Update on Developments in the Diagnosis and Prognostic Evaluation Patients With MDS

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Update on Developments in the Diagnosis and Prognostic Evaluation of Patients With Myelodysplastic Syndromes (MDS): Consensus Statements and Report From an Expert Workshop

Leuk Res. 2012 Mar 1;36(3):264-270, U Platzbecker, V Santini, GJ Mufti, D Haase, et al

Abstract

Several new treatments for myelodysplastic syndromes (MDS) have recently become available, or are in development. Patients who could benefit from active treatment must be effectively identified and followed up. Therefore, guidelines for the diagnosis and prognostic evaluation of MDS need to be kept up to date with technological and scientific advances. An expert workshop was convened to review currently available and emerging diagnostic technologies and developments in prognostic classification systems, to ensure appropriate management of individual patients. The panel also provided suggestions to ensure adherence to guidelines and highlighted the mandatory requirement for cytogenetic evaluation in patients with MDS.

[url]http://www.lrjournal.com/article/S0145-2126(11)00537-6/fulltext
[url]http://download.journals.elsevierhealth.com/pdfs/journals/0145-2126/PIIS0145212611005376.pdf

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Verstovsek S et al. Consistent benefit of ruxolitinib over placebo in spleen volume reduction and symptom improvement across subgroups and overall survival advantage: Results from COMFORT-I. Proc ASH 2011;Abstract 278.

Consistent Benefit of Ruxolitinib Over Placebo in Spleen Volume Reduction and Symptom Improvement Across Subgroups and Overall Survival Advantage: Results From COMFORT-I
Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical Advances I
Monday, December 12, 2011: 7:00 AM
Room 6B (San Diego Convention Center)
Srdan Verstovsek, MD, PhD1, Ruben A. Mesa, MD2, Jason Gotlib, MD, MS3, Richard S. Levy, MD4*, Vikas Gupta, MD, FRCP, FRCPath5, John F. DiPersio, MD, PhD6, John Catalano, MD7, Michael W. Deininger8, Carole B. Miller, MD9*, Richard T. Silver, MD10, Moshe Talpaz, MD11, Elliott F. Winton, MD12, Jimmie H. Harvey Jr., MD13*, Murat O. Arcasoy, MD14, Elizabeth Hexner, MD15, Roger M. Lyons, MD16, Ronald Paquette, MD, PhD17*, Azra Raza, MD18, Kris Vaddi, PhD4*, Sue Erickson-Viitanen, PhD4*, William Sun, PhD4*, Victor A. Sandor, MD, CM4* and Hagop M. Kantarjian1

1University of Texas MD Anderson Cancer Center, Houston, TX
2Mayo Clinic, Scottsdale, AZ
3Medicine/Hematology, Stanford University Cancer Institute, Stanford, CA
4Incyte Corporation, Wilmington, DE
5Medical Oncology & Hematology, Princess Margaret Hospital, Toronto, ON, Canada
6Washington University School of Medicine, St. Louis, MO
7Frankston Hospital, Frankston, Victoria, Australia
8University of Utah Huntsman Cancer Institute, Salt Lake City, UT
9Saint Agnes Cancer Institute, Baltimore, MD
10Weill Medical College of Cornell University, New York, NY
11University of Michigan, Ann Arbor, MI
12Emory University School of Medicine, Atlanta, GA
13Birmingham Hematology & Oncology Associates, Birmingham, AL
14Duke University Health System, Durham, NC
15Abramson Cancer Center at The University of Pennsylvania, Philadelphia, PA
16Cancer Care Centers of South Texas/US Oncology, San Antonio, TX
17UCLA Medical Hematology & Oncology, Los Angeles, CA
18Columbia Presbyterian Medical Center, New York, NY

Background: Overactive JAK-STAT signaling as a result of gain-of-function mutations (eg, JAK2V617F) and/or high circulating levels of inflammatory cytokines is considered to play a key role in the pathogenesis of myeloproliferative neoplasms. Ruxolitinib, a selective oral inhibitor of JAK1 and JAK2, demonstrated a significant reduction in spleen volume (SV) and improvements in myelofibrosis (MF)-related symptoms in a double-blind placebo-controlled trial (COMFORT-I). The objective of this analysis was to evaluate the efficacy of ruxolitinib across patient (pt) subgroups in COMFORT-I.

Methods: Pts with MF were randomized to start placebo or ruxolitinib at a dose of 15 mg or 20 mg PO BID depending on baseline platelet count (100-200 X109/L or >200 X109/L, respectively). The dose was optimized for efficacy and safety during treatment. SV change was measured by MRI; MF symptoms were assessed using a daily diary (modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0) over 1 wk prior to dosing and throughout the 24 wks of dosing. The percent changes from baseline to wk 24 in SV and MFSAF Total Symptom Score (TSS, a measure of combined scores for abdominal discomfort, pain under ribs on left side, early satiety, itching, night sweats, and bone/muscle pain) were compared for ruxolitinib and placebo pts across the following subgroups: MF disease subtype, age, International Prognosis Scoring System (IPSS) risk group, presence/absence of JAK2V617F mutation, baseline hemoglobin, baseline spleen size (palpable spleen length), and baseline TSS. Survival was estimated by Kaplan-Meier method.

Changes in SV and TSS Across Subgroups: 309 pts were randomized: 155 to ruxolitinib and 154 to placebo. Ruxolitinib demonstrated consistent benefit compared with placebo in both SV and TSS across all subgroups evaluated.

The impact of symptom severity on response was evaluated by baseline TSS quartiles (maximum score for TSS = 60). Ruxolitinib pts with baseline TSS of <8.5, 8.5-<16.5, 16.5-<25.5 and ≥25.5 had mean percent changes in SV of -28.0, -31.4, -31.7 and -34.8, respectively, vs +8.1 for all placebo pts combined. The mean percent change in TSS for these same subgroups was -40.5, -47.2, -48.1 and -48.2 vs +41.8 for all placebo pts combined. These data indicate that pts with modest to marked symptoms all benefit from ruxolitinib therapy in terms of both SV and TSS.

Survival Analysis: 13 ruxolitinib and 24 placebo pts died during the study or during extended follow-up (median follow-up of 52 and 51 wks, respectively), representing a hazard ratio (95% CI) of 0.499 (0.254, 0.98) (p=0.0395). For ruxolitinib- and placebo-treated pts, respectively, the probability of survival (95% CI) >48 wks was 0.98 (0.92, 0.99) and 0.90 (0.81, 0.95) for pts with baseline hemoglobin values ≥10 g/dL and 0.84 (0.72, 0.91) and 0.77 (0.63, 0.86) for pts with baseline hemoglobin <10 g/dL.

Conclusions: Pts receiving ruxolitinib had higher response rates than placebo based on reductions in SV and improvements in TSS at wk 24 regardless of baseline subgroup: MF disease subtype, age (≤65 or >65 y), IPSS risk group (intermediate-2 or high-risk), presence or absence of JAK2V617F mutation, hemoglobin level (≥10 g/dL or <10 g/dL), palpable spleen length (≤10 cm or >10 cm), and symptom severity (TSS quartile). In addition, the overall survival analysis suggested a benefit with ruxolitinib therapy over placebo.

Disclosures: Verstovsek: Incyte: Research Funding. Mesa: Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib: Incyte: Consultancy, Research Funding. Levy: Incyte: Employment, Equity Ownership. Gupta: Incyte: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Catalano: Incyte: Honoraria; Novartis: Honoraria. Deininger: BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Miller: Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton: Incyte: Consultancy. Arcasoy: Incyte: Research Funding. Lyons: Alexion: Consultancy, Honoraria; Telik: Research Funding; Incyte: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Vaddi: Incyte: Employment. Erickson-Viitanen: Incyte: Employment. Sun: Incyte: Employment. Sandor: Incyte: Employment. Kantarjian: Incyte: Research Funding; Novartis: Consultancy, Research Funding.

AMERICAN SOCIETY OF HEMATOLOGY

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Harrison CN et al. Ruxolitinib provides reductions in splenomegaly across subgroups: An analysis of spleen response in the COMFORT-II study. Proc ASH 2011;Abstract 279.

Ruxolitinib Provides Reductions in Splenomegaly Across Subgroups: An Analysis of Spleen Response in the COMFORT-II Study

Program: Oral and Poster Abstracts

Type: Oral

Session: 634. Myeloproliferative Syndromes: Clinical Advances I
Monday, December 12, 2011: 7:00 AM Room 6B (San Diego Convention Center)

Claire N. Harrison, DM, FRCP, FRCPath 1, Jean-Jacques Kiladjian, MD, PhD 2, Heinz Gisslinger, MD 3, Dietger Niederwieser, MD 4, Francesco Passamonti, MD 5, Roger J. Waltzman, MD 6, Norbert Hollaender, PhD 7, Deborah S. Hunter, PhD 8, Richard S. Levy, MD 8, Laurent Knoops, MD, PhD 9, Francisco Cervantes, MD, PhD 10, Alessandro M. Vannucchi, MD 11, Tiziano Barbui, MD 12 and Giovanni Barosi, MD 13

1. Dept. of Haematology, Guy's and St. Thomas NHS FoundationTrust, London, United Kingdom
2. Centre d'Investigation Clinique (CIC), Hôpital Saint-Louis, Paris, France
3. Medical University of Vienna, Vienna, Austria
4. University of Leipzig, Leipzig, Germany
5. Depèartment of Internal Medicine, Fondazione Macchi, Division of Hematology, Varese, Italy
6. Novartis Pharmaceuticals Corporation, East Hanover, NJ
7. Novartis Oncology (INC424), Biometrics & Data Management (BDM), Novartis Pharma AG, Basel, Switzerland
8. Incyte Corporation, Wilmington, DE
9. Cliniques univeristaires Saint-Luc and Ludwig Institute for Cancer Research, Brussels, Belgium
10. Hematology Department, Hospital Clínic, Barcelona, Spain
11. Department of Clinical Care, UF Hematology, University of Florence, Florence, Italy
12. A.O. Ospedali Riuniti di Bergamo, Bergamo, Italy
13. IRCCS Policlinico S. Matteo Foundation, Pavia, Italy

Background:

COMFORT-II is a randomized, open-label, phase 3 study evaluating the safety and efficacy of ruxolitinib, a potent and selective oral inhibitor of JAK1 and JAK2, in patients with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). Patients who received ruxolitinib had significantly greater reductions in spleen volume compared with those who received best available therapy (BAT). The primary and key secondary endpoints of the study were both met: the proportion of patients achieving ≥35% reduction in spleen volume at week 48 (28.5%, ruxolitinib; 0%, BAT; P < .0001) and week 24 (31.9%, ruxolitinib; 0%, BAT; P < .0001), respectively. Subgroup analysis was performed on both the 48- and 24-week endpoints.

Methods:

In the COMFORT-II study, 219 patients were randomized (2:1) to receive ruxolitinib (15 or 20 mg twice daily [bid] based on the baseline platelet count [100– 200 × 109/L or >200 × 109/L, respectively]) or BAT of the investigator's choice. The proportions of ruxolitinib-treated patients achieving the primary and key secondary endpoints were analyzed by subgroup for gender (male or female), age (≤65 or >65 years), starting dose (15 or 20 mg bid), baseline MF type (PMF, PPV-MF, or PET-MF), previous hydroxyurea (hydroxycarbamide) use (yes or no), baseline palpable spleen length (≤10 or >10 cm), baseline spleen volume (>median or ≤median), JAK2V617F mutation (presence or absence), and International Prognostic Scoring System (IPSS) risk category (intermediate-2 or high) (Cervantes F, et al, Blood, 2009;113(13):2895-2901). In addition, the relationships between these factors and spleen volume reduction were investigated by multivariate logistic regression.

Results:

The proportion of patients in each subgroup with ≥ 35% reduction in spleen volume from baseline at week 48.

The response rate was higher in patients receiving ruxolitinib than in patients receiving BAT in all subgroups; no patients in the BAT group reached a ≥35% reduction in spleen volume at week 48. All subgroups receiving ruxolitinib responded and all subgroup comparisons had overlapping 95% confidence intervals. At week 24, a trend for a higher response rate was observed in patients who received a starting dose of 20 mg bid compared with those who received a starting dose of 15 mg bid; however, the response rates among these patients at week 48 were not different. No significant difference in response rates was observed between patients with the JAK2V617F mutation compared with those without the mutation. Results of the subgroup analysis were confirmed by the multivariate models. A significant effect of the ruxolitinib starting dose was seen when response rates were modeled at week 24 but not when modeled at week 48.

Conclusions:

Recent findings from the COMFORT-II study show that patients who received ruxolitinib had significantly greater reductions in splenomegaly than did patients who received BAT. In this analysis, ruxolitinib was shown to be more effective than BAT at reducing spleen volume in all patient subgroups regardless of gender, age, mutation status, IPSS risk category, baseline spleen size, MF subtype, or ruxolitinib starting dose.

Disclosures:

Harrison: Novartis: Honoraria; Incyte: Honoraria; S*Bio: Honoraria; Celgene: Honoraria; Sanofi Aventis: Honoraria. Kiladjian: Novartis: Honoraria; Celgene: Honoraria. Gisslinger: Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau; Aop-Orphan: Speakers Bureau. Niederwieser: Novartis: Speakers Bureau. Passamonti: Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Waltzman: Novartis: Employment. Hollaender: Novartis Pharma AG: Employment. Hunter: Incyte Corporation: Employment, Equity Ownership. Levy: Incyte Corporation: Employment, Equity Ownership. Knoops: Novartis: Consultancy. Cervantes: Bristol-Myers-Squibb: Speakers Bureau; Novartis: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Vannucchi: Novartis: Honoraria. Barosi: Novartis: Consultancy.

AMERICAN SOCIETY OF HEMATOLOGY

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COMFORT-I and COMFORT-II: Long-Term Results with Ruxolitinib for Myelofibrosis

Verstovsek S et al. Long-term outcome of ruxolitinib treatment in patients with myelofibrosis: Durable reductions in spleen volume, improvements in quality of life, and overall survival advantage in COMFORT-I. Proc ASH 2012

[url]http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/800?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=800& searchid=1&FIRSTINDEX=0&volume=120&issue=21&resour cetype=HWCIT

Cervantes F et al. Long-term safety, efficacy, and survival findings from Comfort-II, a Phase 3 study comparing ruxolitinib with best available therapy (BAT) for the treatment of myelofibrosis (MF). Proc ASH 2012

[url]http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/801?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=801& searchid=1&FIRSTINDEX=0&sortspec=relevance&resourc etype=HWCIT

COMFORT-I and COMFORT-II: Long-Term Results with Ruxolitinib for Myelofibrosis

[url]http://www.researchtopractice.com/sites/default/files/5mjc/5MJCASH2013/3/1/pdf/5MJC1-ASH13_Downloadable.pdf

Harrison CN et al. Expand: A Phase 1b, open-label, dose-finding study of ruxolitinib in patients with myelofibrosis and baseline platelet counts between 50 x 109/L and 99 x 109/L. Proc ASH 2012

[url]http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/177?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=177& searchid=1&FIRSTINDEX=0&sortspec=relevance&resourc etype=HWCIT

EXPAND: A Phase Ib Dose-Finding Study of Ruxolitinib in Patients with Myelofibrosis and Low Platelet Counts

[url]http://www.researchtopractice.com/sites/default/files/5mjc/5MJCASH2013/3/2/pdf/5MJC2-ASH13_Downloadable.pdf