Hematopoietic Progenitor Cell Transplantation in Children, Adolescents, and Young Adults With Relapsed Mature B-Cell NHL

Authors: Aliza Gardenswartz MDa and Mitchell S. Cairo MDa,b,c,d,e
View More View Less
  • a Departments of Pediatrics,
  • | b Pathology,
  • | c Medicine,
  • | d Microbiology and Immunology, and
  • | e Cell Biology and Anatomy, Maria Fareri Children’s Hospital at Westchester Medical Center, New York Medical College, Valhalla, New York.
Restricted access

Although children, adolescents, and young adults with newly diagnosed B-cell non-Hodgkin’s lymphoma enjoy excellent overall survival with current chemoimmunotherapy, those with relapsed and/or refractory disease have a dismal prognosis. Although most clinicians would agree that hematopoietic progenitor cell transplantation after reinduction therapy is frontline therapy for these patients, there is no consensus as to what type of hematopoietic progenitor cell transplantation promises the best event-free and overall survival. This review outlines the disparate types of stem cell therapy that have been used in this difficult-to-treat population as well as the role of maintenance and CAR T-cell therapy in conjunction with stem cell therapy.

Submitted February 18, 2020; accepted for publication July 7, 2020.

Disclosures: Dr. Gardenswartz has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors. Dr. Cairo has disclosed that he is a scientific advisor for, serves on the speaker’s bureau for, and receives grant/research support from Jazz Pharmaceuticals; is a scientific advisor for Amgen; and serves on the speaker’s bureau for and receives grant/research support from Servier.

Funding: This work was supported in part from grants from the Pediatric Cancer Research Foundation and 1U54 CA232561-01/A1.

Correspondence: Mitchell S. Cairo, MD, Maria Fareri Children’s Hospital at Westchester Medical Center, New York Medical College, 40 Sunshine Cottage Road, Skyline Office 1N-D12, Valhalla, NY 10595. Email: mitchell_cairo@nymc.edu
  • 1.

    Cairo M, Auperin A, Perkins SL, et al. . Overall survival of children and adolescents with mature B cell non-Hodgkin lymphoma who had refractory or relapsed disease during or after treatment with FAB/LMB 96: a report from the FAB/LMB 96 study group. Br J Haematol 2018;182:859869.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Cairo MS, Sposto R, Gerrard M, et al. . Advanced stage, increased lactate dehydrogenase, and primary site, but not adolescent age (≥ 15 years), are associated with an increased risk of treatment failure in children and adolescents with mature B-cell non-Hodgkin’s lymphoma: results of the FAB LMB 96 study. J Clin Oncol 2012;30:387393.

    • Search Google Scholar
    • Export Citation
  • 3.

    Goldman S, Smith L, Galardy P, et al. . Rituximab with chemotherapy in children and adolescents with central nervous system and/or bone marrow-positive Burkitt lymphoma/leukaemia: a Children’s Oncology Group Report. Br J Haematol 2014;167:394401.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    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;109:27362743.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Gross TG, Hale GA, He W, et al. . Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 2010;16:223230.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Harris RE, Termuhlen AM, Smith LM, et al. . Autologous peripheral blood stem cell transplantation in children with refractory or relapsed lymphoma: results of Children’s Oncology Group study A5962. Biol Blood Marrow Transplant 2011;17:249258.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Jourdain A, Auperin A, Minard-Colin V, et al. . Outcome of and prognostic factors for relapse in children and adolescents with mature B-cell lymphoma and leukemia treated in three consecutive prospective “Lymphomes Malins B” protocols. A Société Française des Cancers de l’Enfant study. Haematologica 2015;100:810817.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Bradley MB, Cairo MS. Stem cell transplantation for pediatric lymphoma: past, present and future. Bone Marrow Transplant 2008;41:149158.

  • 9.

    Cairo MS, Woessmann W, Pagel J. Advances in hematopoietic stem cell transplantation in childhood and adolescent lymphomas. Biol Blood Marrow Transplant 2013;19(1 Suppl)S3843.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Burkhardt B, Pillon M, Taj M, et al. . Role of HSCT in children and adolescents with refractory or relapsed NHL [abstract]. Br J Haematol 2018;182(Suppl 1):Abstract 30.

    • Search Google Scholar
    • Export Citation
  • 11.

    Naik S, Martinez CA, Omer B, et al. . Allogeneic hematopoietic stem cell transplant for relapsed and refractory non-Hodgkin lymphoma in pediatric patients. Blood Adv 2019;3:26892695.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Woessmann W. XI. How to treat children and adolescents with relapsed non-Hodgkin lymphoma? Hematol Oncol 2013;31(Suppl 1):6468.

  • 13.

    Dahi PB, Moskowitz CH, Giralt SA, et al. . Novel agents may positively impact chemotherapy and transplantation in subsets of diffuse large B-cell lymphoma. Expert Rev Hematol 2019;12:407418.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Smith EP, Li H, Friedberg JW, et al. . Tandem autologous hematopoietic cell transplantation for patients with primary progressive or recurrent Hodgkin lymphoma: a SWOG and Blood and Marrow Transplant Clinical Trials Network phase II trial (SWOG S0410/BMT CTN 0703). Biol Blood Marrow Transplant 2018;24:700707.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Morschhauser F, Brice P, Fermé C, et al. . Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkin’s lymphoma: results of the prospective multicenter H96 trial by the GELA/SFGM study group. J Clin Oncol 2008;26:59805987.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Monjanel H, Deconinck E, Perrodeau E, et al. . Long-term follow-up of tandem high-dose therapy with autologous stem cell support for adults with high-risk age-adjusted international prognostic index aggressive non-Hodgkin Lymphomas: a GOELAMS pilot study. Biol Blood Marrow Transplant 2011;17:935940.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Hohloch K, Sahlmann CO, Lakhani VJ, et al. . Tandem high-dose therapy in relapsed and refractory B-cell lymphoma: results of a prospective phase II trial of myeloablative chemotherapy, followed by escalated radioimmunotherapy with (131)I-anti-CD20 antibody and stem cell rescue. Ann Hematol 2011;90:13071315.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Hohloch K, Zeynalova S, Chapuy B, et al. . Modified BEAM with triple autologous stem cell transplantation for patients with relapsed aggressive non-Hodgkin lymphoma. Ann Hematol 2016;95:11211128.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Carella AM, Cavaliere M, Lerma E, et al. . Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin’s disease and non-Hodgkin’s lymphoma. J Clin Oncol 2000;18:39183924.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Crocchiolo R, Castagna L, Fürst S, et al. . Tandem autologous-allo-SCT is feasible in patients with high-risk relapsed non-Hodgkin’s lymphoma. Bone Marrow Transplant 2013;48:249252.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Crocchiolo R, Castagna L, Garciaz S, et al. . Tandem autologous-allogeneic stem cell transplantation as a feasible and effective procedure in high-risk lymphoma patients. Haematologica 2015;100:e423427.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Chen YB, Li S, Fisher DC, et al. . Phase II trial of tandem high-dose chemotherapy with autologous stem cell transplantation followed by reduced-intensity allogeneic stem cell transplantation for patients with high-risk lymphoma. Biol Blood Marrow Transplant 2015;21:15831588.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Satwani P, Jin Z, Martin PL, et al. . Sequential myeloablative autologous stem cell transplantation and reduced intensity allogeneic hematopoietic cell transplantation is safe and feasible in children, adolescents and young adults with poor-risk refractory or recurrent Hodgkin and non-Hodgkin lymphoma. Leukemia 2015;29:448455.

    • Search Google Scholar
    • Export Citation
  • 24.

    Gardenswartz A, Mehta B, El-Mallawany N, et al. . Safety and efficacy of myeloablative conditioning autologous stem cell transplantation, targeted immunotherapy, and reduced intensity conditioning allogeneic stem cell transplantation in children, adolescents, and young adults with relapsed/refractory mature B‐cell non Hodgkin lymphoma [abstract]. Br J Haematol 2018;182(Suppl 1):Abstract 28.

    • Search Google Scholar
    • Export Citation
  • 25.

    Moskowitz CH, Nademanee A, Masszi T, et al. . Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2015;385:18531862.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Kanate AS, Kumar A, Dreger P, et al. . Maintenance therapies for Hodgkin and non-Hodgkin lymphomas after autologous transplantation: a consensus project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT. JAMA Oncol 2019;5:715722.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Flerlage JE, von Buttlar X, Krasin M, et al. . Brentuximab vedotin as consolidation after hematopoietic cell transplant for relapsed Hodgkin lymphoma in pediatric patients. Pediatr Blood Cancer 2019;66:e27962.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Gisselbrecht C, Schmitz N, Mounier N, et al. . Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the Collaborative Trial in Relapsed Aggressive Lymphoma. J Clin Oncol 2012;30:44624469.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Pettengell R, Schmitz N, Gisselbrecht C, et al. . Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol 2013;31:16241630.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Le Gouill S, Thieblemont C, Oberic L, et al. . Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med 2017;377:12501260.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Palanca-Wessels MC, Czuczman M, Salles G, et al. . Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol 2015;16:704715.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Morschhauser F, Flinn IW, Advani R, et al. . Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS). Lancet Haematol 2019;6:e254265.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Sehn LH, Herrera AF, Flowers CR, et al. . Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2020;38:155165.

  • 34.

    Tilly H, Morschhauser F, Bartlett NL, et al. . Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study. Lancet Oncol 2019;20:9981010.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Chavez JC, Bachmeier C, Kharfan-Dabaja MA. CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products. Ther Adv Hematol 2019;10:2040620719841581.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Dave H, Jerkins L, Hanley PJ, et al. . Driving the CAR to the bone marrow transplant program. Curr Hematol Malig Rep 2019;14:561569.

  • 37.

    Chu Y, Flower A, Cairo MS. Modification of expanded NK cells with chimeric antigen receptor mRNA for adoptive cellular therapy. Methods Mol Biol 2016;1441:215230.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Batlevi CL, Matsuki E, Brentjens RJ, et al. . Novel immunotherapies in lymphoid malignancies. Nat Rev Clin Oncol 2016;13:2540.

  • 39.

    van der Stegen SJ, Hamieh M, Sadelain M. The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov 2015;14:499509.

  • 40.

    Chu Y, Gardenswartz A, Termuhlen AM, et al. . Advances in cellular and humoral immunotherapy - implications for the treatment of poor risk childhood, adolescent, and young adult B-cell non-Hodgkin lymphoma. Br J Haematol 2019;185:10551070.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Schuster SJ, Bishop MR, Tam CS, et al. . Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2019;380:4556.

  • 42.

    Locke FL, Ghobadi A, Jacobson CA, et al. . Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol 2019;20:3142.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Rivers J, Annesley C, Summers C, et al. . Early response data for pediatric patients with non-Hodgkin lymphoma treated with CD19 chimeric antigen receptor (CAR) T-cells [abstract]. Br J Haematol 2018;182(Suppl 1):Abstract 29.

    • Search Google Scholar
    • Export Citation
  • 44.

    Taraseviciute A, Broglie L, Phelan R, et al. . What is the role of hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) in the age of chimeric antigen receptor T-cell (CART) therapy? J Pediatr Hematol Oncol 2019;41:337344.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Kochenderfer JN, Dudley ME, Carpenter RO, et al. . Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 2013;122:41294139.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Brudno JN, Somerville RP, Shi V, et al. . Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-Cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol 2016;34:11121121.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Philip T, Hartmann O, Biron P, et al. . High-dose therapy and autologous bone marrow transplantation in partial remission after first-line induction therapy for diffuse non-Hodgkin’s lymphoma. J Clin Oncol 1988;6:11181124.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Loiseau HA, Hartmann O, Valteau D, et al. . High-dose chemotherapy containing busulfan followed by bone marrow transplantation in 24 children with refractory or relapsed non-Hodgkin’s lymphoma. Bone Marrow Transplant 1991;8:465472.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Bureo E, Ortega JJ, Muñoz A, et al. . Bone marrow transplantation in 46 pediatric patients with non-Hodgkin’s lymphoma. Bone Marrow Transplant 1995;15:353359.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Ladenstein R, Pearce R, Hartmann O, et al. . High-dose chemotherapy with autologous bone marrow rescue in children with poor-risk Burkitt’s lymphoma: a report from the European Lymphoma Bone Marrow Transplantation Registry. Blood 1997;90:29212930.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Fanin R, Ruiz de Elvira MC, Sperotto A, et al. . Autologous stem cell transplantation for T and null cell CD30-positive anaplastic large cell lymphoma: analysis of 64 adult and paediatric cases reported to the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 1999;23:437442.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52.

    Kobrinsky NL, Sposto R, Shah NR, et al. . Outcomes of treatment of children and adolescents with recurrent non-Hodgkin’s lymphoma and Hodgkin’s disease with dexamethasone, etoposide, cisplatin, cytarabine, and l-asparaginase, maintenance chemotherapy, and transplantation: Children’s Cancer Group Study CCG-5912. J Clin Oncol 2001;19:23902396.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Levine JE, Harris RE, Loberiza FR Jr, et al. . A comparison of allogeneic and autologous bone marrow transplantation for lymphoblastic lymphoma. Blood 2003;101:24762482.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Woessmann W, Peters C, Lenhard M, et al. . Allogeneic haematopoietic stem cell transplantation in relapsed or refractory anaplastic large cell lymphoma of children and adolescents—a Berlin-Frankfurt-Münster group report. Br J Haematol 2006;133:176182.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55.

    Won SC, Han JW, Kwon SY, et al. . Autologous peripheral blood stem cell transplantation in children with non-Hodgkin’s lymphoma: a report from the Korean society of pediatric hematology-oncology. Ann Hematol 2006;85:787794.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Giulino-Roth L, Ricafort R, Kernan NA, et al. . Ten-year follow-up of pediatric patients with non-Hodgkin lymphoma treated with allogeneic or autologous stem cell transplantation. Pediatr Blood Cancer 2013;60:20182024.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 803 246 7
PDF Downloads 366 168 30
EPUB Downloads 0 0 0