Phase I-II study of lenalidomide and alemtuzumab in refractory chronic lymphocytic leukemia (CLL): effects on T cells and immune checkpoints.
This phase I-II study explored safety, immunomodulatory and clinical effects of lenalidomide (weeks 1-16) and alemtuzumab (weeks 5-16) in 23 patients with refractory chronic lymphocytic leukemia. Most patients had Rai stage III/IV disease and were heavily pretreated (median 4 prior therapies), and 61% had del(17p)/del(11q). Eleven of 19 evaluable patients (58%) responded, with a median response duration of 12 months (1-29+); time to progression was short in non-responders. Lenalidomide had a narrow therapeutic dose range, 2.5 mg/day was not efficient, and maximum tolerated dose was 5 mg/day. Grade 3-4 neutropenia and thrombocytopenia occurred in 84 and 55%, 30% had febrile neutropenia, and CMV-reactivation requiring valganciclovir occurred in 30% of patients. The frequency of proliferating (Ki67+) CD8+T cells was increased at week 4, with further increase in both the CD4+and CD8+subsets (p < 0.01 and <0.05), which was accompanied by significant upregulation of HLA-DR after addition of alemtuzumab. Antigen-experienced cells increased at week 4 as the frequency of effector memory cells increased in the CD8+subset (p < 0.003), while effector cells decreased in both the CD8+and CD4+subsets (p < 0.0001 and p < 0.01). The Th1/Th2 balance was unchanged at week 4 but shifted toward a Th2 profile after combination therapy. At end of treatment, the frequency of Th17 and regulatory T cells was reduced (p < 0.01), naïve T cells decreased, and effector memory T cells increased (p < 0.05 and p < 0.01). Granzyme B+T cells increased at 30-week follow-up (p < 0.05). PD-1 expression was unaffected. In conclusion, low-dose lenalidomide and alemtuzumab induced major perturbations of T cells, including increased proliferative activity and cytotoxic potential.
Department of Hematology, Karolinska University Hospital Solna, 171 76, Stockholm, Sweden. maria.winqvist@karolinska.se.|Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. maria.winqvist@karolinska.se.
Maria
M
Winqvist
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Fariba
F
Mozaffari
Department of Hematology, Karolinska University Hospital Solna, 171 76, Stockholm, Sweden.|Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Marzia
M
Palma
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Sandra
S
Eketorp Sylvan
Department of Hematology, Karolinska University Hospital Solna, 171 76, Stockholm, Sweden.|Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Lotta
L
Hansson
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Håkan
H
Mellstedt
Department of Hematology, Karolinska University Hospital Solna, 171 76, Stockholm, Sweden.|Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Anders
A
Österborg
Department of Hematology, Karolinska University Hospital Solna, 171 76, Stockholm, Sweden.|Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Jeanette
J
Lundin
D000368:Aged; D000369:Aged, 80 and over; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D060890:B7-H1 Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives
D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D006684:HLA-DR Antigens; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000074323:Alemtuzumab; D013792:Thalidomide; D000077269:Lenalidomide
Alemtuzumab; Chronic lymphocytic leukemia; Immune checkpoints; Lenalidomide; T cells