Open access journal of the Ferrata-Storti Foundation, a non-profit organization
Articles

IGHV mutational status and outcome for patients with chronic lymphocytic leukemia upon treatment: a Danish nationwide population-based study

Department of Hematology, Odense University Hospital, Odense;Department of Hematology, Rigshospitalet, Copenhagen;Department of Clinical Research, University of Southern Denmark, Odense;Department of Epidemiology Research, Statens Serum Institut, Copenhagen
Department of Hematology, Odense University Hospital, Odense;Department of Clinical Research, University of Southern Denmark, Odense;Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, Odense
Department of Hematology, Rigshospitalet, Copenhagen;Department of Epidemiology Research, Statens Serum Institut, Copenhagen
Department of Epidemiology Research, Statens Serum Institut, Copenhagen
Department of Hematology, Odense University Hospital, Odense
Department of Hematology, Rigshospitalet, Copenhagen
Department of Hematology, Zealand University Hospital, Roskilde
Department of Hematology, Herlev Hospital, Herlev, Denmark
Department of Hematology, Rigshospitalet, Copenhagen
Department of Hematology, Rigshospitalet, Copenhagen
Vol. 105 No. 6 (2020): June, 2020 https://doi.org/10.3324/haematol.2019.220194

Abstract

Patients 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.

Introduction

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.

Methods

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.

Figure 1.Consort diagrams displaying inclusion and exclusion criteria. All patients in the Chronic Lymphocytic Leukemia registry with complete data were included in the main analyses. (A) Treatment-specific analyses were conducted for the four main treatment groups as illustrated (B) Patients eligible for clinical record review, with detailed data on first- and second-line treatment, were included in the analyses of treatment-free survival from the time of treatment. CLL: chronic lymphocytic leukemia; IGHV: immunoglobulin heavy-chain variable region gene; U-CLL: unmutated IGHV CLL; M-CLL: mutated IGHV CLL; CIT: chemoimmunotherapy; FC: fludarabine and cyclophosphamide; B: bendamustine; R: rituximab; Chlor: Chlorambucil; FCR: fludarabine, cyclophosphamide and rituximab; BR: bendamustine and rituximab; CD20-Chlor: chlorambucil and anti-CD20 antibodies.

Statistical analysis

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)

Ethics

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.

Results

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.

Table 1.Baseline characteristics and demographics at time of diagnosis for patients with chronic lymphocytic leukemia with unmutated, mutated and unknown IGHV mutational status from the Danish CLL registry.

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.

Figure 2.Outcomes of patients with mutated or unmutated immunoglobulin heavy-chain variable region gene chronic lymphocytic leukemia in the Danish CLL registry. (A) Overall survival from the time of diagnosis. (B) Treatment-free survival from the time of diagnosis. (C). Overall survival from the time of first treatment. M-CLL: chronic lymphocytic leukemia with mutated immunoglobulin heavy-chain variable region gene; U-CLL: chronic lymphocytic leukemia with unmutated immunoglobulin heavy-chain variable region gene.

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).

Table 2.Baseline characteristics of chronic lymphocytic leukemia patients from the Danish CLL registry divided by treatment group.

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)].

Figure 3.Overall survival of patients in the Danish CLL registry from the start of first-line treatment according to treatment group and immunoglobulin heavy-chain variable region gene mutational status. (A) Overall survival of patients treated with fludarabine, cyclophosphamide and rituximab (FCR), or bendamustine and rituximab (BR). (B) Overall survival of patients treated with chlorambucil and anti-CD20 antibodies (CD20-Clb) or chlorambucil monotherapy (Clb). M-CLL: chronic lymphocytic leukemia with mutated immunoglobulin heavy-chain variable region gene; U-CLL: chronic lymphocytic leukemia with unmutated immunoglobulin heavy-chain variable region gene.

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.

Figure 4.Treatment-free survival from the start of first-line treatment according to treatment group and immunoglobulin heavy-chain variable region gene mutational status. (A) Patients treated with fludarabine, cyclophosphamide and rituximab (FCR), bendamustine and rituximab (BR), chlorambucil (Clb), or chlorambucil and anti-CD20 antibodies (CD20-Clb), including patients with both known and unknown immunoglobulin heavy-chain variable region gene (IGHV) mutational status. (B) Patients fit for intensive treatment with FCR of BR, or unfit patients treated with Clb or CD20-Clb, and with IGHV mutated (M-CLL) or unmutated (U-CLL) CLL. (C) Patients treated with FCR or BR with U-CLL or M-CLL. (D) Patients treated with CD20-Clb or Clb with U-CLL or M-CLL.

Discussion

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.

Conclusions

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.

Acknowledgments

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.

Footnotes

  • ↵# 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.

References

  1. Nabhan C, Chaffee KG, Slager SL. Analysis of racial variations in disease characteristics, treatment patterns, and outcomes of patients with chronic lymphocytic leukemia. Am J Hematol. 2016; 91(7):677-680. Google Scholar
  2. Google Scholar
  3. da Cunha-Bang C, Simonsen J, Rostgaard K. Improved survival for patients diagnosed with chronic lymphocytic leukemia in the era of chemoimmunotherapy: a Danish population-based study of 10455 patients. Blood Cancer J. 2016; 6(11):e499. Google Scholar
  4. Hallek M, Fischer K, Fingerle-Rowson G. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010; 376(9747):1164-1174. PubMedhttps://doi.org/10.1016/S0140-6736(10)61381-5Google Scholar
  5. Fischer K, Bahlo J, Fink AM. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016; 127(2):208-215. PubMedhttps://doi.org/10.1182/blood-2015-06-651125Google Scholar
  6. Eichhorst B, Fink AM, Bahlo J. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016; 17(7):928-942. PubMedhttps://doi.org/10.1016/S1470-2045(16)30051-1Google Scholar
  7. Cramer P, Isfort S, Bahlo J. Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group (GCLLSG). Haematologica. 2015; 100(11):1451-1459. PubMedhttps://doi.org/10.3324/haematol.2015.124693Google Scholar
  8. Goede V, Fischer K, Engelke A. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015; 29(7):1602-1604. PubMedhttps://doi.org/10.1038/leu.2015.14Google Scholar
  9. Farooqui MZ, Valdez J, Martyr S. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015; 16(2):169-176. PubMedhttps://doi.org/10.1016/S1470-2045(14)71182-9Google Scholar
  10. Byrd JC, Furman RR, Coutre SE. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013; 369(1):32-42. PubMedhttps://doi.org/10.1056/NEJMoa1215637Google Scholar
  11. International C, An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016; 17(6):779-790. PubMedhttps://doi.org/10.1016/S1470-2045(16)30029-8Google Scholar
  12. da Cunha-Bang C, Christiansen I, Niemann CU. The CLL-IPI applied in a population-based cohort. Blood. 2016; 128(17):2181-2183. PubMedhttps://doi.org/10.1182/blood-2016-07-724740Google Scholar
  13. Damle RN, Wasil T, Fais F. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999; 94(6):1840-1847. PubMedGoogle Scholar
  14. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999; 94(6):1848-1854. PubMedGoogle Scholar
  15. Stilgenbauer S, Schnaiter A, Paschka P. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014; 123(21):3247-3254. PubMedhttps://doi.org/10.1182/blood-2014-01-546150Google Scholar
  16. Thompson PA, Tam CS, O’Brien SM. Fludarabine, cyclophosphamide, and ritux- imab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016; 127(3):303-309. PubMedhttps://doi.org/10.1182/blood-2015-09-667675Google Scholar
  17. Rossi D, Terzi-di-Bergamo L, De Paoli L. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood. 2015; 126(16):1921-1924. PubMedhttps://doi.org/10.1182/blood-2015-05-647925Google Scholar
  18. Lin KI, Tam CS, Keating MJ. Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens. Blood. 2009; 113(14):3168-3171. PubMedhttps://doi.org/10.1182/blood-2008-10-184853Google Scholar
  19. da Cunha-Bang C, Geisler CH, Enggaard L. The Danish National Chronic Lymphocytic Leukemia Registry. Clin Epidemiol. 2016; 8:561-565. Google Scholar
  20. Pedersen CB. The Danish Civil Registration System. Scand J Public Health. 2011; 39(7 Suppl):22-25. PubMedhttps://doi.org/10.1177/1403494810387965Google Scholar
  21. Schmidt M, Pedersen L, Sorensen HT. The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol. 2014; 29(8):541-549. PubMedhttps://doi.org/10.1007/s10654-014-9930-3Google Scholar
  22. Shanafelt TD, Wang V, Kay NE. A Randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912). Blood. 2018; 132(Suppl 1):LBA-4-LBA-4. Google Scholar
  23. Lepretre S, Aurran T, Mahe B. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012; 119(22):5104-5110. PubMedhttps://doi.org/10.1182/blood-2011-07-365437Google Scholar
  24. Munir T, Howard DR, McParland L. Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL. Leukemia. 2017; 31(10):2085-2093. Google Scholar
  25. Woyach JA, Ruppert AS, Heerema NA. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018; 379(26):2517-2528. PubMedhttps://doi.org/10.1056/NEJMoa1812836Google Scholar
  26. Sylvan SE, Asklid A, Johansson H. First-line therapy in chronic lymphocytic leukemia: a Swedish nation-wide real-world study on 1053 consecutive patients treated between 2007 and 2013. Haematologica. 2019; 104(4):797-804. PubMedhttps://doi.org/10.3324/haematol.2018.200204Google Scholar
  27. Robak T, Burger JA, Tedeschi A. Single-agent ibrutinib versus chemoimmunotherapy regimens for treatment-naive patients with chronic lymphocytic leukemia: a cross-trial comparison of phase 3 studies. Am J Hematol. 2018; 93(11):1402-1410. Google Scholar
  28. O’Brien S, Furman RR, Coutre S. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018; 131(17):1910-1919. PubMedhttps://doi.org/10.1182/blood-2017-10-810044Google Scholar
  29. Goede V, Fischer K, Busch R. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014; 370(12):1101-1110. PubMedhttps://doi.org/10.1056/NEJMoa1313984Google Scholar
  30. Hillmen P, Robak T, Janssens A. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015; 385(9980):1873-1883. PubMedhttps://doi.org/10.1016/S0140-6736(15)60027-7Google Scholar
  31. Goede V, Fischer K, Dyer MJ. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphocytic leukemia and comorbidities: final survival analysis of the CLL11 study. EHA Learning Center. 2018; 215923:S151. Google Scholar
  32. Moreno C, Greil R, Demirkan F. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019; 20(1):43-56. Google Scholar
  33. Hallek M, Cheson BD, Catovsky D. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018; 131(25):2745-2760. PubMedhttps://doi.org/10.1182/blood-2017-09-806398Google Scholar
  34. Laurenti L, Innocenti I, Autore F. Bendamustine in combination with rituximab for elderly patients with previously untreated B-cell chronic lymphocytic leukemia: a retrospective analysis of real-life practice in Italian hematology departments. Leuk Res. 2015; 39(10):1066-1070. PubMedhttps://doi.org/10.1016/j.leukres.2015.07.009Google Scholar
  35. Fischer K, Cramer P, Busch R. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012; 30(26):3209-3216. PubMedhttps://doi.org/10.1200/JCO.2011.39.2688Google Scholar
  36. Jain P, Nogueras Gonzalez GM, Kanagal-Shamanna R. The absolute percent deviation of IGHV mutation rather than a 98% cut-off predicts survival of chronic lymphocytic leukaemia patients treated with fludarabine, cyclophosphamide and rituximab. Br J Haematol. 2018; 180(1):33-40. Google Scholar
  37. Al-Sawaf O, Bahlo J, Robrecht S. Outcome of patients aged 80 years or older treated for chronic lymphocytic leukaemia. Br J Haematol. 2018; 183(5):727-735. Google Scholar
  38. Fischer K, Al-Sawaf O, Bahlo J. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019; 380(23):2225-2236. Google Scholar
  39. Jain N, Keating M, Thompson P. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019; 380(22):2095-2103. Google Scholar
  40. Hutchins LF, Unger JM, Crowley JJ, Coltman CA, Albain KS. Under -representation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999; 341(27):2061-2067. PubMedhttps://doi.org/10.1056/NEJM199912303412706Google Scholar
  41. Lewis JH, Kilgore ML, Goldman DP. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol. 2003; 21(7):1383-1389. PubMedhttps://doi.org/10.1200/JCO.2003.08.010Google Scholar
  42. Goede V, Cramer P, Busch R. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German Chronic Lymphocytic Leukemia Study Group trials. Haematologica. 2014; 99(6):1095-1100. PubMedhttps://doi.org/10.3324/haematol.2013.096792Google Scholar
  43. Wieringa A, Boslooper K, Hoogendoorn M. Comorbidity is an independent prognostic factor in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP: a population-based cohort study. Br J Haematol. 2014; 165(4):489-496. Google Scholar
  44. Zhao H, Wang T, Wang Y. Comorbidity as an independent prognostic factor in elderly patients with peripheral T-cell lymphoma. Onco Targets Ther. 2016; 9:1795-1799. Google Scholar
  45. Foster MC, Coresh J, Hsu CY. Serum beta-trace protein and beta2-microglobulin as predictors of ESRD, mortality, and cardiovascular disease in adults with CKD in the Chronic Renal Insufficiency Cohort (CRIC) study. Am J Kidney Dis. 2016; 68(1):68-76. PubMedhttps://doi.org/10.1053/j.ajkd.2016.01.015Google Scholar
  46. Delgado J, Pratt G, Phillips N. Beta2-microglobulin is a better predictor of treatment-free survival in patients with chronic lymphocytic leukaemia if adjusted according to glomerular filtration rate. Br J Haematol. 2009; 145(6):801-805. PubMedhttps://doi.org/10.1111/j.1365-2141.2009.07699.xGoogle Scholar
  47. Rostgaard K, Vaeth M, Rootzen H. Do changes in lymph node status distribution explain trends in survival of breast cancer patients in Denmark¿. Eur J Cancer Prev. 2006; 15(5):398-404. PubMedhttps://doi.org/10.1097/00008469-200610000-00004Google Scholar

Data Supplements

Figures & Tables

Article Information

Vol. 105 No. 6 (2020): June, 2020 : Articles
 
DOI
https://doi.org/10.3324/haematol.2019.220194
Pubmed
31582540
Pubmed Central
PMC7271602
 
Published
2020-06-01
Published By
Ferrata Storti Foundation, Pavia, Italy
Print ISSN
0390-6078
Online ISSN
1592-8721
 

Article Usage

Online Views
15681
PDF Downloads
1153

Statistics from Altmetric.com

No Data
Navigate
For Authors
For Reviewers
For Advertisers
Education
Privacy
More
Copyright © 2024 by the Ferrata Storti Foundation | Web design ￫ | Development ￫
ISSN 0390-6078 print | ISSN 1592-8721 online