InternalMed_Harrison

InternalMed_Harrison. and the emerging long-term low rates of significant organ toxicities, the ultimate goal of CML therapy in the research setting is to achieve eradication of the disease (molecular cure) that is prolonged and durable, with recovery of nonneoplastic, nonclonal hematopoiesis off TKI therapy. The first step toward this aim is to obtain the highest rates of undetectable BCR-ABL1 transcripts lasting for at least 2 or more years. Recommendations provided by the National Comprehensive Cancer Network (NCCN) and by the European LeukemiaNet (ELN) discuss optimal/expected, suboptimal/warning, and failure response scenarios at different time points of TKI treatment duration. Unfortunately, they may have been misinterpreted in current practice, because oncologists often report that their aim of treatment is the achievement of major molecular response and disease eradication. Significantly, a substantial proportion of oncologists consider a change of TKI therapy in a patient in complete cytogenetic


InternalMed_Harrison

InternalMed_Harrison. is the achievement of major molecular response and disease eradication. Significantly, a substantial proportion of oncologists consider a change of TKI therapy in a patient in complete cytogenetic response if they note “loss of major molecular response” (increase of BCR-ABL1 transcripts ([IS] from <0.1% to >0.1%). This perception may be the result of confusion regarding the NCCN and ELN guidelines, which have been updated often as a result of maturing data and have multiple treatment endpoint considerations. Although such endpoints have been suggested by these recommendations as possible criteria for failure, it is important to emphasize that no randomized study has yet shown that a change of TKI treatment in patients with complete cytogenetic response because of a loss of major molecular response, versus changing at the time of cytogenetic relapse, has been shown to improve survival. This is likely because of the high efficacy of salvage TKI therapy at the time of cytogenetic


InternalMed_Harrison

InternalMed_Harrison. response, versus changing at the time of cytogenetic relapse, has been shown to improve survival. This is likely because of the high efficacy of salvage TKI therapy at the time of cytogenetic relapse.


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InternalMed_Harrison. Side effects of TKIs are generally mild to moderate, although with long-term TKI therapy, they could affect the patient’s quality of life. Serious side effects occur in less than 5–10% of patients. With imatinib therapy, common mild to moderate side effects include fluid retention, weight gain, nausea, diarrhea, skin rashes, periorbital edema, bone or muscle aches, fatigue, and others (rates of 10–20%). In general, second-generation TKIs are associated with lower rates of these bothersome adverse events. However, dasatinib is associated with higher rates of myelosuppression (20–30%), particularly thrombocytopenia, and with pleural (10–25%) or pericardial effusions (≤5%). Nilotinib is associated with higher rates of hyperglycemia (10–20%), pruritus and skin rashes, and headaches. Nilotinib is also associated with rare events of pancreatitis (<5%). Bosutinib is associated with higher rates of early and self-limited gastrointestinal complications like diarrhea (50–70%). Ponatinib is


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InternalMed_Harrison. is also associated with rare events of pancreatitis (<5%). Bosutinib is associated with higher rates of early and self-limited gastrointestinal complications like diarrhea (50–70%). Ponatinib is associated with higher rates of skin rashes (10–15%), pancreatitis (5%), elevations of amylase/lipase (10%), and vasospastic/vasoocclusive events (10–20%). Nilotinib and dasatinib may cause prolongation of the QTc interval; therefore, they should be evaluated cautiously in patients with prolonged QTc interval on electrocardiogram (>470–480 ms), and drugs given for other medical conditions should have relatively smaller or no effects on QTc. These side effects can often be dose-dependent and are generally reversible with treatment interruptions and dose reductions. Dose reductions can be individualized. However, the lowest estimated effective doses of TKIs (from different studies and treatment practices) are imatinib 300 mg daily; nilotinib 200 mg twice daily; dasatinib 20 mg daily; bosutinib


InternalMed_Harrison

InternalMed_Harrison. However, the lowest estimated effective doses of TKIs (from different studies and treatment practices) are imatinib 300 mg daily; nilotinib 200 mg twice daily; dasatinib 20 mg daily; bosutinib 300 mg daily; and ponatinib 15 mg daily.


InternalMed_Harrison

InternalMed_Harrison. With long-term follow-up, rare but clinically relevant serious toxicities are emerging. Renal dysfunction and renal failure (creatinine elevations >2–3 mg/dL) are observed in 2–3% of patients and reverse with TKI discontinuation and empirical use of other TKIs. Pulmonary hypertension has been reported with dasatinib (<1–2%) and should be considered in a patient with shortness of breath and a normal chest x-ray (echocardiogram with emphasis on measurement of pulmonary artery pressure). This may be reversible with dasatinib discontinuation and occasionally the use of sildenafil citrate. Systemic hypertension has been observed more often with ponatinib therapy, as well as other TKIs. Hyperglycemia and diabetes have been noted more frequently with nilotinib. Finally, midand small-vessel vasoocclusive and vasospastic events have been reported at low but significant rates with nilotinib and ponatinib and should be considered possibly TKI-related and represent indications to interrupt or


InternalMed_Harrison

InternalMed_Harrison. and vasospastic events have been reported at low but significant rates with nilotinib and ponatinib and should be considered possibly TKI-related and represent indications to interrupt or reduce the dose of the TKI. These events include angina, coronary artery disease, myocardial infarction, peripheral arterial occlusive disease, transient ischemic attacks, cerebral vascular accidents, Raynaud’s phenomenon, and accelerated atherosclerosis. Although these events are uncommon (<5%), they are clinically significant for the patient’s long-term prognosis and occur at significantly higher rates than in the general population (5–20 times more often).


InternalMed_Harrison

InternalMed_Harrison. Allogeneic SCT, a curative modality in CML, is associated with longterm survival rates of 40–60% when implemented in the chronic phase. It is associated with early (1-year) mortality rates of 5–30%. Although the 5to 10-year survival rates were reported to be around 50–60% (and considered as cure rates), about 10–15% of patients die in the subsequent 1–2 decades from subtle long-term complications of the transplant (rather than from CML relapse). These are related to chronic graft-versus-host disease (GVHD), organ dysfunction, development of second cancers, and hazard ratios for mortality higher than in the normal population. Other significant morbidities include infertility, chronic immune-mediated complications, cataracts, hip necrosis, and other morbidities affecting quality of life. The cure and early mortality rates in chronic-phase CML are also associated with several factors: patient age, duration of chronic phase, whether the donor is related or unrelated, degree of matching,


InternalMed_Harrison

InternalMed_Harrison. cure and early mortality rates in chronic-phase CML are also associated with several factors: patient age, duration of chronic phase, whether the donor is related or unrelated, degree of matching, preparative regimen, and others. In accelerated-phase CML, the cure rates with allogeneic SCT are 20–40%, depending on the definition of acceleration. Patients with clonal evolution as the only criterion have cure rates of up to 40–50%. Patients undergoing allogeneic SCT in second chronic phase have cure rates of 40–50%. The cure rates with allogeneic SCT in blastic phase CML are ≤15%. Post–allogeneic SCT strategies are now implemented in the setting of molecular or cytogenetic relapse or in hematologic relapse/transformation. These include the use of TKIs for prevention or treatment of relapse, donor lymphocyte infusions, and second allogeneic SCTs, among others. TKIs appear to be highly successful at reinducing cytogenetic/molecular remissions in the setting of cytogenetic or molecular


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InternalMed_Harrison. donor lymphocyte infusions, and second allogeneic SCTs, among others. TKIs appear to be highly successful at reinducing cytogenetic/molecular remissions in the setting of cytogenetic or molecular relapse after allogeneic SCT.


InternalMed_Harrison

InternalMed_Harrison. Choice and Timing of Allogeneic SCT Allogeneic SCT was considered first-line CML therapy before 2000. The maturing positive experience with TKIs has now relegated its use to after first-line TKI failures. An important question is the optimal timing and sequence of TKIs and allogeneic SCT (whether allogeneic SCT should be used as secondor third-line therapy). Among patients who present with or evolve to blastic phase, combinations of chemotherapy and TKIs should be used to induce remission, followed by allogeneic SCT as soon as possible. The same applies to patients who evolve from chronic to accelerated phase. Patients with de novo accelerated-phase CML may do well with long-term TKI therapy (estimated 8-year survival rate 75%); the timing of allogeneic SCT depends on their optimal response to TKI (achievement of complete cytogenetic response). Among patients who relapse in chronic phase, the treatment sequence depends on several factors: (1) patient age and availability of


InternalMed_Harrison

InternalMed_Harrison. response to TKI (achievement of complete cytogenetic response). Among patients who relapse in chronic phase, the treatment sequence depends on several factors: (1) patient age and availability of appropriate donors; (2) risk of allogeneic SCT; (3) presence or absence of clonal evolution and mutations; (4) patient’s prior history and comorbidities; and (5) patient and physician preferences (Table 133-3). Patients with T315I mutations at relapse should be offered ponatinib and considered for allogeneic SCT (because of the short follow-up with ponatinib). Patients with mutations involving Y253H, E255K/V, and F359V/C/I respond better to dasatinib or bosutinib. Patients with mutations involving V299L, T315A, and F317L/F/I/C respond better to nilotinib. Comorbidities such as diabetes, hypertension, pulmonary hypertension, chronic lung disease, cardiac conditions, and pancreatitis may influence the choice for or against a particular TKI. Patients with clonal evolution, unfavorable mutations,


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InternalMed_Harrison. pulmonary hypertension, chronic lung disease, cardiac conditions, and pancreatitis may influence the choice for or against a particular TKI. Patients with clonal evolution, unfavorable mutations, or lack of major/complete cytogenetic


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InternalMed_Harrison. Consideration of CML Phase Use of TKI Allogeneic SCT Note: Mutations involving Y253H, E255K/V, or F359V/C/I: prefer dasatinib or bosutinib. Mutations involving V299L, T315A, or F317L/F/I/C: prefer nilotinib.


InternalMed_Harrison

InternalMed_Harrison. response within 1 year of salvage TKI therapy have short remission 693 durations and should consider allogeneic SCT as more urgent in the setting of salvage. Patients without clonal evolution or mutations at relapse and who achieve a complete cytogenetic response with TKI salvage, have long-lasting complete remissions and may delay the option of allogeneic SCT to third-line therapy. Finally, older patients (age 65–70 years or older) and those with high risk of mortality with allogeneic SCT may forgo this curative option for several years of disease control in chronic phase with or without cytogenetic response (Table 133-3). Historically, before the availability of TKIs, patients without cytogenetic response on interferon α or hydroxy-urea had expected short median survival times (2–3 years) with expected rapid disease transformation. The maturing experience with TKIs suggests a different course, whereby patients may remain in chronic phase on TKI-based therapies (combinations


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InternalMed_Harrison. years) with expected rapid disease transformation. The maturing experience with TKIs suggests a different course, whereby patients may remain in chronic phase on TKI-based therapies (combinations including hydroxyurea, cytarabine, decitabine, and others), with or without cytogenetic response, for many years. Table 133-3 summarizes a general guidance to the choice of TKIs versus allogeneic SCT.


InternalMed_Harrison

InternalMed_Harrison. Achievement of complete cytogenetic response by 12 months of imatinib therapy and its persistence later, the only consistent prognostic factor associated with survival, is now the main therapeutic endpoint in CML. Failure to achieve a complete cytogenetic response by 12 months or occurrence of later cytogenetic or hematologic relapse is considered as treatment failure and an indication to change therapy. Because salvage therapy with other TKIs reestab lishes good outcome, it is important to ensure patient compliance to continued TKI therapy and change therapy at the first sign of cytogenetic relapse. Patients on frontline imatinib therapy should be closely monitored until documentation of complete cytogenetic response, at which time they can be monitored every 6 months with peripheral blood FISH and PCR studies (to check for concordance of results), or more frequently if there are concerns about changes in BCR-ABL1 transcripts (e.g., every 3 months). Monitoring by molecular studies