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Double-hit B-cell lymphomas

Sietse M. Aukema, Reiner Siebert, Ed Schuuring, Gustaaf W. van Imhoff, Hanneke C. Kluin-Nelemans, Evert-Jan Boerma and Philip M. Kluin

Data supplements

Article Figures & Data

Figures

  • Figure 1

    Schematic scenarios for the origin of follicular lymphoma, MCL, BL (MYC-IG single hit lymphomas), and DH lymphomas. (A) Follicular lymphoma; (B) MCL; (C) BCL2+/MYC+ DH lymphoma with 2 scenarios, one with an origin from relatively common benign “follicular lymphoma–like B cells” that can be detected in most healthy persons, and the other from a preexistent follicular lymphoma. (D) CCND1+/MYC+ DH lymphoma with 2 scenarios, one with an origin from rare benign “MCL-like B cells” that can be detected in few healthy persons, and the other from a preexistent MCL. (E) BL; (F) BCL6+/MYC+ DH lymphoma with unknown order of events. For readability possible occurrence of the t(14;18) at later stages of B-cell development (including the GC) and (secondary) involvement of RAG1/2 and/or other mechanisms herein are not displayed in the figure (see “Oncogenes involved in DH lymphomas”). AICDA indicates activation-induced cytidine deaminase; RAG1/2, recombinase activating gene 1/2. Not drawn to scale.

  • Figure 2

    Distribution of morphologies according to breakpoints. For readability of the figure BCL3+/MYC+ and 9p13+/MYC+ DHs (n = 10) are omitted. SH indicates single hit.

Tables

  • Table 1

    Incidence of chromosomal breakpoints in unselected series of diffuse large B cell lymphoma

    StudyN*MYC+ total, n (%)MYC+ SH, n (%)BCL2+/MYC+ DH, n (%)BCL6+/MYC+ DH, n (%)BCL2+/BCL6+/MYC+ TH, n (%)All DH and TH, n (%)All DH & TH / MYC cases, n/N (%)BCL2+ SH, n (%)BCL6+ SH, n (%)
    Barrans et al114 2010245-26435 (14)6 (2)19 (8)3 (1)7 (3)29 (12)29/35 (83)55 (21)64 (24)
    Obermann et al130 20092209 (4)7 (3)1 (0)1 (0)02 (1)§2/9 (22)NANA
    Yoon et al129 2008137-15614 (7)11 (7)1 (1)1 (1)1 (1)3 (3)3/14 (21)3 (2)22 (16)
    Tibiletti et al131 20097412 (16)3 (4)4 (7)4 (7)1 (1)9 (12)9/12 (75)12 (15)30 (39)
    Copie-Bergman et al132 200968-712 (3)2 (3)0000014 (20)21 (30)
    van Imhoff et al133 200658-599 (15)5 (8)3 (5)1 (2)04 (7)4/9 (44)7 (12)14 (24)
    Savage et al128 200913512 (9)9 (7)3 (2)NANANA3/12 (25)NANA
    Klapper et al108 2008#11714 (8)NANANANANANANANA
    • All cases had DLBCL as morphology.

    • SH indicates single hit; DH, double hit; TH, triple hit; and NA, not available.

    • * Number of cases on which FISH was performed; variable numbers because of some failures in individual tests.

    • FISH on conventional tissue sections.

    • FISH on tissue microarray.

    • § Original paper included 1 CCND1+/MYC+ DH that is not shown in table.

    • DLBCL was selected for primary nodal localization.

    • Cases from clinical trials were selected for patients with poor-risk DLBCL.

    • # No FISH for BCL2 and BCL6 was performed in the study.

  • Table 2

    DH and TH lymphomas in the Mitelman database

    DH lymphomasNPercentage of all 326 DH casesMYC-IG fusion, %MYC-IGK or IGL fusion (% of cases with MYC-IG fusion)*
    BCL2+/MYC+203626649
    BCL6+/MYC+2683113
    BCL2+/BCL6+/MYC+53165350
    CCND1+/MYC+34102043
    BCL3+/MYC+52
    9p13+/MYC+41
    BCL3+/9p13+/MYC+ TH10
    Total DH and TH cases326100
    MYC only
        Burkitt lymphoma2059818
        Other lymphomas1586134
        Total689
    • MYC+ indicates 8q24 breakpoint; BCL2+, 18q21; BCL6+, 3q27; CCND1+, 11q13; BCL3+, 19q13; and 9p13+, yet unidentified locus.

    • * One case had a complex t(8;14;22)(q24;q32;q11), another case both a t(8;14)(q24;q32) and t(8;22)(q24;q11). Arbitrarily, both cases were considered as having two MYC-IG events.

  • Table 3

    Clinical features of DH lymphomas

    StudyNo. of DH/total study size (%)DHs with prior history of indolent lymphoma, n/N (%)*Age, median (range)Stage III/IV, n/N (%)LDH > ULN, n/N (%)BM+, n/N (%)CNS+, n/N (%)>1E site, n/N (%)IPI HI-H, n/N (%)
    Bertrand et al40 200710/17 (59)1/10 (10)58 (45-81)7/10 (70)NANANANA5/9 (56)
    Johnson et al15 200954/54 (100)20/54 (46)62 (24-93)41/54 (76)27/54 (50)32/45 (71)§NA19/54 (35)38/54 (70)
    Kanungo et al13 200614/14 (100)None55 (29-72)NA13/14 (93)11/14 (79)3/14 (21)8/14 (57)NA
    Le Gouill et al10 200716/16 (100)4/16 (25)61 (36-73)16/16 (100)16/16 (100)15/16 (94)8/16 (50)14/16 (88)13/16 (81)
    Macpherson et al112 1999#15/39 (38)6/13 (46)65**12/13 (92)8/10†† (80)9/13 (69)NA8/13 (62)9/10 (90)††
    Niitsu et al12 200919/19 (100)None61 (29-79)19/19 (100)19/19 (100)16/19 (84)4/19 (21)12/19 (63)17/19 (89)
    Snuderl et al14 2010‡‡20/20 (100)3/20§§ (15)64 (32-91)18/19 (95)18/18 (100)10/17 (59)5/11 (45)6/20 (30)17/20 (85)
    Tomita et al11 2009‖‖27/27 (100)4/23 (17)51 (36-79)22/23 (96)25/27 (93)15/23 (65)2/23 (9)15/23 (65)20/23 (87)
    • LDH indicates lactate dehydrogenase; ULN, upper limit of normal; BM+, bone marrow involvement; CNS+, central nervous system involvement; >1E, involvement of >1 extranodal site; IPI, International Prognostic Index; HI, high-intermediate (IPI score 3); H, high (IPI score 4 or 5); and NA, no specific information available.

    • * Follicular lymphoma, n = 29; chronic lymphocytic leukemia, n = 1; and low-grade lymphoma (not otherwise specified), n = 8.

    • LDH values available but no ULN provided.

    • IPI not available in 1 case.

    • § Not available in 9 cases.

    • IPI score at least low-intermediate (IPI score 2 or higher). No specific information about distribution between patients in low-intermediate and HI groups available.

    • Involvement of > 1 extranodal site calculation was based on data presented in the original paper.

    • # For the clinical parameters only information for BCL2+/MYC+DH cases (n = 13) was available; for BCL6+/MYC+ DH (n = 2) cases no specific information was available.

    • ** No age-range for DHs available.

    • †† LDH and IPI not available in all cases.

    • ‡‡ For some cases not all clinical parameters were available.

    • §§ Three cases with confirmed preexisting follicular lymphoma.

    • ‖‖ Lymphoma type DH (n = 23), leukemia type DH (n = 4).

  • Table 4

    Treatment and survival of DH lymphomas

    StudyNo. of DH/total study size (%)Treatment regimen*Overall response rate, n/N (%)Median survival, y
    Bertrand et al40 200710/17 (59)NA5/10 (50)< 1§
    Johnson et al15 200954/54 (100)RCHOP (11/54);HDC+/− SCT (6/54); CHOP (23/54); P (14/54)NAHD, 0.26; RCHOP, 1.40; CHOP-like, 0.42; P 0.07
    Kanungo et al13 200614/14 (100)CT-NOS (11); R (1); CT and BMT (1); CT, BMT, and RT (1)NA< 1§
    Le Gouill et al10 200716/16 (100)CEEP/COPADM + Auto-SCT/BEAM (1); CHOP/IVAM (1); COPADM/CYVE (3); COPADM (1); COPADM + Auto-SCT/BEAM (1); COPADM + Allo-SCT/Bu/Cy (1) CEEP/DHAP + Auto-SCT/BEAM (1); RCHOP (4); CHOP (1); Steroids# (1); R-CEEP Allo-SCT/TBI/Cy (1)12/16 (75)0.42
    Macpherson et al112 199915/39 (38)CHOP-variant or cyclophosphamide + MTX (6); HDC +/− SCT (3); P (4)NA0.21
    Niitsu et al12 200919/19 (100)CyclOBEAP (6); CHOP + HD MTX (3); CHOP (4); RCHOP (3), CyclOBEAP + R (3)17/19 (89)1.50
    Snuderl et al14 201020/20 (100)R-ICE + MTX/ASCT (1); CHOP (1); RCHOP (3); RCHOP + MTX (6); RCHOP + MTX + ASCT (1); R-EPOCH + MTX (3); CODOX- + MTX/R-IVAC (3); P (1); NK(1)10/20** (50)0.38
    Tomita et al11 200927/27 (100)CHOP or CODOX-M/IVAC or HyperCVAD (+ R, n = 14; -R, n = 8)††6/23 (26)††0.50‡‡
    • NA indicates not available; RCHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; HDC, high-dose chemotherapy; SCT, stem cell transplantation; P, palliative; R, rituximab; CT-NOS, intensive combination chemotherapy, not otherwise specified; BMT, bone marrow transplantation; RT, radiotherapy; CEEP, cyclophosphamide, etoposide, epidoxorubicin, and cisplatin; COPADM, cyclophosphamide, vincristine, prednisone, doxorubicin, and high-dose methotrexate; BEAM, carmustine, etoposide, cytarabine, and melphalan; IVAM, ifosfamide, etoposide, cytarabine, and methotrexate; CYVE, cytarabine and etoposide; Bu, busulfan; Cy, cyclophosphamide; DHAP, dexamethason, high-dose cytarabine, and cisplatin, TBI, total body irradiation; MTX, methotrexate; CyclOBEAP, cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisone; HD, high dosage; R-ICE, rutuximab plus ifosfamide, carboplatin, and etoposide plus rituximab; ASCT, autologous stem cell transplantation; EPOCH, rituximab plus etoposide, doxorubicin, vincristine, prednisone, and cyclophosphamide; CODOX, cyclophosphamide, vincristine, and doxorubicin; IVAC, ifosfamide, etoposide, and high-dose cytarabine; NK, not known; and CVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone.

    • * For details about the treatment regimens we refer to the original papers.

    • Overall response rate (ORR), complete remission (unconfirmed) + partial response.

    • Dead before treatment, n = 1.

    • § Calculation of median survival is based on data presented in the original paper.

    • Auto-SCT, n = 3; Allo-SCT, n = 1.

    • Given for low-grade B-cell lymphoma, NOS.

    • # Steroids as palliative therapy.

    • ** Therapy ongoing, n = 1.

    • †† Lymphoma-type DH only, n = 23.

    • ‡‡ Twenty-three DH lymphomas and 4 DH leukemias.