The present multicenter study is the first to compare centers adopting transfusions only and centers adopting rHuEPO6 transfusion. We believe it strongly suggests that rHuEPO can reduce the need for blood transfusions in infants with HS. Furthermore our data give some indications about the timing of rHuEPO therapy: at 30 days of life the reticulocyte count is significantly higher in the rHuEPO group, whereas at 180 days it is comparable in the two groups. We can deduce that rHuEPO should be started as early as possible in all infants with anemia at birth or showing a rapid fall in Hb values and that a therapy discon-tinuation schedule can be based upon the presence of a satisfactory plateau in Hb values at about 5-6 months of age. In conclusion, rHuEPO therapy should be considered in infants suffering from HS, with the aim of improving quality of life and limiting bothfinancial cost and exposure to donor blood products.
A C K N O W L E D G M E N T S
Giuseppe Furfari is acknowledged for electronic CRF design. Paola Vitagliano is acknowledged for helping in data collection. The Parents’ Association A.S.L.T.I.-Liberi di crescere is acknowledged for supporting the activity of the Pediatric Onco-Hematology Unit of A. R.N.A.S. Ospedali Civico, Di Cristina e Benfratelli. No specific fund-ing was received for this study.
C O N F L I C T O F I N T E R E S T
The authors have no conflicts of interest to disclose.
Piero Farruggia1, Giuseppe Puccio2, Ugo Ramenghi3, Raffaella Colombatti4, Paola Corti5, Angela Trizzino1, Angelica Barone6, Gianluca Boscarol7, Fabrizia Ferraro1, Paolo Grotto8, Laura Lo Valvo9, Laura Luti10, Sofia Maria Rosaria Matarese11, Clara Mosa1, Maria Caterina Putti4, Laura Rubert12, Giovan Battista Ruffo13, Laura Sainati4, Immacolata Tartaglione11, Giovanna Russo9, Silverio Perrotta11 1Pediatric Hematology and Oncology Unit, Oncology Department, A.R.N.A.S. Ospedali Civico, Di Cristina e Benfratelli, Palermo, Italy 2Department of Sciences for Health Promotion and Mother and Child Care, University of Palermo, Palermo, Italy 3Department of Pediatric and Public Health Sciences, University of Torino, Torino, Italy 4Pediatric Hematology-Oncology Clinic, Department of Child and Maternal Health, Azienda Ospedaliera-Universita di Padova, Padova, Italy 5
Fondazione Monza e Brianza per il bambino e la sua mamma, Monza, Italy 6Department of Pediatric Onco-Hematology, University Hospital, Parma, Italy
7
Department of Pediatrics, Central Teaching Hospital Bolzano, Bolzano/ Bozen, Italy 8
U.O.C. Pediatria, Treviso Hospital, Treviso, Italy 9Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy 10Pediatric Hematology Oncology, Bone Marrow Transplant, Azienda Ospedaliero Universitaria Pisana, Ospedale S. Chiara, Pisa, Italy 11
Department of Woman, Child and General and Specialist Surgery, Universita degli studi della Campania “Luigi Vanvitelli”, Napoli, Italy
12
Oncoematologia pediatrica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy 13
U.O.C. Ematologia con Talassemia, A.R.N.A.S. Ospedali Civico, Di Cristina e Benfratelli, Palermo, Italy
Correspondence
Dr. Piero Farruggia, U.O.C. di Oncoematologia Pediatrica, A.R.N.A.S. Ospedali Civico, Di Cristina e Benfratelli, Piazza Nicola Leotta 4, 90127 Palermo, Italy. Email: piero.farruggia@arnascivico.it; pfarruggia@libero.it
R E F E R E N C E S
[1] Lux SE, Palek J. Disorders of the red cell membrane. In: Handin RI, Lux SE, Stossel TP, eds. Blood, Principles and Practice of Hematology. Philadelphia: J.B. Lippincott; 1995:1701–1718.
[2] Tchernia G, Delhommeau F, Perrotta S, et al.; ESPHI working group on hemolytic Anemias, Recombinant erythropoietin therapy as an alternative to blood transfusions in infants with hereditary spherocy-tosis. Hematol J. 2000;1:146–152.
[3] Neuman-Laniec M, Wierzba J, Irga N, et al. Recombinant erythropoie-tins—an alternative therapy to red cell blood transfusions in infants with hereditary spherocytosis. Przeglad Lekarski. 2002;59:871–872. [4] Schiff M, Hays S, Sann L, Putet G. Recombinant Human
Erythropoie-tin (r-HuEPO) therapy in a newborn with hereditary spherocytosis. Arch Pediatrics. 2003;10:333–336.
[5] Hosono S, Hosono A, Mugishima H, et al. Successful recombinant erythropoietin therapy for a developing anemic newborn with heredi-tary spherocytosis. Pediatr Int. 2006;48:178–180.
[6] Morrison JF, Neufeld EJ, Grace RF. The use of erythropoietin-stimulating agents versus supportive care in newborns with hereditary spherocyto-sis: a single centre’s experience. Eur J Haematol. 2014;93:161–164.
Received: 7 March 2017
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Accepted: 9 March 2017 DOI 10.1002/ajh.24715Ibrutinib in very elderly
patients with relapsed/
refractory chronic lymphocytic
leukemia: A real-world
experi-ence of 71 patients treated in
France: A study from the
French Innovative Leukemia
Organization (FILO) group
To the Editor:
Infirst-line therapy, 20% of patient with chronic lymphocytic leukemia (CLL) are even 80 years old or over, rendering therapeutic decisions often challenging. Due to the common comorbidity burden and fre-quency of adverse cytogenetics associated with this elderly population,
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these patients are often excluded from clinical trials participation. Ibru-tinib, a first-in-class inhibitor of Bruton’s tyrosine kinase, has been approved for the treatment of relapsed/refractory CLL, including those with del(17)/TP53 mutations in thefirst-line setting. However, a few very elderly patients have been included in ibrutinib clinical trials. Nevertheless, these studies reported overall response rates of>80%, with unprecedented progression-free survival (PFS)/overall survival (OS), significantly superior to those achieved in other relapse/refractory ibrutinib trials using immunochemotherapy or immunotherapy alone, irrespective of age, and associated with relatively mild toxicity. Despite these impressive results, real-world data from everyday clinical prac-tices is highly sought after for concrete evidence regarding the impact
of ibrutinib therapy in our very-elderly patient management. In France, 428 patients received ibrutinib from December 2013 to November 21, 2014, being accorded temporary authorization for use (ATU) from the French National Agency for Medicines and Health Product Safety (ANSM). We herein describe the key baseline characteristics and out-comes involving 71 patients aged>75 years, the oldest cohort ever reported outside clinical trials. The patient data was collected from medical files by primary care physicians and entered into electronic case report forms. The study protocol was approved by the French Innovative Leukemia Organization scientific committee and by relevant health authorities. The study was conducted in accordance with national ethical recommendations, as well as the Declaration of Hel-sinki. The patients eligible for ibrutinib ATU all experienced relapsed/ refractory active disease (according to iwCLL 2008 criteria) and were scheduled to receive 420 mg/day ibrutinib. Endpoints were survival and ibrutinib-related safety. Since no bone marrow biopsy was per-formed at months 6-12, the recorded responses are only partial, irre-spective of lymphocytosis. At the latest follow-up (as of December 2015), PFS was calculated from ibrutinib initiation to, either relapse or death, duration of response from ibrutinib initiation to relapse, and OS from ibrutinib initiation to death due to any cause. The median age was 79 years, thus 8-10 years higher than that of patients included in clini-cal trials or real-life practice cohorts to date. The median number of previous therapies was three (range: 1-9), including FC/FCR in 73.2%, R-bendamustine in 46.5%, rituximab in 86%, ofatumumab in 8.5%, and alemtuzumab in 26.7%. This population was heavily pretreated and at very high risk, with 26.2% exhibiting 17p deletions and 19.4% p53 mutations. In total, 70/71 patients started ibrutinib at 420 mg/day and one at 280 mg/day. Of the 71 patients, 37 (52.1%) had to either reduce (40.8%) or even temporarily stop ibrutinib (26.8%) within the first treatment year. The median time to dose reduction was 8 weeks (range: 2-52). Drug withdrawal was defined as a therapy discontinua-tion for over 7 days, eventually followed by either reduced dosing or full dose resumption at 420 mg/day. The most common causes for drug reduction/withdrawal were infection (10.5%), programmed sur-gery (8%), arthralgia (13%), bleeding (3%), diarrhea (5.2%), atrial fibrilla-tion (2.6%), and hematological toxicity (15.8%). Out of 39 patients, 10 were restarted on full dose at 420 mg/day after toxicity had been resolved. Permanent ibrutinib discontinuation was reported in 32.4% of patients, following a median 5-month exposure (range: 1-16 months), due to CLL progression in only 5.6%. The primary safety con-cerns comprised infection (5.6%), bleeding (11.3%), cardiac problems (7%), and hematological toxicity (5.6%). At last follow-up, 63.4% of patients were alive on therapy, 15.5% alive off therapy, and 21.1% had died from various causes: 6/15 from CLL (including 3/6 Richter), 7/15 from infection, and 2/15 from heart disease. Efficacy analysis at months 6 and 12 revealed increasing partial response rates PR) (38.8% and 57.8%, respectively), along with decreasing rates of PR1 lymphocytosis (46.9% and 35.6%, respectively), stable disease (8.2% and 2.2%, respectively), and progressive disease (6.1% and 4.4%, respectively), as presented in Table 1. Overall response rates were
T A B L E 1 Patient characteristics
Description N 5 71
Gender male 50 (70.4%)
Median treatment lines before Ibrutinib 3 (1-9)
2 lines 34 (48.6%) >2 lines 37 (51.4%) Del(17p)/TP53 mutated 26,2/19,4% Vascular comorbidities Hypertension 23 (33.8%) Thrombosis 7 (10.3%) Arteritis 5 (7.4%) Cardiological comorbidities Ischemia 7 (10.3%) Arrythmia 9 (13.2%) Valvular 3 (4.4%) Anticoagulant therapy 8 (11.9%) Antiagregant therapy 20 (29.9%)
Median age at ibrutinib initiation 79.3 (75-89.9)
More than 80 years 28 (39.4%)
Creatinine clearance (ml/mn) 30-60 21 (31.3%) 60-90 32 (47.8%) >90 14 (20.9%) Binet stage: A, B, C 4.4%, 27.9%, 67.6% ORR at 6 months N5 49 Stable disease 4 (8.2%) Partial response (PR) 14 (28.6%) PR with lymphocytosis 23 (46.9%) Progression 3 (6.1%) ORR at 12 months N5 45 Stable disease 1 (2.2%) Partial response 18 (40.0%) PR with lymphocytosis 16 (35.6%) Progression 2 (4.4%)
Drug intake>7 days 19 (26.8%)
Drug reduction to 280 mg/day 28 (40.0%) Drug reduction after drug initiation> 7 days 11 (15.5%)
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85.7% and 93.4% at 6 and 12 months, respectively, thereby confirming the RESONATE trial findings.1,2 The safety pro
file proved relatively well-known3and manageable by means of dose reduction, consisting of grade 1-2 bleeding (19%), cardiac toxicity (7%), diarrhea (24%), and myalgia/arthralgia (20%), frequencies decreasing over the first 6 months. It should be noted that infection was reported in 21% of cases within thefirst 6 months, its incidence decreasing to 10.5% after 12 months, in line with the Sun et al. results.4The PFS and OS rates at 12 months were 77% and 91%. The estimated median OS was 21 months, seemingly unprecedented in this age population. These outcomes were not impacted by CLL-related factors. Reducing the ibrutinib dose did not affect clinical outcomes (Supporting Information 1). Though fewer patients achieved>90% target occupancy at <420 mg/day, there was still a clear correlation between this biological endpoint, chosen due to no dose-limiting toxicity achieved in thefirst human ibrutinib studies, and objective response rates (ORR) or survival rates. The only factor influencing PFS (HR 5 4.430; P 5 .016) and duration of response (HR5 4.931, P5 .024) was arteritis/myocardial ischemia antecedents (Sup-porting Information 2). This parameter had no impact on OS. The drug withdrawal for>7 days tended to be associated with reduced response duration, yet dose reduction from 420 to 280 mg/day did not demon-strate the same effect. In this series, the estimated median OS was 21 months. In this real-world cohort of very elderly patients, del(17p)/ TP53 mutations were found to have a smaller impact on PFS/DoR than comorbidities (HR5 0.827, P 5 .683; HR 5 0.631; P 5 0.543) had. The predominant cause of permanent drug withdrawal was bleeding symptoms.5
In conclusion, our series from the French early access program supports the use of ibrutinib in very elderly patients, thereby con firm-ing its efficacy profile requiring adequate toxicity management, with dose reductions often being efficient.
C O N F L I C T O F I N T E R E S T
All authors declare they have no conflicts of interest
A U T H O R C O N T R I B U T I O N S
Conception and design: LY, PF, and ASM; Collection and assembly of data: LY, HL, AC, PF, and ASM; Provision of patients: LY, HL, AC, MSD, OT, LMF, JD, FC, SDG, AD, SG, JPV, DG, VL, PF, and ASM; Data analysis and interpretation: LY, FS, and ASM; Manuscript writ-ing: LY and ASM; Final approval of manuscript: all authors
A C K N O W L E D G M E N T S
Authors would like to thank all the FILO clinicians who entered the data into the electronic case report forms. This work was partly sup-ported by Agence Nationale de la Recherche through the project CAPTOR (ANR-11-PHUC 0001).
Anne-Sophie Michallet1, Arnaud Campidelli2, Helene Lequeu3, Marie-Sarah Dilhuydy4, Olivier Tournilhac5,
Luc-Matthieu Fornecker6, Jehan Dupuis7, Florence Cymbalista8, Sophie De Guibert9, Alain Delmer10, Jean-Pierre Vilque11, David Ghez12, Veronique Leblond13, Fabien Subtil14, Pierre. Feugier2, Loic Ysebaert15 1Department of hematology, Centre Leon Berard, CLCC, Lyon, France 2Brabois hospital, Department of hematology, CHU Nancy, Vandoeuvre les Nancy, France 3Department of hematology, Hospices Civils de Lyon, Lyon, France 4Haut Lev^eque hospital, Deaptment of hematology, CHU Bordeaux, Bordeaux, France 5Estaing hospital, CHU Clermont Ferrand, Clermont Ferrand, France 6Civil hospital, CHU Strasbourg, Strasbourg, France 7Henri Mondor hospital, lymphoid unit, APHP, Paris, France 8Avicenne Hospital, APHP, Paris, France 9Department of hematology, CHU Rennes, Rennes, France 10Robert Debre hospital, CHU Reims, Reims, France 11Hematology institute Basse Normandie, CHU Caen, Caen, France 12Department of hematology, Institut Gustave Roussy, Paris, France 13UPMC University Paris 6 GRC11 GRECHY, APHP H^opital Pitie Salpetrière, Paris, France 14Department of biosatistics, Hospices Civils de Lyon, Lyon, France 15IUCT Oncopole, Toulouse, France
Correspondence
Anne-Sophie Michallet, Hematology department, Centre Leon Berard, 28 rue Laennec, FR-69008 Lyon, France.
Email: anne-sophie.michallet@lyon.unicancer.fr Funding information
Agence Nationale de la Recherche, Grant/Award number: project CAPTOR (ANR-11-PHUC 0001)
R E F E R E N C E S
[1] Byrd JC, Brown JR, O’brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014; 371(3):213.
[2] Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibru-tinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014;15(10): 1090–1099.
[3] Jaglowski SM, Jones JA, Nagar V, et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lym-phocytic leukemia: a phase 1b/2 study. Blood. 2015;126(7):842– 850.
[4] Sun C, Tian X, Lee YS, et al. Partial reconstitution of humoral immunity and fewer infections in patients with chronic lympho-cytic leukemia treated with ibrutinib. Blood. 2015;126(19):2213– 2219.
[5] Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol. 2015;1(1):80–87.
S U P P O R T I N G I N F O R M A T I O N
Additional Supporting Information may be found online in the sup-porting information tab for this article.
CORRESPONDENCE
