Current Hematologic Malignancy Reports

, Volume 13, Issue 6, pp 484–493 | Cite as

Hematopoietic Stem Cell Transplantation in the Era of Engineered Cell Therapy

  • Jacob S. AppelbaumEmail author
  • Filippo Milano
CART and Immunotherapy (M Ruella, Section Editor)
Part of the following topical collections:
  1. Topical Collection on CART and Immunotherapy


Purpose of Review

Cellular therapy using T cells modified to express chimeric antigen receptors (CAR-T cells) has had striking success in patients that have failed previous treatment for CD19+ B cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or acute lymphoblastic leukemia (ALL). Curative therapy for this group of diseases has previously been limited to allogeneic hematopoietic cell transplantation HCT (alloHCT). The recent results of CAR-T cell therapy raise the question of how best to integrate CAR-T cell therapy and alloHCT in the care of these patients.

Recent Findings

Within the past 2 years, results from larger trials and increased follow-up of patients treated with CD19 CAR-T cell therapy suggest that some may achieve durable remission without transplant.


The balance of efficacy and toxicity for CAR-T cell therapy and alloHCT vary by disease type, disease status at the time of treatment, patient characteristics, and the specific therapy employed. There are early signals that subsequent transplantation of patients who have achieved remission with CAR-T may be a potentially viable (though expensive) strategy.


Cord blood Stem cell transplant CAR-T cells CD-19 CD-20 BCMA 


Funding Information

This work was supported by a T32 institutional training grant from the National Institutes of Health to Jacob Appelbaum (5T32HL007093).

Compliance with Ethical Standards

Conflict of Interest

Jacob S. Appelbaum and Filippo Milano declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    •• Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18 Case reports describing the first two patients to receive meaningful doses of CAR-T cells for hematologic malignancy.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010 Nov 18;116(20):4099–102.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    • Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44 Phase 2 trial treating 111 patients with 2 × 10 6 CAR-T (ZUMA-1). PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    • Schuster SJ, Bishop M, Tam C, Waller EK, Borchmann P. Primary analysis of Juliet: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. In: ASH Abstract [Internet]. 2017 [cited 2018 Mar 21]. p. 577. Available from: Initial report of the phase 2 trial treating 99 patients with tisengenlecleucel for r/r DLBCL.
  5. 5.
    •• Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG, Turtle CJ, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30(2):492–500 Study provides rationale and data to support the cooperativity of CD4 and CD8 cells in therapeutic efficacy. PubMedCrossRefGoogle Scholar
  6. 6.
    •• Turtle CJ, Hanafi L-A, Berger C, Hudecek M, Pender B, Robinson E, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor–modified T cells. Sci Transl Med. 2016;8(355):355ra116–6 Careful analysis of patients treated with CAR-T identified pitfalls of CAR-T cell therapy, including the development of immune responses to CAR proteins, predictors of cytokine release syndrome, dynamics of CAR-T expansion, and the importance of fludarabine in lymphodepletion. Google Scholar
  7. 7.
    • Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48 Phase 2 trial of tisegenlecleucel for children and young adults with ALL. PubMedCrossRefGoogle Scholar
  8. 8.
    •• Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–59 Long-term follow-up provides insight into the outcomes of patients who achieve remission by CAR-T cell therapy and the importance of differences in T cell persistence between various CAR-T cell products.PubMedCrossRefGoogle Scholar
  9. 9.
    Kuruvilla J. The role of autologous and allogeneic stem cell transplantation in the management of indolent B-cell lymphoma. Blood. 2016;127(17):2093–100.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhou Y, Slack R, Jorgensen JL, Wang SA, Rondon G, Lima M de, et al. The effect of peritransplant minimal residual disease in adults with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk. 2014;14(4):319–326.Google Scholar
  11. 11.
    Bar M, Wood BL, Radich JP, Doney KC, Woolfrey AE, Delaney C, et al. Impact of minimal residual disease, detected by flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute lymphoblastic leukemia. Leuk Res Treat. 2014;2014:1–9.CrossRefGoogle Scholar
  12. 12.
    Zhang M, Fu H, Lai X, Tan Y, Zheng W, Shi J, et al. Minimal residual disease at first achievement of complete remission predicts outcome in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia. PLOS ONE. 2016;11(10):e0163599.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Sarina B, Castagna L, Farina L, Patriarca F, Benedetti F, Carella AM, et al. Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Blood. 2010;115(18):3671–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Rigacci L, Puccini B, Dodero A, Iacopino P, Castagna L, Bramanti S, et al. Allogeneic hematopoietic stem cell transplantation in patients with diffuse large B cell lymphoma relapsed after autologous stem cell transplantation: a GITMO study. Ann Hematol. 2012;91(6):931–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Gill S, Maus MV, Porter DL. Chimeric antigen receptor T cell therapy: 25 years in the making. Blood Rev. 2016;30(3):157–67.PubMedCrossRefGoogle Scholar
  16. 16.
    June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64–73.PubMedCrossRefGoogle Scholar
  17. 17.
    • Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 2008;112(6):2261–71 First study to demonstrate safety of CAR-T cells in humans.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–1517.Google Scholar
  19. 19.
    Turtle CJ, Hanafi L-A, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126(6):2123–38.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Brudno JN, Somerville RPT, Shi V, Rose JJ, Halverson DC, Fowler DH, 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(10):1112–21.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Ghosh A, Smith M, James SE, Davila ML, Velardi E, Argyropoulos KV, et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat Med. 2017;23(2):242–9.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25(1):285–95.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    •• Crump M, Neelapu SS, Farooq U, Neste EVD, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800–8 Retrospective analysis illustrating the poor prognosis of patients with r/r DLBCL and justifying the use of CAR-T cell therapy. PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    • Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–54 Results of 28 patients treated with r/r DLBCL or follicular lymphoma showing high response rates. PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Nagle SJ, Kaitlin W, Schuster Stephen J, Nasta Sunita D, Edward S, Rosemarie M, et al. Outcomes of patients with relapsed/refractory diffuse large B-cell lymphoma with progression of lymphoma after autologous stem cell transplantation in the rituximab era. Am J Hematol. 2013;88(10):890–4.PubMedCrossRefGoogle Scholar
  26. 26.
    • Abramson JS, Palomba ML, Gordon LI, Lunning MA, Arnason JE, Wang M, et al. High durable CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001): defined composition allows for dose-finding and definition of pivotal cohort. Blood. 2017;130(Suppl 1):581–1 Phase 2 study of 74 patients treated with JCAR017 for aggressive lymphoma. Double- and triple-hit patients had an ORR of 81%. Defined composition of the CAR product revealed a therapeutic window of improved safety. Google Scholar
  27. 27.
    •• Klyuchnikov E, Bacher U, Kröger NM, Hari PN, Ahn KW, Carreras J, et al. Reduced-intensity allografting as first transplantation approach in relapsed/refractory grades one and two follicular lymphoma provides improved outcomes in long-term survivors. Biol Blood Marrow Transplant. 2015;21(12):2091–9 In considering transplant of low-grade lymphomas, this paper illustrates the differences in short- and long-term outcomes with auto- versus alloHCT. In addition, it provides a comparison point for the success of treatments, i.e., 5-year OS of 66 to 74%. PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740–53.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera J-M, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836–47.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Turtle CJ, Hay KA, Hanafi L-A, Li D, Cherian S, Chen X, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor–modified T cells after failure of ibrutinib. J Clin Oncol. 2017;35(26):3010–20.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Jones JA, Mato AR, Wierda WG, Davids MS, Choi M, Cheson BD, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(1):65–75.PubMedCrossRefGoogle Scholar
  32. 32.
    Krämer I, Stilgenbauer S, Dietrich S, Böttcher S, Zeis M, Stadler M, et al. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017;130(12):1477–80.PubMedCrossRefGoogle Scholar
  33. 33.
    Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant. 2010;16(9):1245–56.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    •• Gardner R, Wu D, Cherian S, Fang M, Hanafi L-A, Finney O, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016;127(20):2406–10 Study showing target antigen loss is a key method of therapeutic escape.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Kantarjian HM, O’Brien S, Smith TL, Cortes J, Giles FJ, Beran M, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol. 2000;18(3):547–7.Google Scholar
  36. 36.
    Sureda A, Bader P, Cesaro S, Dreger P, Duarte RF, Dufour C, et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015. Bone Marrow Transplant. 2015;50(8):1037–56.PubMedCrossRefGoogle Scholar
  37. 37.
    Majhail NS, Farnia SH, Carpenter PA, Champlin RE, Crawford S, Marks DI, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2015;21(11):1863–9.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Faderl S, O’Brien S, Pui C-H, Stock W, Wetzler M, Hoelzer D, et al. Adult acute lymphoblastic leukemia. Cancer. 2010;116(5):1165–76.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Issa GC, Kantarjian HM, Yin C, Cameron QW, Farhad R, Deborah T, et al. Prognostic impact of pretreatment cytogenetics in adult Philadelphia chromosome–negative acute lymphoblastic leukemia in the era of minimal residual disease. Cancer. 2017;123(3):459–67.PubMedCrossRefGoogle Scholar
  40. 40.
    Brüggemann M, Schrauder A, Raff T, Pfeifer H, Dworzak M, Ottmann OG, et al. Standardized MRD quantification in European ALL trials: Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. Leukemia. 2010;24(3):521–35.PubMedCrossRefGoogle Scholar
  41. 41.
    Schrappe M. Detection and management of minimal residual disease in acute lymphoblastic leukemia. ASH Educ Program Book. 2014;2014(1):244–9.Google Scholar
  42. 42.
    • Tavernier E, Boiron J-M, Huguet F, Bradstock K, Vey N, Kovacsovics T, et al. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia. 2007;21(9):1907–14.PubMedCrossRefGoogle Scholar
  43. 43.
    • Kantarjian HM, Thomas D, Ravandi F, Faderl S, Jabbour E, Garcia-Manero G, et al. Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration. Cancer. 2010 116(24):5568–5574. References 32 and 33 provide benchmarks for outcomes of experimental therapies for relapsed/refractory ALL. Google Scholar
  44. 44.
    Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109(3):944–50.PubMedCrossRefGoogle Scholar
  45. 45.
    Haso W, Lee DW, Shah NN, Stetler-Stevenson M, Yuan CM, Pastan IH, et al. Anti-CD22–chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood. 2013;121(7):1165–74.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev. Clin Oncol. 2018;15(1):31–46.PubMedCrossRefGoogle Scholar
  47. 47.
    Kato K, Miyamoto T, Yonemoto K, Uchida N, Ogawa H, Fukuda T, et al. Second allogeneic hematopoietic stem cell transplantation (allo-HSCT) for relapse of hematological malignancies after first allo-HSCT. Blood. 2014;124(21):3947–7.Google Scholar
  48. 48.
    Nagler A, Labopin M, Beelen D, Ciceri F, Volin L, Shimoni A, et al. Long-term outcome after a treosulfan-based conditioning regimen for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Cancer. 2017;123(14):2671–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21(8):922–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Gerecitano JF, Roberts AW, Seymour JF, Wierda WG, Kahl BS, Pagel JM, et al. A phase 1 study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with relapsed/refractory non-Hodgkin lymphoma. Blood. 2015;126(23):254–4.Google Scholar
  51. 51.
    Goy A, Ramchandren R, Ghosh N, Munoz J, Morgan DS, Dang NH, et al. A multicenter open-label, phase 1b/2 study of ibrutinib in combination with lenalidomide and rituximab in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Blood. 2016;128(22):473–3.Google Scholar
  52. 52.
    van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, et al. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD study. J Clin Oncol. 2017;35(5):544–51.PubMedCrossRefGoogle Scholar
  53. 53.
    van Kampen RJW, Canals C, Schouten HC, Nagler A, Thomson KJ, Vernant J-P, et al. Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin’s lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol. 2011;29(10):1342–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Klyuchnikov E, Bacher U, Kroll T, Shea TC, Lazarus HM, Bredeson C, et al. Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how? Bone Marrow Transplant. 2014;49(1):1–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Sebban C, Brice P, Delarue R, Haioun C, Souleau B, Mounier N, et al. Impact of rituximab and/or high-dose therapy with autotransplant at time of relapse in patients with follicular lymphoma: a GELA study. J Clin Oncol. 2008;26(21):3614–20.PubMedCrossRefGoogle Scholar
  56. 56.
    Sebban C, Mounier N, Brousse N, Belanger C, Brice P, Haioun C, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood. 2006;108(8):2540–4.PubMedCrossRefGoogle Scholar
  57. 57.
    Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014;15(12):1311–8.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Fowler NH, Samaniego F, Turturro F, Neelapu S, Forbes S, Westin J, et al. The immunologic doublet of lenalidomide plus obinutuzumab is highly active in relapsed/refractory follicular lymphoma, results of a phase I/II study. Hematol Oncol. 2017;35:268–9.CrossRefGoogle Scholar
  59. 59.
    Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008–18.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Zinzani PL, Topp MS, Yuen SL, Rusconi C, Fleury I, Pro B, et al. Phase 2 study of venetoclax plus rituximab or randomized VEN plus bendamustine+rituximab (BR) versus BR in patients with relapsed/refractory follicular lymphoma: interim Data. Blood. 2016;128(22):617–7.Google Scholar
  61. 61.
    Bartlett NL, Costello BA, LaPlant BR, Ansell SM, Kuruvilla JG, Reeder CB, et al. Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial. Blood. 2017;1:blood-2017-09-804641.Google Scholar
  62. 62.
    Trněný M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, et al. Lenalidomide versus investigator’s choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 2016;17(3):319–31.PubMedCrossRefGoogle Scholar
  63. 63.
    Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, et al. Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009;27(23):3822–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Dreyling M, Morschhauser F, Bouabdallah K, Bron D, Cunningham D, Assouline SE, et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017;28(9):2169–78.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Kuo H-P, Ezell SA, Schweighofer KJ, Cheung LWK, Hsieh S, Apatira M, et al. Combination of ibrutinib and ABT-199 in diffuse large B-cell lymphoma and follicular lymphoma. Mol Cancer Ther. 2017;16(7):1246–56.PubMedCrossRefGoogle Scholar
  66. 66.
    • Cohen AD, Garfall AL, Stadtmauer EA, Lacey SF, Lancaster E, Vogl DT, et al. B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) for multiple myeloma (MM): initial safety and efficacy from a phase I study. Blood. 2016;128(22):1147–7 Initial safety study of BCMA CAR-T cells.Google Scholar
  67. 67.
    Berdeja JG, Lin Y, Raje N, Munshi N, Siegel D, Liedtke M, et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-Bcma CAR T cell therapy. Blood. 2017;130(Suppl 1):740–0.Google Scholar
  68. 68.
    • Updated results of ongoing multicenter phase I study of bb2121 anti-BCMA CAR T cell therapy continue to demonstrate deep and durable responses in patients with late-stage relapsed/refractory multiple myeloma at ASCO Annual Meeting (NASDAQ:CELG) [Internet]. [cited 2018 Jul 18]. Available from: Impressive safety and efficacy data with preserved safety profile for myeloma.
  69. 69.
    • Chekmasova AA, Horton HM, Garrett TE, Evans JW, Griecci J, Hamel A, et al. A novel and highly potent CAR T cell drug product for treatment of BCMA-expressing hematological malignances. Blood. 2015;126(23):3094–3094. Evidence that BCMA CAR-T cells can recognize target cells with < 1000 copies of target antigen on their surface. Google Scholar
  70. 70.
    •• Perna F, Berman SH, Soni RK, Mansilla-Soto J, Eyquem J, Hamieh M, et al. Integrating proteomics and transcriptomics for systematic combinatorial chimeric antigen receptor therapy of AML. Cancer Cell. 2017;32(4):506–519.e5 Key paper illustrating the challenges of identifying suitable antigens for CAR-T cells to treat myeloid malignancies. PubMedCrossRefGoogle Scholar
  71. 71.
    Fan M, Li M, Gao L, Geng S, Wang J, Wang Y, et al. Chimeric antigen receptors for adoptive T cell therapy in acute myeloid leukemia. J Hematol OncolJ Hematol Oncol. 2017;10:151.CrossRefGoogle Scholar
  72. 72.
    Petrov JC, Wada M, Pinz KG, Yan LE, Chen KH, Shuai X, et al. Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. Leukemia. 2018;25:1.Google Scholar
  73. 73.
    Wang Q, Wang Y, Lv H, Han Q, Fan H, Guo B, et al. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther. 2015;23(1):184–91.PubMedCrossRefGoogle Scholar
  74. 74.
    Porter DL, Hwang W-T, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139–9.Google Scholar
  75. 75.
    Bishop DC, Xu N, Tse B, O’Brien TA, Gottlieb DJ, Dolnikov A, et al. PiggyBac-engineered T cells expressing CD19-specific CARs that lack IgG1 Fc spacers have potent activity against B-ALL xenografts. Mol Ther [Internet]. 2018 10 [cited 2018 Jul 27];0(0). Available from:
  76. 76.
    Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S, et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016;126(9):3363–76.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Qasim W, Zhan H, Samarasinghe S, Adams S, Amrolia P, Stafford S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med. 2017;9(374):eaaj2013.PubMedCrossRefGoogle Scholar
  78. 78.
    Li Y, Hermanson DL, Moriarity BS, Kaufman DS. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell. 2018;23(2):181–192.e5.PubMedCrossRefGoogle Scholar
  79. 79.
    McCurdy SR, Kasamon YL, Kanakry CG, Bolaños-Meade J, Tsai H-L, Showel MM, et al. Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide. Haematologica. 2017;102(2):391–400.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Milano F, Gooley T, Wood B, Woolfrey A, Flowers ME, Doney K, et al. Cord-blood transplantation in patients with minimal residual disease. N Engl J Med. 2016;375(10):944–53.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Segal Eric, Martens Michael, Wang Hai-Lin, Brazauskas Ruta, Weisdorf Daniel, Sandmaier Brenda M., et al. Comparing outcomes of matched related donor and matched unrelated donor hematopoietic cell transplants in adults with B-cell acute lymphoblastic leukemia. Cancer. 2017;123(17):3346–3355.Google Scholar
  82. 82.
    Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912–9.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Hay KA, Hanafi L-A, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T cell therapy. Blood. 2017;1:blood-2017-06-793141.Google Scholar
  84. 84.
    Turtle CJ, Hay KA, Juliane G, Hanafi L-A, Li D, Chaney C, et al. Biomarkers of cytokine release syndrome and neurotoxicity after CD19 CAR-T cells and mitigation of toxicity by cell dose. Blood. 2016;128(22):1852–2.Google Scholar
  85. 85.
    Shlomchik WD. Graft-versus-host disease. Nat Rev. Immunol. 2007;7(5):340–52.PubMedCrossRefGoogle Scholar
  86. 86.
    Lee SJ, Logan B, Westervelt P, Cutler C, Woolfrey A, Khan SP, et al. Comparison of patient-reported outcomes in 5-year survivors who received bone marrow vs peripheral blood unrelated donor transplantation: long-term follow-up of a randomized clinical trial. JAMA Oncol. 2016;2(12):1583–9.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016;387(10020):770–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of MedicineUniversity of WashingtonSeattleUSA
  2. 2.Fred Hutchinson Cancer Research CenterSeattleUSA

Personalised recommendations