The results of this randomization have been previously reported (Matutes is the observed events, is the expected events, and Var is the variance. del by FISH); intermediate risk C without deletion (10%) and with at least one of: unmutated genes and/or usage, 11q deletion, \2 microglobulin 4?mg/l; good risk C none of the above and mutated genes (Oscier SF3B1and mutations, and expression (Gonzalez assay measuring drug resistance, which could be used by the treating physician to guide the choice of second\line treatment. The results of this randomization have been previously reported (Matutes is the observed events, is the expected events, and Var is the variance. A plot of OS after progression by second\line treatments was drawn to show the relative effect of these treatments within subgroups defined by randomized arm. Within each subgroup, the observed minus expected (OCE) number of events and its variance (Var) are given. Multivariate analyses were performed by means of stepwise generalized linear modelling. Values of fludarabine 6% [OR 223 (109C458), or mutations remained in remission. Open in a separate window Figure 1 Treatment history of patients in the Leukaemia Research Fund (LRF) chronic lymphocytic leukaemia (CLL)4 trial. Consort diagram showing the treatment history of the 777 trial patients, from randomization until latest follow\up (censored at 31 October 2010). CR, complete remission; PR, partial remission. *This number included 19% (chlorambucil {median 20?months; hazard ratio [HR] 053 (95% CI: PGF 044C063), fludarabine [median 24?months, HR 061 (050C076), (%)(%)all other treatments (all other treatments 12% (8C15); HR 052 (042C065), all other treatments, in the subsequent analyses. FC\based combinations/SCT were used as second\line treatments in an equal proportion of patients in the three randomized trial arms (28% chlorambucil, 33% fludarabine, 32% FC, all other treatments {10% [7C14]; HR 064 (052\079), mutated status; low beta\2 microglobulin level; absence of deletions of 11q and NOTCH1and [OR 021 (007C067), intermediate/poor)Length of first\line PFSLong ( 3?years)233107 (46) 00001 00001 Short ( 3?years)50069 (14)019 (013C027)026 (015C046)No. of lines of treatment123572 (31) 00001 00005 225071 (28)090 (061C133)088 (047C166);3 or more24833 (13)035 (022C055)025 (012C055)Responses to treatmentCR (first\line)11041 (37) 00001 004 Fraxinellone CR (but not until 2nd/3rd\line)6823 (34)086 (046C162)237 (088C639)No CR555112 (20)043 (027C066)081 (040C162)Second\line treatmentFC\based combinations/SCT14647 (32) 00001 Not includedd All other treatments35257 (16)041 (026C064) Open in a separate window FC\based combinations/SCT, combination treatments based on fludarabine with cyclophosphamide, or stem cell transplant (including autografts and allografts); CR, complete response; CI, confidence interval; PFS, progression\free survival. a44 overseas patients, who had not reached 10\year survival by the end of clinical follow\up, are excluded from this analysis (see Methods section). Thus the percentages shown here do not correspond to those shown in Fig?2A, which include these 44 patients censored at the date of last known contact. bPoor risk C known deletion 10%; intermediate risk C Fraxinellone without deletion (10%) and with at least one of: unmutated genes and/or usage, 11q deletion, \2 microglobulin 4?mg/l; good risk C none of the above and mutated genes (Oscier mutation status (cut\off 98%a)Mutated20587 (43) 00001Unmutated32140 (12)beta\2 microglobulin (cut\off 4?mg/la)Low286100 (35) 00001High23326 (11)11q deletionNo456127 (28)00002Yes11613 (11) deletion (cut\off Fraxinellone 10%a)No531138 (26)00007Yes330 (0) mutationNo482126 (26)00008Yes401 (3) mutationNo417108 (26)003Yes455 (11) mutationNo360107 (30)00004Yes737 (10)CD38 expression (cut\off 7%a)Negative19785 (43) 00001Positive33047 (14)Zap70 expression (cut\off 10%a)Negative24179 (33)00004Positive23343 (18) expression (cut\off RQ 40b)Low24579 (32)00001High26646 (17)13q deletionNo23040 (17)0001Yes342100 (29)trisomy 12No481121 (25)04Yes9119 (21) Open in a separate window See also Oscier (2010) and Oscier (2013) for multivariate analysis of molecular/laboratory prognostic factors in LRF CLL4. RQ, real time relative quantification. aOscier (2010). bGonzalez (2013). cChi\squared test. Discussion For patients with CLL requiring treatment and entered into a randomized clinical trial, the ensuing disease course is diverse, ranging from disease progression to first remissions lasting a decade or more. In this study we have focussed on the long\term outcomes in the LRF CLL4 trial, examining the effect of salvage treatments on survival and identifying some of the characteristics associated with survival of 10?years or more. OS from randomization remained nearly identical in the three trial arms at every point throughout the years, in spite of the significantly longer first\line PFS in the FC arm. Our main findings suggest that both favourable prognostic markers at randomization as well as effective salvage therapy contributed to 10\year survival. The 24% of patients who survived 10?years differed in both their pre\treatment characteristics and their response to salvage therapy compared to those with poorer outcomes. They were more likely to be younger.