TREATMENT Acute Myeloid Leukemia
Treatment of the newly diagnosed patient with AML is usually divided into two phases, induction and postremission management (Fig. 14-2). 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. INDUCTION CHEMOTHERAPY
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.
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.
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 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.
Incorporation of novel and molecular targeting agents into these regimens is currently under investigation. For patients with FLT3-ITD 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.
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 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.
After one cycle of the 7 and 3 chemotherapy induction regimen, if persistence of leukemia is documented, the patient is usually re-treated 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. POSTREMISSION THERAPY
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.
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 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 14-5).
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.
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.
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 autologous HSCT (5% mortality rate), but the relapse rate is higher than with allogeneic HSCT, due to the absence of the graft-versus-leukemia (GVL) effect seen with allogeneic HSCT and possible contamination of the autologous stem cells with residual tumor cells.
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 14-5). 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.
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.
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 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 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. SUPPORTIVE CARE
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.
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 bleeding, 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 these patients if CMV-negative products are not available.
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 varicella-zoster seropositive, antiviral prophylaxis should be initiated (e.g., acyclovir, valacyclovir).
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. 30). 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 (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, or known colonization 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 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 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. TREATMENT FOR REFRACTORY OR RELAPSED AML
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.
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.
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 14-5). 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 FLT3- and 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 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. TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA
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 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%.
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 anthracycline-based chemotherapy.
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.
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.
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.
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.