Page 1509 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 84 Malignant Lymphomas in Childhood 1341

is owing to the fact that it is usually possible to salvage relapse after some cases, although its role in therapy remains controversial. Novel
161
initial therapy. If salvage therapy for such patients can be targeted approaches include the incorporation of immunotherapeutic agents
and relatively nontoxic (e.g., by using novel agents such as brentux- into multiagent chemotherapy regimens. For example, there is
162
imab), then using a less intense initial regimen may be appropriate. increasing experience with the anti-CD20 antibody rituximab in
65
Currently, however, salvage therapy for the majority of patients is pediatric patients with B-cell lymphomas. A radiolabeled form of
typically more toxic and can lead to an unacceptable incidence of late this product (Yttrium-90; Zevalin) has also yielded promising pre-
+
163
171
events such as cardiac toxicities and secondary malignancies. liminary results in children. CD30 lymphomas such as ALCL,
Therefore, strategies using a less intense frontline regimen should be mediastinal B-large cell lymphoma, and HL are also candidates for
investigated only within the context of a clinical trial. Researchers in CD30 antibody therapy. Novel immunotherapeutic approaches
future clinical studies therefore will attempt to address this important include the use of surface protein–specific cytotoxic T lymphocytes;
issue by evaluating the prognostic significance of achieving PET- this approach is effective in the prevention and treatment of EBV-
negative disease after one or two cycles of chemotherapy and the use related PTLD, NHL, and HL. 119,125 Agents targeting specific molecu-
of frontline brentuximab to replace more toxic modalities such as lar lesions (e.g., the ALK inhibitor for ALCL) are promising and are
bleomycin and radiation therapy. already in phase I studies in children, and the implementation of
anti-idiotype and antisense strategies are also being studied.
The continued investigation of molecular abnormalities and
RARE SUBTYPES OF LYMPHOMA pathogenic mechanisms of malignant transformation associated with
childhood lymphomas is essential. Microchip gene arrays have already
Other subtypes that are observed rarely in children deserve mention, identified clinically relevant subtypes of large B-cell lymphomas in
172
but the rarity of these neoplasms in children make generalizations adults. Gene array analyses of BL, ALCL, and T-lymphoblastic
173
and therapeutic recommendations difficult. Follicular lymphomas disease have also been reported. Similar studies are ongoing for
(characterized by the arrangement of malignant cells in aggregates childhood lymphomas, and preliminary results for T-lymphoblastic
174
separated by normal cells), which account for approximately 30% of leukemia/lymphoma have been published. Flow-sorting tissue for
adult NHLs, are extremely rare in children. Children with follicular HRS and intratumor T cells and optimizing low-input exome
lymphomas tend to present with cervical lymph node involvement sequencing are beginning to overcome the limitations of genomic
175
164
(although primary tumors of the testis have been reported ) with evaluation in HL. Comprehensive molecular characterization of
early-stage disease and have an excellent prognosis. 165,166 Unlike most childhood lymphomas may help to further refine disease classifica-
cases of follicular lymphoma in adults, where aberrant expression of tion, provide a means of detecting minimal residual disease (MRD)
176
BCL2 [usually as a result of the t(14;18) translocation] is thought to during clinical remission, and enhance assessment of early response.
play an important role in lymphomagenesis, the majority of cases of Monitoring is facilitated by the finding that the level of MRD in the
follicular lymphomas in children demonstrate neither the t(14;18) peripheral blood is comparable to that in the BM in children present-
translocation nor BCL2 expression. BCL2 expression appears to ing with advanced-stage lymphomas. Additionally, a more complete
occur more frequently in older children and is associated with understanding of the molecular pathogenesis of pediatric HL and
advanced-stage disease at presentation and a more aggressive clinical NHLs will provide clues to new and better treatments directed
course. 165 toward tumor-specific molecular lesions.
Marginal zone B-cell lymphomas arising in mucosa-associated
lymphoid tissue can arise in extranodal sites. They tend to present
with localized disease and infrequently disseminate. NK cell lym- SUGGESTED READINGS
phoma and NK-like T-cell lymphomas usually involve the upper
aerodigestive tract (midline lethal granuloma, angiocentric T-cell Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab
lymphoma), but they can present in the skin as well. 167–169 They are in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311,
rare in children, follow a very aggressive clinical course, and are often 2015.
fatal, but they may respond to high-dose chemotherapy with stem Attarbaschi A, Beishuizen A, Mann G, et al: Children and adolescents with
169
cell transplant. Peripheral T-cell lymphomas include a variety of follicular lymphoma have an excellent prognosis with either limited che-
neoplasms that have not yet been further specified. These lymphomas motherapy or with a “watch and wait” strategy after complete resection.
are rare in children but in advanced stage at presentation, often in Ann Hematol 92:1537, 2013.
association with systemic symptoms; hemophagocytic syndrome is Bollard CM, Rooney CM, Heslop HE: T-cell therapy in the treatment of
common; and an aggressive course is the rule. post-transplant lymphoproliferative disease. Nat Rev Clin Oncol 9:510,
2012.
Bollard CM, Gottschalk S, Torrano V, et al: Sustained complete responses in
FUTURE DIRECTIONS patients with lymphoma receiving autologous cytotoxic T lymphocytes
targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol
Although there have been dramatic improvements in the treatment 32:798, 2014.
of children with NHL and HL over the past 25 years, approximately Bonn BR, Rohde M, Zimmermann M, et al: Incidence and prognostic
25% of children with these tumors still relapse or fail to respond to relevance of genetic variations in T-cell lymphoblastic lymphoma in
initial therapy. Additionally, late effects such as anthracycline-related childhood and adolescence. Blood 121:3153, 2013.
cardiomyopathy, secondary malignancies such as epipodophyllotoxin- Burkhardt B, Oschlies I, Klapper W, et al: Non-Hodgkin’s lymphoma in
related acute myeloid leukemia, and endocrine abnormalities such as adolescents: experiences in 378 adolescent NHL patients treated accord-
cyclophosphamide-related azoospermia remain a concern. 163,170 Thus, ing to pediatric NHL-BFM protocols. Leukemia 25:153, 2011.
a major task is to develop treatment strategies that provide a cure for Burkhardt B, Reiter A, Landmann E, et al: Poor outcome for children and
the remaining 25% while reducing treatment-related morbidity. adolescents with progressive disease or relapse of lymphoblastic lym-
Several approaches appear promising. phoma: a report from the Berlin-Frankfurt-Muenster Group. J Clin Oncol
The identification of both clinical and biologic features at the time 27:3363, 2009.
of diagnosis that predict treatment failure will enable investigators to Burkhardt B, Woessmann W, Zimmermann M, et al: Impact of cranial radio-
refine existing risk-adapted therapeutic approaches. Strategies to be therapy on central nervous system prophylaxis in children and adolescents
considered for children at high risk for treatment failure include the with central nervous system-negative stage III or IV lymphoblastic
intensification of existing regimens and the incorporation of new lymphoma. J Clin Oncol 24:491, 2006.
active or novel agents. More intensive therapy may require either Campo E, Swerdlow SH, Harris NL, et al: The 2008 WHO classification
autologous or allogeneic hematopoietic stem cell support. The of lymphoid neoplasms and beyond: evolving concepts and practical
administration of colony-stimulating factors may be necessary in applications. Blood 117:5019, 2011.