14 research outputs found
ΠΠ΅Π±ΡΡ Π²ΠΎΡΠΏΠ°Π»ΠΈΡΠ΅Π»ΡΠ½ΠΎΠΉ ΡΠΊΠ΅Π»Π΅ΡΠ½ΠΎ-ΠΌΡΡΠ΅ΡΠ½ΠΎΠΉ ΠΏΠ°ΡΠΎΠ»ΠΎΠ³ΠΈΠΈ Ρ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ², ΠΏΠΎΠ»ΡΡΠ°ΡΡΠΈΡ ΠΏΡΠΎΡΠΈΠ²ΠΎΠΎΠΏΡΡ ΠΎΠ»Π΅Π²ΠΎΠ΅ Π»Π΅ΡΠ΅Π½ΠΈΠ΅ ΠΈΠ½Π³ΠΈΠ±ΠΈΡΠΎΡΠ°ΠΌΠΈ PD-1/PD-L1-ΠΏΡΡΠΈ
Objective: to describe musculoskeletal immune-mediated adverse events (iAEs) associated with the therapy of solid tumors with immune checkpoint inhibitors (ICIs, inhibitors of the PD-1/PD-L1 pathway).Patients and methods. 13 patients receiving ICIs therapy with musculoskeletal iAEs were examined. The average age of patients was 59Β±10 years. All cases had a histologically verified diagnosis of a malignant solid neoplasm: melanoma (n=5), kidney cancer (n=3), bladder cancer (n=2), non-small cell lung cancer (n=1), breast cancer (n=1), cervical cancer (n=1). All patients were prescribed inhibitors of the PD-1/PD-L1 signaling pathway: nivolumab (n=6), pembrolizumab (n=3), atezolizumab (n=3), prolgolimab (n=1). In 7 (54%) patients, in addition to musculoskeletal disorders, other AEs were also detected: thyroiditis (n=3), neuropathy (n=2), rash (n=1), dry syndrome (n=1), hepatitis (n=1). The median time from the start of antitumor immunotherapy (IT) to the onset of musculoskeletal pathology was 20 [9; 48] weeks.Results and discussion. Clinical manifestations of musculoskeletal pathology included: synovitis in 9 (69%) patients, tenosynovitis in 11 (85%), enthesitis in 4 (31%), morning stiffness in the joints for more than 30 minutes in 4 (31%). In 11 cases, musculoskeletal pathology was persistent (in 9 patients with arthritis and 2 with periarthritis) and in 2 β transient. The knee (77%), shoulder (69%) and hand (54%) joints were most frequently affected, with bilateral involvement in 9 (69%) patients. Inflammatory changes in the joints were represented by mono- (n=1), oligo- (n=3) and polyarthritis (n=5), including those involving the small joints of the hands and/or feet (n=5) and predominantly affecting the joints of the lower limbs (n=3). In 3 patients with arthritis, periarticular changes dominated in clinical picture (in 2 patients with symmetrical polyarthritis and severe tenosynovitis, in another 1 patient β with RS3PE syndrome). The severity of musculoskeletal pathology was assessed using the CTCAE v5.0 toxicity criteria: grade 1 was documented in 2 (15.5%), grade 2 in 9 (69%), and grade 3 in 2 (15, 5%) patients. Laboratory workup revealed elevation of ESR β₯30 mm/h (median β 34 [14; 42] mm/h) in 7 out of 12 (58%) patients, elevation of CRP level >5 mg/l (median β 7.2 [4.6; 12.9] mg/l) β in 7 out of 10 (70%). In 7 out of 10 patients, antinuclear antibodies (Hep2) were detected in titers: 1:160 (n=2), 1:320 (n=3), 1:640 (n=2). Rheumatoid factor and antibodies to cyclic citrullinated peptide were not detected in any case. Therapy for musculoskeletal AEs included non-steroidal anti-inflammatory drugs (n=10), oral systemic glucocorticoids β GC (n=5), methotrexate β MT (n=1) and hydroxychloroquine (n=5), intra-articular administration of GC (n=1). Five patients with arthritis required long-term therapy (median duration β 12 [3; 12] months), in 1 patient with polyarthritis and severe tenosynovitis, antitumor IT was interrupted for the duration of the course of MTX treatment.Conclusion. It has been shown that musculoskeletal iAEs have heterogeneous manifestations and may require long-term treatment and in rare cases, anticancer therapy interruption. Additional studies and close cooperation between rheumatologists and oncologists are needed to obtain a more complete understanding of the nature and spectrum of musculoskeletal AEs, to identify their clinical, laboratory and instrumental features, and to develop an management of patients algorithm.Π¦Π΅Π»Ρ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ β ΠΎΠΏΠΈΡΠ°ΡΡ ΡΠΊΠ΅Π»Π΅ΡΠ½ΠΎ-ΠΌΡΡΠ΅ΡΠ½ΡΠ΅ ΠΈΠΌΠΌΡΠ½ΠΎΠΎΠΏΠΎΡΡΠ΅Π΄ΠΎΠ²Π°Π½Π½ΡΠ΅ Π½Π΅ΠΆΠ΅Π»Π°ΡΠ΅Π»ΡΠ½ΡΠ΅ ΡΠ²Π»Π΅Π½ΠΈΡ (ΠΈΠΠ―), Π°ΡΡΠΎΡΠΈΠΈΡΠΎΠ²Π°Π½Π½ΡΠ΅ Ρ ΡΠ΅ΡΠ°ΠΏΠΈΠ΅ΠΉ ΡΠΎΠ»ΠΈΠ΄Π½ΡΡ
ΠΎΠΏΡΡ
ΠΎΠ»Π΅ΠΉ ΠΈΠ½Π³ΠΈΠ±ΠΈΡΠΎΡΠ°ΠΌΠΈ ΠΊΠΎΠ½ΡΡΠΎΠ»ΡΠ½ΡΡ
ΡΠΎΡΠ΅ΠΊ (ΠΠΠ’, ΠΈΠ½Π³ΠΈΠ±ΠΈΡΠΎΡΡ PD-1/PD-L1-ΠΏΡΡΠΈ).ΠΠ°ΡΠΈΠ΅Π½ΡΡ ΠΈ ΠΌΠ΅ΡΠΎΠ΄Ρ. ΠΠ±ΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΎ 13 ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² ΡΠΎ ΡΠΊΠ΅Π»Π΅ΡΠ½ΠΎ-ΠΌΡΡΠ΅ΡΠ½ΡΠΌΠΈ ΠΈΠΠ―, ΠΏΠΎΠ»ΡΡΠ°ΡΡΠΈΡ
ΡΠ΅ΡΠ°ΠΏΠΈΡ ΠΠΠ’. Π‘ΡΠ΅Π΄Π½ΠΈΠΉ Π²ΠΎΠ·ΡΠ°ΡΡ Π±ΠΎΠ»ΡΠ½ΡΡ
β 59Β±10 Π»Π΅Ρ. ΠΡΠ΅Ρ
ΡΠ»ΡΡΠ°ΡΡ
ΠΈΠΌΠ΅Π»ΡΡ Π³ΠΈΡΡΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈ Π²Π΅ΡΠΈΡΠΈΡΠΈΡΠΎΠ²Π°Π½Π½ΡΠΉ Π΄ΠΈΠ°Π³Π½ΠΎΠ· Π·Π»ΠΎΠΊΠ°ΡΠ΅ΡΡΠ²Π΅Π½Π½ΠΎΠ³ΠΎ ΡΠΎΠ»ΠΈΠ΄Π½ΠΎΠ³ΠΎ Π½ΠΎΠ²ΠΎΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π½ΠΈΡ: ΠΌΠ΅Π»Π°Π½ΠΎΠΌΠ° (n=5), ΡΠ°ΠΊ ΠΏΠΎΡΠΊΠΈ (n=3), ΡΠ°ΠΊ ΠΌΠΎΡΠ΅Π²ΠΎΠ³ΠΎ ΠΏΡΠ·ΡΡΡ (n=2), Π½Π΅ΠΌΠ΅Π»ΠΊΠΎΠΊΠ»Π΅ΡΠΎΡΠ½ΡΠΉ ΡΠ°ΠΊ Π»Π΅Π³ΠΊΠΎΠ³ΠΎ (n=1), ΡΠ°ΠΊ ΠΌΠΎΠ»ΠΎΡΠ½ΠΎΠΉ ΠΆΠ΅Π»Π΅Π·Ρ (n=1), ΡΠ°ΠΊ ΡΠ΅ΠΉΠΊΠΈ ΠΌΠ°ΡΠΊΠΈ (n=1). ΠΡΠ΅ΠΌ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠ°ΠΌ Π±ΡΠ»ΠΈ Π½Π°Π·Π½Π°ΡΠ΅Π½Ρ ΠΈΠ½Π³ΠΈΠ±ΠΈΡΠΎΡΡ ΡΠΈΠ³Π½Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΠΏΡΡΠΈ PD-1/PD-L1: Π½ΠΈΠ²ΠΎΠ»ΡΠΌΠ°Π± (n=6), ΠΏΠ΅ΠΌΠ±ΡΠΎΠ»ΠΈΠ·ΡΠΌΠ°Π± (n=3), Π°ΡΠ΅Π·ΠΎΠ»ΠΈΠ·ΡΠΌΠ°Π± (n=3), ΠΏΡΠΎΠ»Π³ΠΎΠ»ΠΈΠΌΠ°Π± (n=1). Π£ 7 (54%) ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ², ΠΊΡΠΎΠΌΠ΅ ΡΠΊΠ΅Π»Π΅ΡΠ½ΠΎ-ΠΌΡΡΠ΅ΡΠ½ΡΡ
Π½Π°ΡΡΡΠ΅Π½ΠΈΠΉ, ΡΠ°ΠΊΠΆΠ΅ Π²ΡΡΠ²Π»ΡΠ»ΠΈΡΡ Π΄ΡΡΠ³ΠΈΠ΅ ΠΈΠΠ―: ΡΠΈΡΠ΅ΠΎΠΈΠ΄ΠΈΡ (n=3), Π½Π΅Π²ΡΠΎΠΏΠ°ΡΠΈΡ (n=2), ΡΡΠΏΡ (n=1), ΡΡΡ
ΠΎΠΉ ΡΠΈΠ½Π΄ΡΠΎΠΌ (n=1), Π³Π΅ΠΏΠ°ΡΠΈΡ (n=1). ΠΠ΅Π΄ΠΈΠ°Π½Π° Π²ΡΠ΅ΠΌΠ΅Π½ΠΈ ΠΎΡ Π½Π°ΡΠ°Π»Π° ΠΏΡΠΎΡΠΈΠ²ΠΎΠΎΠΏΡΡ
ΠΎΠ»Π΅Π²ΠΎΠΉ ΠΈΠΌΠΌΡΠ½ΠΎΡΠ΅ΡΠ°ΠΏΠΈΠΈ (ΠΠ’) Π΄ΠΎ Π΄Π΅Π±ΡΡΠ° ΡΠΊΠ΅Π»Π΅ΡΠ½ΠΎ-ΠΌΡΡΠ΅ΡΠ½ΠΎΠΉ ΠΏΠ°ΡΠΎΠ»ΠΎΠ³ΠΈΠΈ ΡΠΎΡΡΠ°Π²ΠΈΠ»Π° 20 [9; 48] Π½Π΅Π΄.Π Π΅Π·ΡΠ»ΡΡΠ°ΡΡ ΠΈ ΠΎΠ±ΡΡΠΆΠ΄Π΅Π½ΠΈΠ΅. ΠΠ»ΠΈΠ½ΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΏΡΠΎΡΠ²Π»Π΅Π½ΠΈΡ ΡΠΊΠ΅Π»Π΅ΡΠ½ΠΎ-ΠΌΡΡΠ΅ΡΠ½ΠΎΠΉ ΠΏΠ°ΡΠΎΠ»ΠΎΠ³ΠΈΠΈ Π²ΠΊΠ»ΡΡΠ°Π»ΠΈ: ΡΠΈΠ½ΠΎΠ²ΠΈΡ Ρ 9 (69%) Π±ΠΎΠ»ΡΠ½ΡΡ
, ΡΠ΅Π½ΠΎΡΠΈΠ½ΠΎΠ²ΠΈΡ Ρ 11 (85%), ΡΠ½ΡΠ΅Π·ΠΈΡ Ρ 4 (31%), ΡΡΡΠ΅Π½Π½ΡΡ ΡΠΊΠΎΠ²Π°Π½Π½ΠΎΡΡΡ Π² ΡΡΡΡΠ°Π²Π°Ρ
Π±ΠΎΠ»Π΅Π΅ 30 ΠΌΠΈΠ½ Ρ 4 (31%). Π 11 ΡΠ»ΡΡΠ°ΡΡ
ΡΠΊΠ΅Π»Π΅ΡΠ½ΠΎΠΌΡΡΠ΅ΡΠ½Π°Ρ ΠΏΠ°ΡΠΎΠ»ΠΎΠ³ΠΈΡ Π½ΠΎΡΠΈΠ»Π° ΠΏΠ΅ΡΡΠΈΡΡΠΈΡΡΡΡΠΈΠΉ Ρ
Π°ΡΠ°ΠΊΡΠ΅Ρ (Ρ 9 ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ Π°ΡΡΡΠΈΡΠΎΠΌ ΠΈ 2 Ρ ΠΏΠ΅ΡΠΈΠ°ΡΡΡΠΈΡΠΎΠΌ) ΠΈ Π² 2 β ΡΡΠ°Π½Π·ΠΈΡΠΎΡΠ½ΡΠΉ. ΠΠ°ΠΈΠ±ΠΎΠ»Π΅Π΅ ΡΠ°ΡΡΠΎ ΠΏΠΎΡΠ°ΠΆΠ°Π»ΠΈΡΡ ΠΊΠΎΠ»Π΅Π½Π½ΡΠ΅ (77%), ΠΏΠ»Π΅ΡΠ΅Π²ΡΠ΅ (69%) ΡΡΡΡΠ°Π²Ρ ΠΈ ΡΡΡΡΠ°Π²Ρ ΠΊΠΈΡΡΠ΅ΠΉ (54%) Ρ Π΄Π²ΡΡΡΠΎΡΠΎΠ½Π½ΠΈΠΌ Π²ΠΎΠ²Π»Π΅ΡΠ΅Π½ΠΈΠ΅ΠΌ Ρ 9 (69%) ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ². ΠΠΎΡΠΏΠ°Π»ΠΈΡΠ΅Π»ΡΠ½ΡΠ΅ ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΡ ΡΡΡΡΠ°Π²ΠΎΠ² Π±ΡΠ»ΠΈ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»Π΅Π½Ρ ΠΌΠΎΠ½ΠΎ- (n=1), ΠΎΠ»ΠΈΠ³ΠΎ- (n=3) ΠΈ ΠΏΠΎΠ»ΠΈΠ°ΡΡΡΠΈΡΠΎΠΌ (n=5), Π² ΡΠΎΠΌ ΡΠΈΡΠ»Π΅ Ρ Π²ΠΎΠ²Π»Π΅ΡΠ΅Π½ΠΈΠ΅ΠΌ ΠΌΠ΅Π»ΠΊΠΈΡ
ΡΡΡΡΠ°Π²ΠΎΠ² ΠΊΠΈΡΡΠ΅ΠΉ ΠΈ/ΠΈΠ»ΠΈ ΡΡΠΎΠΏ (n=5) ΠΈ ΠΏΡΠ΅ΠΈΠΌΡΡΠ΅ΡΡΠ²Π΅Π½Π½ΡΠΌ ΠΏΠΎΡΠ°ΠΆΠ΅Π½ΠΈΠ΅ΠΌ ΡΡΡΡΠ°Π²ΠΎΠ² Π½ΠΈΠΆΠ½ΠΈΡ
ΠΊΠΎΠ½Π΅ΡΠ½ΠΎΡΡΠ΅ΠΉ (n=3). Π£ 3 Π±ΠΎΠ»ΡΠ½ΡΡ
Ρ Π°ΡΡΡΠΈΡΠΎΠΌ Π² ΠΊΠ»ΠΈΠ½ΠΈΡΠ΅ΡΠΊΠΎΠΉ ΠΊΠ°ΡΡΠΈΠ½Π΅ ΠΏΡΠ΅ΠΎΠ±Π»Π°Π΄Π°Π»ΠΈ ΠΏΠ΅ΡΠΈΠ°ΡΡΠΈΠΊΡΠ»ΡΡΠ½ΡΠ΅ ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΡ (Ρ 2 ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ ΡΠΈΠΌΠΌΠ΅ΡΡΠΈΡΠ½ΡΠΌ ΠΏΠΎΠ»ΠΈΠ°ΡΡΡΠΈΡΠΎΠΌ ΠΈ ΡΡΠΆΠ΅Π»ΡΠΌ ΡΠ΅Π½ΠΎΡΠΈΠ½ΠΎΠ²ΠΈΡΠΎΠΌ, Π΅ΡΠ΅ Ρ 1 β Ρ RS3PE-ΡΠΈΠ½Π΄ΡΠΎΠΌΠΎΠΌ). Π’ΡΠΆΠ΅ΡΡΡ ΡΠΊΠ΅Π»Π΅ΡΠ½ΠΎ-ΠΌΡΡΠ΅ΡΠ½ΠΎΠΉ ΠΏΠ°ΡΠΎΠ»ΠΎΠ³ΠΈΠΈ Π±ΡΠ»Π° ΠΎΡΠ΅Π½Π΅Π½Π° Ρ ΠΏΠΎΠΌΠΎΡΡΡ ΠΊΡΠΈΡΠ΅ΡΠΈΠ΅Π² ΡΠΎΠΊΡΠΈΡΠ½ΠΎΡΡΠΈ CTCAE v5.0: 1-Ρ ΡΡΠ΅ΠΏΠ΅Π½Ρ ΡΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½Π° Ρ 2 (15,5%), 2-Ρ β Ρ 9 (69%) ΠΈ 3-Ρ β Ρ 2 (15,5%) ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ². ΠΡΠΈ Π»Π°Π±ΠΎΡΠ°ΡΠΎΡΠ½ΠΎΠΌ ΠΎΠ±ΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠΈ ΡΠ²Π΅Π»ΠΈΡΠ΅Π½ΠΈΠ΅ Π‘ΠΠ β₯30 ΠΌΠΌ/Ρ (ΠΌΠ΅Π΄ΠΈΠ°Π½Π° β 34 [14; 42] ΠΌΠΌ/Ρ) Π²ΡΡΠ²Π»Π΅Π½ΠΎ Ρ 7 ΠΈΠ· 12 (58%) Π±ΠΎΠ»ΡΠ½ΡΡ
, ΠΏΠΎΠ²ΡΡΠ΅Π½ΠΈΠ΅ ΡΡΠΎΠ²Π½Ρ Π‘Π Π >5 ΠΌΠ³/Π» (ΠΌΠ΅Π΄ΠΈΠ°Π½Π° β 7,2 [4,6; 12,9] ΠΌΠ³/Π») β Ρ 7 ΠΈΠ· 10 (70%). Π£ 7 ΠΈΠ· 10 Π±ΠΎΠ»ΡΠ½ΡΡ
ΠΎΠ±Π½Π°ΡΡΠΆΠ΅Π½ Π°Π½ΡΠΈΠ½ΡΠΊΠ»Π΅Π°ΡΠ½ΡΠΉ ΡΠ°ΠΊΡΠΎΡ (Hep2) Π² ΡΠΈΡΡΠ°Ρ
: 1:160 (n=2), 1:320 (n=3), 1:640 (n=2). Π Π΅Π²ΠΌΠ°ΡΠΎΠΈΠ΄Π½ΡΠΉ ΡΠ°ΠΊΡΠΎΡ ΠΈ Π°Π½ΡΠΈΡΠ΅Π»Π° ΠΊ ΡΠΈΠΊΠ»ΠΈΡΠ΅ΡΠΊΠΎΠΌΡ ΡΠΈΡΡΡΠ»Π»ΠΈΠ½ΠΈΡΠΎΠ²Π°Π½Π½ΠΎΠΌΡ ΠΏΠ΅ΠΏΡΠΈΠ΄Ρ Π½Π΅ Π²ΡΡΠ²Π»Π΅Π½Ρ Π½ΠΈ Π² ΠΎΠ΄Π½ΠΎΠΌ ΡΠ»ΡΡΠ°Π΅. Π’Π΅ΡΠ°ΠΏΠΈΡ ΡΠΊΠ΅Π»Π΅ΡΠ½ΠΎ-ΠΌΡΡΠ΅ΡΠ½ΡΡ
ΠΈΠΠ― Π²ΠΊΠ»ΡΡΠ°Π»Π° ΠΏΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ Π½Π΅ΡΡΠ΅ΡΠΎΠΈΠ΄Π½ΡΡ
ΠΏΡΠΎΡΠΈΠ²ΠΎΠ²ΠΎΡΠΏΠ°Π»ΠΈΡΠ΅Π»ΡΠ½ΡΡ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² (n=10), ΠΎΡΠ°Π»ΡΠ½ΡΡ
ΡΠΈΡΡΠ΅ΠΌΠ½ΡΡ
Π³Π»ΡΠΊΠΎΠΊΠΎΡΡΠΈΠΊΠΎΠΈΠ΄ΠΎΠ² β ΠΠ (n=5), ΠΌΠ΅ΡΠΎΡΡΠ΅ΠΊΡΠ°ΡΠ° β ΠΠ’ (n=1) ΠΈ Π³ΠΈΠ΄ΡΠΎΠΊΡΠΈΡ
Π»ΠΎΡΠΎΡ
ΠΈΠ½Π° (n=5), Π²Π½ΡΡΡΠΈΡΡΡΡΠ°Π²Π½ΠΎΠ΅ Π²Π²Π΅Π΄Π΅Π½ΠΈΠ΅ ΠΠ (n=1). ΠΡΡΡ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ Π°ΡΡΡΠΈΡΠΎΠΌ Π½ΡΠΆΠ΄Π°Π»ΠΈΡΡ Π² ΠΏΡΠΎΠ΄ΠΎΠ»ΠΆΠΈΡΠ΅Π»ΡΠ½ΠΎΠΉ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ (ΠΌΠ΅Π΄ΠΈΠ°Π½Π° Π΄Π»ΠΈΡΠ΅Π»ΡΠ½ΠΎΡΡΠΈ β 12 [3; 12] ΠΌΠ΅Ρ), Ρ 1 ΠΏΠ°ΡΠΈΠ΅Π½ΡΠ° Ρ ΠΏΠΎΠ»ΠΈΠ°ΡΡΡΠΈΡΠΎΠΌ ΠΈ ΡΡΠΆΠ΅Π»ΡΠΌ ΡΠ΅Π½ΠΎΡΠΈΠ½ΠΎΠ²ΠΈΡΠΎΠΌ ΠΏΡΠΎΡΠΈΠ²ΠΎΠΎΠΏΡΡ
ΠΎΠ»Π΅Π²Π°Ρ ΠΠ’ Π±ΡΠ»Π° ΠΏΡΠ΅ΡΠ²Π°Π½Π° Π½Π° Π²ΡΠ΅ΠΌΡ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΈΡ ΠΊΡΡΡΠ° Π»Π΅ΡΠ΅Π½ΠΈΡ ΠΠ’.ΠΠ°ΠΊΠ»ΡΡΠ΅Π½ΠΈΠ΅. ΠΠΎΠΊΠ°Π·Π°Π½ΠΎ, ΡΡΠΎ ΡΠΊΠ΅Π»Π΅ΡΠ½ΠΎ-ΠΌΡΡΠ΅ΡΠ½ΡΠ΅ ΠΈΠΠ― ΠΈΠΌΠ΅ΡΡ Π³Π΅ΡΠ΅ΡΠΎΠ³Π΅Π½Π½ΡΠ΅ ΠΏΡΠΎΡΠ²Π»Π΅Π½ΠΈΡ ΠΈ ΠΌΠΎΠ³ΡΡ ΠΏΠΎΡΡΠ΅Π±ΠΎΠ²Π°ΡΡ Π΄Π»ΠΈΡΠ΅Π»ΡΠ½ΠΎΠ³ΠΎ Π»Π΅ΡΠ΅Π½ΠΈΡ, Π° Π² ΡΠ΅Π΄ΠΊΠΈΡ
ΡΠ»ΡΡΠ°ΡΡ
β ΠΈ ΠΏΡΠΈΠΎΡΡΠ°Π½ΠΎΠ²ΠΊΠΈ ΠΏΡΠΎΡΠΈΠ²ΠΎΠΎΠΏΡΡ
ΠΎΠ»Π΅Π²ΠΎΠΉ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ. ΠΠ»Ρ ΠΏΠΎΠ»ΡΡΠ΅Π½ΠΈΡ Π±ΠΎΠ»Π΅Π΅ ΠΏΠΎΠ»Π½ΠΎΠ³ΠΎ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»Π΅Π½ΠΈΡ ΠΎ ΠΏΡΠΈΡΠΎΠ΄Π΅ ΠΈ ΡΠΏΠ΅ΠΊΡΡΠ΅ ΡΠΊΠ΅Π»Π΅ΡΠ½ΠΎ-ΠΌΡΡΠ΅ΡΠ½ΡΡ
ΠΈΠΠ―, Π²ΡΠ΄Π΅Π»Π΅Π½ΠΈΡ ΠΈΡ
ΠΊΠ»ΠΈΠ½ΠΈΠΊΠΎ-Π»Π°Π±ΠΎΡΠ°ΡΠΎΡΠ½ΡΡ
ΠΈ ΠΈΠ½ΡΡΡΡΠΌΠ΅Π½ΡΠ°Π»ΡΠ½ΡΡ
ΠΎΡΠΎΠ±Π΅Π½Π½ΠΎΡΡΠ΅ΠΉ, ΡΠ°Π·ΡΠ°Π±ΠΎΡΠΊΠΈ Π°Π»Π³ΠΎΡΠΈΡΠΌΠ° ΠΊΡΡΠ°ΡΠΈΠΈ Π½Π΅ΠΎΠ±Ρ
ΠΎΠ΄ΠΈΠΌΡ Π΄ΠΎΠΏΠΎΠ»Π½ΠΈΡΠ΅Π»ΡΠ½ΡΠ΅ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΠΈ ΡΠ΅ΡΠ½ΠΎΠ΅ ΡΠΎΡΡΡΠ΄Π½ΠΈΡΠ΅ΡΡΠ²ΠΎ ΡΠ΅Π²ΠΌΠ°ΡΠΎΠ»ΠΎΠ³ΠΎΠ² ΠΈ ΠΎΠ½ΠΊΠΎΠ»ΠΎΠ³ΠΎΠ²
BTK, NuTM2A, and PRPF19 are Novel KMT2A Partner Genes in Childhood Acute Leukemia
Chromosomal rearrangements of the human KMT2A/MLL gene are associated with acute leukemias, especially in infants. KMT2A is rearranged with a big variety of partner genes and in multiple breakpoint locations. Detection of all types of KMT2A rearrangements is an essential part of acute leukemia initial diagnostics and follow-up, as it has a strong impact on the patientsβ outcome. Due to their high heterogeneity, KMT2A rearrangements are most effectively uncovered by next-generation sequencing (NGS), which, however, requires a thorough prescreening by cytogenetics. Here, we aimed to characterize uncommon KMT2A rearrangements in childhood acute leukemia by conventional karyotyping, FISH, and targeted NGS on both DNA and RNA level with subse-quent validation. As a result of this comprehensive approach, three novel KMT2A rearrangements were discovered: ins(X;11)(q26;q13q25)/KMT2A-BTK, t(10;11)(q22;q23.3)/KMT2A-NUTM2A, and inv(11)(q12.2q23.3)/KMT2A-PRPF19. These novel KMT2A-chimeric genes expand our knowledge of the mechanisms of KMT2A-associated leukemogenesis and allow tracing the dynamics of minimal residual disease in the given patients. Β© 2021 by the authors. Licensee MDPI, Basel, Switzerland.Funding: KMT2A rearrangement assessment was supported by the Russian Science Foundation (grant no. 19-75-10056). Quantitative RT-PCR for MRD monitoring was supported by Russian Presidential (grant no. MK-1645.2020.7)
The role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia: literature review and own experience
Aim. The analysis of experience of nelarabine use in refractory/relapsed T-cell acute lymphoblastic leukemia (T-ALL) depending on the immunophenotype and the line of therapy. Materials and methods. All the patients with relapsed or refractory T-ALL aged from 0 to 18 years who received treatment with nelarabine as a part of the therapeutic element R6 were included in the study. For all patients a detailed immunological analysis of leukemia cells with discrimination of immunological variants TI, TII, TIII or TIV was performed. Patients administered with nelarabine as a first therapeutic element were referred to the first-line therapy group, other patients were referred to the second-line therapy group. Nelarabine was administered as intravenous infusion at a dose of 650 mg/m2, on days 1-5. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) was considered for all patients. Results. From 2009 to 2017, 54 patients with refractory/relapsed T-ALL were treated with nelarabine. Five-year event-free survival (EFS) and overall survival (OS) was 28% for all patients, cumulative risk of relapse (CIR) was 27%. EFS was significantly higher in nelarabine first-line therapy group in comparison with second-line therapy group (34Β±8% vs 8Β±8%, p=0,05). In patients after allo-HSCT EFS, OS and CIR were 51Β±10%, 50Β±10% and 39,1Β±9,5% accordingly. The best results were achieved in patients with TI immunophenotype. No toxicity-related mortality as well as severe neurologic complications or discontinuation of therapy associated with use of nelarabine were reported. Conclusion. The use of nelarabine is an effective strategy for the treatment of relapsed and refractory T-ALL. The best treatment outcomes were obtained in patients with TI immunophenotype and in the first-line therapy group. Optimal dosage regimens can be established during controlled clinical trials
The MLL recombinome of acute leukemias in 2017
Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients
Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia
The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation
The MLL recombinome of acute leukemias in 2017
Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.</p
The MLL recombinome of acute leukemias in 2017
Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients