CHAPTER 14: ACUTE AND CHRONIC MYELOID LEUKEMIA

TREATMENT: Acute Myeloid Leukemia

Treatment of a newly diagnosed patient with AML is usually divided into two phases, induction and postremission management (Fig. 14-2). The initial goal is to quickly induce CR. When 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 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. 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. Cytarabine is usually administered as a continuous intravenous infusion for 7 days. Anthracycline therapy generally consists of daunorubicin intravenously on days 1, 2, and 3 (the 7 and 3 regimen). Treatment with idarubicin for 3 days in conjunction with cytarabine by 7-day continuous infusion is at least as effective as daunorubicin in younger patients. The addition of etoposide may improve the CR duration. When combined with cytarabine in a 7 and 3 regimen, a higher dose of anthracycline (i.e., daunorubicin 90 mg/m²) improves outcome compared with a lower dose (i.e., daunorubicin 45 mg/m²).

After induction chemotherapy, if persistence of leukemia is documented, the patient is usually retreated with cytarabine and an anthracycline in doses similar to those given initially, but for 5 and 2 days, respectively. Our recommendation, however, is to consider changing therapy in this setting.

With the 7 and 3 cytarabine/daunorubicin regimen outlined above, 65–75% of adults with de novo AML younger than age 60 years achieve CR. Two-thirds achieve CR after a single course of therapy, and one-third require two courses. About 50% of patients who do not achieve CR 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. A higher induction treatment–related mortality rate and frequency of resistant disease have been observed with increasing age and in patients with prior hematologic disorders (MDS or myeloproliferative syndromes) or chemotherapy treatment for another malignancy.

Patients who fail to attain CR after two induction courses should be treated with an allogeneic hematopoietic stem cell transplant (HSCT) if an appropriate donor exists. Whether achievement of cytoreduction of disease burden with a salvage treatment should be attempted before a patient with refractory disease after two induction courses can proceed to HSCT is controversial.

High-dose cytarabine-based regimens have high CR rates after a single cycle of therapy. When given in high doses, more cytarabine may enter the cells; saturate the cytarabine-inactivating enzymes; and increase 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. In two randomized studies, high-dose cytarabine with an anthracycline produced CR rates similar to those achieved with standard 7 and 3 regimens. However, the CR duration was longer after high-dose cytarabine than after standard-dose cytarabine.

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 includes myelosuppression, 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 elderly AML patients.

Because of the negative impact of age on outcome when treatment with conventional chemotherapy is administered, clinical trials in elderly patients have focused on new agents or alternative approaches such as reduced-intensity allogeneic HSCT. Among these, one promising therapy is decitabine, a nucleoside analogue that inhibits DNA methyltransferase, reverses aberrant DNA methylation, and subsequently induces transcription of otherwise silenced tumor suppressor genes in AML cells. Interestingly, this effect on inhibiting DNA methyltransferase occurs at a much lower dose than previously used with this agent to produce a cytotoxic effect in AML. Low-dose decitabine yields complete responses in older patients with AML, including those with unfavorable karyotypes. Other agents with relatively favorable toxicity profiles such as clofarabine have activity in older patients with AML.

SUPPORTIVE CARE Measures geared to supporting patients through several weeks of granulocytopenia 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 human leukocyte antigen (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 graft-versus-host disease (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.

Infectious complications remain the major cause of morbidity and death during induction and postremission chemotherapy for AML. Antibacterial (i.e., quinolones) and antifungal (e.g, fluconazole, 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.

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. 29). An antibiotic regimen adequate to treat gram-negative organisms should be instituted at the onset of fever in a granulocytopenic 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–cilastin, meropenem, piperacillin–tazobactam, or an extended-spectrum antipseudomonal cephalosporin (cefepime or ceftazidime); an aminoglycoside in combination with an antipseudomonal penicillin (e.g., piperacillin); an aminoglycoside in combination with an extended-spectrum antipseudomonal cephalosporin; and ciprofloxacin in combination with an antipseudomonal penicillin. Aminoglycosides should be avoided if possible in patients with renal insufficiency. Empirical vancomycin should be initiated in neutropenic patients with catheter-related infections, blood cultures positive for gram-positive bacteria before final identification and susceptibility testing, hypotension or shock, and increased risk for viridans group streptococcal bacteremia.

Caspofungin (or similar echinocandin) or liposomal amphotericin B should be considered for antifungal treatment if fever persists 4–7 days following initiation of empiric antibiotic therapy in a patient who has received fluconazole prophylaxis. 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/or 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, and those participating in clinical trials.

TREATMENT OF PROMYELOCYTIC LEUKEMIA Tretinoin is an oral drug that induces the differentiation of leukemic cells bearing the t(15;17). APL is responsive to cytarabine and daunorubicin, but about 10% of patients treated with these drugs die from DIC induced by the release of granule components by dying tumor cells. Tretinoin does not produce 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 chemotherapy appears to be among the most effective treatments for APL, leading to CR rates of 90–95%. 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.

Given the progress made in APL, resulting in high cure rates, the goals are to identify patients with very low risk of relapse where attempts are being made to decrease the amount of therapy administered and to identify patients at greatest risk of relapse in order to develop new approaches to increase cure.

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 utilized after achievement of CR and before consolidation therapy with anthracycline-based chemotherapy. Additionally, studies combining arsenic trioxide with tretinoin in the absence of chemotherapy are ongoing and preliminarily have shown promise in those patients "unfit" to receive chemotherapy. Furthermore, combinations of arsenic trioxide, tretinoin, and/or chemotherapy and/or gemtuzumab ozogamicin, a monoclonal CD33 antibody linked to the cytotoxic agent calicheamicin, have shown favorable response in high-risk APL patients (i.e., those presenting with a leukocyte count ≥10,000/μL) at diagnosis. 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.

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 t(15;17) is now considered standard for postremission monitoring of APL.

Patients who continue in molecular remission may benefit from maintenance therapy with tretinoin. Patients in molecular, cytogenetic, or clinical relapse should be salvaged with arsenic trioxide; it produces meaningful responses in up to 85% of patients and can be followed by HSCT.

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. Once relapse has occurred, AML is generally curable only by HSCT.

Postremission therapy is designed to eradicate residual leukemic cells to prevent relapse and prolong survival. Postremission therapy in AML is often based on age (younger than ages 55–65 years and older than ages 55–65 years). For younger patients, most studies include intensive chemotherapy and allogeneic or autologous HSCT. High-dose cytarabine 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 postremission to four cycles of high (3 g/m², every 12 hours 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 aged ≤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. For older patients, exploration of attenuated intensive therapy that includes either chemotherapy or reduced-intensity allogeneic HSCT has been pursued. Postremission therapy is a setting for introduction of new agents (Table 14-4).

Allogeneic HSCT is used in patients ages <70–75 years with an HLA-compatible donor who have high-risk cytogenetics. 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, as the impact of aggressive therapy on outcome is unknown. Relapse following allogeneic HSCT occurs in only a small fraction of patients, but treatment-related toxicity is relatively high; complications include venoocclusive 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. Purging tumor from the autologous stem cells has not lowered the relapse rate with autologous HSCT.

Randomized trials comparing intensive chemotherapy and autologous and allogeneic HSCT have shown an improved duration of remission with allogeneic HSCT compared with 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. While stem cells were previously harvested from the bone marrow, virtually all efforts currently collect these from the blood following mobilization regimens. Prognostic factors may help select patients in first CR for whom transplant is most effective.

Our approach includes allogeneic HSCT if feasible in first CR for patients with high-risk karyotypes (Fig. 14-2). Patients with CN-AML who have other poor risk factors (e.g., an antecedent hematologic disorder, or failure to attain remission with a single induction course) and patients lacking a favorable genotype (e.g., patients who do not have CEBPA mutations or NPM1 mutations without FLT3-ITD) are also potential candidates. If a suitable HLA donor does not exist, investigational therapeutic approaches are considered. As 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. New transplant strategies, including reduced-intensity HSCT, are being explored for consolidation of high-risk AML patients (Chap. 30). Patients with t(8;21) and inv(16) are treated with repetitive doses of high-dose cytarabine, which offers a high frequency of cure without the morbidity of transplant. In 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.

Autologous HSCT is generally applied to AML patients only 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).

RELAPSE Once relapse occurs, patients are rarely cured with further standard-dose chemotherapy. Patients eligible for allogeneic HSCT should receive transplants expeditiously at the first sign of relapse. Long-term disease-free survival is approximately the same (30–50%) with allogeneic HSCT in first relapse or in second remission. Autologous HSCT rescues about 20% of relapsed patients with AML who have chemosensitive disease. The most important factors predicting response at relapse are the length of the previous CR, whether initial CR was achieved with one or two courses of chemotherapy, and the type of postremission therapy. Because of the poor outcome of patients in early first relapse (<12 months), it is justified (for patients without HLA-compatible donors) to explore innovative approaches, such as new drugs or immunotherapies (Table 14-4). Patients with longer first CRs (>12 months) generally relapse with drug-sensitive disease and have a higher chance of attaining a CR. However, cure is uncommon, and treatment with novel approaches should be considered if allogeneic HSCT is not possible. New agents that may have clinical activity in AML are needed, and many are being tested in clinical trials (Table 14-4).

For elderly patients (age >60 years) for whom clinical trials are not available, gemtuzumab ozogamicin is another alternative. The CR rate with this agent is ~30%. However, its effectiveness in early relapsing (<6 months) or refractory AML patients is limited, possibly due to calicheamicin being a potent MDR1 substrate. Toxicity, including myelosuppression, infusion toxicity, and venoocclusive disease, can be observed with gemtuzumab ozogamicin. Pretreatment with glucocorticoids can diminish many of the associated infusion reactions. Studies are examining this treatment in combination with chemotherapy for both young and older patients with previously untreated AML. This agent has been withdrawn from the U.S. market at the request of the U.S. FDA due to concerns about the product's safety and clinical benefit as shown in trials subsequent to those leading to its accelerated approval.

TREATMENT: Chronic Myeloid Leukemia

The therapy of CML is changing rapidly because we have a proven curative treatment (allogeneic transplantation) that has significant toxicity and a new targeted treatment (imatinib) with outstanding outcome based on 8-year follow-up data. We recommend starting with TK inhibitors and reserving allogeneic transplantation for those who develop imatinib resistance.

At present, the goal of therapy in CML is to achieve prolonged, durable, nonneoplastic, nonclonal hematopoiesis, which entails the eradication of any residual cells containing the BCR-ABL1 transcript. Hence, the goal is complete molecular remission and cure. A proposed imatinib treatment algorithm for the newly diagnosed CML patient is presented in Table 14-5.

IMATINIB MESYLATE Imatinib mesylate (Gleevec) functions through competitive inhibition at the ATP-binding site of the Abl kinase in the inactive conformation, which leads to inhibition of tyrosine phosphorylation of proteins involved in Bcr-Abl signal transduction. It shows specificity for Bcr-Abl, the receptor for platelet-derived growth factor, and Kit TK. Imatinib induces apoptosis in cells expressing Bcr-Abl.

In newly diagnosed CML, imatinib (400 mg/d) is more effective than IFN-α and cytarabine. The complete hematologic remission rate of patients treated with imatinib was 95% compared with 56% in patients treated with IFN-α and cytarabine. Similarly, the complete cytogenetic remission rate at 18 months was 76% with imatinib compared with 15% with IFN-α and cytarabine. The rate of complete cytogenetic remission in imatinib-treated patients differed by Sokal score: the rate in those with low-risk disease was 89% compared with 82% for patients with intermediate-risk disease and 69% for those with high-risk disease.

All imatinib-treated patients who achieved major molecular remission (26%), defined as ≥3 log reduction in BCR-ABL1 transcript level at 18 months compared with pretreatment level, were progression-free at 5 years. The progression-free survival (PFS) at 5 years for patients achieving complete cytogenetic remission but less pronounced molecular remission is 98%. The 5-year PFS for patients not achieving complete cytogenetic remission at 18 months was 87%. These results have led to a consensus that molecular responses can be used as a treatment goal in CML. Specific milestones have been developed for chronic-phase CML patients (Table 14-5). They differ between the Americans (NCCN) and the Europeans (ELN), with more strict milestones by the latter. For example, in the NCCN milestones, chronic-phase CML patients who do not achieve any cytogenetic remission following 6 months of imatinib should be offered other treatment approaches, but in the ELN milestones, the same recommendation is offered following 3 months of imatinib treatment. We favor the ELN approach and expect the NCCN milestones to align with the ELN ones in the very near future.

Progression to accelerated or blastic phases of the disease was noted in 3% of patients treated with imatinib compared with 8.5% of patients treated with IFN-α and cytarabine during the first year. Over time, the annual incidence of disease progression on imatinib decreased gradually to <1% during the fourth year and beyond, and no patient who achieved major molecular response by 12 months progressed to the accelerated or blastic phases of the disease.

Treatment is currently recommended for life unless patients are enrolled in a clinical trial with a specific question of treatment discontinuation. An early trial evaluating the effect of imatinib discontinuation after at least 2 years of complete molecular remission revealed molecular relapse in 6 of 12 patients. Interestingly, 6 of 10 patients who were treated with IFN-α before imatinib maintained molecular remission, while both patients who were not exposed to IFN-α relapsed. These results raised the hypothesis that IFN-α may have a protective effect against relapse, possibly by eradicating the leukemia-initiating cells. This hypothesis is supported by the randomized trial comparing imatinib with imatinib plus IFN-α; preliminary results from this trial revealed better major molecular response for the combination, although a significant number of patients discontinued IFN-α treatment during the first year due to toxicity. Finally, a recent IFN-α maintenance study, following imatinib discontinuation, demonstrated maintained molecular remission in 15 (75%) of 20 patients. IFN's mechanism of action in this situation is unclear.

Imatinib is administered orally. The main side effects are fluid retention, nausea, muscle cramps, diarrhea, and skin rashes. The management of these side effects is usually supportive. Myelosuppression is the most common hematologic side effect. Myelosuppression, while rare, may require holding drug and/or growth factor support. Doses <300 mg/d seem ineffective and may lead to development of resistance.

Four mechanisms of resistance to imatinib have been described to date. These are (1) gene amplification, (2) mutations at the kinase site, (3) enhanced expression of multidrug exporter proteins, and (4) alternative signaling pathways functionally compensating for the imatinib-sensitive mechanisms. All four mechanisms are being targeted in clinical trials.

BCR-ABL1 gene amplification and decreased intracellular imatinib concentrations are addressed by intensifying the therapy with higher (≤ 800 mg/d) imatinib doses. Three randomized trials have been published so far. The first randomized study compared 400 mg/d with 800 mg/d in newly diagnosed CML patients and revealed improved major molecular responses at 3, 6, and 9 months but similar results at 12 months. A similar study comparing 600 mg/d with 800 mg/d showed a borderline benefit for the higher dose based on both cytogenetic and major molecular responses at 12 months, while a third study concentrating only on high-risk (Sokal) patients failed to show any significant difference between 400 mg/d and 800 mg/d at 12 months. All of these studies have too short follow-up times to evaluate dosing effect on survival.

Mutations at the kinase domain occur in approximately half of imatinib-resistant chronic-phase cases and even more frequently in the more advanced phases of the disease. These mutations are being targeted by novel TK inhibitors that have a different conformation than imatinib, demonstrating activity against most imatinib-resistant mutations. Nilotinib (Tasigma), similar to imatinib, binds to the kinase domain in the inactive conformation. Dasatinib (Sprycel) binds to the kinase domain in the open conformation and inhibits the SRC (sarcoma) family of kinases, addressing the last mechanism of resistance. CML with the T315I mutation is resistant to imatinib, nilotinib, and dasatinib. In addition, nilotinib is also resistant to E255K/V and Y253F/H, and dasatinib is also resistant to X299L and F317L.

Dasatinib is approved by the FDA at a dose of 100 mg/d for the treatment of all stages of CML with resistance or intolerance to prior therapy, including imatinib. Nilotinib is approved by the FDA at a dose of 400 mg twice daily for the treatment of chronic- and accelerated-phase CML with resistance or intolerance to prior therapy, including imatinib. Both are oral agents dasatinib is given once daily while daily, and nilotinib is given twice daily with food restrictions before and after dosing. Their toxicity profiles are similar to that of imatinib with small but significant differences. Dasatinib causes pleural effusions in 22% of patients, with 7% developing grade 3–4 toxicity. Nilotinib was associated with sudden death in 6 of approximately 550 CML patients. A suspected relationship to nilotinib was reported in two of these cases and led to a requirement for additional cardiac monitoring while using this drug. A randomized trial in chronic-phase imatinib-resistant CML patients showed superiority of switching to dasatinib over increasing imatinib to 800 mg/d. Finally, randomized trials have demonstrated that either nilotinib or dasatinib is more effective than imatinib as first-line treatment in newly diagnosed chronic-phase CML patients in time to complete hematologic and cytogenetic remission and major molecular response at 1 year and led to their approval for the first line setting. Similar results are likely with bosutinib, another Src and Abl TK inhibitor. These studies are expanding the armamentarium for newly diagnosed CML patients.

These new agents have already changed the treatment algorithm of CML. For example, patients who do not achieve any cytogenetic remission at 6 months (or 3 months by ELN) on imatinib are now offered dasatinib, nilotinib, or HSCT. IFN-α is FDA approved for CML but is only offered if all other options have failed.

The encouraging results with imatinib have led clinicians to offer it as first-line therapy for newly diagnosed CML patients, including those who otherwise would have benefited from transplant (e.g., young patients with a matched sibling donor). Prior exposure to imatinib does not affect transplant outcome. Similar data, in smaller series, were also described for dasatinib and nilotinib treatment before HSCT. However, delaying HSCT for high-risk patients (Sokal/Hasford criteria) may result in disease progression. HSCT after disease progression is associated with poorer outcome. Therefore, we recommend close monitoring of TK inhibitors response in these patients.

NEW AGENTS Several new agents are now in development for CML with T315I and patients who fail all currently available TK inhibitors. These include omacetaxine, XL228, FTY720, AP24534, DCC-2036, PH-739358, and sorafenib (Table 14-6).

ALLOGENEIC HSCT Allogeneic HSCT is complicated by early mortality owing to the transplant procedure. Outcome of HSCT depends on multiple factors, including (1) the patient (e.g., age and phase of disease); (2) the type of donor (e.g., syngeneic [monozygotic twins] or HLA-compatible allogeneic, related or unrelated); (3) the preparative regimen (myeloablative or reduced-intensity); (4) GVHD; and (5) posttransplantation treatment.

Posttransplantation Treatment Posttransplant BCR-ABL1 transcript levels have served as early predictors for hematologic relapse following HSCT. These should facilitate risk-adapted approaches with immunosuppression or TK inhibitor(s) or a combination of the two. Donor leukocyte infusions (without any preparative chemotherapy or GVHD prophylaxis) can induce hematologic and cytogenetic remissions in patients with CML who have relapsed after allogeneic HSCT but carry the risk of significant GVHD.

Imatinib can control CML that has recurred after allogeneic HSCT but is sometimes associated with myelosuppression and recurrence of severe GVHD. Imatinib after allogeneic HSCT is being studied for prevention of relapse in patients with advanced disease at the time of transplantation (i.e., patients at high risk for relapse), patients undergoing reduced-intensity transplants, or patients with slow reduction of BCR-ABL1 message following transplantation. Imatinib has also been combined with donor lymphocytes to induce rapid molecular remissions in CML patients with disease relapse after allogeneic HSCT. Of interest are studies with newer TK inhibitors following transplantation for imatinib-resistant CML.

INTERFERON Before imatinib, when allogeneic HSCT was not feasible, IFN-α therapy was the treatment of choice. Only longer follow-up of patients treated with imatinib will prove whether IFN-α will still have a role in the treatment of CML. Its mode(s) of action in CML is still unknown.

CHEMOTHERAPY Initial management of patients with chemotherapy is currently reserved for rapid lowering of WBC counts, reduction of symptoms, and reversal of symptomatic splenomegaly. Hydroxyurea, a ribonucleotide reductase inhibitor, induces rapid disease control. The initial dose is 1–4 g/d; the dose should be halved with each 50% reduction of the leukocyte count. Unfortunately, cytogenetic remissions with hydroxyurea are uncommon. Busulphan, an alkylating agent that acts on early progenitor cells, has a more prolonged effect. However, we do not recommend its use because of its serious side effects, which include unexpected, and occasionally fatal, myelosuppression in 5–10% of patients; pulmonary, endocardial, and marrow fibrosis; and an Addison-like wasting syndrome.

AUTOLOGOUS HSCT Autologous HSCT could potentially cure CML if cells are collected at complete molecular remission. However, since patients who achieve this degree of response do not relapse, this treatment modality has been abandoned by most groups.

LEUKAPHERESIS AND SPLENECTOMY Intensive leukapheresis may control the blood counts in chronic-phase CML; however, it is expensive and cumbersome. It is useful in emergencies in which leukostasis-related complications, such as pulmonary failure or cerebrovascular accidents, are likely. It may also have a role in the treatment of pregnant women, in whom it is important to avoid potentially teratogenic drugs.

Splenectomy was used in CML in the past because of the suggestion that evolution to the acute phase might occur in the spleen. However, this does not appear to be the case, and splenectomy is now reserved for symptomatic relief of painful splenomegaly unresponsive to imatinib or chemotherapy or for significant anemia or thrombocytopenia associated with hypersplenism. Splenic radiation is used rarely to reduce the size of the spleen.

MINIMAL RESIDUAL DISEASE The kinetics of BCR-ABL1 transcript elimination is currently replacing qualitative detection of the BCR-ABL1 message as an index of tumor burden despite a lack of standard acceptable methodology. A consensus panel has proposed ways to harmonize the different methods and to use a conversion factor so that individual laboratories will be able to express BCR-ABL1 transcript levels on an agreed upon scale.

Slow reduction of BCR-ABL1 transcripts following HSCT correlates with the possibility of hematologic relapse. However, the definition of "slow reduction" depends on the preparative regimen (reduced-intensity vs fully myeloablative) and the selection of time points to measure the transcript levels. While persistent RT-PCR positivity at 6 months was regarded as an indication for additional therapy in the past, current studies utilize periods between engraftment and day 100 for evaluating the clearance rate of BCR-ABL1 transcripts and recommending additional therapies. Large trials with longer follow-up are needed to establish consensus guidelines.

The randomized trial of imatinib versus IFN-α and cytarabine was the first to establish the concept of log₁₀ reduction of BCR-ABL1 transcript from a standardized baseline for untreated patients. This measurement unit was developed instead of either the transcript numbers expressed per microgram of leukocyte RNA or the ratio of BCR-ABL1 to a housekeeping gene on a log scale. In this randomized trial, patients who achieved ≥3 log reduction of BCR-ABL1 message had an extremely low probability of relapse, with a median follow-up of 96 months.

These studies also established the value and convenience of using peripheral blood instead of bone marrow testing as a means to assess disease status in patients who achieve complete cytogenetic responses. However, one still needs to consider following CML patients in complete cytogenetic remission and at least major molecular remission with occasional cytogenetic bone marrow testing. This should be performed if they develop cytopenia late in the treatment course as such patients are at risk of developing cytogenetic aberrations, especially monosomy 7, in t(9;22)-negative cells and secondary MDS/AML. Other aberrations in the t(9;22)-negative cells are frequently transient, and their clinical significance is unclear. Development of secondary MDS/AML is rare.

TREATMENT OF BLAST CRISIS Treatments for primary blast crisis, including imatinib, are generally ineffective. Only 52% of patients treated with imatinib achieved hematologic remission (21% complete hematologic remission), and the median overall survival time was 6.6 months. Patients who achieve complete hematologic remission or whose disease returns to a second chronic phase should be considered for allogeneic HSCT. Other approaches include induction chemotherapy tailored to the phenotype of the blast cell followed by TK inhibitors with or without additional chemotherapy and HSCT. Blast crisis following initial therapy with imatinib carries a dismal prognosis even if the patient is treated with dasatinib or nilotinib.