5

Selected Hematologic Malignancies and Histiocytoses

Pediatric hematologic malignancies are a heterogeneous group of cancers that begin in blood-forming tissue, such as cells formed in the bone marrow or cells of the immune system. The epidemiology of these malignancies is discussed in Chapter 2. The functional limitations associated with these cancers and their treatments are addressed in Chapter 4. This chapter covers two groups of hematologic malignancies found in children and adolescents—leukemia and lymphoma—as well as the distinct disease histiocytosis, briefly described below:

• Leukemia is a type of cancer that starts in blood-forming tissue, such as the bone marrow, most often in white blood cells. The most common form of pediatric cancer is acute lymphoblastic leukemia (ALL). Acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and juvenile myelomonocytic leukemia (JMML) are also observed.
• Lymphoma is a disease in which cancer cells form in the lymph system, which is part of the body’s immune system. There are two main types of lymphoma—Hodgkin lymphoma and non-Hodgkin lymphoma.
• Histiocytosis is a generic name for a group of syndromes characterized by an elevated level of immune cells called histiocytes. The cause of these syndromes is not known, but they frequently behave like cancer and are treated by cancer specialists.

OVERVIEW

This section provides a general description of several important aspects of the hematologic malignancies and histiocytoses discussed in this chapter. It provides information about the sources for the chapter and describes the general approach to the diagnosis, histology, staging, risk classification, and treatment, as well as common long-term consequences, of leukemia, lymphoma, and histiocytoses.

The main sources for information on hematologic malignancies in this review include the Physician Data Query®, the National Cancer Institute’s comprehensive cancer resource, resources of the Children’s Oncology Group (COG), and manuscripts describing the outcomes of COG clinical trials for the treatment of hematologic malignancies.

The general approach to the diagnosis of leukemia begins with a physical exam and history and specific diagnostic tests. Diagnostic tests include a complete blood count (CBC) with differential. It provides information on the number of different blood cell lines (white blood cells, red blood cells, and platelets), with the differential describing the different types and proportions of the various white blood cells (e.g., neutrophils, leukocytes, lymphoblasts). Other tests include blood chemistry studies, bone marrow aspiration and biopsy, cytogenetic analysis to check for any abnormalities in the chromosomes of the blood or bone marrow cells, immunophenotyping to identify the types of antigens or markers on the surface of the cancer cells, lumbar puncture to check for the spread of leukemia cells to the brain and spinal cord, and a chest x-ray to determine which leukemia cells have formed a mass in the middle of the chest. Treatment for leukemia is driven by risk group: standard (low), high, and very high risk. Risk groups are determined by multiple factors, including age of the patient at diagnosis, white blood cell types and counts, tumor genetics, and spread of disease (PDQ Pediatric Editorial Board, 2020a).

The diagnosis of lymphoma begins with a physical examination and evaluation of symptom history. For childhood Hodgkin lymphoma, additional diagnostic tests include laboratory studies (CBC, chemistries, and markers of inflammation), anatomic and functional imaging, lymph node biopsy for pathologic examination of the tumor cells, and bone marrow biopsy and aspirate (PDQ Pediatric Editorial Board, 2020c). For childhood non-Hodgkin lymphoma, diagnosis involves laboratory studies (CBC, chemistries, and markers of inflammation), lymph node biopsy for pathologic examination of tumor cells, bone marrow biopsy and aspiration, lumbar puncture, anatomic and functional imaging, and liver function tests (PDQ Pediatric Editorial Board, 2020d). Treatment for lymphoma is driven by disease type and risk group.

The general approach to the treatment of histiocytosis begins with a physical exam and history and specific diagnostic tests to establish the pathologic diagnosis. Diagnostic tests may include blood tests, BRAF V600E assessment,

urine tests, bone marrow aspirate and biopsy, radiologic and imaging tests (e.g., computed tomography scan, fluorine F 18-fludeoxyglucose positron emission tomography scan, magnetic resonance imaging), and biopsy (PDQ Pediatric Editorial Board, 2020e). Treatment for histiocytosis is driven by risk group and site of involvement.

DIAGNOSIS, PROGNOSIS, TREATMENT, AND OUTCOMES BY MALIGNANCY

For each of the three types of hematologic malignancy, this section reviews the drivers of risk classification, the therapy, and the expected outcomes of that therapy. Annex Tables 5-1 and 5-2 summarize the diagnostic, prognostic, and treatment information for each of the malignancies discussed.

Leukemia

Acute Lymphoblastic Leukemia

As noted, ALL, also called acute lymphocytic leukemia, is the most common hematologic malignancy in childhood. ALL is an aggressive type of leukemia that is characterized by the presence of too many premature white blood cells, called lymphoblasts, in the bone marrow and peripheral blood. These lymphoblasts stem from either B lymphocytes or T lymphocytes. The malignancy can spread to the lymph nodes, spleen, liver, central nervous system (CNS), testes in boys, and other organs. ALL often presents with fever, easy bruising or bleeding, petechiae, fatigue, and/or bone pain. It is confirmed through bone marrow biopsy demonstrating that greater than 25 percent of the bone marrow is replaced by lymphoblasts (PDQ Pediatric Editorial Board, 2020a). Of note, patients with B or T lymphoblasts identified in a lymph node or occupying more than 25 percent of the bone marrow are diagnosed with acute lymphoblastic (or lymphocytic) lymphoma, whose outcomes and treatment mirror those of patients with ALL.

ALL has been categorized by the COG as standard (low), high, and very high risk for relapse (Schultz et al., 2007). Risk groups are determined by age at diagnosis, white blood cell count, B or T lymphoblast subtype, tumor genetics, presence of lymphoblasts in the cerebrospinal fluid (CSF), and initial response to therapy. Additional prognostic features have been identified and are increasingly used to determine risk categorization and guide treatment choices. These features include using gene expression profiling and molecular methods to determine the likelihood of minimal residual disease (MRD) after therapy. Subtypes such as early T cell precursor phenotype or Philadelphia-like genotype are associated with worse survival outcomes (Jain et al., 2016; Roberts et al., 2018).

Approximately 98 percent of children with ALL will attain remission. Among patients aged 1–18 years with newly diagnosed ALL treated with current protocols, approximately 85 percent are expected to be long-term event-free survivors, with more than 90 percent surviving 5 years (PDQ Pediatric Editorial Board, 2020a). However, subsets of patients with high- and very high-risk features do have survival rates significantly lower than 85–90 percent (Hunger et al., 2012; Shultz et al., 2007).

Treatment for ALL includes combination chemotherapy given in different phases over the course of 2–3 years. Treatment regimens are tailored for risk groups. Initial treatment includes induction, followed by consolidation/intensification, followed by maintenance. Treatment cycles are approximately every 4–8 weeks. Induction and consolidation/intensification include both inpatient and outpatient delivery of treatment. Maintenance therapy is given primarily on an outpatient basis. Chemotherapy is administered orally, intravenously, and intrathecally (directly in the spinal fluid). Cranial or craniospinal radiation is used in high-risk and very high-risk patients who have leukemic cells identified in the CSF.

One key to improving outcomes in ALL is early detection of certain targetable genetic abnormalities, including the BCR-ABL fusion kinase inhibited by imatinib (see Chapter 3 and Annex Table 3-4) and other, similar genetic changes that drive growth and can be effectively blocked using a small-molecule targeted inhibitor added to standard therapy. Also critical has been the advent of newer technologies that can detect up to 1 leukemic cell in up to 10,000 cells (so-called MRD), such that if the malignancy is still present at the end of the first phases of treatment, early intensification of therapy can be used in an effort to reduce the risk of recurrence. There are varying approaches to patients with refractory or relapsed disease, depending on the biology and genetics of the subtype, the time of relapse, and the number of relapses. These treatments may include further multi-agent chemotherapy, stem cell transplantation, and/or chimeric antigen receptor (CAR) T cell therapy.

Substantial advances have been made in the development of immunotherapies for children and young adults with relapsed or treatment-refractory ALL that target surface antigens (markers) present on leukemia cells (Barsan et al., 2020). The U.S. Food and Drug Administration’s (FDA’s) approval of the CD19-targeted CAR T cell therapy tisagenlecleucel for relapsed or refractory B cell ALL in patients up to 25 years of age, based on a response rate of 81 percent, serves as one example (Maude et al., 2018). Trials of CAR T cell therapies that target other cell surface markers expressed on leukemia cells (CD22) or several surface markers simultaneously (CD19 and CD22) and are designed to overcome treatment resistance are ongoing. Monoclonal antibody therapies, such as inotuzumab ozogamicin, a conjugate of a CD22 antibody and a toxin that kills leukemia cells, are

another approach to targeting leukemia cells. Inotuzumab ozogamicin has generated substantial responses, including complete remission, in adults and children with refractory ALL. It is approved by FDA for adults with refractory B-ALL, and studies in children are ongoing. Blinatumomab is an anti-CD19/anti-CD3 bispecific monoclonal antibody that has been found to be superior to standard chemotherapy alone for children with high- or intermediate-risk relapsed B-ALL with respect to both survival and side effect profiles, with a higher rate of undetectable residual disease enabling more patients to proceed to stem cell transplantation. While a proportion of children do relapse after receiving these new immunotherapies, the achievement of complete remission is a major advance, meaningfully prolonging life and improving quality of life for children with no other effective treatment options, offering the chance for hematopietic stem cell transplantation in some patients, and providing long-term disease control in others.

With increasing success in the treatment of ALL, therapies have been modified to address the impact of late effects in long-term survivors of ALL. ALL treatment protocols almost always include high-dose glucocorticoids in combination with vincristine, mercaptopurine, methotrexate (MTX), asparaginase, anthracyclines, and topoisomerase II inhibitors. Currently, most long-term ALL survivors have lower risk of significant late effects based on their cumulative exposure to any individual therapy. In the 1970s and 1980s, cranial or craniospinal irradiation was used for prophylaxis at doses of 24 or 18 Gy, but with recognition of late effects (including growth impairment, pituitary deficiency, obesity and metabolic syndrome, and cataracts, as well as secondary malignant neoplasms [SMN]), radiation was reduced or eliminated in favor of higher-dose systemic therapy and intensive intrathecal (IT) therapy. Currently, SMN are most often observed in the small minority of patients exposed to cranial radiation or total-body irradiation. MTX and corticosteroids (as well as cranial irradiation) are associated with neurocognitive deficits, including impairment to executive function (see Chapter 4). Steroid exposure is associated with osteonecrosis/avascular necrosis (see Chapter 4). Most ALL survivors are exposed to anthracyclines, which are associated with left ventricular dysfunction, although most survivors treated with modern therapy receive doses (<250 mg/m²) posing lower risk of this late effect. Alkylators are associated with impairment of fertility, although overall cumulative exposures in current up-front therapies are low risk for this outcome. The risk of alkylator-associated late effects increases in survivors exposed to relapse therapy or stem cell transplantation.

Acute Myeloid Leukemia

AML is characterized by malignant transformation of myeloid cells. Presenting signs and symptoms are similar to those of ALL: fever, easy

bruising or bleeding, petechiae, fatigue, and/or bone pain. To meet the criteria for leukemia, a bone marrow biopsy must consist of >20 percent leukemic blasts. The World Health Organization classification system has been expanded since its inception to include specific gene mutations in 2008 and leukemia biomarkers in 2016. With emerging technologies aimed at providing improved morphologic, immunophenotypic, and genetic data, AML classification is expected to continue to evolve to provide prognostic and biologic guidelines for clinicians (Arber et al., 2016). Importantly, risk factors for AML include elevated white blood count at diagnosis, pathologic subtype (acute promyelocytic leukemia is more favorable), Down syndrome (more favorable), and response to therapy/MRD.

Three-year survival rates for AML are fair, at about 65 percent (Gamis et al., 2014). Patients with the subtype acute promyelocytic leukemia have survival rates of 75–80 percent (Bally et al., 2012) but can be at increased risk of severe bleeding complications, including stroke, at the time of diagnosis.

Treatment for pediatric AML includes high-dose multi-agent chemotherapy with or without allogeneic stem cell transplantation. Treatment includes CNS-directed therapy, with IT chemotherapy included in most pediatric AML protocols. Treatment usually entails induction to induce remission followed by consolidation/intensification. The decision on stem cell transplantation is determined by genetic markers and response to therapy, both initially and for patients who relapse. Given the profound myelosuppression associated with AML therapies, patients are often hospitalized for the great majority of their 4–5 months of treatment. Some AML subtypes have biomarkers or genetic markers that indicate the addition of therapy with monoclonal antibodies or targeted agents (e.g., sorafenib; see Chapter 3, Annex Table 3-4). Based on the successes of CAR T cell therapy in ALL, clinical trials with this therapy for relapsed AML are ongoing or in development (Mardiana and Gill, 2020). Advances in supportive care, including use of hematopoietic growth factors and antifungal and antimicrobial prophylaxis, have improved the outcomes of pediatric AML. The approach to acute promyelocytic leukemia includes all-trans retinoic acid (ATRA) and arsenic with or without anthracycline chemotherapy, followed by maintenance therapy. The treatment for acute promyelocytic leukemia lasts about 5–6 months, followed by 2–3 years of maintenance. For the most part, therapy for acute promyelocytic leukemia is delivered in the outpatient setting. ATRA is given orally, and arsenic is given by intravenous infusion.

Risk of late effects in AML patients is associated with the cumulative doses of chemotherapy and, for those undergoing stem cell transplantation, exposure to total-body irradiation. Most AML patients receive high doses of anthracycline chemotherapy (>300 mg/m²), which is associated with left ventricular dysfunction. Second cancer risk includes therapy-related AML/MDS in some

patients exposed to epipophyllotoxins or alkylators and solid tumors, observed most often in patients treated with total-body irradiation.

Myelodysplastic Syndrome

MDS is a heterogenous group of disorders characterized by inappropriate bone marrow production of blood cells, resulting in decreased levels of white blood cells, red blood cells, and platelets. MDS is diagnosed by bone marrow biopsy and aspirate that show both decreased production and dysplastic (abnormal) features of the cells that make up the bone marrow. While the etiology of MDS in children is not entirely clear, it is often associated with bone marrow failure syndromes (e.g., Fanconi anemia, Diamond-Blackfan anemia, dyskeratosis congenita, and congenital neutropenia, among others). In cases of MDS in which a genetic abnormality is identified in the bone marrow cells, transformation to AML is likely. Given the frequency with which MDS evolves into AML, patients with MDS are most often treated with stem cell transplantation before that transformation occurs.

Chronic Myelogenous Leukemia

CML is the most common chronic myeloproliferative disorder in childhood, although it occurs primarily in adults. Most cases of pediatric CML occur in children over the age of 6. CML involves all the bone marrow (blood) cell lines. While the white blood count in patients with CML can be extremely elevated, their bone marrow does not indicate increased leukemic blasts during the chronic phase of the disease. CML is caused by the presence of the Philadelphia chromosome, and is diagnosed when a translocation between chromosomes 9 and 22 ([t(9;22)]) resulting in a fusion of the BCR and ABL1 genes is identified in the bone marrow or peripheral blood (PDQ Pediatric Editorial Board, 2020b) (see Chapter 3). Treatment includes indefinite tyrosine kinase inhibitor therapy, given orally on an outpatient basis. Patients who have an inadequate response to tyrosine kinase inhibitors or have advanced-phase disease are treated with allogeneic stem cell transplantation. The 5-year survival rate is about 80–90 percent (Deininger et al., 2009). The late effects of tyrosine kinase inhibitors are not yet well established in long-term survivors.

Juvenile Myelomonocytic Leukemia

JMML presents with hepatosplenomegaly, lymphadenopathy, fever, and skin rash, along with an elevated white blood count and increased circulating monocytes. JMML is the most common myeloproliferative syndrome in young children, occurring at a median age of just under 2 years. Patients

often present with an elevated hemoglobin F, hypersensitivity of the leukemic cells to granulocyte-macrophage colony-stimulating factor, monosomy 7, and leukemic cell mutations in a gene involved in RAS pathway signaling. Most patients are treated with high-dose chemotherapy and require allogeneic stem cell transplantation. With stem cell transplantation, the 5-year survival rate is about 64 percent (Locatelli et al., 2005).

Lymphoma

Hodgkin Lymphoma

Hodgkin lymphoma is a type of lymphoma that originates from lymphocytes and can occur anywhere in the lymphatic system. There are two major types of Hodgkin lymphoma: classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. In classical Hodgkin lymphoma, nodular-sclerosing is the most common subtype, followed by mixed cellularity, lymphocyte-rich, and lymphocyte-depleted. Children less than 14 years of age have a higher prevalence of nodular lymphocyte-predominant and Epstein-Barr virus (EBV)-associated mixed-cellularity disease. Most commonly, patients present with painless adenopathy in the supraclavicular or cervical area. Mediastinal disease is present in about 75 percent of adolescents with the disease (PDQ Pediatric Editorial Board, 2020c). In 15–20 percent of patients, extranodal involvement is seen, most commonly in the lung, liver, bones, and bone marrow (stage IV) (PDQ Pediatric Editorial Board, 2020c). Diagnosis is made by finding Hodgkin cells, such as multinucleated Reed-Sternberg cells, in lymph nodes. Childhood Hodgkin lymphoma is categorized as low, intermediate, or high risk. These risk groups, although not entirely consistent across clinical trials, are determined by a combination of stage, presence or absence of bulk disease, and presence or absence of B symptoms (fever, weight loss, night sweats).

Approximately 90–95 percent of children with Hodgkin lymphoma can be cured (Friedman et al., 2014; Giulino Roth et al., 2015; Kelly et al., 2019), which has driven the therapeutic focus to ensuring that long-term morbidity is concurrently minimized in these patients. Treatment programs use a risk-based and response-adapted approach in which patients receive multi-agent chemotherapy with or without low-dose involved-field, involved-site, or, more recently, involved-node radiotherapy (Friedman et al., 2014; Keller et al., 2018; Kelly et al., 2019; Nachman et al., 2002). Duration of treatment depends on risk group (2–4 months for low-risk, 4–5 months for intermediate-risk, and 5–6 months for high-risk disease), and use of radiotherapy is determined by both initial response to chemotherapy and presence of bulk disease at presentation. Survival for low- or intermediate-risk Hodgkin lymphoma is excellent, and survival for high-risk Hodgkin

lymphoma is still very good (>80 percent) (Kelly et al., 2019). The targeted agent brentuximab vedotin and immunotherapeutic PD-1 inhibitors are being studied in combination with standard therapy in newly diagnosed patients. Importantly, even for those who relapse, rates of salvage (ability to achieve remission after recurrence or progression) exceed 70 percent (Gopal et al., 2015). Salvage approaches include the use of combination chemotherapy, brentuximab vedotin, and PD-1 inhibition. The cure rate following salvage with autologous stem cell transplantation with or without radiotherapy and with or without maintenance brentuximab vedotin is more than 50 percent (Satwani et al., 2015).

Multi-agent chemotherapy for Hodgkin lymphoma is intensive, often being administered over the first 3 days of a 21-day cycle. Patients often experience significant side effects, including fatigue, nausea, vomiting, and risk of fever and neutropenia, which impairs their ability to attend school. While Hodgkin lymphoma is highly curable, the therapy is associated with high rates of chronic health problems and subsequent cancers (Armstrong et al., 2016; Gibson et al., 2018). The highest rates of morbidity are associated with exposure to radiotherapy, but exposure to bleomycin, alkylator chemotherapy, and anthracycline chemotherapy also impacts these risks. Subsequent cancer risks (including but not limited to breast cancer, thyroid cancer, colorectal cancer, and skin cancer) are associated with the field and dose of radiation exposure (Turcotte et al., 2018). Risk of cardiopulmonary dysfunction is associated with both exposure to anthracyclines and bleomycin and chest radiotherapy. Recent studies suggest that cumulative exposures to anthracyclines of more than 250 mg/m² significantly increase survivors’ risk of cardiac dysfunction (Armenian et al., 2015; Mulrooney et al., 2009). Alkylator exposure is associated with an increased risk of endocrinopathy, particularly infertility. Again, increased cumulative exposure to these agents is associated with increased risk of long-term morbidity. The late effects of brentuximab vedotin and PD-1 inhibitors are not well understood in pediatric patients.

Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma can begin in B lymphocytes, T lymphocytes, or natural killer cells.

There are three major subtypes of childhood non-Hodgkin lymphoma: mature B cell non-Hodgkin lymphoma, lymphoblastic lymphoma, and anaplastic large-cell lymphoma. Several other, rarer subtypes are seen in children as well. Mature B cell non-Hodgkin lymphomas include Burkitt lymphoma and Burkitt leukemia, which are different forms of the same disease and are aggressive disorders of B lymphocytes. Burkitt has been linked to infection with EBV (Magrath, 2012), although this infection is more likely to occur in patients in Africa than in those in the United States. Burkitt leukemia/

lymphoma is diagnosed when a sample of tissue is biopsied and a certain change in the MYC gene is found. Another mature B cell lymphoma is diffuse large B cell lymphoma, the most common form of non-Hodgkin lymphoma. It is a type of B cell non-Hodgkin lymphoma that grows quickly in the lymph nodes but can also affect the spleen, liver, bone marrow, or other organs. Diffuse large B cell lymphoma is more likely to occur in adolescents than in children. Still another type of mature B cell non-Hodgkin lymphoma is primary mediastinal B cell lymphoma, which develops from B cells in the mediastinum and may spread to the lymph nodes and distant organs. This disease is more likely to occur in older adolescents. Lymphoblastic lymphoma is a type of lymphoma that affects mainly T lymphocytes and occurs commonly in the mediastinum. Lymphoblastic lymphoma is similar in biology and treatment to lymphoblastic leukemia (see the above discussion of leukemia for diagnosis and treatment). Anaplastic large-cell lymphoma affects mainly T cell lymphocytes. It can form in the lymph nodes, skin, or bone or even the gastrointestinal tract or lungs. Patients with anaplastic T cell lymphoma have a CD-30 receptor on the surface of their tumor cells, and the cells often have mutations in the ALK gene. Other rare types of pediatric lymphoma include follicular lymphoma, marginal cell lymphoma, primary CNS lymphoma, and posttransplant lymphoproliferative disorder (PTLD).

Treatment for non-Hodgkin lymphoma is based largely on the subtype. Mature B cell lymphomas, including Burkitt, diffuse large B cell lymphoma, and primary mediastinal B cell lymphoma, generally are treated with multiagent chemotherapy with or without the anti-CD-20 monoclonal antibody treatment rituximab. These treatment protocols often include CNS-directed therapies with IT chemotherapy. Anaplastic large-cell lymphoma is treated with multi-agent chemotherapy. More recently, targeted therapies including ALK inhibitors and brentuximab vedotin, as well as the immunotherapeutic PD-1 inhibitors, have been introduced in the treatment paradigm for anaplastic large-cell lymphoma, especially in patients with chemotherapy-resistant disease (Prokoph et al., 2018). PTLD is approached with surgery as well as reduction in immunosuppression with or without rituximab and/or chemotherapy. Follicular lymphoma is treated with surgery only or chemotherapy with or without rituximab. Marginal-zone lymphomas can be approached with treatment for the underlying autoimmune condition, surgery alone, radiation alone, or rituximab with or without chemotherapy. Lymphoblastic lymphoma is treated according to leukemia protocols (see the above discussion of leukemia).

Cure rates are favorable in most non-Hodgkin lymphomas. Therapies last 2–6 months and can be intensive. For example, childhood Burkitt lymphoma therapy occurs over 2–3 months. Most of the treatment is delivered in the hospital and is associated with significant fatigue, nausea, vomiting, and risk of fever and neutropenia. Risk of late effects is associated with specific exposures to chemotherapy agents and radiation. Treatment with

high-dose MTX and IT MTX can be associated with neurocognitive impairments, and patients and survivors should be screened for these issues (Ehrhardt et al., 2018; Krull et al., 2016).

Histiocytoses

Langerhans Cell Histiocytosis

In Langerhans cell histiocytosis (LCH), immature dendritic immune cells form tumors that can affect various parts of the body. LCH may involve a single organ (single-system), either at a single site (unifocal) or multiple sites (multifocal), or it may involve multiple organs (multisystem LCH), either affecting a limited number of organs or being disseminated. Specific organs are considered high or low risk when involved at disease presentation, indicating risk of mortality. Involvement of the CNS can be associated with long-term sequelae including diabetes insipidus. High-risk organs include the liver, spleen, and hematopoietic system; high-risk patients are typically less than 2 years old (PDQ Pediatric Editorial Board, 2020e). Low-risk organs include the skin, bone, lungs, lymph nodes, gastrointestinal tract, pituitary gland, thyroid, thymus, and CNS (PDQ Pediatric Editorial Board, 2020e).

Treatment decisions are based on low- versus high-risk organ involvement and the presence of unifocal, multifocal, or multisystem disease. Patients presenting with low-risk skin lesions can be treated with observation, chemotherapy, steroids, or radiation. Bone and other low-risk organs can be treated with curettage, surgery with or without steroids, low-dose chemotherapy, or observation. CNS lesions can be treated with targeted therapy, chemotherapy, retinoid therapy, or intravenous immunoglobulin therapy. Low-risk patients have favorable outcomes. High-risk patients are treated with chemotherapy and steroids and in the event of severe liver disease, liver transplantation. Outcomes for high-risk LCH are fair.

Most children with histiocytoses recover. Chemotherapy agents utilized for LCH include steroids, vinblastine, etoposide, MTX, and Ara-C, among others. Some patients have a characteristic mutation in the BRAF gene that can be targeted with a small-molecule inhibitor. Risk of late effects in survivors is associated with exposures to these agents, as well as late complications of surgeries and exposure to radiotherapy. Refer to Chapter 3 for more information about possible long-term or late effects.

Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder in which histiocytes and lymphocytes build up in organs that may include the skin, spleen, and liver and destroy other blood cells. HLH can be inherited (familial

HLH) or may be caused by certain conditions or diseases, including infections, immunodeficiency, and cancer. In general, HLH has poor outcomes. Treatment includes treating any underlying conditions (e.g., infection) in combination with chemotherapy and immunotherapy, plus allogeneic stem cell transplantation (Henter et al., 2002; Trottestam et al., 2011). The anti-interferon antibody emapalumab is the first FDA-approved therapy for relapsed or refractory HLH.

FINDINGS AND CONCLUSIONS

Findings

5-1 Despite the success of multimodal therapy in treating hematologic malignancies, the acute toxicities of radiation, chemotherapy, and stem cell transplantation remain high.

5-2 The increased survival rates of children with pediatric hematologic malignancies have enabled greater understanding of the long-term and late toxicities of the various modalities of therapy, which impose a high burden in these malignancies.

5-3 Histiocytoses, a disease category distinct from hematologic malignancies, are heterogeneous with respect to their presentation and treatment, which ranges from local intervention (e.g., biopsy, curettage) to stem cell or organ transplantation.

5-4 Several targeted therapies have become standard treatment for newly diagnosed subsets of leukemia and lymphoma.

5-5 Certain immunotherapies have U.S. Food and Drug Administration approval for the treatment of relapsed pediatric leukemia and are being studied for newly diagnosed and relapsed Hodgkin and non-Hodgkin lymphoma.

5-6 Targeted and immunotherapies for pediatric hematologic malignancies offer promise for reducing toxicity and addressing hematologic cancers in patients with limited treatment options.

5-7 Participation in clinical trials is considered the standard of care for many children with hematologic malignancies.

Conclusions

5-1 Clinical trials are needed to improve or maintain survival in children with hematologic malignancies while limiting acute toxicity and mitigating late effects of treatment, including secondary malignant neoplasms (SMN).

5-2 Further studies are required to understand how novel targeted and immunotherapies can be incorporated into the treatment of newly diagnosed as well as relapsed and refractory patients with hematologic malignancies and histiocytoses.

5-3 Although cure rates for hematologic malignancies and histiocytoses are high in many cases, so, too, is the burden of toxicities and late effects, which can lead to functional impairments. Studies to understand late effects of novel therapies and intervention studies to examine mitigation of late effects and SMN in hematologic malignancies are therefore needed.

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ANNEX TABLE 5-1
Selected Hematologic Malignancies and Histiocytoses: Diagnostic and Prognostic Information

ANNEX TABLE 5-2
Selected Hematologic Malignancies and Histiocytoses: Treatment Information

* In addition to the treatment durations listed, which are based on standard treatment protocols, the committee estimates, based on the members’ clinical expertise, that patients typically require an additional 3–18 months to recover from the acute effects of treatment with radiation and/or chemotherapy.

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