leukemia: results of german chronic lymphocytic leukemia incan- .chronic lymphocytic leukemia aicle

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  • Chronic Lymphocytic Leukemia Articles

    haematologica | 2014; 99(6) 1095


    Combined chemoimmunotherapy with fludarabine,cyclophosphamide and rituximab has become the standard ofcare in previously untreated patients with chronic lympho-cytic leukemia (CLL).1,2 This regimen and comparable treat-ments have since been explored in different clinical settings invarious CLL trials.3-7 Most participants in these studies wererelatively young and not affected by additional health prob-lems. However, many CLL patients in routine practice areelderly and suffer from comorbidities.8,9

    Recently, comorbidity was identified as an adverse prog-nostic factor in patients with untreated or treated CLL.9,10 Theunderlying causes of the shorter survival of these patientshave remained unclear so far, resulting in uncertaintywhether treatment approaches in patients with CLL andcomorbidity should focus on the prevention of therapy-relat-ed morbidity and mortality or whether the potential loss ofdisease control associated with such a strategy will offset itsnet benefits by increasing disease-related morbidity and mor-tality.To better understand the modes of interaction between

    comorbidity and CLL therapy, we assessed the comorbidityburden in patients enrolled in the CLL4 and CLL5 trials of the

    German Chronic Lymphocytic Leukemia Study Group(GCLLSG)11,12 and investigated its impact on treatment out-come in detail.


    Study populationFrom June 1999 until July 2003, a total of 581 patients from

    Germany and Austria were accrued to the CLL4 and CLL5 trials of theGCLLSG: 375 younger patients (up to 65 years) were enrolled in theCLL4 trial and randomized to receive either fludarabine alone or flu-darabine plus cyclophosphamide; 206 elderly patients (65 years orolder) were enrolled in the CLL5 trial and were treated with either flu-darabine or chlorambucil. In both studies, the diagnosis of CLL wasconfirmed according to the 1996 guidelines of the National CancerInstitute sponsored Working Group (NCI-WG).13 Only treatment-nave patients fulfilling the NCI-WG/IWCLL criteria for treatmentrequirement were included.13,14 Study treatments were administered aspreviously reported.11,12 Treatment response and status of remissionduring follow-up were assessed according to the NCI-WG guide-lines.13 Treatment toxicity was judged according to the NCI CommonToxicity Criteria (CTC version 2.0).15 For patients who died the causeof death was determined by the treating physician based on the avail-able clinical information and sometimes autopsy reports. Based on

    2014 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2013.096792The online version of this article has a Supplementary Appendix.Manuscript received on August 15, 2013. Manuscript accepted on February 26, 2014.Correspondence: valentin.goede@uk-koeln.de

    This study investigated the impact of comorbidity in 555 patients with chronic lymphocytic leukemia enrolled intwo trials of the German Chronic Lymphocytic Leukemia Study Group on first-line treatment with fludarabine pluscyclophosphamide, fludarabine, or chlorambucil. Patients with two or more comorbidities and patients with lessthan two comorbidities differed in overall survival (71.7 versus 90.2 months; P

  • this on-site documentation, causes of death were grouped into thefollowing categories: therapy-related, CLL-related, CLL-unrelated,or unknown. Both studies were approved by the InstitutionalReview Board and Ethics Committee of the University of Munichand performed in accordance with the Declaration of Helsinki.

    Comorbidity assessmentFor both trials, comorbid conditions present at baseline had to

    be assessed and documented in the patients case report form bythe treating physician. Further quantification of the comorbidityburden by use of specific comorbidity scores was not part of thestudy protocols. Thus, all comorbid conditions reported withinthe case report form were captured only in a qualitative manner.Health problems resulting from the CLL itself and CLL as the pri-mary disease were not recorded as comorbidity.To assess the comorbidity burden for each patient individually

    in the absence of quantitative data derived from scores, the num-ber of comorbidities was calculated as the sum of all conditionsabstracted from the patients case report form according to therules described above. Since information on the severity of comor-bid conditions was mostly unobtainable, a retrospective scoring ofcomorbidity by use of a validated comorbidity score was not reli-ably possible (although an attempt was made to calculate theCharlson comorbidity index from the available data).16 For a gen-eral description of the spectrum of comorbidities in the study pop-ulation, each of the concomitant diseases was assigned to diseasecategories abstracted from the Cumulative Illness Rating Scale.17

    Statistical analysisThe statistical analysis was performed with SPSS 17 software

    (SPSS Inc., USA) and based on data collected by December 17th

    2009 for the CLL4 trial and August 1st 2007 for the CLL5 trial (parts

    of this analysis were also performed earlier on a 2005 dataset andpreviously presented in abstract format). Estimates of overall andprogression-free survival were calculated using the Kaplan-Meiermethod. The log-rank test was used to compare survival timesbetween groups. A Cox regression model was applied for univari-ate and multivariate analyses to estimate hazard ratios. Parametersothers than survival were compared using the c2 test and theFisher exact test.Further details on the methods of this study are available in the

    Online Supplementary Appendix.


    Baseline characteristicsOf the 581 patients recruited into the CLL4 and CLL5

    trials, 555 were eligible for this analysis. Twenty-sixpatients were excluded because of inaccurate diagnosis(n=5), no need of therapy (n=2), previous therapy (n=3),consent issues (n=6), or other reasons (n=10). The charac-teristics of the study population are summarized in Table1. The median time of follow-up for all patients was 58months. Patients treated within the CLL4 and CLL5 trialswere younger and older, respectively (median: 58 versus 70years).

    Comorbidity burdenThe patients comorbidity burden at baseline is present-

    ed in Table 2 and Online Supplementary Table S1. Fifty-threepercent of the patients had at least one concurrent disease.The number of comorbidities ranged from zero to seven(median: 1) and increased continuously with advanced age(P

  • trial) and older (CLL5 trial) patients. In a multivariateanalysis including additional variables with potentialimpact on overall survival (gender, age, performance sta-tus, disease stage, thymidine kinase and b2-microglobulinlevels, and treatment regimen), comorbidity maintainedits independent prognostic value (Figure 1). The Charlsoncomorbidity index was also prognostic, but less suitablefor further endpoint studies because of the limited numberof subjects with higher scores (Online Supplementary FigureS1). Specific comorbidities predicting overall survivalcould not be identified.Higher 1-year and 5-year mortality rates in the group of

    patients with 2 comorbidities were attributable to a com-bined increase of therapy-related, CLL-related, and CLL-unrelated deaths during and after treatment (Table 3).However, deaths considered CLL-related by the treatingphysicians contributed most to increased mortality inthese patients.

    Impact of comorbidity on treatment efficacyPatients with 2 comorbidities had an overall response

    to treatment of 75% compared to 85% in patients with

  • discontinued in 45% of patients with 2 comorbiditiescompared to 31% of those with < 2 comorbidities (P 3.5 mg/L

    0 0.5 1.0 1.5 2.0 2.5 3.0 3.5Hazard ratio (95% CI)

    Cumulative PF

    S (%


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  • explained by differences in administered treatment regi-mens and trial allocation. Likely, the observed loss of dis-ease control in patients with increased comorbidity wasalso due to more dose reductions and treatment discontin-uations in these patients. Despite these dose reductionsand treatment discontinuations, toxicity rates in suchpatients were still equivalent to those in subjects with lit-tle or no comorbidity. Together, these observations sug-gest that CLL patients with increased comorbidity are atgreater risk of dose attenuations which will limit therapy-related morbidity, but at the expense of higher CLL-relat-ed morbidity and, thereby, mortality.Treatments able to achieve durable control of CLL

    rather than only symptom control or undue protectionfrom potential side effects thus appear important for thesepatients. In our study, disease control in such patients wasbest obtained through the most intensive therapy (com-bined chemotherapy). A limitation of this study is, how-ever, that it was restricted to chemotherapy-treated CLLpatients prior to the introduction of monoclonal antibod-ies and other experimental compounds. It does not, there-fore, enable a specific therapeutic regimen to be recom-mended for patients with increased comorbidity. Neitherdoes it allow a definitive conclusion that, over adverseevents and intercurrent illness, uncontrolled CLL due todose attenuations will also be the major threat to thesepatients in the era of chemoimmunotherapy. Nonetheless,current standard therapy with fludarabine, cyclophos-

    phamide and rituximab in community-based patients wasrecently associated with limited adherence to the dosingschedule and a significant risk of


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