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Editorials
favorable cytogenetic group had the expected longer sur- vival when given chemotherapy + GO rather than chemotherapy alone. The Southwest Oncology Group has also failed to notice an effect of CD33 SNPs on out- come in adults (M Othus, 2018, personal communication).
Even the minority of patients who benefit from GO might benefit more from development of improved anti- CD33 therapeutics.17 One possibility here is use of bispe- cific antibodies (BiAbs) that engage CD33 but also direct T cells toward AML cells. An obvious model for this approach is blinatumomab,18 a CD3/CD19 molecule built in the Bispecific T-cell Engager (BiTE) format. A first series of CD33/CD3 BiAbs, including the BiTE AMG 330 and the tandem diabody AMV-564, have recently entered clin- ical tests.
Like GO, all CD33 BiAbs (and other CD33-directed therapeutics) currently under investigation recognize the V set domain, which is located distally on CD33. However, preliminary studies with artificial CD33 mole- cules show that membrane proximal binding enhances the immune effector cell functions of CD33 antibodies (R Walter, 2018, personal communication). Development of antibodies recognizing such proximal sites is likely to be an area of examination in GO’s second and, hopefully, subsequent acts.
References
1. Walter R, Appelbaum F, Estey E, and Bernstein I Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood. 2012;119(26):6198-6208.
2. McKoy J, Angelotta C, Bennett C, et al. Gemtuzumab ozogamicin-asso- ciated sinusoidal obstructive syndrome (SOS): an overview from the research on adverse drug events and reports (RADAR) project. Leuk Res. 2007;31(5):599-604.
3. Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508-1516.
4. de Lima M, Strom S, Keating M, et al. Implications of potential cure in acute myelogenous leukemia: development of subsequent cancer and return to work. Blood. 1997;90(12):4719-4724.
5. Lambert J, Pautas C, Terré C et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019;104(1):113-119.
6. Niktoreh N, Lerius B, Zimmermann M et al. Gemtuzumab ozogam- icin in children with relapsed or refractory acute myeloid leukemia: a report by Berlin-Frankfurt-Münster study group. Haematologica. 2019;104(1):120-127.
7. Gamis AS, Alonzo TA, Meshinchi S, et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531.J Clin Oncol. 2014;32(27):3021-3032.
8. Burnett AK, Goldstone A, Hills RK, et al. Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission. J Clin Oncol. 2013;31(10):1293-1301.
9. EsteyE,OthusM,LeeSJ,AppelbaumFR,GaleRP.Newdrugapprovals in acute myeloid leukemia: what's the best endpoint? Leukemia. 2016;30(3):521-525.
10. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from ran- domised controlled trials. Lancet Oncol. 2014;15(9)986-996.
11. Pollard JA, Loken M, Gerbing RB, et al. CD33 Expression and Its Association With Gemtuzumab Ozogamicin Response: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531. J Clin Oncol. 2016;34(7):747-755.
12. OlombelG,GuerinE,GuyJ,etal.ThelevelofblastCD33expression positively impacts the effect of gemtuzumab ozogamicin in patients with acute myeloid leukemia Blood. 2016;127(17) 2157-2160.
13. Khan N, Hills RK, Virgo P, et al. Expression of CD33 is a predictive factor for effect of gemtuzumab ozogamicin at different doses in adult acute myeloid leukaemia. Leukemia. 2017;31(5):1059-1068.
14. Tsimberidou A, Estey E, Cortes J, et al. Gemtuzumab, fludarabine, cytarabine, and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high-risk myelodysplastic syndromes. Cancer. 2003;97(6):1481-1487.
15. Lamba JK, Chauhan L, Shin M, et al. CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From Randomized Phase III Children's Oncology Group Trial AAML0531. J Clin Oncol. 2017;35(23):2674- 2682.
16. Gale R, Pope T, Wright M, et al. No evidence that CD33 splicing SNP impacts the response to GO in younger adults with AML treated on UK MRC/NCRI trials. Blood. 2018;131(4):468-471.
17. Walter R Investigational CD33-targeted therapeutics for acute myeloid leukemia. Expert Opin Investig Drugs 2018; 27(4): 339-348
18. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017;376(9):836-847.
Lenalidomide can be safely combined with chlorambucil and rituximab in older patients with chronic lymphocytic leukemia
Candida Vitale1 and Alessandra Ferrajoli2
1Division of Hematology, University of Torino, A.O.U. Città della Salute e della Scienza di Torino, Italy and 2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
E-mail: aferrajo@mdanderson.org doi:10.3324/haematol.2018.206359
The clinical activity of lenalidomide in chronic lym- phocytic leukemia (CLL) was first reported more
1,2
than 10 years ago. Since then, this agent has been
studied in various combinations with anti-CD20 mono- clonal antibodies, chemotherapy, chemo-immunotherapy and B-cell receptor (BCR)-targeting agents. These studies have shown clinical responses; however, most importantly,
they have also highlighted unique and unexpected toxici- ties, in particular when lenalidomide was combined with chemo-immunotherapy and targeted agents.
In this issue of Haematologica, Kater and colleagues report the experience of the HOVON CLL study group on the fea- sibility and efficacy of the combination of lenalidomide, chlorambucil, and rituximab in treatment-naïve patients
haematologica | 2019; 104(1)
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