correspondence
Trisomy 12 is associated with an abbreviated redistribution lymphocytosis during treatment with the BTK inhibitor ibrutinib in patients with chronic lymphocytic leukaemia B cell receptor (BCR) signalling is essential for the proliferation and survival of chronic lymphocytic leukaemia (CLL) cells (Herishanu et al, 2011) and is enhanced by interactions between CLL cells and the tissue microenvironment (Burger, 2011). Signals from the BCR are transduced by downstream kinases, including SYK, BTK and PI3K-d (Woyach et al, 2012). BTK (Byrd et al, 2013) and PI3K-d (Furman et al, 2014) inhibitors have potent therapeutic effect. Transient redistribution lymphocytosis is an early clinical feature during treatment with kinase inhibitors (Byrd et al, 2013; Furman et al, 2014), which probably relates to inhibition of CLL cell migration and adhesion due to disruption of chemokine receptor and integrin signalling (de Gorter et al, 2007; Ponader et al, 2012). The magnitude and duration of redistribution lymphocytosis in ibrutinib-treated patients with CLL are variable, but the factors underlying this variability are largely unknown. Prolonged lymphocytosis (PRL), defined as absolute lymphocyte count (ALC) ≥50% of baseline for ≥12 months, is more common in patients with mutated IGHV gene and del(13q) as a sole abnormality (Woyach et al, 2014). To further characterize redistribution lymphocytosis in clinically relevant CLL subgroups, we correlated lymphocytosis pattern with other clinical variables, focusing on cytogenetics. We analysed 89 patients treated with ibrutinib monotherapy on investigational protocols at the MD Anderson Cancer Center between June 2010 and August 2013. The following were evaluated according to baseline prognostic variables: time to peak (TTPeak) ALC, percentage rise from baseline (%rise), time to 50% reduction from baseline level (TT50%) and time to normalization or nadir (TTNadir). Percentage changes rather than absolute changes in ALC were analysed to normalize for different baseline ALC. Statistical analysis was performed using SPSS version 21 (IBM Corporation, Armonk, NY, USA) and GraphPad Prism 6 (La Jolla, CA, USA). Chi-square testing was used for binary outcome variables. Mann–Whitney or Kruskall–Wallis tests were used to evaluate continuous variables. Event-free survival (EFS) analysis was performed using the Kaplan– Meier method and dichotomous variables compared using the log rank test. An event was defined as disease progression, initiation of alternative salvage therapy, permanent discontinuation of study drug due to toxicity or death from any cause. All P-values are two-sided, with a significance level of 005. Event numbers were insufficient for multivariate EFS analysis. ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
Median age of the patients was 66 (range 38–83) years. Forty (45%) patients were treatment-na€ıve and 49 (55%) were relapsed/refractory; 14/49 relapsed/refractory patients had fludarabine-refractory disease. Forty-one (46%) had Rai stage III or IV disease, 30 (34%) had bulky adenopathy (≥5 cm) and 39/80 (49%) had baseline b2-microglobulin ≥40 mg/l. Fifty-seven (64%) had unmutated IGHV gene, 18 (202%) were mutated and the remainder had no polymerase chain reaction product available. Fluorescence in situ hybridization (FISH) categories were as follows: del(13q) 21 (236%), negative 21 (236%), trisomy 12 (T12) 6 (67%), del(11q) 14 (157%) and del(17p) 27 (303). Ten patients had T12 and additional del(17p). Median TTPeak was 28 d, median %rise was 108%, median TT50% was 16 weeks and median TTNadir was 24 weeks. The 16 patients with T12 showed a distinct pattern of lymphocytosis; those with T12 and del(17p) had an identical pattern of lymphocytosis to patients with T12 without 17p-, but had higher initial ALC. An attenuated rise in ALC was seen (median TTPeak 7 d vs. 28 d for the total cohort, P = 002, median %rise of 56% vs. 108% for the total cohort, P = 002) followed by a rapid reduction to
Trisomy 12 is associated with an abbreviated redistribution lymphocytosis during treatment with the BTK inhibitor ibrutinib in patients with chronic lymphocytic leukaemia B cell receptor (BCR) signalling is essential for the proliferation and survival of chronic lymphocytic leukaemia (CLL) cells (Herishanu et al, 2011) and is enhanced by interactions between CLL cells and the tissue microenvironment (Burger, 2011). Signals from the BCR are transduced by downstream kinases, including SYK, BTK and PI3K-d (Woyach et al, 2012). BTK (Byrd et al, 2013) and PI3K-d (Furman et al, 2014) inhibitors have potent therapeutic effect. Transient redistribution lymphocytosis is an early clinical feature during treatment with kinase inhibitors (Byrd et al, 2013; Furman et al, 2014), which probably relates to inhibition of CLL cell migration and adhesion due to disruption of chemokine receptor and integrin signalling (de Gorter et al, 2007; Ponader et al, 2012). The magnitude and duration of redistribution lymphocytosis in ibrutinib-treated patients with CLL are variable, but the factors underlying this variability are largely unknown. Prolonged lymphocytosis (PRL), defined as absolute lymphocyte count (ALC) ≥50% of baseline for ≥12 months, is more common in patients with mutated IGHV gene and del(13q) as a sole abnormality (Woyach et al, 2014). To further characterize redistribution lymphocytosis in clinically relevant CLL subgroups, we correlated lymphocytosis pattern with other clinical variables, focusing on cytogenetics. We analysed 89 patients treated with ibrutinib monotherapy on investigational protocols at the MD Anderson Cancer Center between June 2010 and August 2013. The following were evaluated according to baseline prognostic variables: time to peak (TTPeak) ALC, percentage rise from baseline (%rise), time to 50% reduction from baseline level (TT50%) and time to normalization or nadir (TTNadir). Percentage changes rather than absolute changes in ALC were analysed to normalize for different baseline ALC. Statistical analysis was performed using SPSS version 21 (IBM Corporation, Armonk, NY, USA) and GraphPad Prism 6 (La Jolla, CA, USA). Chi-square testing was used for binary outcome variables. Mann–Whitney or Kruskall–Wallis tests were used to evaluate continuous variables. Event-free survival (EFS) analysis was performed using the Kaplan– Meier method and dichotomous variables compared using the log rank test. An event was defined as disease progression, initiation of alternative salvage therapy, permanent discontinuation of study drug due to toxicity or death from any cause. All P-values are two-sided, with a significance level of 005. Event numbers were insufficient for multivariate EFS analysis. ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
Median age of the patients was 66 (range 38–83) years. Forty (45%) patients were treatment-na€ıve and 49 (55%) were relapsed/refractory; 14/49 relapsed/refractory patients had fludarabine-refractory disease. Forty-one (46%) had Rai stage III or IV disease, 30 (34%) had bulky adenopathy (≥5 cm) and 39/80 (49%) had baseline b2-microglobulin ≥40 mg/l. Fifty-seven (64%) had unmutated IGHV gene, 18 (202%) were mutated and the remainder had no polymerase chain reaction product available. Fluorescence in situ hybridization (FISH) categories were as follows: del(13q) 21 (236%), negative 21 (236%), trisomy 12 (T12) 6 (67%), del(11q) 14 (157%) and del(17p) 27 (303). Ten patients had T12 and additional del(17p). Median TTPeak was 28 d, median %rise was 108%, median TT50% was 16 weeks and median TTNadir was 24 weeks. The 16 patients with T12 showed a distinct pattern of lymphocytosis; those with T12 and del(17p) had an identical pattern of lymphocytosis to patients with T12 without 17p-, but had higher initial ALC. An attenuated rise in ALC was seen (median TTPeak 7 d vs. 28 d for the total cohort, P = 002, median %rise of 56% vs. 108% for the total cohort, P = 002) followed by a rapid reduction to
