Key Points

  • Evidence exists that ELN criteria for response in ET and PV issued in 2009 do not provide relevant measures of benefit for patients.

  • Revised recommendations for assessing response are provided.

Abstract

Standardized response criteria to interpret and compare clinical trials are needed for approval of new therapeutic agents by regulatory agencies. The European LeukemiaNet (ELN) response criteria for essential thrombocythemia (ET) and polycythemia vera (PV) issued in 2009 have been widely adopted as end points in a number of recent clinical trials. However, evidence exists that they do not predict response or provide clinically relevant measures of benefit for the patients. This article presents revised recommendations for assessing response in ET and PV provided by a working group established by ELN and International Working Group-Myeloproliferative Neoplasms Research and Treatment. New definitions of complete and partial remission incorporate clinical, hematological, and histological response assessments that include a standardized symptom assessment form and consider absence of disease progression and vascular events. We anticipate that these criteria will be adopted widely to facilitate the development of new and more effective therapies for ET and PV.

Introduction

In 2009, investigators met under the advocacy of the European LeukemiaNet (ELN) Consortium and developed recommendations for response assessment for patients with essential thrombocythemia (ET) and polycythemia vera (PV).1  These criteria were adopted as a standardized metric for designing and reporting the results generated from recent trials.2-6  However, limitations of the ELN criteria have become apparent, based on the evidence that they do not represent a direct measure of benefit for patients.7  In fact, achieving a complete response according these criteria did not correlate with lower incidence of thrombosis or improved survival.8,9  Moreover, the discovery of JAK2 V617F mutation and other molecular abnormalities in ET and PV has unveiled new targets for therapies that have led to the development of novel experimental agents aimed at modifying the natural history of these diseases. As a consequence, the investigators engaged in clinical research and the pharmaceutical companies progressing toward drug approval optimally should be evaluating new drugs using end points that are capable of measuring the effects of such drugs on clinically relevant benefit for the patients. These considerations made it apparent that a revision of the initial response criteria was needed. As a result, the ELN Consortium in conjunction with the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) assembled an international group of investigators to develop a revised set of criteria for defining response in these disorders to be used in clinical trials of new agents.

Study design

An 18-member expert panel (EP) composed of individuals with experience in clinics and hematopathology of myeloproliferative neoplasms was created. The EP defined the aims of the project, framed the operative context, and participated in the consensus development process aimed at providing the response definitions.

The methodology has been previously described.1  During the initial meeting, the EP agreed that the aim of the project was to revise the definition of response to treatments that could be used for evaluating the results of clinical trials aimed at measuring the activity of drugs intended to modify the biology and natural history of ET and PV. To achieve this goal, questionnaires were mailed to each member of the panel asking the member to list candidate criteria, taking into account existing evidence and personal knowledge and experience. All the questionnaires were returned and the candidate criteria were ranked according to their priority votes. The final version of the criteria was further discussed in a consensus meeting using nominal group technique.

Results and discussion

The new recommendations were based on the concept that standardized criteria for measuring the response to therapies in ET and PV patients should primarily measure the antiproliferative activity and capture the long-term effects of new and experimental drugs. The application of these response definitions should be limited to clinical trials. with the understanding that they are not warranted in clinical practice. The EP listed 4 categories of response criteria to be included for the evaluation of complete or partial remissions in patients with ET or PV (Tables 1 and 2). The definition of response required normalization of symptoms and signs of the disease, remission of peripheral blood counts, absence of vascular events without signs of progression of disease, and bone marrow histological abnormalities. A patient-reported quality-of-life instrument was used for the definition of normalization of symptoms through an ad hoc specific questionnaire (Myelorpoliferative Neoplasm-Symptoms Assessment Form Total Symptom Score [MPN-SAF TSS]).10,11  The EP claimed that defining response durability (12 weeks) was of importance. Partial remission differed from complete remission because of the lack of correction of histological abnormalities, indicating that the candidate drug had not been able to interfere with the underlying disease process. Besides response, the long-term evaluation of the patients included also the definition of no response and disease progression.12,13 

Table 1

Response criteria for ET

 Criteria 
Complete remission  
 A Durable* resolution of disease-related signs including palpable hepatosplenomegaly, large symptoms improvement,† AND 
 B Durable* peripheral blood count remission, defined as: platelet count ≤400 ×109/L, WBC count <10 × 109/L, absence of leukoerythroblastosis, AND 
 C Without signs of progressive disease, and absence of any hemorrhagic or thrombotic events, AND 
 D Bone marrow histological remission defined as disappearance of megakaryocyte hyperplasia and absence of >grade 1 reticulin fibrosis. 
Partial remission 
 A Durable* resolution of disease-related signs including palpable hepatosplenomegaly, and large symptoms improvement, AND 
 B Durable* peripheral blood count remission, defined as: platelet count ≤400 × 109/L, WBC count <10 × 109/L, absence of leukoerythroblastosis, AND 
 C Without signs of progressive disease, and absence of any hemorrhagic or thrombotic events, AND 
 D Without bone marrow histological remission, defined as the persistence of megakaryocyte hyperplasia. 
No response Any response that does not satisfy partial remission 
Progressive disease Transformation into PV, post-ET myelofibrosis, myelodysplastic syndrome or acute leukemia‡ 
 Criteria 
Complete remission  
 A Durable* resolution of disease-related signs including palpable hepatosplenomegaly, large symptoms improvement,† AND 
 B Durable* peripheral blood count remission, defined as: platelet count ≤400 ×109/L, WBC count <10 × 109/L, absence of leukoerythroblastosis, AND 
 C Without signs of progressive disease, and absence of any hemorrhagic or thrombotic events, AND 
 D Bone marrow histological remission defined as disappearance of megakaryocyte hyperplasia and absence of >grade 1 reticulin fibrosis. 
Partial remission 
 A Durable* resolution of disease-related signs including palpable hepatosplenomegaly, and large symptoms improvement, AND 
 B Durable* peripheral blood count remission, defined as: platelet count ≤400 × 109/L, WBC count <10 × 109/L, absence of leukoerythroblastosis, AND 
 C Without signs of progressive disease, and absence of any hemorrhagic or thrombotic events, AND 
 D Without bone marrow histological remission, defined as the persistence of megakaryocyte hyperplasia. 
No response Any response that does not satisfy partial remission 
Progressive disease Transformation into PV, post-ET myelofibrosis, myelodysplastic syndrome or acute leukemia‡ 

Molecular response is not required for assignment as complete response or partial response. Molecular response evaluation requires analysis in peripheral blood granulocytes. Complete response is defined as eradication of a preexisting abnormality. Partial response applies only to patients with at least 20% mutant allele burden at baseline. Partial response is defined as ≥50% decrease in allele burden.

WBC, white blood cell.

*

Lasting at least 12 wk.

Large symptom improvement (≥10-point decrease) in MPN-SAF TSS.10 

For the diagnosis of PV see World Health Organization criteria (WHO)13 ; for the diagnosis of post-ET myelofibrosis, see the IWG-MRT criteria12 ; for the diagnosis of myelodysplastic syndrome and acute leukemia, see WHO criteria.13 

Table 2

Response criteria for PV

 Criteria 
Complete remission  
 A Durable* resolution of disease-related signs including palpable hepatosplenomegaly, large symptoms improvement† AND 
 B Durable* peripheral blood count remission, defined as Ht lower than 45% without phlebotomies; platelet count ≤400 × 109/L, WBC count <10 × 109/L, AND 
 C Without progressive disease, and absence of any hemorrhagic or thrombotic event, AND 
 D Bone marrow histological remission defined as the presence of age-adjusted normocellularity and disappearance of trilinear hyperplasia, and absence of >grade 1 reticulin fibrosis 
Partial remission 
 A Durable* resolution of disease-related signs including palpable hepatosplenomegaly, large symptoms improvement† AND 
 B Durable* peripheral blood count remission, defined as Ht lower than 45% without phlebotomies; platelet count ≤400 × 109/L, WBC count <10 × 109/L, AND 
 C Without progressive disease, and absence of any hemorrhagic or thrombotic event, AND 
 D Without bone marrow histological remission defined as persistence of trilinear hyperplasia. 
No response Any response that does not satisfy partial remission 
Progressive disease Transformation into post-PV myelofibrosis, myelodysplastic syndrome or acute leukemia‡ 
 Criteria 
Complete remission  
 A Durable* resolution of disease-related signs including palpable hepatosplenomegaly, large symptoms improvement† AND 
 B Durable* peripheral blood count remission, defined as Ht lower than 45% without phlebotomies; platelet count ≤400 × 109/L, WBC count <10 × 109/L, AND 
 C Without progressive disease, and absence of any hemorrhagic or thrombotic event, AND 
 D Bone marrow histological remission defined as the presence of age-adjusted normocellularity and disappearance of trilinear hyperplasia, and absence of >grade 1 reticulin fibrosis 
Partial remission 
 A Durable* resolution of disease-related signs including palpable hepatosplenomegaly, large symptoms improvement† AND 
 B Durable* peripheral blood count remission, defined as Ht lower than 45% without phlebotomies; platelet count ≤400 × 109/L, WBC count <10 × 109/L, AND 
 C Without progressive disease, and absence of any hemorrhagic or thrombotic event, AND 
 D Without bone marrow histological remission defined as persistence of trilinear hyperplasia. 
No response Any response that does not satisfy partial remission 
Progressive disease Transformation into post-PV myelofibrosis, myelodysplastic syndrome or acute leukemia‡ 

Molecular response is not required for assignment as complete response or partial response. Molecular response evaluation requires analysis in peripheral blood granulocytes. Complete response is defined as eradication of a preexisting abnormality. Partial response applies only to patients with at least 20% mutant allele burden at baseline. Partial response is defined as ≥ 50% decrease in allele burden.

WBC, white blood cell.

*

Lasting at least 12 wk.

Large symptom improvement (≥10-point decrease) in MPN-SAF TSS.10 

For the diagnosis of post-PV myelofibrosis, see the IWG-MRT criteria12 ; for the diagnosis of myelodysplastic syndrome and acute leukemia, see WHO criteria.

The main aim of the project was to provide response definitions in ET and PV that were clinically relevant, practical, and reproducible by investigators and clinicians working at different institutions. Absence of vascular event for response is a restrictive criterion because vascular events are rather common in the age group characteristic of polycythemic and thrombocythemic patients and are not necessarily related with the disease. However, the EP agreed that this criterion is operationally justified. Even though some of the therapeutic agents in use today have proven capable of reducing the allele burden of JAK2 V617F mutation in PV,14  molecular remission was not included in the definition of complete and partial remission both in ET and in PV. A concern of the EP in providing a definition of molecular response was that not all patients with ET are mutated in the JAK2 gene and the low sensitivity to change of this parameter in patients bearing the mutation.15  Moreover, patients may also have additional molecular defects besides JAK2V617F, and a remission of 1 mutated clone is not always accompanied by remission of other clones.16  According to the proposed definition of response, a complete remission can occur in spite of the persistence of a mutated malignant clone. For this reason, use of the term “complete remission” should not be interpreted as being equivalent to complete eradication of the malignant clone.

Monitoring changes in bone marrow histology after treatment is not presently routine in clinical practice and in clinical trials in patients with ET and PV. However, the EP concluded that drugs that are capable of changing the natural course of the disease need to be assessed for their impact on marrow histopathology. Definitions of histological response were based on effects on megakaryocyte hyperplasia for ET and cellularity and reticulin fibrosis for PV. For both histological responses, a quantitative definition of remission was not provided, and the EP proposed a qualitative concept that should be individually graded by the pathologist evaluating the biopsies. Variability in the experience of pathologists at different institutions, compounded by variability in specimen quality, may result in a wide range in the interpretation and significance of the bone marrow reports. A central review is recommended for studies in which the primary goal is to assess overall activity of a new agent.

We believe that the response criteria presented in this article are a promising new tool for assessing therapeutic outcomes in patients with ET and PV being treated with novel therapeutic agents. These criteria hopefully will provide a means by which to compare the results derived from treating different patient cohorts with various candidate therapeutic agents and are recommended to the academic and pharmaceutical company community in order to facilitate communication within these communities.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Acknowledgments

The authors thank Prof Rudigher Hehlmann, chair of the ELN Consortium, for providing encouragement and logistic help for the project.

This work was supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano) “Special Program Molecular Clinical Oncology 5x1000” to AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM) (G.B. and A.M.V.) and by National Cancer Institute grant P01CA108671GB (J.-J.K., A.M.V., R.H., and T.B.). A detailed description of the AGIMM project is available at http://www.progettoagimm.it.

Authorship

Contribution: G.B., A.T., and T.B. designed the research; G.B., R.M., G.F., C.H., J.-J.K., E.L., M.F.M., F.P., A.M.V., C.B., H.G., J.S., S.V., R.H., A.P., F.C., A.T., and T.B. formed the panel of experts who produced recommendations; G.B. wrote the preliminary version of the paper; and all authors participated in writing significant sections of the paper.

Conflict-of-interest disclosure: J.-J.K. participated in advisory boards for Novartis and AOP-orphan; S.V. participated in advisory boards for Geron, Incyte, and Sanofi; M.F.M. participated in advisory boards for Novartis, Shire, BMS, and Sanofi; F.P. participated in advisory boards for Sanofi, Celgene, Roche, Novartis, and Incyte; C.B. participated in advisory boards for Novartis; E.L. participated in advisory boards for Novartis; J.S. participated in advisory boards for Novartis; T.B. participated in advisory boards for Novartis and Sanofi; A.M.V. participated in advisory boards for Novartis; and G.B. participated in advisory boards for Novartis and Sanofi. The remaining authors declare no competing financial interests.

Correspondence: Giovanni Barosi, Center for the Study of Myelofibrosis, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, Viale Golgi 19, 27100 Pavia, Italy; e-mail: barosig@smatteo.pv.it.

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