AbstractPatients with chronic lymphocytic leukemia and unmutated immunoglobulin heavy-chain variable region gene (IGHV) have inferior survival from time of treatment in clinical studies. We assessed real-world outcomes based on mutational status and treatment regimen in a nationwide population-based cohort, comprising all 4,135 patients from the Danish chronic lymphocytic leukemia registry diagnosed between 2008 and 2017. In total, 850 patients with known mutational status received treatment: 42% of patients received intensive chemoimmunotherapy consisting of fludarabine, cyclophosphamide plus rituximab, or bendamustine plus rituximab; 27% received chlorambucil in combination with anti-CD20 antibodies or as monotherapy, and 31% received other, less common treatments. No difference in overall survival from time of first treatment according to mutational status was observed, while treatment-free survival from start of first treatment was inferior for patients with unmutated IGHV. The median treatment-free survival was 2.5 years for patients treated with chlorambucil plus anti-CD20, and 1 year for those who received chlorambucil monotherapy. The 3-year treatment-free survival rates for patients treated with fludarabine, cyclophosphamide plus rituximab, and bendamustine plus rituximab were 90% and 91% for those with mutated IGHV, and 76% and 53% for those with unmutated IGHV, respectively, and the 3-year overall survival rates were similar for the two regimens (86-88%). Thus, it appears that, in the real-world setting, patients progressing after intensive chemoimmunotherapy as first-line therapy can be rescued by subsequent treatment, without jeopardizing their long overall survival. Intensive chemoimmunotherapy remains a legitimate option alongside targeted agents, and part of a personalized treatment landscape in chronic lymphocytic leukemia, while improved supportive care and treatment options are warranted for unfit patients.
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the Western world and half of the patients with this condition require treatment within 5 years of diagnosis.1 According to Danish national CLL guidelines,32 standard first-line treatment includes fludarabine, cyclophosphamide plus rituximab (FCR) for younger, fit patients,54 and bendamustine plus rituximab (BR) for patients above 65 years old.76 Furthermore, chlorambucil, either as monotherapy or combined with anti-CD20 antibodies (CD20-chlorambucil), is recommended for unfit patients with significant comorbidity.8 Patients with del(17p)/TP53 mutations are treated with targeted agents (ibrutinib, idelalisib-rituximab or venetoclax).109 The Danish guidelines are updated biannually and the changes over time have been described previously.3
Immunoglobulin heavy-chain variable region gene (IGHV) mutational status is an acknowledged prognostic factor in CLL and is included in the disease-specific International Prognostic Index (CLL-IPI).1211 In previous studies, patients with unmutated IGHV (U-CLL) had shorter survival from diagnosis compared with patients with mutated IGHV (M-CLL), and inferior remission duration and survival from the start of chemoimmunotherapy.181265
We present data on the impact of IGHV mutational status on overall survival (OS) and treatment-free survival (TFS) from the time of treatment in the world’s largest, nationwide, population-based cohort of consecutive, un -selected patients with CLL receiving different treatment regimens.
Data sources and study population
The Danish CLL registry contains data on all patients diagnosed with CLL in Denmark since 2008.19 As of August 2017, the registry contained information on 4,135 CLL patients, who were included in the present study (Figure 1A). The CLL registry contains data on sex, dates of birth, diagnosis, and treatment, type of treatment, IGHV mutational status, and other disease characteristics including cytogenetics, TP53 mutations, and β2-microglobulin levels at the time of diagnosis. Information on vital status is included in the CLL registry through regular linkage with the Danish Civil Registration System.2120 Patients with missing data regarding key variables were excluded from the study. Patients were followed from the date of diagnosis in 2008-2017, until the time of death, emigration, or August 2017, whichever came first. All treatments of minimum one series were considered. For the subset of patients who had received first-line treatment at Odense University Hospital, in the Capital Region, or in the Zealand Region between 2008-2016, detailed information on second-line treatment was collected through review of the patients’ clinical records. Together, these regions cover over half of the Danish population. These patients were followed from the date of diagnosis in 2008-2016, until the time of death, emigration, or mid-2018 (ranging from May-November, depending on the date of the patients’ record review), whichever came first.
The patients’ characteristics are reported for those with U-CLL and M-CLL and for treatment groups, and compared using parametric or non-parametric descriptive statistics, depending on the data distribution. Kaplan-Meier survival analyses were used to assess survival. TFS from the time of diagnosis (TFSd) was defined as the time to first treatment, end of follow-up, or death¸ whichever came first. OS was determined starting from either the time of diagnosis (OSd) or the time of first-line treatment initiation (OSt), until death, or end of follow-up, whichever came first. TFSt, defined as the time from initiation of first-line treatment to initiation of second-line treatment, death or end of follow-up, whichever came first, was studied for the sub-population with detailed information on second-line treatment from medical record review. OSt and TFSt were the primary endpoints of the study, while OSd and TFSd were secondary endpoints. We explored the prognostic significance of IGHV status, treatment regimen, del(17p) status, elevated β2-microglobulin level, sex, age, and Binet stage for risk of death or treatment, using multi-variable Cox regression models to calculate hazard ratios (HR). All HR presented have been adjusted for these variables, except for TFSt, which was adjusted for sex, age, del(17)p/TP53-mutation, and Binet stage. Unadjusted HR were calculated but are not presented in this paper as they were not of clinical relevance. Log-rank tests were used to test for homogeneity of outcomes between exposures. Data analysis was performed using STATA (StataCorp. 2015. Stata Statistical Software: Release 15.1 College Station: StataCorp LP, TX, USA)
The study was approved by the Danish Health and Medicine Authorities (jr. n. 3-3013-1141/1) and the Danish Data Protection Agency (jr. n. RH-2015-96 03856). Results for subgroups including fewer than five patients were reported as “less than five” to ensure anonymity of individual patients, in accordance with Danish legislation.
Characteristics at time of diagnosis of chronic lymphocytic leukemia
In total, 4,135 patients with a median follow-up time of 3.5 years were available for analysis, of whom two were excluded because of incomplete data. Information on IGHV mutational status was available for 3,197 (77%) patients, of whom 1,017 (32%) had U-CLL and 2,180 (68%) had M-CLL (Figure 1A). The characteristics of the patients, divided according to mutational status, are listed in Table 1. Among patients with unknown IGHV status, 255 (27%) received treatment during follow-up, compared with 481 (47%) of U-CLL and 369 (17%) of M-CLL patients. Distributions of sex and age at diagnosis were comparable between U-CLL and M-CLL patients, whereas prognostic factors were unevenly distributed, with del(13q) found in 28% of U-CLL patients and 53% of M-CLL patients. The prevalences of del(17p) (7%), del(11q) (16%) and trisomy(12) (16%) were higher among U-CLL patients than among M-CLL patients (4%, 2% and 11%, respectively). Of the U-CLL patients, 30% were categorized as having Binet stage B/C, compared with 13% of M-CLL patients, and 19% had a high level of β2-microglobulin (>4.0 mg/L), compared with 10% of M-CLL patients.
IGHV status and prognosis from the time of diagnosis
Patients with unmutated IGHV had shorter OSd [HR=1.23, 95% confidence interval (95% CI): 1.01-1.50], compared with patients with M-CLL, and shorter TFSd (HR=2.24, 95% CI: 1.95-2.57) (Figure 2A, B). The 5-year OSd was 71% (95% CI: 68-74) for U-CLL patients and 81% (95% CI: 79-83) for those with M-CLL. The 5-year TFSd for U-CLL patients was 31% (95% CI: 27-35), compared with 68% (95% CI: 65-70) for those with M-CLL. Patients with unknown IGHV status had a shorter 5-year OSd (61%, 95% CI: 57-64) than patients with U-CLL or M-CLL, while the 5-year TFSd (45%, 95% CI: 41-49) in this group was between that of U-CLL and M-CLL patients (data not shown). Overall, 92 (9%) patients with U-CLL, 263 (12%) patients with M-CLL, and 227 (24%) patients with unknown IGHV status died without receiving CLL treatment, while the numbers of events for OSd, and TFSd, were, respectively, 263 and 573 for patients with U-CLL, 384 and 632 for patients with M-CLL, and 360 and 482 for patients with unknown IGHV status.
Characteristics of treatment groups
Among the 850 treated patients with known IGHV status, 235 (28%) received FCR, 122 (14%) BR, 89 (10%) CD20-chlorambucil, 139 (16%), chlorambucil alone and 265 (31%) other, less common, treatments. Outcome was assessed separately for subgroups of patients treated with one of the four main treatment regimens (FCR, BR, CD20-chlorambucil and chlorambucil), as illustrated in Figure 1A. Patients who received other types of treatment were not studied in detail because of their small numbers. A subgroup of 99 patients received rituximab in combination with either an undefined type of chemotherapy, or other treatment: these patients were not, therefore, included in the detailed analyses. Baseline characteristics for treatment subgroups are detailed in Table 2. The median time of follow-up from treatment was 3.9 years for patients given FCR, 2.8 years for those given chlorambucil, and 2.1 years for patients treated with BR or CD20-chlorambucil. Patients treated with FCR were younger at the time of treatment (median 62 years) than patients treated with BR (median 70 years), while patients treated with CD20-chlorambucil (median 78 years) or chlorambucil (median 80 years) were the oldest. Binet B/C and U-CLL were more common among FCR-treated patients (56% and 64%, respectively) than among patients treated with BR, CD20-chlorambucil, or chlorambucil (34-42% and 52-58%, respectively). A smaller proportion of FCR-treated patients had a high β2-microglobulin level or high/very high CLL-IPI score, compared with the other treatment groups (Table 2).
Overall survival after first-line treatment
The median follow-up time from first-line treatment was 2.9 years. No difference in OSt was observed between patients with U-CLL (171 deaths) and those with M-CLL (121 deaths) [3-year OSt 74% (95% CI: 70-78) and 72% (95% CI: 66-77), respectively] (Figure 2C). Patients with unknown IGHV status had an inferior OSt compared with U-CLL and M-CLL patients (133 deaths) [3-year OSt 59% (95% CI: 53- 65)] (data not shown). No impact on OSt was observed based on unmutated IGHV status (HR=0.99, 95% CI: 0.75-1.32), Binet stage B/C at diagnosis (HR 1.01, 95% CI: 0.76-1.35), or male sex (HR=0.97, 95% CI: 0.73-1.29). Age above 65 years at the time of treatment (HR=3.18, 95% CI: 2.12- 4.77), high β2-microglobulin level (HR=1.92, 95% CI: 1.42-2.60), and del(17p) (HR=1.79, 95% CI: 1.21-2.65) were statistically significantly associated with shorter OSt.
During follow-up, 40 patients treated with FCR, 11 with BR, 37 with CD20-chlorambucil and 94 with chlorambucil, died. No difference was observed in 3-year OSt rates between patients treated with FCR (88%, 95% CI: 83-92%] and BR (86%, 95% CI: 75-93%) (Figure 3A), or between those treated with CD20-chlorambucil (59%, 95% CI: 47-70%) and chlorambucil monotherapy (53%, 95% CI: 45-61%) (Figure 3B). No statistically significant variation by IGHV-status was found for OSt, regardless of whether the treatment regimens were pooled or separate [pooled: HR=1.15 (95% CI: 0.80-1.66), FCR-treated: HR=1.21 (95% CI: 0.53-2.77), BR-treated: HR=0.78 (95% CI: 0.14-4.15), CD20-chlorambucil-treated: HR=0.86 (95% CI: 0.38-1.91) and chlorambucil-treated: HR=1.31 (95% CI: 0.75-2.28)].
Treatment-free survival after first-line treatment
Among 513 patients eligible for record review, 11 were excluded because of incomplete data. Of the remaining 502 patients, 384 patients received one of the four major treatment regimens, which were studied in detail (Figure 1B). Comparing the four main treatment regimens, also including patients with unknown IGHV status, FCR produced the longest median TFSt (6.0 years, 95% CI: 4.5-6.7 years), followed by BR (3.9 years, 95% CI: 3.4-5.1 years) (Figure 4A). The median TFSt for chlorambucil-treated patients was 1 year (95% CI: 0.8-1.3 years), and that for CD20-chlorambucil-treated patients was 2.5 years (95% CI: 1.8-3.3) (Figure 4A). There were 39, 27, 11, and 36 events among U-CLL patients and 9, 7, 11, and 26 events among M-CLL patients, treated with FCR, BR, CD20-chlorambucil, and chlorambucil, respectively. TFSt was significantly shorter for patients with U-CLL than for those with M-CLL, following both intensive (FCR or BR) (HR=3.46, 95% CI: 1.93-6.19) and non-intensive (CD20-chlorambucil or chlorambucil) (HR=2.04, 95% CI: 1.24-3.37) treatment (Figure 4B). The 3-year TFSt for U-CLL patients treated with intensive regimens (68%, 95% CI: 58-76) was inferior compared with that of M-CLL patients (91%, 95% CI: 81-96), also when treatments were assessed separately (FCR: HR=2.56, 95% CI: 1.19-5.50; BR: HR=7.50, 95% CI: 2.80-20.1) (Figure 4C). This was most evident for patients treated with BR, who had an estimated 3-year TFSt of 91% (95% CI: 74-97%) for those with M-CLL and 53% (95% CI: 36-68%) for those with U-CLL, while the difference for FCR-treated patients was smaller (90%, 95% CI: 76-96%) and 76% (95% CI: 64-84%), respectively (Figure 4C). For CD20-chlorambucil-and chlorambucil-treated patients, no statistically significant difference according to IGHV status was observed when treatments were assessed separately (HR=2.19, 95% CI: 0.77-6.28 and HR=1.74, 95% CI: 0.97-3.12, respectively) (Figure 4D). Out of the 502 patients studied, 233 received second-line treatment during follow-up. Among patients who received second-line treatment, the mutational status was known for 167 (72%), of whom 117 (70%) had U-CLL. Of these unmutated cases, 33 (28%) received targeted treatment, compared with six (12%) of mutated patients.
We present real-world data on the prognosis of CLL, from diagnosis and from time of first-line treatment, based on IGHV mutational status from the hitherto largest nationwide, population-based cohort. The main novel finding is the lengthy OSt of both M-CLL and U-CLL patients treated with either FCR or BR, despite inferior TFSt of U-CLL patients; reflecting U-CLL patients’ response to salvage treatment. We confirm previous findings of U-CLL being associated with shorter OSd and TFSd compared with M-CLL.1412
In clinical trial reporting, progression-free survival (PFS), defined as the time until death or disease progression, is commonly used to evaluate treatment outcome. Previous studies have reported superior PFS for M-CLL patients compared with U-CLL,171665 and M-CLL patients without del(17p) or del(11q) in particular have long PFS upon chemoimmunotherapy.17 The 3-year PFS rates reported in previous clinical trials with FCR (66-83%)24221665 or BR (77% for M-CLL)256 and in the real-world setting with FCR (60-80%),2617 are high, but inferior to those achieved with ibrutinib-based treatment (83-96%).28272522 Upon chlorambucil treatment the median PFS was 9 months in a Swedish real-world setting26 and 11 months in clinical trials,3029 compared with 1.3-2.4 years upon CD20-chlorambucil treatment in clinical trials.3229
Here we report the data for treatment-free survival, which can be clinically more relevant as many patients do not meet the International Workshop on CLL criteria for treatment at disease progression.33 Our results reveal a superior TFSt for M-CLL patients compared with U-CLL patients, when treated with FCR, BR, or non-intensive treatment regimens. We observed high 3-year TFSt rates for M-CLL patients treated with FCR (90%) or BR (91%) and for U-CLL patients treated with FCR (76%), similar to the findings of a smaller retrospective study of BR-treated patients who had a 3-year TFSt of 90%.34 This is especially impressive considering the median age of 70 years of the patients treated with BR in our study. Only 6% of M-CLL patients in our study had high-risk cytogenetics, consistent with the long TFSt of M-CLL patients that we observed.
A 3-year OSt of 86-88% was demonstrated for patients treated with either FCR or BR. These findings are comparable with those from randomized clinical trials of FCR (84-91%)24221665 and BR (89-92%),35256 and other real-world studies of FCR-treated patients (83-95%).2617 However, the overall superior OSt for M-CLL patients previously reported as a dichotomous variable171664 and as a continuous variable,36 was not observed in our study. This could reflect that the follow-up time in our study may have been too short for differences in OSt to manifest, and that factors such as comorbidity and subsequent lines of treatment may have been unevenly distributed across groups. Furthermore, a tendency to favor FCR over other treatment options for patients with U-CLL was observed. This might reflect physicians’ choice of treatment intensification based on recognition of the inferior prognosis for this group of patients. More than twice as many U-CLL patients received second-line treatment and more than five times as many were given targeted agents compared with M-CLL patients. This is likely due to the shorter TFSt of U-CLL patients, again in recognition of their inferior prognosis, and may in part explain why no difference in OSt was observed.
A previous study demonstrated that the prognostic impact of IGHV status upon chemoimmunotherapy is not driven by a difference in complete remission rate, but rather by earlier relapse due to the aggressiveness of the disease in U-CLL patients.18 The long OSt after treatment with FCR or BR for both U-CLL and M-CLL patients in our study emphasizes that patients who progress after first-line chemoimmunotherapy may be salvaged with targeted treatment, or even repeated chemoimmunotherapy. A recent conference presentation described superior PFS, improved OS, and less toxicity with ibrutinib plus rituximab compared with FCR; however, subgroup analyses indicated that the benefit was mainly for U-CLL patients.22 The findings were similar, also mainly with impact on U-CLL patients, for ibrutinib-based regimens in comparison with BR, although without a difference in OS.25 Cross-over was not allowed in these studies; thus, it remains to be systematically assessed in a clinical trial whether patients with progressive disease may be salvaged with targeted agents in second-line treatment. In view of the long period off treatment in general, and the possibility of a clinical cure for a substantial subgroup of M-CLL patients, chemoimmunotherapy remains a legitimate treatment option with robust data on safety and long-term outcome in the era of targeted agents. Thus, we suggest that intensive chemoimmunotherapy should be part of a personalized treatment landscape in CLL alongside targeted treatment, with treatment options adapted based on shared decision-making, guided by robust data from clinical trials and real-world evidence.
We found that patients treated with chlorambucil as monotherapy had a poor TFSt regardless of IGHV status. Within 1 year of initiation of first-line treatment with chlorambucil, 50% of the patients had had an event. Patients treated with CD20-chlorambucil, with a median age of 78 years and representing a frail patient population, had a median TFSt of 2.5 years. A similar median TFSt of 3.4 years was observed in patients of comparable age receiving CD20-chlorambucil in randomized controlled trials.37 The superior outcome of patients treated with CD20-chlorambucil, compared with chlorambucil suggests that chlorambucil as monotherapy must be considered obsolete. As baseline characteristics were similar between the groups in our study, our findings indicate that chlorambucil should be replaced by CD20-chlorambucil or by more effective and less toxic novel treatments. Considering the results of our study, as well as those of clinical trials, new treatment options and improved supportive care are warranted for patients unfit for intensive chemoimmunotherapy. The recently published studies on venetoclax plus obinutuzumab and ibrutinib-based frontline therapy, compared with CD20-chlorambucil, broaden the options for these patients. Subgroup findings indicate that mainly U-CLL patients benefit from targeted therapy, as also seen when compared with intensive chemoimmunotherapy regimens.39383225
In contrast to a clinical trial setting, inclusion of patients above 65 years and more patients with significant comorbidities in our cohort4140 may have reduced the impact of IGHV status as a prognostic factor.4442 Clinical trial populations in CLL studies exploring IGHV status and chemoimmunotherapy had a median age of 57-73 years,321665 compared with 62-80 years in our study, further emphasizing the importance of assessing real-world data. The higher prevalence of elevated β2-microglobulin levels in the treatment groups with a higher median age in our study may reflect decreased renal function4645 and thus the comorbidity of these patients, rather than more aggressive CLL. The impact of comorbidity and frailty in the real-world population reported here is also reflected by a 3-year OSt of 59% for patients treated with CD20-chlorambucil compared with over 80% in the CLL11 trial.8
Cancer patients for whom data registration is incomplete have previously been found to have poorer outcome,47 which was also seen for patients with unknown IGHV status in the present study, when comparing both OSd and OSt in these patients with those of patients with mutated or unmutated IGHV. Patients with unknown IGHV status had a superior TFSd compared with that of U-CLL patients. This reflects that many patients with unknown IGHV status die, probably due to CLL-unrelated causes, without ever receiving treatment for CLL.
The main strength of this study is its nationwide cohort, without the selection bias introduced in clinical trials, and the near completeness of data. Inherent in the retrospective design of the study, patients were assigned therapy by the treating physicians based on clinical assessment of fitness and clinical guidelines, in line with the described age distribution. The discrepancy in baseline characteristics between the treatment groups is a weakness of our study, although we have adjusted for known dissimilarities between the groups. However, as stated above, factors such as number and type of subsequent lines of treatments, and distribution of comorbidities across groups of patients, are unknown. Uneven distribution of these factors could in part explain the discrepancy between our results and those of previous studies regarding the significance of IGHV status in relation to OSt. More patients were diagnosed with CLL during the latter half of the study period, likely due to earlier detection of CLL, leading to a shorter follow-up time than anticipated. The short median follow-up time was also driven by the high mortality in this population, resulting in over half of the treated patients dying during follow-up.
This population-based study demonstrates excellent OSt with FCR or BR for both U-CLL and M-CLL patients, indicating that patients who progress after first-line chemoimmunotherapy may be salvaged with second- or later-line treatments. In view of the long treatment-free period and the possibility of clinical cure for a substantial subgroup of M-CLL patients, intensive chemoimmunotherapy remains a valid treatment option and part of a personalized treatment landscape in CLL alongside targeted agents. Patients treated with chlorambucil-based regimens have a poor outcome; thus, improved supportive care and targeted treatment options, as seen in recent randomized controlled trials, are warranted for patients who are unfit for intensive chemoimmunotherapy.
We would like to thank Fanny Kullberg for her work in collecting information from medical records. This study was supported in part by grants from Janssen and Novo Nordisk Foundation. The funding sources had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication.
- ↵# CdC-B and CU contributed equally as co-senior authors.
- Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/6/1621
- Received February 22, 2019.
- Accepted September 26, 2019.
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