Literature Scan
New and noteworthy research from the medical literature landscape
CLINICAL NEWS
CLL-IPI : A New International Staging System for Chronic Lymphocytic Leukemia
A new prognostic model combining genetic , biochemical , and clinical parameters can enable a more targeted management of chronic lymphocytic leukemia ( CLL ) in both clinical practice and clinical trials , according to a report published in Lancet Oncology . The revised staging system , called the CLL-International Prognostic Index ( CLL-IPI ), represents a collaboration among multiple international study groups .
“ The management of patients with CLL is undergoing improvements due to novel therapies and a plethora of biologic and genetic variables that add prognostic information to the classic clinical staging systems ,” the authors , members of the International CLL-IPI Working Group , wrote . CLL-IPI , which was developed following an analysis of 27 prognostic factors for overall survival , could serve as a simple , reliable , and easily applicable method of risk stratification for patients with CLL , they added .
The international group of researchers conducted a literature search for phase II and phase III clinical trials of CLL published between January 1 , 1950 , and December 31 , 2010 , including eight prospective trials in their analyses . In total , the studies included 3,473 treatmentnaïve patients at both early and advanced CLL stages ( median age , 61 years ; range , 27-86 years ) from France , Germany , Poland , the United Kingdom , and the United States . Patients were followed for a median of 80 months .
The full analysis dataset was randomly divided into training ( n = 2,308 ; 67 %) and internal-validation ( n = 1,164 ;
33 %) datasets . The researchers externally validated the model in two additional datasets : a cohort from the Mayo Clinic in Rochester , Minnesota ( n = 838 ), and the SCALE Scandinavian populationbased case-control study ( n = 416 ). Mean patient age in these cohorts was 62 years ( range = 25-89 years ), and these patients were followed for a median of 63 months .
From the group of 27 baseline factors the CLL-IPI researchers examined in the training dataset , five emerged as independent prognostic markers for overall survival ( OS ):
• TP53 status ( no abnormalities vs . del17p , TP53 mutations , or both )
• IGHV mutational status ( mutated vs . unmutated )
• Serum ß 2
-microglobulin ( B2M ) concentration ( ≤3.5 mg / L vs . > 3.5 mg / L )
• Clinical stage ( Binet A or Rai 0 vs . Binet B-C or Rai I-IV )
• Age ( ≤65 years vs . > 65 years )
Each variable was then assigned an individual weight ( TABLE 1 ). The researchers then added all of these factors together , derived a prognostic score ranging from 0-10 , and identified four risk groups with significantly different rates of OS at five years ( p < 0.001 for all ):
• Low-risk patients ( score = 0-1 ): 93.2 % ( 95 % CI 90.5-96.0 )
TABLE 1 . Multivariate Analysis of Independent Predictors for Overall Survival in the CLL-IPI System
Variable Adverse factor Coefficient
Hazard ratio
Grading Age > 65 years 0.555 1.7 1
Clinical stage
Del17p and / or TP53 mutation
Binet B / C or Rai I-IV
Deleted and / or mutated
0.499 1.6 1
0.665 2.0 4
IGHV mutation status Unmutated 0.941 2.6 2 B2M level , mg / L > 3.5 mg / L 1.442 4.2 2
CLL-IPI = Chronic Lymphocytic Leukemia-International Prognostic Index
• Intermediate risk ( score = 2-3 ): 79.3 % ( 95 % CI 75.5-83.2 )
• High risk ( score = 4-6 ): 63.3 % ( 95 % CI 57.9-68.8 )
• Very-high risk ( score = 7-10 ): 23.3 % ( 95 % CI 12.5-34.1 )
When the five-year OS was assessed in the external validation cohorts , rates in each risk group were similar to those in the training cohort : 94 percent ( low risk ), 91 percent ( intermediate risk ), 68 percent ( high risk ), and 21 percent ( very high risk ), respectively ( p < 0.001 for all ).
Earlier results of the CLL-IPI study were presented at the 2015 American Society of Clinical Oncology Annual Meeting , where Nadine Kutsch , MD , from the University Hospital of Cologne , in Germany , discussed the implications of CLL-IPI for the management of CLL with ASH Clinical News .
“ In times of novel therapies and improved prognosis for patients with CLL , the traditional staging system developed by Rai and Binet more than 30 years ago no longer discriminate enough ,” Dr .
Kutsch said . “[ The use of CLL-IPI ] leads to an advancement of the classic clinical staging systems and a refinement in prognosis for CLL . Importantly , this is a modular score ,” she added , meaning that any new prognostic marker could easily be validated and incorporated into the score .
She also provided treatment recommendations for the different patient risk subgroups :
• Low : Watch-and-wait approach
• Intermediate : Do not treat , except when the patient is symptomatic
• High : Treat , except when the patient is asymptomatic
• Very high : Treat in experimental protocol with non-cytotoxic drugs , if possible ( no chemotherapy or chemoimmunotherapy )
However , it is unknown how newly developed CLL therapies and newly identified molecular mutations would be incorporated into this revised staging system .
REFERENCE
International CLL-IPI working group . An international prognostic index for patients with chronic lymphocytic leukaemia ( CLL-IPI ): a meta-analysis of individual patient data . Lancet Oncol . 2016 ; S1470- 2045:30029-8 .
Adding Liposomal Doxorubicin to Bortezomib Does Not Improve Survival Compared with Bortezomib Alone
In a 2007 interim analysis of a phase III randomized trial , the combination of bortezomib and pegylated liposomal doxorubicin ( PLD ), compared with bortezomib monotherapy , reduced disease progression and prolonged overall survival ( OS ) in patients with relapsed / refractory multiple myeloma ( MM ). However , according to follow-up data published in Cancer , the OS benefits of the bortezomib-PLD combination therapy did not persist .
“ Despite the superiority in time-toprogression and an early trend in OS favoring the combination therapy in the interim analysis , the long-term follow-up results revealed similar OS for bortezomib- PLD combination therapy and bortezomib monotherapy ,” the authors , led by Robert Z . Orlowski , MD , PhD , from the University of Texas MD Anderson Cancer Center , in Houston , Texas , wrote . “[ The results ] underscore the need for long-term follow-up of phase III trials .”
The phase III , open-label , randomized , active-controlled , multicenter study included 646 patients with confirmed
ASHClinicalNews . org ASH Clinical News
33