Page 1506 - Hematology_ Basic Principles and Practice ( PDFDrive )

1338 Part VII Hematologic Malignancies

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In addition, with the remarkable activity of brentuximab vedotin and EBV-specific T-cell direct therapy. The advantage of T cell–
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(tubulin inhibitor-conjugated monoclonal anti-CD30) in ALCL, based therapies over antibody therapy is that EBV-specific T-cell
this has led the COG researchers to pursue testing the efficacy and immune reconstitution is restored, thus reducing the risk for disease
toxicity of adding these two targeted biologic agents with standard recurrence. Responses to donor-derived EBV-specific T-cell therapies
ALCL-99 chemotherapy in pediatric patients newly diagnosed with developed at multiple centers for pediatric patients range from 70%
ALCL (ANHL12P1). to 85%. 119,120 Immune-based therapies are generally preferred in
this population because the use of chemotherapy in patients with
LPD post-HSCT is associated with high mortality rates secondary
Relapsed Non-Hodgkin Lymphoma Management to increased infectious complications. However, hydroxyurea- and
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immune-based therapies may be an option for patients with CNS
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There is no standard treatment for relapsed NHL. Treatment usually disease. After SOT, modalities such as radiotherapy or surgical
consists of intensive chemotherapy to induce a complete or partial resection for localized LPD can result in complete remission. One
response, followed by autologous or allogeneic stem cell transplant. study evaluated the efficacy of low-dose cyclophosphamide and
Recent studies suggest that allogeneic transplant may be more effec- prednisone for pediatric patients with PTLD after SOT. Efforts at
tive than autologous transplant for relapsed NHL, particularly for reducing the immune suppression had failed in all patients, and all
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LBL. Outcomes are significantly better for patients with complete had received six cycles. The 2-year EFS and OS were 67% and 73%,
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remission prior to transplant. Radiation may be useful prior to respectively. Subsequently, in a phase II study (COG-ANHL0221),
transplant in selected patients with an incomplete response to the COG evaluated the addition of the CD20 monoclonal antibody
chemotherapy. to the previously reported regimen of low-dose cyclophosphamide and
Outcomes vary by histologic subtype. Relapsed BL and DLBCL prednisone regimen (http://clinicaltrials.gov/show/NCT00066469).
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are often chemoresistant, and survival is only 10% to 20%. The All patients had refractory PTLD after SOT or CD20 EBV PTLD
COG used rituximab, ifosfamide, carboplatin, and etoposide for in pediatric patients following SOT. The study showed that the addi-
salvage therapy in this population, achieving a 60% response rate tion of the CD20 monoclonal antibody to the previously reported
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(complete and partial). Patients who achieve a complete remission regimen of low-dose cyclophosphamide and prednisone had EFS
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should proceed to stem cell transplant. Relapsed LBL is also fre- and OS of 71% and 83%, respectively. Therefore, to build on the
quently chemoresistant, and reported survival is 10% to 40%. 107–109 success of this first cooperative group trial for PTLD, the COG now
Salvage regimens used for ALL may be employed for LBL, and propose to administer “off-the-shelf” third-party allogeneic latent
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nelarabine has demonstrated a 40% response rate in this setting membrane protein cytotoxic T lymphocytes (EBV/LMP-CTLs)
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for T-ALL and T-LBL in a phase II COG study. Survival for to determine its safety and efficacy in combination with rituximab
relapsed ALCL is better than for other NHLs, reaching 40% to in patients with PTLD post-SOT. This would represent the first
60%. 28,107,111 Vinblastine monotherapy as salvage therapy resulted multicenter study of its kind combining antibody therapy with off-
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in a complete remission rate of 83% in one study. Brentuximab the-shelf antigen-specific T-cell therapy for this disease. Finally, for
vedotin, an antibody against CD30, has been used successfully in patients refractory to these low-dose regimens or patients with defini-
adults with relapsed ALCL but has not been well-studied in chil- tive features of malignancy, standard lymphoma chemotherapeutic
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dren yet. Crizotinib, an ALK inhibitor, has also shown promise regimens are used, depending on histological subtype (e.g., BL- vs.
in adults in early clinical trials for patients with relapsed ALCL DLBCL- vs. HL-directed therapy).
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and has shown remarkable results in phase I studies in children.
Autologous transplant has been used successfully for some patients,
but allogeneic transplant may have better outcomes and is preferred HODGKIN LYMPHOMA
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for patients with BM or CNS involvement, early relapse, and CD30
ALCL. 28,105,114 Epidemiology
HL comprises 10% of all lymphomas and approximately 10% of
Posttransplant Lymphoproliferative Disease pediatric cancers and has a bimodal incidence, with one peak at
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15–34 years of age and a second peak in the sixth decade of life. In
Posttransplant lymphoproliferative disease (PTLD) is discussed in children, the highest peak is among 15–19-year-olds (29 per million
other chapters in this book. Therefore, this section serves merely to per year) and is least frequent in children under 5 years of age. There
summarize the issues specific for the pediatric population. The major is an age-dependent sex predominance, with a male predominance in
pediatric populations where PTLD is seen most frequently are children under 5 years old (male:female ratio of 5.3 : 1) and a slight
patients with congenital immune deficiencies or patients after BM or female predominance in children aged 15–19 years (male:female ratio
solid organ transplant (SOT). Further, stem cell transplant recipients of 0.8 : 1). HL (especially the nodular sclerosing subtype) is classically
with underlying immunodeficiencies such as Wiskott-Aldrich syn- associated with higher socioeconomic status, increased incidence in
drome represent an independent risk group for EBV-associated single-family homes, smaller family sizes, and a higher level of
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lymphoproliferative disease (LPD). Patients with primary, congeni- maternal education. In contrast, mixed cellularity HL is inversely
tal immunodeficiencies such as X-linked agammaglobulinemia and related to socioeconomic status. It is commonly postulated that
AT have an incidence of EBV-associated LPD ranging from 0.7% to delayed exposure to some environmental antigen may trigger devel-
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15%. The incidence of PTLD after SOT is higher in children than opment of HL, and that higher rates of certain childhood infections
in the adult population. The disease is heterogeneous, but in children (e.g., varicella, measles, mumps, rubella) are negatively associated
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it is most frequently of B-cell origin and EBV-associated. In the with HL development. HL has been shown to have a genetic pre-
United States, approximately 150 new cases are diagnosed in children disposition, although this is incompletely understood. Siblings of
each year. patients with HL have a two- to ninefold increased risk of developing
Numerous therapeutic approaches to PTLD have been explored HL. There is also an increased risk among parent-child pairs, though
in children, but generally there has been a paucity of multicenter not between spouses, supporting a genetic rather than a uniquely
collaborative studies for this disease. Withdrawal or reduction of environmental predisposition. Environmental factors are nevertheless
immunosuppression is often considered as firstline therapy for PTLD, involved in HL. Approximately 40% of all HL cases in economically
but the choice depends on whether the patient has a recovering developed countries harbor EBV in the Hodgkin and Reed-Sternberg
immune system sufficient to eradicate EBV-infected B cells and on (HRS) cells. EBV positivity of the malignant HRS populations is
stage and disease histology. For the pediatric hematopoietic stem cell more common in children under 10 years of age and is highly associ-
transplant (HSCT) patient, strategies have included reduction in ated with childhood HL with mixed cellularity subtype (approxi-
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immune suppression, rituximab, donor lymphocyte infusions, mately 80% of cases), characteristically seen in developing countries.