out to all as the normal physiology of the Inflammatory Process. Any disease is an aberration of the aforementioned.
Today in the email from the NEJM and MD Anderson writers as primary contributors this was lifted with quite significant results.
THIS IS A NORMAL BLOOD SMEAR (above)
THIS IS A BLOOD SMEAR REVEALING chronic lymphocytic Leukemia(immediately above)
Original
Article
Ibrutinib as Initial Therapy for
Patients with Chronic Lymphocytic Leukemia
Jan A. Burger, M.D.,
Ph.D., Alessandra Tedeschi, M.D., Paul M. Barr, M.D., Tadeusz Robak, M.D.,
Ph.D., Carolyn Owen, M.D., Paolo Ghia, M.D., Ph.D., Osnat Bairey, M.D., Peter
Hillmen, M.B., Ch.B., Ph.D., Nancy L. Bartlett, M.D., Jianyong Li, M.D., David
Simpson, M.B., B.S., Sebastian Grosicki, M.D., Ph.D., Stephen Devereux,
F.R.C.P., F.R.C.Path., Ph.D., Helen McCarthy, F.R.C.P., F.R.C.Path., Ph.D.,
Steven Coutre, M.D., Hang Quach, M.B., B.S., M.D., Gianluca Gaidano, M.D.,
Ph.D., Zvenyslava Maslyak, M.D., Don A. Stevens, M.D., Ann Janssens, M.D.,
Fritz Offner, M.D., Ph.D., Jiří Mayer, M.D., Michael O’Dwyer, M.D., Andrzej
Hellmann, M.D., Ph.D., Anna Schuh, M.D., Ph.D., Tanya Siddiqi, M.D., Aaron
Polliack, M.D., Constantine S. Tam, M.B., B.S., Deepali Suri, M.S., Mei Cheng,
Ph.D., Fong Clow, Sc.D., Lori Styles, M.D., Danelle F. James, M.D., and Thomas
J. Kipps, M.D., Ph.D. for the RESONATE-2 Investigators
N Engl J Med 2015;
373:2425-2437December 17,
2015DOI: 10.1056/NEJMoa1509388
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Background
Chronic lymphocytic
leukemia (CLL) primarily affects older persons who often have coexisting
conditions in addition to disease-related immunosuppression and
myelosuppression. We conducted an international, open-label, randomized phase 3
trial to compare two oral agents, ibrutinib and chlorambucil, in previously
untreated older patients with CLL or small lymphocytic lymphoma.
Methods
We randomly assigned
269 previously untreated patients who were 65 years of age or older and had CLL
or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary
end point was progression-free survival as assessed by an independent review
committee.
Results
The median age of the
patients was 73 years. During a median follow-up period of 18.4 months,
ibrutinib resulted in significantly longer progression-free survival than did
chlorambucil (median, not reached vs. 18.9 months), with a risk of progression
or death that was 84% lower with ibrutinib than that with chlorambucil (hazard
ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival;
the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with
chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib
group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall
response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%,
P<0.001). The rates of sustained increases from baseline values in the
hemoglobin and platelet levels were higher with ibrutinib. Adverse events of
any grade that occurred in at least 20% of the patients receiving ibrutinib
included diarrhea, fatigue, cough, and nausea; adverse events occurring in at
least 20% of those receiving chlorambucil included nausea, fatigue,
neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a
grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the
patients in the ibrutinib group are continuing to take ibrutinib.
Conclusions
Ibrutinib was superior
to chlorambucil in previously untreated patients with CLL or small lymphocytic
lymphoma, as assessed by progression-free survival, overall survival, response
rate, and improvement in hematologic variables. (Funded by Pharmacyclics and
others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.)
Supported by Pharmacyclics,
by grants (CA016672 and 5P01CA081534-14) from the National Institutes of
Health, and by the MD Anderson Moon Shot Program in CLL. Dr. Burger is a
Scholar of the Leukemia and Lymphoma Society.
Disclosure forms
provided by the authors are available with the full text of this article at
NEJM.org.
Dr. Burger reports
receiving fees for serving on advisory boards from Janssen and grant support from
Pharmacyclics, Gilead Sciences, and Portola Pharmaceuticals; Dr. Barr,
receiving consulting fees from Pharmacyclics and AbbVie; Dr. Owen, receiving
honoraria and fees for serving on advisory boards from Janssen, Gilead
Sciences, Roche, and Lundbeck; Dr. Ghia, receiving fees for serving on advisory
boards from AbbVie, Gilead Sciences, H3 Biomedicine, Janssen, Pharmacyclics,
and Roche, consulting fees from Adaptive Biotechnologies, lecture fees from
Gilead Sciences and Janssen, and grant support from Gilead Sciences,
GlaxoSmithKline, and Roche; Dr. Hillmen, receiving lecture fees from
Pharmacyclics; Dr. Bartlett, receiving fees for serving on advisory boards from
Gilead Sciences and Seattle Genetics; Dr. Gaidano, receiving fees for serving
on advisory boards from Janssen, Roche, Amgen, Novartis, GlaxoSmithKline, and
Karyopharm Therapeutics, and grant support from Celgene; Dr. Siddiqi, receiving
lecture fees from Pharmacyclics and Janssen; Dr. Tam, receiving honoraria from
Janssen; Ms. Suri, Dr. Cheng, Dr. Clow, Dr. Styles, and Dr. James, being
employees of Pharmacyclics; and Dr. Clow, Dr. Styles, and Dr. James, holding
stock in AbbVie. No other potential conflict of interest relevant to this
article was reported.
This article was
published on December 6, 2015, at NEJM.org.
We thank all the
patients who participated in this trial and their supportive families; Cathy
Zhou, M.S., of Pharmacyclics, for statistical analysis support; and Maoko
Naganuma Carter, M.Sc., C.M.P.P., for medical writing support in the preparation
of an earlier version of the manuscript.
Source Information
From the University of
Texas MD Anderson Cancer Center, Houston (J.A.B.); Azienda Ospedaliera Niguarda
Cà Granda (A.T.) and Università Vita-Salute San Raffaele and IRCCS Istituto
Scientifico San Raffaele (P.G.), Milan, and the Department of Translational
Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara (G.G.) — all
in Italy; Wilmot Cancer Institute, University of Rochester, Rochester, NY
(P.M.B.); Medical University of Lodz and Copernicus Memorial Hospital, Lodz
(T.R.), the Department of Cancer Prevention, School of Public Health, Medical
University of Silesia, Katowice (S.G.), and the Department of Hematology,
University Clinical Center of Medical University of Gdansk, Gdansk (A.H.) — all
in Poland; Tom Baker Cancer Centre, Calgary, AB, Canada (C.O.); Rabin Medical
Center, Beilinson Hospital and Sackler Faculty of Medicine, Tel Aviv
University, Tel Aviv (O.B.), and Hadassah University Hospital, Hebrew
University Medical School, Jerusalem (A.P.) — both in Israel; Leeds Teaching
Hospitals, St. James Institute of Oncology, Leeds (P.H.), Kings College
Hospital, London (S.D.), Royal Bournemouth Hospital, Bournemouth (H.M.), and
University of Oxford, Oxford (A.S.) — all in the United Kingdom; Washington
University School of Medicine, St. Louis (N.L.B.); Jiangsu Province Hospital,
Nanjing, China (J.L.); North Shore Hospital, Auckland, New Zealand (D.
Simpson); Stanford University School of Medicine, Stanford (S.C.), City of Hope
National Medical Center, Duarte (T.S.), Pharmacyclics, Sunnyvale (D. Suri,
M.C., F.C., L.S., D.F.J.), and Moores Cancer Center, University of California,
San Diego, San Diego (T.J.K.) — all in California; St. Vincent’s Hospital,
University of Melbourne (H.Q.), and Peter MacCallum Cancer Centre and St.
Vincent’s Hospital (C.S.T.), Melbourne, VIC, Australia; Institute of Blood
Pathology and Transfusion Medicine, National Academy of Medical Sciences of
Ukraine, Lviv, Ukraine (Z.M.); Norton Cancer Institute, Louisville, KY
(D.A.S.); University Hospital Leuven, Leuven (A.J.), and University Hospital
Ghent, Ghent (F.O.) — both in Belgium; Fakultní Nemocnice Brno, Brno, Czech
Republic (J.M.); and University College Hospital Galway, Galway, Ireland
(M.O.).
Address reprint
requests to Dr. Burger at the Department of Leukemia, University of Texas MD
Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, or at jaburger@mdanderson.org.
A complete list of the
RESONATE-2 investigators is provided
