Leukemias and Lymphomas
Meghan A. Higman
Robert J. Arceci
Departments of Oncology and Pediatrics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland 21205.
Leukemias and lymphomas constitute approximately 45% to 50% of all childhood malignancies (1), with the majority of the children and adolescents presenting acutely and at times critically ill from the manifestations of their disease. Classification of pediatric leukemias and lymphomas continues to evolve from a morphological classification to rely increasingly on accurate and sophisticated immunophenotypic, cytochemical, and cytogenetic techniques. Table 39-1 outlines the standard World Health Organization (WHO) classification of acute myeloid leukemia. Improved classification has guided advances in disease-specific therapy that have resulted in improved disease-free survival (DFS) and ultimate long-term survival. Table 39-2 outlines a classification of acute myeloid leukemia based on FAB type. Several reviews of the treatment of pediatric hematologic malignancies have been published (2,3,4). Marked improvements in the DFS in children have resulted through the continued efforts of cooperative groups, including the Children’s Cancer Group (CCG) and the Pediatric Oncology Group (POG)—now combined into a single entity, the Children’s Oncology Group (COG). Children treated on trials performed through these groups and similar consortia in Europe have been shown to have a more improved event-free survival than children who are not, and so have become the gold standard for pediatric oncology care. All children with leukemia and lymphoma should be treated according to either a cooperative group protocol or a large, single-institution clinical research protocol, if at all possible. They should be referred for treatment to pediatric cancer centers in which there are concentrations of relevant expertise, access to clinical research protocols, and the support of other subspecialties able to care for the needs of these children.
SUPPORTIVE CARE
Integral to any chemotherapeutic regimen for childhood malignancies including leukemias and lymphomas is effective supportive care in the setting of a center familiar with the care of these children. Improvements in supportive care have allowed for the intensification of chemotherapy and marked improvement in DFS. The delivery of chemotherapy safely and repeatedly, administration of broad-spectrum antibiotics, and close monitoring for end-organ toxicity and infection requires stable central venous access. The most serious chemotherapy-induced problems in the treatment of children with lymphoid malignancies are bleeding, life-threatening infection, tumor lysis syndrome, and leukostasis.
Bleeding usually results from profound thrombocytopenia and can be corrected with leukocyte-poor platelet transfusions. Disseminated intravascular coagulation (DIC) must also be suspected, especially in patients with acute promyelocytic leukemia (FAB M3 AML). The initiation of therapy for M3 AML is a medical emergency in order to avoid complications of uncontrolled bleeding. At the initiation of chemotherapy, DIC may worsen because cell lysis releases intracellular thromboplastin (5). As with other causes of DIC, there is a need to treat the underlying trigger to the coagulation cascade. In the case of leukemia, therapy with either chemotherapy or in the case of M3 AML with differentiation therapy with all-trans-retinoic acid (ATRA) should be initiated. When DIC is present, patients may benefit from the administration of fresh frozen plasma and, in some cases, heparin, low-molecular -weight heparin, or activated protein C has been suggested.
Children with leukemia frequently present with fever and infection at diagnosis and during treatment. Induction therapy for acute myelogenous leukemia (AML) is severely myelosuppressive; the resulting neutropenia is often of long duration and may be complicated by bacterial or fungal infections. Febrile neutropenic patients require an immediate extensive clinical evaluation, including a complete physical exam that includes the perirectal area and cultures of blood and other sites of specific concern. The children should be treated promptly with empiric broad-spectrum antibiotics that cover both Gram-positive and gram-negative bacteria. Antifungal therapy with amphotericin or its liposomal derivatives should be initiated when unexplained fever continues despite the initiation of broad-spectrum antibiotics. More recent studies demonstrate the usefulness of voriconazole in the treatment of suspected or proven aspergillus infection (6). The development of new antifungal agents is expected to improve treatment of fungal infections. Children with lymphoid malignancies are generally given prophylactic antibiotic therapy against Pneumocystis carinii pneumonia. A regimen of trimethoprim-sulfamethoxazole taken 3 days per week is effective for prophylaxis and generally does not add to the chemotherapy-induced myelosuppression. For patients who are sensitive or allergic to trimethoprim-sulfamethoxazole, dapsone, pentamidine (either intravenous or inhaled), and, more recently, atovaquone can be used (7).
TABLE 39-1 WHO Classification of Acute Myeloid Leukemia. | |
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TABLE 39-2 Classification of Acute Myeloid Leukemia Based on FAB Type. | ||||||||||||||||||
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Viral infections that are normally controlled by lymphocytes may be hazardous to individuals undergoing lymphotoxic therapy. Each patient should have titers for varicella-zoster virus (VZV) and, if indicated, HIV measured before receiving blood products and chemotherapy. Treatment with high-dose acyclovir is strongly recommended for all active VZV infections (e.g., chicken pox and herpes zoster) and herpes simplex virus infections. In children with a history of frequent oral ulcers caused by herpes simplex, prophylactic doses of acyclovir or famciclovir is strongly considered during therapy. Patients who have not previously had VZV should receive VZV immunoglobulin within 72 hours of each VZV exposure while on therapy.
Patients with very high white blood cell (WBC) counts (more than 200,000 per mL) are at risk for leukostasis, resulting in life-threatening symptoms including respiratory compromise and central neurologic changes. In symptomatic patients, exchange transfusions or leukapheresis may be indicated to lower the WBC count rapidly. When performed, these measures should be followed promptly by the administration of chemotherapy; otherwise, the blast cell count rises again rapidly. The treatment for patients with high WBC counts may be complicated simultaneously by leukostasis and tumor lysis syndrome.
Tumor lysis syndrome, with hyperkalemia, hyperuricemia, hyperphosphatemia, and hypocalcemia, results from a rapid lysis of leukemic cells and the release of their contents into the serum. This may result from the rapid turnover of dividing cells or killing of the cells with chemotherapy. Evaluations of the renal function, electrolytes, and cell turnover should be performed at presentation of the patient to a medical facility and frequently during the initial phases of chemotherapy. With the administration of allopurinol or rasburicase (8), a recombinant urate oxidase and aggressive hydration, life-threatening electrolyte abnormalities can usually be avoided. Patients who experience oliguria (urine output below 1 mL per kg per hour) may require emergency dialysis, especially if cytoreductive therapy must be initiated before achieving the full effects of preventive measures.
ACUTE MYELOGENOUS LEUKEMIA
AML accounts for 15% to 20% of childhood leukemias (1). AML results from a transformation of a single early hematopoietic cell resulting in the production of an abnormal
population of cells that is morphologically similar to cells early in development. All blast cells in a given patient are the clonal progeny of this one cell of origin. Somatic chromosomal abnormalities can be demonstrated in many cases, and may aid in classifying the type of cell affected and the likelihood of cure with standard therapy. Chromosomal abnormalities may result in the production of a fusion gene and consequent protein such as the translocation of FAB M3 AML, which involves the fusion of a retinoic acid receptor gene with a transcription factor gene called PML. With the exception of M3 AML, the therapy for other forms of AML remains essentially the same among the different morphological subtypes. Subset analyses of national trials continue in an effort to understand an individual’s risks with the plan in future trials to tailor therapy.
population of cells that is morphologically similar to cells early in development. All blast cells in a given patient are the clonal progeny of this one cell of origin. Somatic chromosomal abnormalities can be demonstrated in many cases, and may aid in classifying the type of cell affected and the likelihood of cure with standard therapy. Chromosomal abnormalities may result in the production of a fusion gene and consequent protein such as the translocation of FAB M3 AML, which involves the fusion of a retinoic acid receptor gene with a transcription factor gene called PML. With the exception of M3 AML, the therapy for other forms of AML remains essentially the same among the different morphological subtypes. Subset analyses of national trials continue in an effort to understand an individual’s risks with the plan in future trials to tailor therapy.
Treatment
Therapy for AML can be divided into two phases: an induction phase and an intensive consolidation phase. With intensive myelotoxic chemotherapy, remission is achieved in about 75% to 85% of children with AML (9). Induction chemotherapy rapidly reduces the total body leukemic burden so no clinically detectable disease is apparent by the end of a successful induction phase. Once remission is achieved, consolidation therapy is aimed at eliminating minimal residual disease, with the premise that treatment must be toxic to the bone marrow to kill AML blasts effectively. Studies have demonstrated the lack of benefit of maintenance therapy for the treatment of AML, with the exception of promyelocytic leukemia (10).
Remission Induction
Prognostic factors have not been identified in childhood AML to consistently stratify patients into risk groups that alter their initial therapy. A high WBC count at diagnosis, myelodysplastic changes in the marrow, or cytogenetic abnormalities associated with myelodysplastic syndromes have been generally accepted as poor prognostic factors (11). However, the ability to tailor therapy for the individual remains difficult in this disease and is the focus of ongoing studies.
Remission induction therapy in AML must be intensive enough to induce bone marrow hypoplasia. An exception to this rule may be FAB M3 AML, which may not require bone marrow hypoplasia for remission induction. A number of protocols have been developed to improve remission induction often containing cytarabine and an anthracycline. Studies have demonstrated the benefit of an intensively timed regimen (9). Evaluations by the CCG demonstrated improved DFS by the delivery of chemotherapy in a timed intensive manner, where the therapy is given regardless of peripheral blood white count. The rapid timing of delivery of chemotherapy is altered for uncontrolled or serious infection. Induction therapy results in the clearance of leukemic blasts allowing for the regrowth of normal hematopoietic progenitor cells that were previously displaced from the marrow space by the expanding leukemia. A study performed by the CCG demonstrated the benefit of a timed intensive regimen with 75% of patients obtaining a remission at the completion of two identical cycles of chemotherapy.
Intensive Consolidation Chemotherapy
Consolidation chemotherapy begins after remission induction. In North America, patients with AML who have a human leukocyte antigen (HLA)-identical sibling or 5/6 HLA matched relative are offered allogeneic bone marrow transplantation (BMT) as the preferred consolidation therapy. For patients in first remission who undergo allogeneic transplants for AML, 50% to 70% long-term DFS rates have been demonstrated in several BMT trials depending on risk factors and treatment (12). Individuals who did not have a related allogeneic donor were continued on aggressive chemotherapy and had a 45% to 61% DFS with good long-term follow-up. Many clinical trials that employed similar consolidation chemotherapy protocols reported 30% to 40% DFS rates. Autologous transplants have not demonstrated a survival advantage over standard chemotherapy (12). Alternative donor options may change the role of transplant in the treatment of AML.
Central Nervous System Therapy
As many as 20% to 30% of children with AML have leukemic blasts in their cerebrospinal fluid cytology at diagnosis. Central nervous system (CNS) disease in AML, however, has not been demonstrated to be an independent poor prognostic factor. Patients with AML and asymptomatic CNS leukemia at diagnosis have a failure pattern similar to most patients without cerebrospinal fluid blast cells at diagnosis (13). Intrathecal cytarabine is administered during induction chemotherapy to aid in the treatment of this sanctuary site. In addition, systemic high-dose cytarabine also plays a role in the treatment of CNS leukemia.
Treatment of Relapse
A challenge in pediatric oncology is to design effective therapy for recurrent AML. Relapsed AML is frequently difficult to induce a second remission, especially if the relapse occurs during active chemotherapy. Remission can be reinduced in about 60% to 70% of patients by various regimens (14). Regimens, such as etoposide plus 2-chlorodeoxyadenosine, high-dose cytarabine with or without asparaginase or an anthracycline, and mitoxantrone with cytarabine provide successful reinduction chemotherapy for a significant number of AML patients.
Novel therapies are continually being developed for this population group in order to reinduce remission while minimizing toxicity in this heavily pretreated subgroup. For patients with recurrent FAB M3 AML, ATRA and/or arsenic may provide a remission [for review (15)]. For patients with early bone marrow relapse and an available donor, prompt allogeneic BMT without preceding chemotherapy may be an effective salvage therapy. Frequently, individuals who lack a family donor require additional chemotherapy while an alternative donor is identified for an allogenic transplant. Research is ongoing to identify novel therapies for these patients, including vaccine strategies and development of novel agents.
Novel therapies are continually being developed for this population group in order to reinduce remission while minimizing toxicity in this heavily pretreated subgroup. For patients with recurrent FAB M3 AML, ATRA and/or arsenic may provide a remission [for review (15)]. For patients with early bone marrow relapse and an available donor, prompt allogeneic BMT without preceding chemotherapy may be an effective salvage therapy. Frequently, individuals who lack a family donor require additional chemotherapy while an alternative donor is identified for an allogenic transplant. Research is ongoing to identify novel therapies for these patients, including vaccine strategies and development of novel agents.
Complications of Therapy
The complications of AML therapy are most often the result of intensive chemotherapy-induced bone marrow hypoplasia. Symptomatic anemia and bleeding can be controlled with transfusions of leukocyte-poor, irradiated blood products (i.e., packed red blood cells and platelets). As discussed earlier, all fevers in neutropenic patients need to be evaluated extensively and treated aggressively with broad-spectrum antibiotics and, if required, with the early addition of antifungal (e.g., amphotericin) and antiviral (e.g., acyclovir) agents. Mucositis, vomiting, and diarrhea are common gastrointestinal toxicities. It is extremely important to control the patients’ pain as much as possible. This is frequently accomplished in patients with severe mucocytis with patient-controlled analgesia. Typhlitis is a severe and potentially life-threatening complication that can result in ileus, lower gastrointestinal bleeding, abdominal pain, intestinal perforation, and septic shock. Treatment involves bowel rest, broad-spectrum antibiotics, and intravenous hydration. Surgical intervention during periods of profound neutropenia (less than 200 neutrophils per mL) is reserved for perforation, septic shock, intractable hemorrhage, and acidosis.
CHRONIC MYELOGENOUS LEUKEMIA
Chronic myelogenous leukemia (CML) is rare in children and adolescents. The clinical presentation is similar to that seen in adults and the same mutation is identifiable [t(9;22)]. Currently, children and adolescents with a matched sibling, relative, or a well-matched alternative donor, undergo an allogenic bone marrow transplant. Alpha-interferon with or without cytarabine has been used in this population and was well tolerated, with a small number of patients attaining durable cytogenetic remissions (16). The role of the tyrosine kinase inhibitor, imatinib, in the treatment of young people with this disease is under investigation. The lack of long-term data on the length and durability of the response (17,18) at this time makes it unattractive for long-term therapy for a child or young adult who has an available donor.
Juvenile myelomonocytic leukemia was previously named chronic myelomonocytic leukemia or juvenile chronic myeloid leukemia [for review (19)]. It is a unique and rare leukemia that occurs mainly in infants and small children and lacks the characteristic translocation t(9;22) of CML. It frequently presents with organomegaly and skin involvement. The optimal therapy for these patients has not been defined; however, individuals with an HLA- matched sibling are usually offered this option.
ACUTE LYMPHOBLASTIC LEUKEMIA
Clinical trials have strikingly improved the prognosis of childhood acute lymphoblastic leukemia (ALL) since the mid-1970s, resulting in an overall DFS rate of more than 70% (20, 21). The trials continue to enhance our understanding of the biologic heterogeneity of ALL. Attention is currently directed at identification of diagnostic features that predict high or standard risk for treatment failure. Therapy is tailored to improve DFS and limit long-term effects of therapy.
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