Clinical and biological aspects of aggressive B-cell non-Hodgkin lymphoma in adolescents and young adults

Figures & data

Figure 1 Incidence of NHL subtypes according to age.

Abbreviations: ALCL, anaplastic large cell lymphoma; BL, Burkitt’s lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; LBL, lymphoblastic lymphoma; NHL, non-Hodgkin lymphomas.

Table 1 St Jude’s (Murphy) staging system

Stage	Description
I	A single tumor (extranodal) or a single anatomic area (nodal) with the exclusion of the mediastinum or abdomen
II	A single extranodal tumor with regional node involvement Two single extranodal tumors on the same side of the diaphragm with or without regional node involvement Primary gastrointestinal tumor with or without involvement of associated mesenteric nodes only
IIR	Completely resected intra-abdominal disease
III	Two single extranodal tumors on opposite sides of the diaphragm All primary intrathoracic tumors (mediastinal, pleural, thymic) All paraspinal or epidural tumors regardless of other tumor site All extensive primary intra-abdominal disease Two or more nodal areas on opposite sides of the diaphragm
IIIA	Localized/unresectable intra-abdominal disease
IIIB	Widespread multi-organ abdominal disease
IV	Any of the above with initial CNS and or bone marrow involvement (>25% involvement is defined as acute lymphoblastic leukemia)

Abbreviation: CNS, central nervous system.

Table 2 Ann-Arbor staging

Stage	Description
I	Involvement of a single lymph-node region (I) or of a single extralymphatic organ or site (IE)
II	Involvement of two or more lymph-node regions on the same side of the diaphragm or localized involvement of an extralymphatic organ or site of one or more lymph node regions on the same side of the diaphragm (IIE)
III	Involvement of lymph-node regions on both sides of the diaphragm, which may also be accompanied by localized involvement of extralymphatic organs or site (IIIE) or by involvement of the spleen (IIIS) or both (IIISE)
IV	Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph-node enlargement
B	Unexplained weight loss of more than 10% of the body weight in the 6 months prior Unexplained fever with temperature >38° Night sweats

Table 3 Risk factors classification

French-American- British (FAB)^Citation8	Berlin-Frankfurt- Munster (BFM)^Citation39	Age-adjusted international prognostic index (IPI)^Citation41
		Risk factors Stage Ann-Arbor III–IV LDH > N PS ≥ 2
Group A	R1	Low risk
Resected stage 1 and abdominal completely resected stage II	Stage I or II completely resected	IPI=0
Group B	R2	Low/intermediate risk
All patients not in Group A or C	Stage I or II not resected Stage III with LDH <500 IU/L R3 Stage III with LDH ≥500 to <1,000 IU/L Stage iv with LDH <1,000 IU/L and CNS negative	IPI=1 High/intermediate risk IPI=2
Group C	R4	High risk
Bone marrow disease (≥25% L3 blasts) and or CNS positive	Stage iii or iv with LDH ≥1,000 IU/L and/or CNS positive	IPI=3

Abbreviations: CNS, central nervous system; LDH, lactate dehydrogenase; PS, performance status.

Table 4 DLBCL selected studies including AYA patients

Reference	No of patients	Disease	Age	Treatment	Outcome	Comments
Gerrard et al^Citation42 (p)	23 patients aged ≥ 15 years (total n=140)	Mature B-cell lymphoma (DLBCL: 43%)	Median 10.3 (range 1.8–20)	FAB/LMB 96 Risk Group A	4-year EFS 98.3% 4-year OS 99.2%	Median FU: 50.5 months
Patte et al^Citation43 (p)	102 patients aged 15–21 years (total n=637)	Mature B-cell lymphoma	Median 10.2 (range 2.5–20.5)	FAB/LMB 96 Risk Group B	4-year EFS 92.2% 4-year OS 94.6%	Median FU: 54 months
Cairo et al^Citation44 (p)	27 patients aged 15–19 years (total n=235)	Mature B-cell lymphoma/ALL		FAB/LMB 96 Risk Group C	4-year EFS 79% 4-year OS 82%
Atra et al^Citation45 (p)	112	Mature B-cell lymphoma	Median 8.3 (range 4–19)	UKCCSG9002 (=LMB84)	EFS 83.7% OS 87%	Median FU: 48 months Murphy stage III or IV
Pillon et al^Citation46 (p)	45 patients aged 10–15 years (total n=l44)	Mature B-cell lymphoma (DLBCL: 39)		AIEOP LNH92	EFS 81.8% OS 89.4%	Median FU: 6.23 years Children < 15 years were eligible
Burkhardt et al^Citation5 (p)	55 patients aged 15–18 years (total n=378)	Mature B-cell lymphoma (DLBCL: 55)		NHL-BFM	5-year EFS 79% 5-year OS 86%	Median FU: 4.4 years Female outcome is worse with 5-year EFS 71%
Pfreundschuh et al^Citation49 (a)	413 patients	DLBCL	Median 47 (range 36–55)	MinT trial Patients with aa-IPI 0-1	6-year EFS 74% 6-year OS 90%	Phase III results presented for R-CHOP arm

Notes: (p): pediatric oncology study group; (a): adult’s oncology study group.

Abbreviations: ALL, acute lymphoblastic leukemia; AYA, adolescents and young adults; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; FAB/LMB, French-American-British/Lymphomes Malins B; FU, follow-up; OS, overall survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; UKCCS, United Kingdom Children’s Cancer Study Group.

Table 5 PMBCL selected studies including AYA patients

Reference	No of patients	Disease	Age	Treatment	Outcome	Comments
Coso et al^Citation55 (a)	55 patients aged 16–30 years	DLBCL/PMBCL	Median 26 (range 16–30)	R-CHOP/R-CHOP-like ASCT 58%	5-year EFS 68% 5-year OS 73%	33% of patients were diagnosed with PMBCL
Seidemann et al^Citation56 (p)	30	PMBCL	Median 14.3 (range 1.3–16.7)	NHL-BFM	5-year EFS 70%
Gerrard et al^Citation58 (p)	42	PMBCL	Median 14.3 (range 1.3–16.7)	NHL-BFM	5-year EFS 70%	Treated as intermediate-risk patients
Burkhardt et al^Citation5 (p)	24 patients aged 15–18	PMBCL		NHL-BFM	5-year EFS 57%
Lones et al^Citation57 (p)	20	PMBCL	Median 12.5 (range 4–19)	CCG	5-year EFS 75% 5-year OS 85%
Woessmann et al^Citation67 (p)	15	PMBCL	Median 16 (range 11.5–17.8)	NHL-BFM	2-year EFS 92%	Treated with R-DA-EPOCH
Rieger et al^Citation63 (a)	44	PMBCL	Median 36 (range 27–43)	MinT trial	3-year EFS 78% 3-year OS 89%	Subgroup analysis of the phase III results presented for R-CHOP arm
Dunleavy et al^Citation66 (a)	51	PMBCL	Median 30 (range 19-52)	R-DA-EPOCH	5-year EFS 93% 5-year OS 97%
Savage et al^Citation65 (a)	176 (R-CHOP arm: 96 patients)	PMBCL	NA	R-CHOP/CHOP	5-year TTP: 78% 5-year OS: 88%	Results presented for R-CHOP arm
Vassilakopoulos et al^Citation64 (a)	121 (R-CHOP arm: 76 patients)	PMBCL	31.5	R-CHOP/CHOP	5-year FFP: 81% 5-year OS: 89%	Results presented for R-CHOP arm
Martelli et al^Citation36 (a)	125 (54 patients with FDG-PET/CT CMR)	PMBCL	33	R-CHOP/R-CHOP-like	5-year EFS 98% 5-year OS 100%	Results presented for patients with FDG-PET/CT CMR

Notes: (p): pediatric oncology study group; (a): adult’s oncology study group.

Abbreviations: AYA, adolescents and young adults; ASCT, autologous stem cell transplantation; BFM, Berlin-Frankfurt-Munster; CMR, complete metabolic response; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; FDG-PET, F-fluorodeoxyglucose-positron emission tomography; FFP, freedom from progression; NA, not available; NHL, Non-Hodgkin lymphomas; OS, overall survival; PMBCL, primary mediastinal B-cell lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-DA-EPOCH, dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; TTP, time from treatment progression.

Patte C, Auperin A, Michon J, et al. The Société Française d’Oncologie Pédiatrique LMB89 protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood. 2001;97(11):3370–3379.

 PubMed Web of Science ®Google Scholar

Reiter A, Schrappe M, Tiemann M, et al. Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood. 1999;94(10):3294–3306.

 PubMed Web of Science ®Google Scholar

No author. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329(14):987–994.

 Web of Science ®Google Scholar

Gerrard M, Cairo MS, Weston C, et al. Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin’s lymphoma: results of the FAB/LMB 96 international study. Br J Haematol. 2008;141(6):840–847.

 Web of Science ®Google Scholar

Patte C, Auperin A, Gerrard M, et al. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood. 2007;109(7):2773–2780.

 PubMed Web of Science ®Google Scholar

Cairo MS, Gerrard M, Sposto R, et al. Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood. 2007;109(7):2736–2743.

 PubMed Web of Science ®Google Scholar

Atra A, Imeson JD, Hobson R, et al. Improved outcome in children with advanced stage B-cell non-Hodgkin’s lymphoma (B-NHL): results of the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol. Br J Cancer. 2000;82(8):1396–1402.

 PubMed Web of Science ®Google Scholar

Pillon M, Di Tullio MT, Garaventa A, et al. Long-term results of the first Italian Association of Pediatric Hematology and Oncology protocol for the treatment of pediatric B-cell non-Hodgkin lymphoma (AIEOP LNH92). Cancer. 2004;101(2):385–394.

 Web of Science ®Google Scholar

Burkhardt B, Oschlies I, Klapper W, et al. Non-Hodgkin’s lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols. Leukemia. 2011;25(1):153–160.

 PubMed Web of Science ®Google Scholar

Pfreundschuh M, Trümper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7(5):379–391.

 PubMed Web of Science ®Google Scholar

Coso D, Garciaz S, Esterni B, et al. Large B-cell lymphomas in adolescents and young adults in comparison to adult patients: a matched-control analysis in 55 patients. Leuk Lymphoma. 2014;55(8):1849–1853.

 PubMed Web of Science ®Google Scholar

Seidemann K, Tiemann M, Lauterbach I, et al. Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and adolescent patients: treatment and results from three therapeutic studies of the Berlin-Frankfurt-Münster Group. J Clin Oncol. 2003;21(9):1782–1789.

 PubMed Web of Science ®Google Scholar

Gerrard M, Waxman IM, Sposto R, et al. Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy. Blood. 2013;121(2):278–285.

 Web of Science ®Google Scholar

Lones MA, Perkins SL, Sposto R, et al. Large-cell lymphoma arising in the mediastinum in children and adolescents is associated with an excellent outcome: a Children’s Cancer Group report. J Clin Oncol. 2000;18(22):3845–3853.

 Web of Science ®Google Scholar

Woessmann W, Lisfeld J, Burkhardt B, NHL-BFM Study Group. Therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013; 369(3):282.

 PubMed Web of Science ®Google Scholar

Rieger M, Osterborg A, Pettengell R, et al. Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study. Ann Oncol. 2011;22(3):664–670.

 PubMed Web of Science ®Google Scholar

Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;368(15):1408–1416.

 PubMed Web of Science ®Google Scholar

Savage KJ, Yenson PR, Shenkier T, et al. The outcome of primary mediastinal large B-cell lymphoma (PMBCL) in the R-CHOP treatment era. Blood (ASH Annual Meeting Abstracts). 2012;120(21):303.

 Google Scholar

Vassilakopoulos TP, Pangalis GA, Katsigiannis A, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone with or without radiotherapy in primary mediastinal large B-cell lymphoma: the emerging standard of care. Oncologist. 2012;17(2):239–249.

 PubMed Web of Science ®Google Scholar

Martelli M, Ceriani L, Zucca E, et al. [18F]fluorodeoxyglucose positron emission tomography predicts survival after chemoimmunotherapy for primary mediastinal large B-cell lymphoma: results of the International Extranodal Lymphoma Study Group IELSG-26 Study. J Clin Oncol. 2014;32(17):1769–1775.

 PubMed Web of Science ®Google Scholar