Plenary Session I B-cell Non-Hodgkin's ... - Wiley Online Library

Plenary Session I B-cell Non-Hodgkin’s Lymphoma Invited Oral Presentations 1 Molecular pathogenesis of Burkitt lymphoma: the role of c-MYC RD Favera Institute for Cancer Genetics, Columbia University, New York, NY, USA Burkitt Lymphoma (BL) originates from the malignant transformation of centroblasts within germinal-centers (GC), the site where B cells are selected for high-affinity antibody production and undergo somatic hypermutation (SHM) and class switch recombination (CSR) of Immunoglobulin (Ig) genes. The key genetic lesion associated with BL development is the chromosomal translocation juxtaposing Ig genes to the c-MYC oncogene, which are present in virtually all cases of BL. Recent results have shed light on the normal role of MYC in normal GC development with implications for its role in lymphomagenesis. MYC displays a biphasic pattern of expression during GC formation, involving its transient induction during early GC commitment, its repression by the BCL6 transcription factor in centroblasts in the GC dark-zone, and its re-induction in centrocytes in the light-zone positively selected for re-entry in the dark-zone for an additional round of antigen selection. Inhibition of MYC in vivo leads to GC collapse in mice, indicating an essential role of re-entry in the maintenance of GCs. BL-associated translocations override BCL6mediated repression in the dark-zone, and notably, uncouple MYC expression from positive selection. Thus Ig/MYC translocations may allow B cells to bypass affinity-based selection signals and impose a continuous re-entry phenotype that, by perturbing normal GC dynamics, contributes to lymphomagenesis. References: 1. Victora, G.D., Dominguez-Sola, D., Holmes, A.B., Deroubaix, S., Dalla-Favera, R., Nussenzweig, M.C. Identification of human germinal center light and dark zone cells and their relationship to human B cell lymphomas. Blood, in press. 2. Dominguez-Sola, D., Victora, G., Ying, C.Y., Phan, R.T., Saito, M., Gabriel D. Victora, Carol Y. Ying, Ryan T. Phan, Nussenzweig, M.C., Dalla-Favera, R. c-MYC is required for germinal center selection and cyclic re-entry. Nature Immunology, in press.

2 Therapeutic strategies in lymphoma based on oncogenic B receptor signaling LM Staudt Metabolism Branch, Center for Cancer Research, NCI We have used both structural and functional genomics to discover novel pathogenetic pathways in the most common type of nonHodgkin lymphoma, diffuse large B cell lymphoma (DLBCL). The ABC DLBCL subtype has constitutive activation of the NF-kB pathway, which we traced to the signaling adapter CARD11 using the Achilles heel screen. In ~10% of ABC DLBCL tumor biopsies, we discovered recurrent CARD11 mutations that spontaneously activate NF-kB signaling.

We also defined a ‘chronic active’ form of B cell receptor (BCR) signaling that activates NF-kB in ABC DLBCLs with wild type CARD11. Such ABC DLBCLs are killed by knockdown of BCR signaling components, such as the kinase BTK, or components of the BCR itself. Over one fifth of ABC DLBCLs have mutations in the CD79B or CD79A subunits of the BCR. In 18% of cases, mutations occur in a single tyrosine residue in the critical ‘ITAM’ signaling motif, generating BCRs that avoid negative autoregulation by the LYN tyrosine kinase. Importantly, the BCR pathway offers a wealth of targets that can be exploited therapeutically. We have initiated clinical trials in relapsed/refractory ABC DLBCL of ibrutinib, an irreversible and highly selective small molecule inhibitor of BTK. Thus far, ibrutinib monotherapy has induced a high rate of complete and partial responses, including ‘primary refractory’ tumors that had never responded to any prior therapy. One patient has been in a sustained complete response for over 16 months, taking ibrutinib daily with no discernable side effects. Of note, responses have occurred in patients with and without CD79B mutations, suggesting that BCR pathway addiction may be a prevalent feature in this lymphoma subtype. Given its excellent safety profile and selective mechanism of action, ibrutinib can be combined rationally with both chemotherapy and other signaling modulators to achieve cures for these patients.

3 Prevention and treatment of tumor lysis syndrome in the rasburicase era PJ Galardy Division of Pediatric Hematology-Oncology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA Background: Tumor lysis syndrome (TLS) is a potentially lifethreatening metabolic complication that arises prior to, or following, the initiation of systemic chemo– or immuno–therapy in patients with advanced malignancy, particularly those with disseminated nonHodgkin’s lymphoma (NHL). Despite being characterized by rapid cell growth, NHL is often accompanied by high levels of spontaneous or drug-induced apoptotic cell death. While rapid clinical responses to cytotoxic therapy are desirable, this accelerated cell death results in the release of intracellular contents into the circulation including potassium, phosphorous, and genetic material that is metabolically converted into uric acid. The rapid rise in the plasma concentration of these substances may lead to cardiac arrhythmia, seizure, and renal failure. In addition to the acute sequelae of these complications, TLS may temporarily delay continued tumor-directed therapies, thus compounding its impact. Objectives: To review the pathophysiology and current management strategies for the management of TLS. Results: Recent advances in TLS classification have improved the ability to predict patients at risk for more severe complications. Specifically, the recognition of early forms of TLS, and the association of LDH at presentation with the eventual development of clinically important TLS has improved our management of these high-risk

ª 2012 Blackwell Publishing Ltd, British Journal of Haematology, 159, (Suppl. 1), 1–73

doi:10.1111/j.1365-2141.2012.12053.x

Plenary Session I: B-cell Non-Hodgkin’s Lymphoma – Invited Oral Presentations patients. Improved appreciation of disease pathophysiology has led to avoidance of alkalinization, and to a better understanding of the relative benefits of preventing uric acid generation (allopurinol) versus the elimination of existing uric acid (urate oxidase; Rasburicase) in the acute management of TLS. Recent prospective trial data involving the prospective use of Rasburicase in children, adolescents, at high-risk of TLS reveals the ability to rapidly resolve spontaneous hyperuricemia, and a strong effect in preventing the need for assisted renal support following systemic chemotherapy. Conclusions: While it is impossible to prevent spontaneous TLS, advances in management have improved our ability to treat existing disease and prevent new-onset metabolic and renal complications in patients at high-risk for TLS.

4 Treatment and prognosis of childhood and adolescent B-NHL: LMB and BFM perspective C Patte Institut Gustave Roussy, Villejuif, France Background: LMB and BFM protocols are those most commonly used for B-cell lymphoma with successful results. Although patients stratification is slightly different, courses are differently designed and drug dosages are different in the two regimens, drugs are the same: HDMTX, corticosteroid, vincristine, cyclophosphamide (±ifosfamide), ara-C, doxorubicine, ±VP16.

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Purpose: To analyse and compare results, and to evaluate possibility of doing common studies. Method: Data of BFM95 (Blood2005) and ongoing 04 studies, of SFCE part of FABLMB96 (Blood2007, BJH2008) and ongoing LMB2001/03 studies were merged. In parallel, COG made a pilot study showing the safety of adding rituximab to LMB regimen (Cairo, ASH2008/2010) and BFM made an upfront window pilot study showing response ‡25% in 41% of pts after one rituximab injection 5 days before starting chemotherapy (JCO2010). Results: In the pooled study, 691 patients were in LMB (07/96–12/05) and 935 in BFM (04/96–12/05) studies. After exclusion of 42 PMLBL, for LMB and BFM (in this order for the following results), 4 years EFS was 90% and 89% (NS) for all pts, 98% and 97% for st1, 96% and 98% for st2, 92% and 88% (NS) for st3, 85% and 76% (NS) for st4, 81% and 81% (NS) for B-AL, 79% and 72% for the CNS+ (NS). If considering the higher risk patients: st3 with high LDH (>Nx2, or >500), st4 and B-AL, 4 years EFS was 85% (n = 366) and 84% (n = 393). Conclusion: These similar results encouraged designing common study to address the question of rituximab in higher risk patients. Although this goal could not be achieved, an international prospective study, ‘InterB-NHL_2010_ritux’, is currently opening in 12 European, North American, Australian and NewZealand countries randomising rituximab with the LMB regimen. In BFM, further exploration of the potential effect of only one rituximab injection before chemotherapy is considered.


Plenary Session I: B-cell Non-Hodgkin’s Lymphoma – Peer-Reviewed Oral Presentations

Peer-Reviewed Oral Presentations 5 Improved outcomes in CNS-positive pediatric Burkitt lymphoma/leukemia using rituximab plus FAB group C1 chemotherapy without CNS radiation: a Children’s Oncology Group report

6 Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin’s lymphoma and Burkitt leukemia: dose-escalation does not increase the response rate

JK Frazer1, SC Goldman2, L Smith3, L Harrison4, SL Perkins5, MS Cairo4 1 Depatment of Pediatric Hematology/Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; 2 Depatment of Pediatric Hematology/Oncology, Medical City Children’s Hospital, Dallas, TX, USA; 3Depatment of Biostatistics, Children’s Oncology Group, Arcadia, CA, USA; 4 Depatment of Pediatrics, Medicine, Pathology, Microbiology and Immunology, and Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA; 5Depatment of Pathology, University of Utah, Salt Lake City, UT, USA

J Lisfeld1, B Burkhardt1,2, A Meinhardt1, M Zimmermann1, E Kabı´ckova´3, S Bielack4, U Kontny5, A Gnekow6, A Sauerbrey7, A Reiter1 1 NHL-BFM Study Center, Department of Pediatric Hematology/Oncology, Justus-Liebig University Giessen, Germany; 2Department of Pediatric Hematology and Oncology, University Hospital, Muenster, Germany; 3 Department of Pediatric Hematology and Oncology, University Hospital, Prague, Czech Republic; 4Department of Pediatric Oncology, Hematology, Immunology Olgahospital, Stuttgart, Germany; 5Department of Pediatric Hematology and Oncology, University Hospital, Freiburg, Germany; 6 Children’s Hospital, Augsburg, Germany; 7Helios Children’s Hospital Erfurt, Germany

Background: Children and adolescents with CNS+ mature B-NHL have had inferior outcomes (Miles/Cairo, Br J Haematol, 2012). Adding CNS radiation, high-dose Ara-C, and HD-MTX to group C therapy improved 3-yr EFS to 79% in CNS+ patients (Patte, Blood, 2001). FAB/LMB96 replaced CNS radiation with additional HD-MTX and intrathecal treatments, yielding statistically-comparable results (72% 3-yr EFS; Cairo, Blood, 2007). On that study, 55% of CNS+ patients who failed experienced progression/recurrence in non-CNS sites. Added to chemotherapy, the anti-CD20 antibody rituximab has improved adult DLBCL outcomes (Coiffier, N Engl J Med, 2002; Pfreundschuh, Lancet Oncol, 2006). Objectives: COG pilot study ANHL01P1 tested whether adding rituximab to FAB group C1 chemotherapy was safe and efficacious in children and adolescents with CNS+ mature B-NHL. Design: Patients (£21 years) with CNS+ B-NHL received group C1 therapy (Cairo et al., Blood, 2007), as well as four doses of rituximab (375 mg/m2) during induction and twice in consolidation (Cairo et al., ASCO, 2010). CSF blasts, cranial nerve palsy (CNP), intracerebral mass (ICM), and/or parameningeal extension (PME) defined cases as CNS+. Results: Fifteen group C patients (38%) were CNS+; all had Burkitt morphology. Eight patients were CSF+, with six cases CNP+, 4 PME+, and 1 ICM+. Rituximab had no adverse events. Ninety-three percent of CNS+ patients are alive and disease-free. All 7 BM-/CNS+ patients have NED, and only 1/8 BM+/CNS+ cases progressed (combined CNS and systemic disease). Conclusion: Rituximab plus group C1 therapy was well tolerated. Outcomes (93% EFS/OS) in this small cohort indicate that adding rituximab to group C1 chemotherapy without CNS radiation may reduce systemic relapse rates. Large randomized studies are warranted to test this premise in this formerly high-risk clinical group.

Background/Objectives: In a phase II window study rituximab 375 mg/m2 showed activity as single agent in newly diagnosed pediatric B-cell non-Hodgkin’s lymphoma (B-NHL) and Burkitt leukemia (B-AL) with a the response rate (RR) of 41.4% (Meinhardt A et al., J Clin Oncol, 2010). In a second step we tested whether increasing the rituximab dose to 700 mg/m2 would increase the RR. Methods: Eligibility: age 70%), this trial did not address treatment of some particularly challenging though rarer sub-entities of PTLD such as disease involving the CNS, or CD20 negative disease. Several treatment dilemmas remain for pediatric PTLD. For disease involving the CNS, it remains unclear whether pediatric patients should be treated with intra-thecals, and whether additional chemotherapeutic agents beyond methotrexate and cytarabine (in addition to rituxan) contribute to improved survival. For CD20 negative disease, there is uncertainty regarding which chemotherapeutic drug combinations yield better outcomes, and whether treatment with rituximab is beneficial. Since CD20 negative (and EBV negative) disease present more frequently in later-onset PTLD, the poorer survival noted in late onset PTLD might be partly secondary to the lack of available targeted immunotherapy. Preservation of functioning allografts also remains a challenge given the need to decrease immune suppression. This dilemma is greatest after chemotherapy is complete, particularly in cases achieving only a stable PR. Future studies will require international and extra-pediatric collaborative efforts, ideally including opportunities to address these challenges.

73 Stem cell transplantation for children, adolescents and young adults with relapsed/refractory Non-Hodgkin lymphoma P Satwani Division of Stem Cell Transplantation, Columbia University Medical Center, Morgan Stanley Children’s Hospital of New York-Presbyterian The prognosis of children with relapsed/refractory NHL is poor and the best treatment approach for this group remains a challenge. Autologous stem cell transplantation (AutoSCT) is associated with high risk of disease relapse. Studies in adults have demonstrated a graft versus lymphoma effect after allogeneic stem cell transplantation (AlloSCT), although transplant related mortality (TRM) after myeloablative conditioning (MAC) AlloSCT remains a major concern. Reduced intensity conditioning (RIC) AlloHSCT may potentially reduce TRM. Both North American and European registry data have demonstrated no survival advantage following AlloSCT versus AutoSCT in children with relapsed B-cell NHL. A survival advantage following AlloSCT versus AutoSCT was demonstrated by the CIBMTR in children with lymphoblastic lymphoma (EFS: 40% vs. 4%;


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Plenary Session X: Relapsed/Refractory NHL – Invited Oral Presentations p < 0.01); AlloSCT also has a potential benefit in children with relapsed anaplastic large cell lymphoma (ALCL). The BFM group reported 75% EFS following AlloHSCT in 20 children with relapsed/ refractory ALCL. We are currently conducting a study utilizing a tandem approach of MAC-AutoSCT followed by RIC-AlloSCT in children with relapsed/refractory NHL. The preferred approach for children with B-NHL whose disease remains chemo-sensitive after relapse should be high dose chemotherapy followed by AutoSCT. Conversely, based on the available data, MAC-AlloSCT is preferable in children with relapsed lymphoblastic lymphoma and ALCL.

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We should further explore the role of clinical and biological characteristics, proteomics and genomics in relapsed NHL to identify children who are at high risk of relapse after AutoSCT, so that AlloSCT can be performed upfront. Monoclonal antibodies such as rituximab or brentuximab incorporated into the conditioning regimen or as maintenance therapy following HSCT may further reduce the risk of relapse. Due to small numbers of eligible children only prospective cooperative studies in future might help to optimize therapy in children with relapsed/refractory NHL.


Plenary Session X: Relapsed/Refractory NHL – Peer-Reviewed Oral Presentations

Peer-Reviewed Oral Presentations 74 Risk-adapted therapy for patients with relapsed or refractory ALCL – interim-results of the prospective EICNHL-Trial ALCL-relapse

75 Role of hematopoietic stem cell transplantation for relapsed or refractory pediatric non-Hodgkin lymphomas

W Woessmann1, L Brugieres2, A Rosolen3, M Zimmermann1, A Attarbaschi4, K Mellgren5, D Williams6, A Uyttebroeck7, G Wrobel8, A Reiter1; for the EICNHL-group 1 NHL-BFM study center, Department of Pediatric Hematology and Oncology, Giessen, Germany; 2SFCE NHL study center, Institut Gustav-Roussy, Villejuif, France; 3AIEOP-NHL study center, Department of Pediatric Hematology and Oncology, Padova, Italy; 4NHL-BFM Austria Study Center, St Anna Kinderspital, Department of Pediatrics, Medical University Vienna, Austria; 5NOPHO-NHL study center, The Queen Silvia Children’s Hospital, Gothenburg, Sweden; 6UK-CCLG, Department of Pediatric Hematology and Oncology, CUHFT, Addenbrooke’s Hospital, Cambridge, UK; 7BSPHO, Department of Pediatric Hemato-Oncology, Leuven, Belgium; 8 Department of Pediatric Oncology, Wroclaw, Poland

M Pillon1, A Prete2, R Rondelli2, E Carraro1, M Zecca3, C Messina1, F Fagioli4, E Lanino5, A Rovelli6, C Favre7, D Caselli8, M Ripaldi9, F Locatelli10, A Rosolen1; for the Italian Association of Pediatric Hematology and Oncology AIEOP NHL and HSCT Committee1Pediatric Hemato-Oncology Unit, University Hospital, Padova, Italy; 2Hemato-Oncology Unit, Sant’Orsola Malpighi Hospital, University of Bologna, Bologna, Italy; 3Hemato-Oncology Unit, IRCCS, San Matteo Hospital, Pavia, Italy; 4Hemato-Oncology and Transplant Unit, Regina Margherita University Hospital, Torino, Italy; 5 Hemato-Oncology Unit, Gaslini Children’s Hospital, Genova, Italy; 6S. Gerardo Hospital, Milano-Bicocca University, Fondazione MBBM, Monza, Italy; 7Hemato-Oncology and Transplant Unit, S. Chiara Hospital, University of Pisa, Pisa, Italy; 8Pediatric Hemato-Oncology Department, Meyer University-Hospital, Firenze, Italy; 9Pediatric HematoOncology Unit, Pausilipon Hospital, Napoli, Italy; 10Pediatric Hemato-Oncology Department, IRCCS, Bambino-Gesu` Children’s Hospital, Roma, Italy

Background: Patients with relapse of an anaplastic large cell lymphoma (ALCL) have a survival of more than 50% according to retrospective analyses. Time from diagnosis to relapse and immunophenotype have been described as risk factors. Objective: To test the efficacy of a risk-adapted strategy including autologous or allogeneic blood stem cell transplantation (SCT) and Vinblastine monotherapy for ALCL-relapses. Patients and Methods: Between October 2004 and August 2011, 90 patients were included. Stratification was not possible for 10 pts, leaving 80 protocol pts. Patients with progression during first-line therapy or relapse of CD3-positive ALCL were eligible for allogeneic SCT (group A, goal-2y-EFS 50%). Patients with early relapse of CD3negative ALCL were treated by autologous SCT after BEAM-conditioning (group B, goal-EFS 53%). Patients with relapse of CD3negative ALCL >12 months after diagnosis received 24 months Vinblastine (group C, goal-EFS 75%). Results: Allocation of patients to treatment groups: A, 36 patients (46%), B, 27 patients (34%), C, 15 patients (19%). EFS and OS of 90 study patients were 53 ± 6% and 71 ± 5%, respectively. EFS and OS of 80 protocol patients according to treatment group: A, 57 ± 9% and 64 ± 9%; B, 32 ± 10% and 77 ± 8%; C, 87 ± 9% and 86 ± 10%. Among group A patients, 16 with progression on treatment had an EFS of 29 ± 12%, while EFS of the 20 patients with a relapse of CD3positive ALCL was 82 ± 9%. Conclusion: Allogeneic SCT achieves a high survival rate for patients with relapse of a CD3-positive ALCL and offers a chance for those with refractory disease. Autologous SCT was not effective for patients with relapse of a CD3-negative ALCL. Vinblastine monotherapy achieves high remission rates in patients with a late relapse of an ALCL. Followup is needed to determine long-term efficacy.

Background: Pediatric non-Hodgkin lymphomas (NHL) are high grade lymphomas, and the most frequent subtype are Burkitt (BL), lymphoblastic (LL), diffuse large B-cell (DLCBL) and anaplastic lymphoma (ALCL). First line therapy is well defined and achieve excellent results. Second-line treatment is not completely determined, including the role and type of hematopoietic stem cell transplantation (HSCT). Objective: To evaluate the role of HSCT for the treatment of relapsed or refractory NHL and identify favourable prognostic factors. Methods: Patients aged 25% (B-ALL) without CNS involvement. In the FAB 96 study, 47 patients with isolated B-ALL treated with the standard arm on the randomized study had a 4 year EFS of 94%. Objectives: To study the feasibility, safety, and efficacy of adding Rituximab to the best current chemotherapy FAB 96 for children with mature B-ALL (Burkitt leukemia). Design/Methods: Immunochemotherapy consisted of modified C1 therapy (adriamycin 1 h infusion) as previously described (Cairo et al, Blood, 2007) with the addition of rituximab 375 mg/m2/dose (generously supplied by Genentech) with two doses in each induction cycle and one dose in each consolidation cycle. Results: There were 25 patients with isolated B-ALL (Burkitt leukemia). BM blast percentage at diagnosis averaged 75% (range 29–96%). There were two toxic deaths: one due to typhlitis during the second induction cycle associated with premature discontinuation of leucovorin rescue, and one due to pre-existing pulmonary Aspergillosis. Of the 23 patients who completed therapy only 1 recurrent disease occurred at 3 months with death due to disease at 6 months from diagnosis. The 3-year EFS/OS for the evaluable patients is 91.7% (95% CI 70.6–97.9). The 3-year progression free survival for patients who did not die of toxicity was 95.7% (95% CI 91.9–99.4).

80 Burkitt lymphoma of mediastinum: an unusual localization at diagnosis in childhood M Pillon1, E Giraldi2, L Mussolin1, E Carraro1, ES d’Amore3, A Garaventa4, A Lombardi5, N Santoro6, R De Santis7, R Alaggio8, A Rosolen1; for the Italian Association of Pediatric Hematology and Oncology AIEOP NHL-Committee 1 Pediatric Hemato-Oncology Unit, University Hospital, Padova, Italy; 2Department of Pediatrics, Ospedali Riuniti, Bergamo, Italy; 3Pathology Department, San Bortolo Hospital, Vicenza, Italy; 4Hemato-Oncology Unit, Gaslini Children’s Hospital, Genova, Italy; 5Pediatric Hemato-Oncology Department, IRCCS, Bambino-Gesu` Children’s Hospital, Roma, Italy; 6Department of Pediatrics, University of Bari, Bari, Italy; 7 Pediatric Hemato-Oncology Unit, S.G. Rotondo, Foggia, Italy; 8 Pathology Department, University Hospital, Padova, Italys Background: Burkitt lymphoma (BL) accounts for approximately 40% of all non-Hodgkin Lymphoma (NHL) in childhood. Abdominal or head-neck are the most frequent sites involved at diagnosis, while mediastinal primary site is unusual. Objective: To analyze histo-pathological characteristics and evaluate the clinical outcome of patients affected by BL of mediastinum, enrolled in the AIEOP LNH-97 protocol. Methods: A retrospective study was carried out on children aged