Armin Ghobadi • Amanda Cashen
I. PRESENTATION
Less common presenting symptoms include lymphadenopathy, splenomegaly, and hepatomegaly, which occur more often with acute lymphoblastic leukemia (ALL) than with acute myeloid leukemia (AML). Five percent to 10% of patients with ALL have involvement of the central nervous system (CNS), causing headache, confusion, and/or focal neurologic deficits. Monocytic subtypes of AML can infiltrate the skin (leukemia cutis) or gingiva, leading to purple, nontender papules or gingival hyperplasia, respectively. Tumors composed of myeloid blasts, known as granulocytic sarcomas or chloromas, can involve almost any organ and may precede bone marrow involvement by AML.
A syndrome called leukostasis occurs in up to 50% of patients with AML and an absolute blast count (white blood cell [WBC] count × percent circulating blasts) exceeding 100,000/μL. Symptoms include respiratory compromise and CNS manifestations such as headache or confusion. Emergency leukapheresis can be lifesaving. Transfusion of packed red cells may increase blood viscosity and should be minimized until leukapheresis can be performed.
The presence of a mediastinal mass on chest radiograph is suggestive of T-cell ALL. Osteopenia or lytic lesions may be seen in up to 50% of patients with ALL.
TABLE 27-1 |
Approach to the Newly Diagnosed Patient with Acute Leukemia |
History/examination
Infection: fever; localizing symptoms, especially sinus, mouth, anogenital, skin, and lungs
Hemorrhage: petechiae, ecchymosis, epistaxis, oral/GI bleeding, visual complaints
Symptoms of intracranial bleed, including headache and neurologic deficits
Anemia: exertional dyspnea, CHF, angina, orthostasis, syncope
CNS leukemia: headache, confusion, neurologic deficits
Leukostasis: dyspnea, headache, confusion
Monocytic leukemia: gingival hyperplasia and/or nontender cutaneous nodules
Other
Long-standing symptoms suggest preceding myelodysplasia
Full siblings, allergies, major medical problems
HIV risk factors, previous hepatitis
Previous chemotherapy, exposure to benzene
Routine laboratory testing
Before treatment: blood chemistry, LFT, CBC/manual differential, PT/PTT, FDP, fibrinogen, uric acid, LDH, pregnancy test, HIV, HLA class I/II, urinalysis, type/cross
During treatment: CBC daily and blood chemistry/LFT twice weekly
Radiographic studies
Chest radiograph
MUGA scan
Procedures
Placement of central venous access
Lumbar puncture if CNS leukemia is suspected
Leukapheresis if leukostasis is present
Management of a febrile patient
Culture blood, urine, suspected sites of infection
Inspect indwelling line
Initiate broad-spectrum antibiotics promptly
Cefepime or ceftazidine or imipenem
Vancomycin if line infection suspected
Allergic to β-lactams: ciprofloxacin or levofloxacin and vancomycin
Clinically septic: add gentamicin
Oral or possible intra-abdominal infection: add anaerobic coverage
GI, gastrointestinal; CHF, congestive heart failure; CNS, central nervous system; HIV, human immunodeficiency virus; LFT, liver function tests; CBC, complete blood count; PT, prothrombin time; PTT, partial thromboplastin time; FDP, fibrin degradation products; LDH, lactate dehydrogenase; HLA, human leukocyte antigen; MUGA, multiple-gated acquisition.
Bone marrow aspiration and biopsy and cytogenetic studies including conventional karyotype analysis and fluorescent in situ hybridization (FISH), multicolor flow cytometry and cytochemistry studies are essential for diagnosis and classification of acute leukemias. Molecular studies using reverse transcriptase polymerase chain reaction (RT-PCR) for FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (FLT3-ITD mutation), nucleophosmin gene (NPM-1) mutation, c-Kit mutation, and CCAAT/enhancer binding protein alpha gene (CEBPA) mutation have prognostic importance and therapeutic implications on postremission therapy choices in AML. Although recently supplanted by the World Health Organization (WHO) classification, the French–American–British (FAB) classification remains a commonly used system for the description of acute leukemias. The FAB classification relies on morphology, cytochemistry, and flow cytometry to define subtypes of AML (M0 through M7) and ALL (L1 through L3). Application of these criteria requires a thorough examination of the peripheral blood and bone marrow aspirate with enumeration of blasts, which are characterized by a high nucleus/cytoplasm ratio with fine nuclear chromatin and one or more nucleoli. The FAB criteria define AML when greater than 30% blasts are present in the bone marrow aspirate; greater than 20% blasts define AML in the WHO classification. There are a few exceptions. For diagnosis of acute myelomonocytic leukemia, myeloblasts and promonocytes together should comprise at least 20% of bone marrow cellularity. Acute erythroid leukemia is another exception in which >50% erythroid precursors are present in the bone marrow and myeloblasts should account for >20% of nonerythroid cells. Additionally, t(8;21), inv(16), t(16;16), and t(15;17) are diagnostic of AML regardless of blast percentage in bone marrow. The diagnosis of ALL requires demonstration of at least 20% lymphoblasts in bone marrow. Cytochemistry can be helpful in the diagnosis of acute leukemia (for instance, myeloid blasts are positive for myeloperoxidase), but now flow cytometry is the primary method for determining the leukemia subtype. Lymphoid cells are identified by the presence of CD10, CD19, and CD20 (B cell) or CD2, CD3, CD4, CD5, and CD8 (T cell). Myeloid markers include CD13, CD33, and CD117/c-Kit; CD14 and CD64 (monocytic markers); glycophorin A (erythroid); and CD41 (megakaryocytic).
Subtypes of AML and ALL as defined by the FAB system are of limited prognostic or therapeutic importance. The WHO classification, on the other hand, incorporates cytogenetic and clinical features of known prognostic significance. In the WHO system, AML subtypes are organized into four categories: AML with recurrent genetic abnormalities, AML with multilineage dysplasia (often associated with a preceding myelodysplastic syndrome [MDS]), therapy-related AML, and AML not otherwise categorized (Table 27-2). Therapy-related AML and AML with multilineage dysplasia have a generally poor prognosis, and patients with these subtypes may be candidates for early allogeneic stem cell transplantation. In the WHO classification, ALL is categorized as precursor B-cell ALL or precursor T-cell ALL. Burkitt’s lymphoma/leukemia is grouped with the mature B-cell neoplasms.
It must be emphasized that cytogenetic studies including conventional karyotype and FISH, and molecular studies for FLT3-ITD, NPM1, c-kit, and CEBPA mutations are crucial for the prognosis and treatment of acute leukemia. Therefore, cytogenetic studies and the above-mentioned molecular studies should be obtained on an initial bone marrow and/or peripheral blood sample. Early recognition of APL (FAB-M3, AML with t[15;17]) is particularly important, as these patients are at risk for DIC, and optimal initial treatment includes all-trans-retinoic acid (ATRA; see Section III.B.). Advantages and pitfalls of diagnostic tools commonly used in the diagnosis of APL are summarized in Table 27-3.
TABLE 27-2 |
World Health Organization Classification of Acute Myeloid Leukemia |
AML with recurrent genetic abnormalities
t(8;21); (AML1/ETO)
inv(16) or t(16;16); (CBFβ/MYH11)
APL (AML with t(15;17) and variants)
11q23 (MLL) abnormalities
AML with multilineage dysplasia
With a preceding MDS or myeloproliferative disorder
Without a preceding MDS or myeloproliferative disorder
Therapy-related AML and MDS
Related to an alkylating agent
Related to a topoisonerase II inhibitor
AML not otherwise categorized
Minimally differentiated
Without maturation
With maturation
Acute myelomonocytic leukemia
Acute monoblastic and monocytic leukemia
Acute erythroid leukemia
Acute megaloblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma
AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; MDS, myelodysplastic syndrome.
III. THERAPY AND PROGNOSIS. In the absence of antileukemic therapy, the median survival of newly diagnosed patients is 2 to 4 months. Chemotherapy induces responses in most patients with acute leukemia, although for many patients remission is short-lived. The goal of induction chemotherapy is complete remission (CR), which is a prerequisite for cure. CR is defined as normalization of blood counts (ANC more than 1,500/μL, platelet more than 100,000/μL), with bone marrow aspirate/biopsy demonstrating fewer than 5% blasts. Postremission therapeutic options include additional chemotherapy or stem cell transplantation. Chemotherapy given during CR can include consolidation (intensity similar to that for induction) and maintenance (reduced intensity administered for 18 to 36 months).
TABLE 27-3 |
Advantages and Pitfalls of Diagnostic Tools Commonly Used in the Diagnosis of Acute Promyelocytic Leukemia |
An active area of investigation is the identification of molecular prognostic factors that can guide therapeutic decisions in patients with normal cytogenetics. One such abnormality is FLT3-ITD mutation, which is present in 20% to 30% of all AML cases and 30% to 40% of normal karyotype AML (NK-AML). FLT3-ITD mutation is associated with a high WBC and a worse prognosis. For instance, among 224 AML patients with normal cytogenetics, 5-year survival was 20% for patients with an FLT3 ITD mutation, versus 42% for those with wild type FLT3. NPM-1 mutations are found in 30% of all AMLs and 50% of NK-AMLs. Isolated NPM-1 mutation in NK-AML is associated with higher CR rates and improved DFS and OS, resulting in outcomes similar to good-risk AMLs. However, patients with both NPM-1 mutations and FLT3-ITD mutations have outcomes more similar to isolated FLT3-ITD mutations. CEBPA mutations can be found in approximately 10% and 15% of all AML patients and patients with NK-AML respectively. NK-AML with CEBPA mutation has a better remission duration and OS similar to core binding factor AML [CBF-AML, another term for AML with t(8:21) and AML with inv(16)]. Double mutation of CEBPA (mutation of both alleles) is less common (5% of NK-AML). A recent study showed that OS benefit of CEBPA mutation is limited to patients with double mutations. This study showed the 8-year OS rates of 54%, 31%, and 34% in double mutation of CEBPA, single mutated CEBPA, and wild type CEBPA respectively.
TABLE 27-4 |
AML Risk Status by NCCN |
Risk status |
Cytogenetics |
Molecular abnormalities |
Better-risk |
inv(16) or t(16;16) t(8;21) t(15;17) |
Normal cytogenetics with NPM1 mutation in the absence of FLT3-ITD or isolated biallelic CEBPA mutation |
Intermediate-risk |
Normal cytogenetics +8 alone t(9;11) |
t(8;21, inv(16), and t(16;16) with c-KIT mutation |
Poor-risk |
Complex cytogenetics (>3 clonal chromosomal abnormalities −5, 5q−, −7, 7q− 11q23—non t(9;11) inv(3), t(3;3) t(6;9) t(9;22) |
Normal cytogenetics with FLT3-ITD mutation |
C-Kit mutation is another molecular abnormality with significant prognostic impact in AML with t(8;21) and AML with inv(16). The main mutation clusters are in exon 17 and exon 8. C-kit mutations are seen in approximately 20% to 30% of patients with CBF-AML. In good-risk CBF-AML, c-kit mutation increases the risk of relapse and decreases OS, especially in patients with t(8;21). According to current NCCN guidelines, CBF-AML with c-kit mutation is considered intermediate-risk AML.
For more than 20 years, standard remission induction chemotherapy for AML has included treatment with cytarabine (cytosine arabinoside, ara-C) and an anthracycline. The most common regimen combines 7 days of continuous infusion cytarabine (100 to 200 mg/m2/day) with 3 days of daunorubicin or idarubicin (7 + 3; Table 27-5). A bone marrow examination is repeated 14 to 21 days after starting treatment, and patients with bone marrow cellularity 20% or greater and more than 5% blasts are considered to have residual disease. Patients with persistent disease may achieve a remission after a second, usually abbreviated, course of cytarabine and anthracycline (5 + 2). Sixty percent to 70% of patients achieve a CR after standard induction chemotherapy, with neutrophil (ANC more than 500/μL) and platelet (more than 20,000/μL) recovery occurring an average of 21 to 25 days after the start of therapy. Failure to achieve CR with induction chemotherapy can result from resistant leukemia or early death. Therapy-related mortality increases with age, poor performance status, and underlying organ dysfunction and can be as high as 30% to 40% in elderly patients. Resistant leukemia is associated with a preceding hematologic disorder and adverse cytogenetics, both of which are found more commonly in elderly patients.
TABLE 27-5 |
Acute Myelogenous Leukemia Chemotherapeutic Regimens |
7 and 3 chemotherapeutic regimen for newly diagnosed AMLa
Ara-C, 100 mg/m2/day, as a continuous infusion for 7 days
Idarubicin 12 mg/m2/day or Daunorubicin, 45–90 mg/m2/day × 3 on days 1, 2, 3 of ara-C
Administration of additional chemotherapy: Perform bone marrow on day 14 of chemotherapy; if cellularity is >20% and blasts are >5%, administer second cycle of chemotherapy (5 and 2): same doses as above with 5 days of ara-C and 2 days of daunorubicin
High-dose ara-C consolidation regimenb
Cytosine arabinoside: 3.0 g/m2 in 500-mL D5W infused i.v. over 3-h period every 12 h twice daily, days 1, 3, 5 (total, six doses)
Before each dose, patients must be evaluated for cerebellar dysfunction; if present, stop drug and do not resume; one way to monitor cerebellar function is to have patients sign name on sheet of paper before each dose; for significant change in signature, physician should evaluate patient before any further therapy is given
To avoid chemical keratitis, administer dexamethasone eye drops, 0.1% 2 drops OU q6h starting 1 h before first dose and continued until 48 h after last dose
APL regimensc
ATRA+ATO regimen:
Remission induction: Daily ATO (0.15 mg/kg) IV, plus oral ATRA (45 mg/m2) until morphologic CR or for a maximum of 60 days
Consolidation therapy: ATO(0.15 mg/kg) IV, 5 days per week, 4 weeks on 4 weeks off, for a total of 4 courses, and ATRA (45 mg/m2) daily 2 weeks on and 2 weeks off for a total of 7 courses
ATRA+Chemotherapy:
Remission induction: IV idarubicin (12 mg/m2/day) on days 2, 4, 6, and 8 plus daily oral ATRA (45 mg/m2) until morphologic CR or for a maximum of 60 days
Consolidation therapy: 3 consolidation courses consisting of idarubicin 5 mg/m2/day on days 1–4 (first cycle), mitoxantrone 10 mg/m2/day on days 1–5 (second cycle), and idarubicin 12 mg/m2 on day 1 (third cycle). Additionally, ATRA 45 mg/m2/day is given simultaneously with chemotherapy from day 1 to day 15 during each consolidation cycle
Maintenance therapy: 2-year maintenance therapy with oral 6-mercaptopurine 50 mg/m2/day, intramuscular methotrexate 15 mg/m2/week alternating with ATRA 45 mg/m2/day given for 15 days every 3 months
AML, acute myelogenous leukemia; ara-C, cytosine arabinoside.
aFrom Bloomfield CD, James GW, Gottlieb A, et al. Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B. Blood 1981;58:1203–1212, and Bob L, Gert JO, Wim van P, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009;361:1235–1248, with permission.
bFrom Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994;331:896, with permission.
cFrom Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111–121, with permission.
Patients will invariably relapse if they do not receive additional therapy after achieving CR. In contrast, postremission treatment can result in a cure rate of up to 40%. Commonly used consolidation strategies include high-dose cytarabine (HDAC) or allogeneic stem cell transplantation. HDAC (Table 27-4) can overcome resistance to conventional doses of the drug, producing CR in approximately 40% of patients with resistant leukemia. On this basis, trials of HDAC consolidation for AML in first CR (CR1) were carried out. The value of HDAC consolidation was demonstrated in a CALGB trial, which randomized 596 patients in CR1 to consolidation with four cycles of conventional-dose (100 mg/m2/day × 5 days), intermediate-dose (400 mg/m2/day × 5 days), or high-dose (3.0 g/m2, total of six doses over 5 days) cytarabine. Among patients less than or equal to 60 years old, 4-year progression-free survival was 44% for HDAC consolidation versus 24% for conventional-dose cytarabine. Patients older than 60 did poorly regardless of the type of consolidation they received, with fewer than 20% achieving durable remission. The subgroup analysis of this trial underlines the critical role of cytogenetics for predicting the outcome of consolidation therapy for AML. The estimated likelihood of cure among patients with favorable cytogenetics (t[8;21] and inv16) who received HDAC was 84% versus less than 25% for patients with unfavorable cytogenetics.
HDAC can produce significant neurotoxicity, primarily cerebellar dysfunction and, less commonly, somnolence or confusion. Cerebellar function should be assessed before each dose, and the drug should be stopped if there is evidence of neurotoxicity. A sensitive way to assess cerebellar function is to ask the patient to sign his or her name on a signature record before each dose. Another unique toxicity of HDAC is keratitis, which can be prevented by administration of dexamethasone eye drops, 0.1%, two drops to each eye every 6 hours, from the time treatment is started until 48 hours after HDAC ends. Other potential toxicities of HDAC include an erythematous rash, often worse on the palms and soles, and hepatic dysfunction.
Several trials have examined the role of consolidation with allogeneic transplantation for patients younger than 55 to 60 years with AML in CR1. In these studies, transplantation was associated with improved leukemia-free survival compared with chemotherapy. However, the studies did not consistently show improvement in OS, probably because transplantation is associated with higher treatment-related mortality and because some patients who relapse after consolidation chemotherapy can be salvaged with transplantation. These trials also found that cytogenetic risk group was the major determinant of survival, regardless of whether consolidation was with chemotherapy or transplantation.
The available data from clinical trials allow therapeutic recommendations to be made for some groups. Because 60% to 70% of patients with AML and favorable risk achieve 3-year survival with intensive consolidation that includes HDAC, chemotherapy is the treatment of choice for this group. On the other hand, patients with poor risk have a very low disease-free survival with conventional chemotherapy. For these patients, allogeneic transplant in CR1 is the treatment of choice, if a matched sibling or matched unrelated donor (MUD) can be identified. Optimal treatment for patients with intermediate risk is not clear. Consolidative chemotherapy and allogeneic stem cell transplantation are both accepted postremission strategies for intermediate-risk patients.
When patients with AML relapse after conventional chemotherapy, they generally do so within 3 years. The risk of relapse more than 5 years after diagnosis is 5% or less. For patients with relapsed AML and for those who do not achieve CR despite optimal induction chemotherapy, the only treatment option with curative potential is stem cell transplantation. For patients with an HLA-matched donor, allogeneic transplant is the treatment of choice among those younger than 60. Recent results with reduced intensity regimens suggest that, in the absence of major medical problems, older patients can safely undergo allogeneic transplant. However, relapse is common, and only 20% to 30% of those transplanted in second CR (CR2) are cured. Disease status at transplant (CR2 vs. relapse) and the presence or absence of graft-versus-host disease are the most important prognostic factors.
Because outcomes are poor when patients are transplanted with active AML, an attempt is often made to achieve CR before transplant. Salvage chemotherapeutic regimens for relapsed or refractory disease include HDAC ± an anthracycline, etoposide with mitoxantrone, or fludarabine containing regimens. Participation in a clinical trial is strongly recommended.
Gemtuzumab ozogamicin (Mylotarg), a recombinant, humanized anti-CD33 antibody conjugated to the cytotoxic agent calicheamycin, was approved by FDA in the year 2000 for the treatment of relapsed AML in patients 60 years or older. CD33 is present on leukemic blasts in more than 80% of patients with AML and is also expressed by committed hematopoietic progenitors. When the antibody binds to CD33, calicheamycin is internalized, leading to cell death. Gemtuzumab ozogamicin was removed from the market in 2010 in view of safety concerns raised by a randomized trial.
As soon as the diagnosis of APL is entertained, it is critical to identify and manage APL-associated coagulopathy. Five percent to 10% of patients with APL die of hemorrhagic complications during induction chemotherapy, and approximately half these deaths occur within the first week of diagnosis. Consequently, monitoring DIC with twice-daily serum fibrinogen levels and aggressive replacement with cryoprecipitate (5 to 10 units for fibrinogen less than 100 mg/dL) is common clinical practice during the first weeks of treatment of APL. Patients may also require liberal transfusion of fresh frozen plasma. If coagulopathy or bleeding is present, the platelet count should be maintained greater than 30 to 50,000/μL.
APL is categorized to three risk groups based on white blood count and platelet count: (1) low risk with WBC ≤10,000/μL and platelet count >40,000/μL, (2) intermediate risk with WBC ≤10,000/μL and platelet count <40,000/ μL, and (3) high risk with WBC >10,000/μL. Outcomes of intermediate-risk and low-risk APL are similar when arsenic trioxide (ATO) is used in consolidation treatment; as a result, APL is mainly categorized to high risk with WBC >10,000/μL, and low/intermediate risk with WBC ≤10,000/μL. Treatment of APL has three phases: induction, consolidation, and maintenance. The goal of induction treatment is morphologic CR. Molecular CR (absence of PML/RAR-α in bone marrow by RT-PCR) is the goal of consolidation.
A distinguishing feature of APL is its sensitivity to ATRA. The advantage of including ATRA in the front-line therapy for APL has now been clearly established in several randomized trials, with CR rates ranging from 72% to 95%, and a 3- to 4-year disease-free survival of 62% to 75%. These studies also found that disease-free survival is improved when ATRA is given concurrently with anthracycline-based chemotherapy. ATRA with an anthracycline, often combined with cytarabine, remains the standard of care for patients with high-risk APL.
In some studies, cytarabine was omitted inconsequently from induction and/or consolidation regimens. Given the lack of randomized trials, long-term results of these trials are needed to clarify the role cytarabine plays in the management of APL. A recent randomized phase III trial (APL0406) compared ATRA plus arsenic trioxide (ATO) with ATRA plus idarubicin in low/intermediate-risk APL. The investigational arm received ATRA plus ATO daily until morphologic CR followed by consolidation with ATO 5 days a week for 4 weeks every 8 weeks for 4 courses and ATRA daily for 2 weeks every 4 weeks for 7 courses. The control arm received ATRA plus idarubicin induction followed by consolidation with ATRA plus idarubicin followed by maintenance treatment with ATRA and low-dose chemotherapy. The CR rate was 100% in the ATRA plus ATO arm and 95% in the ATRA plus idarubicin arm. Two-year event-free survival rates were 97% in the ATRA plus ATO arm and 86% in the ATRA plus idarubicin arm, confirming noninferiority and maybe superiority of ATRA plus ATO for induction and consolidation in low-/intermediate-risk APL. On the basis of these results, ATRA plus ATO and ATRA plus idarubicin are both acceptable induction regimens for low-/intermediate-risk patients, but ATRA plus ATO is often preferred for its efficacy and tolerability.
Maintenance is the final phase in APL treatment. Several studies have shown that the addition of maintenance therapy with ATRA and/or chemotherapy after intensive postremission consolidation is associated with improved disease-free and overall survival. However, many questions remain unanswered. There is controversy regarding the benefit of maintenance therapy in APL patients who receive ATO as a part of consolidation and are in molecular CR after consolidation. Additionally, the optimal maintenance regimen is still unknown. In one study, the combination of ATRA (45 mg/m2/day, 15 days every 3 months) with 6-mercaptopurine (90 mg/m2/day, orally) and methotrexate (15 mg/m2/week, orally) was associated with the lowest relapse rates, especially for APL patients with a high WBC. An approach for the treatment of patients with newly diagnosed APL is summarized in the algorithm in Figure 27-1.
Initial response evaluation to induction treatment should be done by bone marrow aspiration and biopsy upon count recovery (approximately 5 weeks after the start day of induction). Owing to differentiation effects of ATRA, early response evaluation (day 14 bone marrow biopsy) will be misleading. The goal of induction treatment is morphologic CR. Cytogenetic studies are usually normal at this time. PCR for PML/RAR-α is usually positive at this time and is not considered induction failure. Molecular CR (PCR negativity) is the goal of consolidation treatment; therefore, evaluation for molecular CR should be done after at least 2 cycles of consolidation. Patients who have not achieved a molecular remission at the completion of consolidation should receive salvage therapy (discussed in the subsequent text). RT-PCR should be used to monitor for disease relapse, and the emergence of a detectable PML-RARα transcript is reason to consider salvage therapy.
The two most important factors affecting CR rates and survival in patients with APL are age and the WBC at diagnosis. Age younger than 30 and WBC less than 5,000 to 10,000/μL are favorable prognostic factors. In contrast, several other biologic features such as the type of PML-RARα isoform, additional karyotypic abnormalities, and expression of the reciprocal RARα-PML transcript do not appear to influence outcome. Recent data suggest that the expression of CD56 antigen on promyelocytes is associated with an increased risk of relapse.
Although ATRA is usually well tolerated, some patients develop a unique complication called retinoic acid syndrome (RAS). RAS occurs usually early after initiation of ATRA (7 to 12 days) and is diagnosed on clinical grounds. It is characterized by unexplained fever (80%), weight gain (50%), respiratory distress (90%), lung infiltrates (80%), pleural (50%) or pericardial effusion (20%), hypotension (10%), and renal failure (40%). RAS is the most serious toxicity of ATRA and is often, but not always, associated with the development of hyperleukocytosis. Its incidence varies from 6% to 25%, and mortality is variable (7% to 27%). The best approach to predict, prevent, or treat this syndrome has not been established. Early institution of corticosteroids (dexamethasone, 10 mg i.v. twice daily) simultaneous with cytoreduction (induction chemotherapy or hydroxyurea) is associated with rapid resolution of the syndrome in most patients. Discontinuation of ATRA is common practice after onset of RAS. RAS has not been observed when ATRA was given as maintenance therapy.
Figure 27-1. Proposed algorithm for patients with newly diagnosed APL (acute promyelocytic leukemia), ATRA, all-trans-retinoic acid.
Approximately 10% to 25% of patients treated with ATRA-based therapy ultimately relapse. The duration of first CR and the achievement of a second PCR-negative remission after reinduction have been shown to be prognostic determinants. The first choice for salvage therapy is usually ATO. In a U.S. trial, 85% of patients treated with relapsed APL treated with ATO achieved a CR, 91% of whom had a molecular remission. However, most patients will relapse without additional therapy, which may include additional course of ATO, chemotherapy, and/or autologous or allogeneic stem cell transplantation. Toxicities of ATO include QT prolongation, which rarely may lead to torsades de pointes, and APL differentiation syndrome, which is similar to RAS.
Patients with APL who undergo autologous stem cell transplantation while in second remission have a 30% 7-year leukemia-free survival. However, after stratification according to PCR status of the grafted marrow, it appears that patients transplanted with PML-RARα–negative marrow cells are more likely to have prolonged clinical and molecular remissions. In contrast, relapse after autologous transplant is inevitable in patients with persistently positive PCR after reinduction and consolidation therapy. Allogeneic stem cell transplantation may be the preferable treatment modality in this setting.
Accurate subtyping of ALL is essential for appropriate treatment. Approximately 70% to 75% of patients have B-precursor, 20% to 25% have T-cell, and approximately 5% have mature B-cell ALL. Mature B-cell ALLexpresses surface-membrane immunoglobulin and is characterized by the t(8;14), which results in fusion of the myc oncogene with part of the immunoglobulin heavy-chain gene. Variant translocations involve mycand light-chain genes (t[2;8], t[8;22]). Mature B-cell ALL is the leukemic equivalent of Burkitt’s lymphoma and is arbitrarily defined by the presence of more than 20% blasts in the bone marrow. B-cell ALL/Burkitt is a rapidly proliferating neoplasm, and treatment is often complicated by TLS. Treatment for mature B-cell ALL differs from that for other types of ALL in that intensive chemotherapy is given over a relatively short period (2 to 8 months) without maintenance chemotherapy. Important components of this therapy include high total doses of cyclophosphamide and/or ifosfamide given in fractions over several days along with HDAC and high-dose methotrexate. Addition of the anti-CD20 monoclonal antibody rituximab to the chemotherapeutic regimen appears to improve CR rate and disease-free survival. Intrathecal chemotherapy is included in the therapy of mature B-cell ALL, because without adequate prophylaxis, CNS relapse is common. With an aggressive combination of chemotherapy and intrathecal therapy, 50% to 70% of patients achieve long-term disease-free survival.
Treatment of B-progenitor and T-cell ALL in adults was adapted from regimens developed for high-risk childhood ALL. Therapy is comprised of four components: induction, consolidation, and maintenance, as well as CNS prophylaxis. For induction, combinations of vincristine, prednisone or dexamethasone, L-asparaginase, and an anthracycline result in CR rates of 75% to 90%. Inclusion of cyclophosphamide and cytarabine appears to increase CR rate and remission duration, particularly among patients with T-cell ALL. Standard consolidation therapy includes treatment with several cycles of chemotherapy that include agents used during induction, along with antimetabolites such as 6-mercaptopurine and methotrexate. Several trials have examined the role of intensive consolidation including HDAC and high-dose methotrexate. Patients with Ph+ ALL benefit from the incorporation of a BCR-ABL tyrosine kinase inhibitor (TKI), such as imatinib, into the treatment regimen.
Whereas CNS relapse is very uncommon in AML, in the absence of CNS prophylaxis, the risk of CNS relapse in ALL exceeds 10%; therefore, consolidation therapy has usually included intrathecal chemotherapy and cranial radiation. However, cranial radiation may be associated with long-term neurologic sequelae including impaired cognition. Recent studies indicate that the combination of intrathecal prophylaxis and CNS-penetrating chemotherapy is associated with a risk of CNS relapse similar to that achieved with intrathecal prophylaxis and cranial radiotherapy.
For patients with B-progenitor and T-cell ALL, induction and consolidation usually occupy the first 6 months after diagnosis. Patients then go on to receive maintenance chemotherapy. The most commonly used regimen includes daily oral 6-mercaptopurine, weekly oral methotrexate, a single intravenous dose of vincristine monthly, and 5 days of prednisone/month. Maintenance therapy is continued until 24 to 36 months after diagnosis. With this approach, the likelihood of 5-year disease-free survival is approximately 25% to 50%.
In addition to the importance of cytogenetics in determining the outcome of ALL, presenting white count and age have independent prognostic significance in multivariate models. Another important factor is the rate of clearance of blast cells; patients who achieve CR rapidly are more likely to achieve durable remission. On the basis of data from CALGB, adult B-progenitor and T-cell ALL can be divided into three prognostic groups. Good-risk patients are characterized by all of the following: absence of adverse cytogenetics; age less than 35; presenting WBC less than 30,000/μL; and remission achieved within 4 weeks of diagnosis. These patients have a 50% to 75% likelihood of 3-year disease-free survival with chemotherapy, so that transplant is reserved for relapse. Poor-risk patients are characterized by any of the following: adverse cytogenetics (particularly t[9;22]); for B progenitor, presenting WBC greater than 100,000/μL; more than 4 weeks to achieve CR; and age older than 60. For these patients, 3-year disease-free survival is 0% to 20% with conventional chemotherapy, so that allogeneic transplant is the treatment of choice for patients younger than 60 with histocompatible donors. Older patients may be candidates for allogeneic transplant if they are in good health. Although no randomized trial has been done to evaluate the effect of TKI maintenance after stem cell transplantation for Ph+ ALL, several small studies suggest maintenance TKI results in a better DFS and OS in Ph+ ALL. The remaining intermediate-risk patients represent approximately one-third of all cases of ALL and primarily include patients younger than 60 with B-progenitor ALL. For these patients, chemotherapy is the treatment of choice, because transplantation has not been proven to improve survival.
Most adult patients with ALL will experience disease relapse. Reinduction is most successful if the patient has been in CR for more than 1 year before relapse. Salvage chemotherapeutic regimens can include HDAC, etoposide, or alkylating agents. The araguanosine analog nelarabine is active in relapsed T-cell ALL. As for patients with relapsed AML, allogeneic stem cell transplantation is the only potentially curative therapy for patients with relapsed ALL, and eligible patients who achieve a second remission should proceed as quickly as possible to transplantation.
Over the last several years, there have been significant advances in immunotherapy for ALL. The majority of ALLs are pre-B ALL with more than 90%, 80%, and 50% expressing CD19, CD22, and CD20 respectively. Immunotherapy for ALL can be classified to four categories: (1) naked antibody, (2) Bispecific T cell engagers (BiTE), (3) chimeric antigen receptor (CAR)–based T cell therapy, and (4) immunotoxins. Several studies have shown that adding rituximab to induction and consolidation of CD20+ pre-B ALL improve DFS and OS. Rituximab is currently being evaluated in a randomized trial for patients with Philadelphia chromosome negative CD20+ ALL. The investigational agent blinatumomab, a CD19 BiTE (Bispecific T cell Engagers), is one of the most promising new treatments for ALL. It has demonstrated activity in elimination of minimal residual disease and high rate of CRs in patients with relapsed ALL. CD19 CAR (Chimeric Antigen Receptor)–based immunotherapy is another emerging treatment for ALL. Several early phase studies have shown promising results. Several studies using CD19 immunotoxin are in early phase of development.
The sudden onset of unexplained cranial nerve palsy in a patient with acute leukemia is usually due to CNS leukemia, regardless of whether the CSF shows blasts. Such patients should be treated as described above. Because isolated CNS relapse of leukemia is generally followed soon thereafter by systemic relapse, salvage chemotherapy followed by allogeneic transplant should be considered if patients relapse with CNS involvement.
IV. COMPLICATIONS AND SUPPORTIVE CARE
Poor response to platelet transfusions may occur when leukocyte contamination of blood products results in alloimmunization. Platelet refractoriness can be reduced by transfusing leukoreduced products and minimizing the number of transfusions a patient receives. Patients with poor increments to platelet transfusions may respond to HLA-matched products. Family members are a potential source of HLA-matched products, although the use of products from related donors may increase the risk of rejecting a subsequent sibling-donor allogeneic stem cell transplant.
An effort should be made to prevent transfusion-related infection with cytomegalovirus (CMV) in any patient who is a potential candidate for allogeneic transplant, as reactivation of CMV after allogeneic transplant can result in life-threatening or fatal disease. To this end, CMV-seronegative patients should receive products that have been collected from seronegative donors. If such products are not available, then the risk of CMV transmission may be reduced by leukoreduction of platelet products. Patients who are CMV seropositive may receive blood products from seropositive or seronegative donors.
Antimicrobial prophylaxis during periods of neutropenia and/or immunosuppression can reduce the incidence of some viral, fungal, and bacterial infections. Acyclovir (400 PO t.i.d. or 125 mg/m2 i.v. b.i.d.) is recommended for patients with a history of cold sores or herpes simplex seropositivity. Patients with ALL are treated with a long course of steroids and are therefore at risk for Pneumocystis pneumonia. They should receive Pneumocystisprophylaxis with either trimethoprim/sulfamethoxazole 1 double strength (DS) b.i.d. 2 days/week, dapsone 100 mg daily, or aerosolized pentamidine, 300 mg monthly. During periods of neutropenia or prolonged steroid use, nystatin (15 mL, swish and swallow 5 times a day) or clotrimazole troche (5 times daily) can reduce oral candidiasis. The use of other antibiotics for infection prophylaxis is controversial. Oral fluoroquinolones reduce the risk of infection with gram-negative organisms, but they are associated with an increased risk of gram-positive bacteremia and fluoroquinolone-resistant Pseudomonas aeruginosa. Because prophylaxis with systemic antifungals has not been shown to reduce the risk of treatment-related mortality, their routine use during induction chemotherapy is not recommended.
Fever greater than 38.3°C in a neutropenic patient (ANC less than 500/μL) requires prompt evaluation and treatment, as bacterial infections can become rapidly life-threatening. Blood and urine should be cultured, and empiric broad-spectrum antibiotics (cefepime or ceftazidime, 1 g i.v.) should be administered. Vancomycin should be added for the following indications: severe mucositis, evidence of a catheter-related infection, fever equal to or greater than 40°C, hypotension, or known colonization with resistant streptococci or staphylococci. Patients with allergy to β-lactams may receive aztreonam or a fluoroquinolone with vancomycin. Febrile patients with hypotension or respiratory distress should receive at least one dose of an aminoglycoside antibiotic (gentamicin 5 mg/kg i.v.). When fevers and neutropenia persist for more than 3 days and no source of infection has been identified, empiric antifungal coverage can be added (caspofungin 70 mg i.v. loading dose × 1 then 50 mg i.v. qd or fluconazole 400 mg i.v. qd). Febrile patients with newly diagnosed or relapsed acute leukemia should receive empiric broad-spectrum antibiotics whether or not they are neutropenic.
Once antibiotics are begun, they are continued until neutrophil recovery (ANC greater than 500/μL), even if fever resolves. Otherwise, the choice and duration of antimicrobial therapy is dictated by the source of infection. Bacteremia is treated with a 10- to 14-day course of antibiotics. Indwelling catheters should be removed for fungemia, persistent bacteremia, or Staphylococcus aureus or Pseudomonas bacteremia. Patients with a history of Aspergillus or Mucor sp. infection should receive prolonged antifungal therapy, especially if profound neutropenia is likely during subsequent courses of chemotherapy.
Typhlitis (neutropenic enterocolitis) is a syndrome of right-sided colonic inflammation in neutropenic patients. It presents with fever, abdominal pain, and tenderness that can mimic appendicitis. The etiology is unclear. Treatment is with broad-spectrum antibiotics, including anaerobic coverage, and nasogastric suction. Surgical intervention is reserved for patients with bowel perforation or suspected bowel necrosis.
VI. EPIDEMIOLOGY AND RISK FACTORS. Approximately 13,000 new cases of acute leukemia are diagnosed in the United States each year. The annual incidence of AML is approximately 3.5 per 100,000 and of ALL is approximately 1.5 per 100,000 persons. Although acute leukemia represents only 5% of all new cancer cases, acute leukemia is the most common cause of cancer death for persons younger than 35 years. ALL has a bimodal age distribution. Most cases occur in childhood, with a peak incidence at approximately age 5 years, and there is a second increase in incidence after 60 years of age. The incidence of AML increases steeply beyond 50 years, and the median age is approximately 65 years.
Fewer than 5% of cases of acute leukemia can be attributed to prior exposure to a leukemogenic agent. Ionizing radiation and benzene are clearly associated with an increased risk of acute AML, with an average latency of approximately 5 years. Two classes of chemotherapeutic agents are associated with an increased risk of acute leukemia (secondary leukemia). Alkylating agents can cause AML approximately 4 to 8 years after exposure. AML that arises in this setting is often associated with a preceding MDS and adverse cytogenetics, particularly abnormalities of chromosomes 5 and 7. Topoisomerase II inhibitors such as etoposide or anthracyclines are associated with AML or mixed lineage leukemia (MLL) with a short (1- to 2-year) latency without a preceding hematologic disorder. The most common cytogenetic abnormalities associated with topoisomerase II inhibitors involve the MLL gene at 11q23. Given the poor prognosis of treatment-related leukemia, allogeneic transplantation in first complete remission (CR) should be considered if a donor is available.
Rare families with a genetic predisposition to acute leukemia have been described, but in the vast majority of cases, there is no clear hereditary risk. However, acute leukemia does occur more frequently in family members than would be expected by chance. Full siblings have an approximately twofold increase in risk, and the concordance rate of infantile leukemias in identical twins has been reported to be as high as 25%. The only infectious agent associated with acute leukemia is human T-lymphocyte leukemia virus (HTLV)-1, which causes T-cell adult leukemia/lymphoma. Congenital disorders that have an increased risk of acute leukemia include Down syndrome, disorders associated with increased chromosomal fragility (Bloom’s syndrome and Fanconi’s anemia), and those associated with immunodeficiency (X-linked agammaglobulinemia and ataxia telangiectasia).
VII. FUTURE DIRECTIONS
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