scholarly journals An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults

Blood ◽  
2015 ◽  
Vol 125 (12) ◽  
pp. 1857-1865 ◽  
Author(s):  
Michael R. Savona ◽  
Luca Malcovati ◽  
Rami Komrokji ◽  
Ramon V. Tiu ◽  
Tariq I. Mughal ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Myelodysplastic Syndromes ◽  
Myeloproliferative Neoplasms ◽  
Response Assessment ◽  
Response Criteria ◽  
Treatment Algorithms ◽  
International Panel ◽  
Assessment Guidelines ◽  
Suitable Treatment

Abstract Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation.

scholarly journals Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials

Blood ◽  
2019 ◽  
Vol 133 (10) ◽  
pp. 1020-1030 ◽  
Author(s):  
U. Platzbecker ◽  
P. Fenaux ◽  
L. Adès ◽  
A. Giagounidis ◽  
V. Santini ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Myelodysplastic Syndromes ◽  
Working Group ◽  
Lower Risk ◽  
Response Assessment ◽  
Response To Treatment ◽  
Response Criteria ◽  
Patient Response ◽  
Erythroid Response ◽  
Clinical Responses

Abstract The heterogeneity of myelodysplastic syndromes (MDSs) has made evaluating patient response to treatment challenging. In 2006, the International Working Group (IWG) proposed a revision to previously published standardized response criteria (IWG 2000) for uniformly evaluating clinical responses in MDSs. These IWG 2006 criteria have been used prospectively in many clinical trials in MDSs, but proved challenging in several of them, especially for the evaluation of erythroid response. In this report, we provide rationale for modifications (IWG 2018) of these recommendations, mainly for “hematological improvement” criteria used for lower-risk MDSs, based on recent practical and reported experience in clinical trials. Most suggestions relate to erythroid response assessment, which are refined in an overall more stringent manner. Two major proposed changes are the differentiation between “procedures” and “criteria” for hematologic improvement–erythroid assessment and a new categorization of transfusion-burden subgroups.

Myelodysplastic syndromes/myeloproliferative overlap neoplasms

2020 ◽  
pp. 191-203
Author(s):  
Eric Padron ◽  
Tariq I. Mughal ◽  
David Sallman ◽  
Alan F. List
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Stem Cell ◽  
Myelodysplastic Syndromes ◽  
Peripheral Blood ◽  
Myeloproliferative Neoplasms ◽  
Bone Marrow Failure ◽  
Disease Outcomes ◽  
Genomic Landscape ◽  
Bone Marrow Dysplasia

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are haematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) that display a paradoxical bone marrow phenotype hallmarked by myeloid proliferation in the context of bone marrow dysplasia and ineffective haematopoiesis. The unfolding MDS/MPN genomic landscape has revealed numerous mutations in signalling genes, such as CBL, JAK2, NRAS, KRAS, CSF3R, and others involving the spliceosome complex. These observations suggest that comutation of genes involved in dysplasia and bone marrow failure along with those of cytokine receptor signalling may, in part, explain the dual MDS/MPN phenotype. The respective MDS/MPN diseases are identified by the type of myeloid subset which predominates in the peripheral blood. Currently there are no standard treatment recommendations for most patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic endpoints and standardized response criteria for clinical trials.

scholarly journals IMG-09. RESPONSE ASSESSMENT IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): RECOMMENDATIONS FROM THE RESPONSE ASSESSMENT IN PEDIATRIC NEURO-ONCOLOGY COMMITTEE

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii356-iii357
Author(s):  
Tabitha Cooney ◽  
Kenneth J Cohen ◽  
Carolina V Guimaraes ◽  
Girish Dhall ◽  
James Leach ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Clinical Trials ◽  
Response Duration ◽  
Response Assessment ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Response Data ◽  
International Panel ◽  
Children And Young Adults ◽  
Magnetic Resonance Imaging Mri

Abstract Optimizing the conduct of clinical trials for diffuse intrinsic pontine glioma (DIPG) involves use of consistent, objective disease assessments and standardized response criteria. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee, an international panel of pediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address unique challenges in assessing response in children with CNS tumors. A subcommittee of RAPNO was formed to specifically address response assessment in children and young adults with DIPG and to develop a consensus on recommendations for response assessment. Distinct issues related to the response assessment of DIPG include its definition and recent molecular classifications, dearth of imaging response data, the phenomena of pseudoprogression, and measuring response in the era of focal drug delivery. The committee has recommended response be assessed using magnetic resonance imaging (MRI) of brain and spine, neurologic examination, and use of supportive medication, i.e. steroids and anti-angiogenic agents. Clinical imaging standards and imaging quality control are defined. Unique recommendations for DIPG response include an eight-week response duration, a twenty-five percent decrease for partial response, and the distinction of pontine and extra-pontine response for trials that use focal drug delivery. The recommendations presented here represent an initial effort to uniformly collect and evaluate response assessment criteria; these recommendations can now be incorporated into clinical trials to assess feasibility and corroboration with patient outcomes.

Survey of Treatment of 1021 Patients with Myelodysplastic Syndromes in a Tertiary Referal Center 2007-2013

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4647-4647
Author(s):  
Jennifer Schemenau ◽  
Kathrin Nachtkamp ◽  
Blanca Xicoy ◽  
Andrea Kuendgen ◽  
Corinna Strupp ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Induction Chemotherapy ◽  
Allogeneic Stem Cell Transplantation ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Iron Chelation ◽  
Transfusion Therapy

Abstract Introduction: Clinical course, prognosis, and therapy are heterogeneous in patients with myelodysplastic syndromes (MDS). Iron chelation, epigenetic treatment, lenalidomide, and allogeneic stem cell transplantation are the only approved therapies. As these treatments are successful only in a minority of patients, other approaches, which do not always meet the criteria of evidence-based medicine, are also used in an individualized manner. In order to get a comprehensive picture of MDS treatment we analysed 1021 patients who were treated between 2007 and 2013. We included patients with RAEB-T (5%) and CMML (10%). Treatment regimens were inititated at our department. Methods: Diagnoses were established within the Düsseldorf MDS Registry. All treatments were documented until 31 Dec 2013. Prognostic risk assessment was performed according to the International Prognostic Scoring System (IPSS) and its revised version (IPSS-R). Results: Median age was 68 years (18-93 years), 13.5 % of patients were >80 years of age. 41% were diagnosed as RCMD, 12% as RAEB I, 15% as RAEB II, 4% as MDSdel(5q), 5% as RARS, and 9% as RCUD. Anemia was present at first diagnosis in 62.5%, hemorrhagic diathesis in 10%, and at least one comorbidity in 51%. Transfusion therapy was the only treatment in 57% of the patients. 43% (n=441) received at least one specific treatment during the course of the disease. The median number of different therapies was 2 (range 1-9). Of these, 29.9% received cytokines (Epo, G-CSF), 14.4% iron chelation, 11.0% immunomodulation (lenalidomide, thalidomide), 8.7% immuno­suppressive treatment (ATG, CSA, AntiCD52), 16.4% cytoreduction (Ara-C, hydroxyurea), and 16.4% valproic acid as a histone-deacetylating agent (HDAC), partly in combination with all-trans retinoic acid. 28.3% were treated with hypomethylating agents (5-azacytidine, decitabine), 14.6% with induction chemotherapy, and 31.1% underwent allogeneic stem cell transplantation. 5,2 % of the patients were treated within clinical trials. Treatment approaches were distributed among IPSS risk groups as follows: cytokines (low: 55.6%/ intermediate-1: 32.8% /intermediate-2: 24.1%/ high: 9.1%), chelation (18.1%/20.9%/8.9%/4.5%), epigenetic treatment (HMA) (6.9%/19.4%/48.1%/54.5%), immunmodulation (19.4%/13.4%/7.6%/2.3%), immunosuppressive treatment (5.6%/17.2%/2.5%/0.0%), HDA (26.4%/16.4% /11.4%/13.6%), induction chemotherapy (5.6%/9.7%/20.3%/34.1%), cyto-reduction (9.7%/13.4%/20.3%/13.6%), and allogeneic stem cell transplantation (13.9%/32.8%/48.1%/54.5%). Using the IPSS-R, results were similar: cytokines (very low: 62.5%/low: 38.0%/intermediate:25.3%/high: 29.6%/very high:11.5%), chelation (15.6%/26.0%/10.1%/14.8%/5.8%), epigenetic treatment (HMA)(6.3%/8.0%/ 30.4%/40.7%/44.2%), immunmodulation (9.4%/18.0%/7.6%/7.4%/5.8%), immunosuppression (9.4%/11.0%/16.5%/3.7%/3.8%), HDA (21.9%/26.0% /13.9 %/11.1%/15.4%), induction chemotherapy (6.3%/7.0%/17.7%/20.4%/26.9%), cytoreduction (12.5%/11.0%/20.3%/14.8%/15.4%) and allogeneic transplan-tation (15.6%/22.0%/36.7%/48.1%/50.0%). More than 96% of the patients who were treated with HMA, induction chemotherapy or allogeneic transplantation had high-risk MDS (at least IPSS intermediate II) either at diagnosis or during the course of the disease. Conclusions: Our survey shows that off-label treatment is frequent in MDS because there is still a lack of efficient therapies for many patients. During the observation period several treatment modalities were employed, varying in number and type according to IPSS and IPSS-R risk groups.Although numerous clinical trials with new compounds were initiated over the last few years, only a minority of MDS patients were eligible to participate. In the future, a further increase in clinical trial activity will hopefully allow a greater proportion of MDS patients to get access to effective treatment. Disclosures Xicoy: Celgene: Honoraria. Kuendgen:Celgene: Honoraria, Research Funding. Kobbe:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Medac: Other; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Other. Gattermann:Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding. Germing:Novartis: Research Funding; Celgene: Honoraria, Research Funding; AMGEN: Research Funding; Janssen-Cilag: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria.

Revised Response Criteria for Malignant Lymphomas From the Members of the International Harmonization Project (IHP) of the Competence Network Malignant Lymphoma, Represented by:.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 18-18 ◽  
Author(s):  
Bruce D. Cheson ◽  
Beate Pfistner ◽  
Malik E. Juweid ◽  
Lena Specht ◽  
Steven T. Rosen ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clin Oncol ◽  
Residual Disease ◽  
Response Assessment ◽  
Study Groups ◽  
Response Criteria ◽  
Regulatory Agencies ◽  
Disease Response ◽  
Hodgkin's Lymphomas ◽  
Pet Scans

Abstract Standardized response criteria are essential for interpretation of clinical data, comparisons among clinical trials, development of new therapies, and approval of agents by regulatory agencies. In 1999, an International Working Group (IWG) developed recommendations for response assessment for non-Hodgkin’s lymphomas (NHL) that were adopted internationally by study groups and regulatory agencies and, subsequently, by clinical trials groups for Hodgkin lymphoma (HL) as well (Cheson et al, J Clin Oncol, 17:1244, 1999). Since their publication, several observations compelled a reassessment and, ultimately, revision of those guidelines, e.g., the availability of FDG-PET scans, new insights into lymphoma pathology and biology, the failure of the IWG guidelines to include HL and extranodal NHL, and features of the original guidelines that were found to be unclear as they were implemented into clinical trials. Most notable of these was the interpretation of the response category of Complete Remission unconfirmed (CRu). In the context of the IHP, a group of international lymphoma investigators with expertise in medical hematology/oncology, radiation oncology, nuclear medicine and imaging, pathology, biostatistics, and pediatrics were convened to revise the IWG guidelines. Committees focused on Response Criteria, Pathology/Biology, Endpoints, and Clinical Features, and discussions were initiated to undertake a major revision of the IWG guidelines. The important modifications that will be presented included, but were not limited to, integration of PET according to recent data (Juweid et al, J Clin Oncol, 23:4652, 2005), to facilitate the distinction between persistent tumor and scar/fibrosis, virtually eliminate the designation of CRu, and improve prediction of outcome. Guidelines were provided for the specific indications where this test can be currently recommended. Other proposals involved the role of flow cytometry and assessment of minimal residual disease. Response criteria for extranodal sites were also incorporated. Adoption of these revised guidelines by study groups will further improve the conduct and interpretation of clinical trials leading to more effective therapies for patients with lymphomas.

scholarly journals Evaluation of International Working Group 2006 Response Criteria in Patients with Higher-Risk Myelodysplastic Syndromes (HR-MDS) Treated with Hypomethylating Agent Monotherapy in the Frontline Setting

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3701-3701
Author(s):  
Jan Philipp Bewersdorf ◽  
Wei Wei ◽  
Anna Jaiani ◽  
Prital Patel ◽  
Rajni Mehta ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Clinical Trials ◽  
Myelodysplastic Syndromes ◽  
Working Group ◽  
Research Funding ◽  
Response Criteria ◽  
The Impact ◽  
Support Research

Abstract Introduction: Monotherapy with hypomethylating agents (HMA) remains the standard of care for patients (pts) with myelodysplastic syndromes (MDS). Response in MDS is based on the modified International Working Group (IWG) 2006 criteria. Prior studies focusing on unselected MDS pts showed that achieving a complete remission (CR) was associated with favorable overall survival (OS). However, the association of other outcomes with OS was less clear and only 20% of HMA-treated MDS pts achieve a CR. For example, pts who achieved <5% bone marrow (BM) blasts are currently classified as marrow CR (mCR), which has not been associated with OS improvement. Therefore, interpreting the significance of mCR reported in various clinical trials is challenging. Clinically meaningful reduction in bleeding or infectious complications can occur at improvements in absolute neutrophil count (ANC) and platelet counts that do not meet the current thresholds used for CR (ANC ≥1.0 × 10 9/L, platelets ≥100 × 10 9/L, and Hb >11 g/dL). To avoid missing clinically meaningful benefits when studying new drugs in clinical trials, a clearly defined response criterion that is less stringent than CR but still captures clinically meaningful hematologic improvement (HI) is needed. Here we sought to evaluate the impact of current IWG 2006 response criteria as well as CRh on OS of pts with HR-MDS treated with frontline HMA monotherapy. Methods: We included all adult (≥18 years) MDS pts treated with frontline HMA (azacitidine [AZA], decitabine [DEC], or ASTX727) monotherapy between 1/1/2012 and 12/31/2020 at Yale University. We decided to use HMA monotherapy as it is the standard care for HR-MDS and to minimize the impact of therapy choice confounding the association of achieved response with OS. Pts were excluded if they received prior treatments for MDS aside from erythropoiesis-stimulating agents and if no baseline with at least one follow-up BM study were available for response assessment. We collected patient and disease characteristics (transfusion burden, IPSS/IPSS-R score, cytogenetics, molecular studies) at baseline. Best responses were assessed based on IWG 2006 criteria for MDS. We defined CRh as <5% BM blasts, platelets ≥50 × 10 9/L, ANC ≥0.5 × 10 9/L and no peripheral blood blasts. We followed pts until death or last follow-up and recorded dates of allogeneic hematopoietic cell transplant (HCT) if applicable. Date of data cut-off for survival status was 5/31/2021. We performed Kaplan-Meier analysis to estimate the duration of overall survival and we used log rank test to test the difference in OS between subgroups of pts. Multiple comparisons were adjusted using the Bonferroni method. Results: A total of 100 pts was included in this analysis (Table 1). Median age was 68 years (yrs; range, 23 - 86), 60% were males, and 79% and 18% of pts received AZA and DEC, respectively. Median number of HMA cycles was 6 (interquartile range [IQR]: 4-10), and 33 pts (33%) underwent HCT. During follow-up, 46 pts (48%) progressed to AML. At a median follow-up of 1.5 yrs (IQR: 0.9 - 2.3 yrs), median OS for the entire pt cohort was 1.9 yrs (Figure 1). OS by response category is shown in Table 2. Median OS was not reached for patients who achieved a CR (95% CI: not reached [NR] - NR) as compared to 1.9 yrs (95% CI: 1.5 yrs - NR) and 2.0 yrs (95% CI: 1.2 yrs - NR) among pts with mCR + HI and mCR without HI, respectively. Median OS among patients with stable disease (SD) was similar (2.0 yrs [95% CI: 1.5 yrs - NR]). Finally, we explored the prognostic value of CRh and found a median OS of 1.9 yrs (95% CI: 1.5 yrs - NR), which appeared comparable to mCR +/- HI or SD. Similar results were found with censoring at time of HCT (Figure 2). Discussion: In this retrospective analysis of MDS pts treated with HMA monotherapy in the frontline setting, achieving CR as best response was associated with improved OS compared with mCR +/- HI and SD. However, as the numbers were small these results should be interpreted with caution, and other clinically relevant outcomes such as freedom of transfusion, infectious or bleeding complications, and patient-reported outcomes were not captured in the current analysis. Our results also apply only to MDS pts treated with HMA monotherapy in the frontline setting. The prognostic implications of CRh need to be evaluated in larger patient cohorts. To overcome these limitations, we are currently in the process of expanding the study to a much larger multi-center, international analysis. Figure 1 Figure 1. Disclosures Neparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Podoltsev: PharmaEssentia: Honoraria; Pfizer: Honoraria; CTI BioPharma: Honoraria; Blueprint Medicines: Honoraria; Incyte: Honoraria; Bristol-Myers Squib: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Brunner: GSK: Research Funding; Aprea: Research Funding; Keros Therapeutics: Consultancy; Agios: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Acceleron: Consultancy; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Janssen: Research Funding. Zeidan: AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Epizyme: Consultancy; Amgen: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Acceleron: Consultancy, Research Funding; Agios: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Jasper: Consultancy; ADC Therapeutics: Research Funding; Jazz: Consultancy; Astex: Research Funding; Daiichi Sankyo: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Geron: Other: Clinical Trial Committees; AstraZeneca: Consultancy; Pfizer: Other: Travel support, Research Funding; BeyondSpring: Consultancy; Ionis: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Janssen: Consultancy; Astellas: Consultancy.

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