for age. The distribution of heavy and light chains among patients with a monoclonal protein was IgG (47.7%), IgM (44.6%), IgA (7.7%), j (72.0%), andk (28.0%). There was an overrepresentation of IgM mono-clonal protein in our cohort compared to a previous population study (17.2%).9Interestingly, most patients (62.5%) with IgM monoclonal pro-tein also had an IgG1 C3d DAT serologic profile.
LPMs were diagnosed more commonly among those with mono-clonal gammopathy (59.7% vs. 32.3%; P< .01; odds ratio 5 3.1 [95% confidence interval 1.7-5.6]; Supporting Information Figure 1). In most cases, such diagnoses were made prior to (78.5%) or within 30 days (14.0%) of the WAIHA diagnosis, while the remainder (7.5%) was diag-nosed subsequently at a median time of 42.2 months (range: 4.4-173.5). Of note, because in our practice, we do not routinely screen for the presence of LPMs, the latter could be underdiagnosed. To deter-mine whether there was a detection bias of LPMs in favor of the group screened for monoclonal gammopathy, we compared the proportion of patients who developed an LPM between those who were and were not screened for monoclonal gammopathy. The screened group was more likely to be associated with having an LPM compared to the non-screened group (38.4% vs. 21.4%; P<0.01; Supporting Information Figure 1). Therefore, an LPM detection bias was present in favor of the group who were screened and we could not determine with certainty the relative risk of developing an LPM among patients with WAIHA patients with a monoclonal gammopathy versus those without.
In conclusion, we found an unexpectedly high prevalence of mono-clonal gammopathy in patients with WAIHA suggesting a potential asso-ciation. Future studies should investigate whether the monoclonal proteins in some patients are also acting as the red cell warm autoantibodies.
C O N F L I C T O F I N T E R E S T
All authors report no competing financial interests.
Aishwarya Ravindran1, Janani Sankaran1,2, Eapen K. Jacob3, Justin D. Kreuter3, C. Christopher Hook1, Morie A. Gertz1, Timothy G. Call1, Rajiv K. Pruthi1, Mark R. Litzow1, Alexandra P. Wolanskyj1, William J. Hogan1, Aneel A. Ashrani1, Kebede H. Begna1, Ariela L. Marshall1, Robert A. Kyle1, Neil E. Kay1, Ronald S. Go1 1
Division of Hematology, Mayo Clinic, Rochester, Minnesota 2Department of Family Medicine, Eastern Virginia Medical School, Norfolk, Virginia 3
Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
Correspondence
Ronald S. Go, MD, Division of Hematology, Mayo Clinic; 200 First Street SW, Rochester, MN 55905, USA.
Email: go.ronald@mayo.edu
R E F E R E N C E S
[1] McShane CM, Murray LJ, Landgren O, et al. Prior autoimmune disease and risk of monoclonal gammopathy of undetermined significance and
multiple myeloma: a systematic review. Cancer Epidemiol Biomarkers Prev. 2014;23:332–342.
[2] Fremeaux-Bacchi V, Guinnepain MT, Cacoub P, et al. Prevalence of monoclonal gammopathy in patients presenting with acquired angio-edema type 2. Am J Med. 2002;113:194–199.
[3] Zand L, Kattah A, Fervenza FC, et al. C3 glomerulonephritis associ-ated with monoclonal gammopathy: a case series. Am J Kidney Dis. 2013;62:506–514.
[4] Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122:1114–1121.
[5] Gertz MA. Cold agglutinin disease and cryoglobulinemia. Clin Lym-phoma. 2005;5:290–293.
[6] Kitamura W, Matsuoka Y, Miyagawa S, et al. Immunochemical analysis of the monoclonal paraprotein in scleromyxedema. J Invest Dermatol. 1978;70:305–308.
[7] Howard CR, Lin TL, Cunningham MT, et al. IgG kappa monoclonal gamm-opathy of undetermined significance presenting as acquired type III Von Willebrand syndrome. Blood Coagul Fibrinolysis. 2014;25:631–633. [8] Barcellini W, Fattizzo B, Zaninoni A, et al. Clinical heterogeneity and
predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood. 2014;124:2930–2936. [9] Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of
monoclo-nal gammopathy of undetermined significance. N Engl J Med. 2006; 354:1362–1369.
[10] Dispenzieri A, Katzmann JA, Kyle RA, et al. Prevalence and risk of progression of light-chain monoclonal gammopathy of undeter-mined significance: a retrospective population-based cohort study. Lancet. 2010;375:1721–1728.
[11] Roumier M, Loustau V, Guillaud C, et al. Characteristics and outcome of warm autoimmune hemolytic anemia in adults: new insights based on a single-center experience with 60 patients. Am J Hematol. 2014;89:E150–E155.
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 supporting information tab for this article.
SUPPORTING INFORMATION FIGURE 1 Algorithm depicting the association of warm autoimmune hemolytic anemia with lymphoplasmacytic malignancies in patients with and without a monoclonal protein. LPM, lymphoplasmacytic malignancy; WAIHA, warm autoimmune hemolytic anemia; w/in, within.
Received: 14 April 2017
|
Accepted: 20 April 2017 DOI 10.1002/ajh.24773Real-world results of ibrutinib
in relapsed/refractory CLL in
France: Early results on a large
series of 428 patients
To the Edior:
Ibrutinib is an inhibitor of Bruton’s tyrosine kinase approved for the treatment of chronic lymphocytic leukemia (CLL), in relapsed/refractory
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but also now frontline setting.1Here, we report on the largest series of poor prognosis relapsed CLL patients included in the French Tempo-rary Authorization for Use procedure (ATU, between December 2013 and November 2014). A total of 428 patients were included in 106 centers throughout France (including 72% in University Hospitals, and 28% in smaller secondary or tertiary Centers) and received ibrutinib 420 mg daily. Main baseline characteristics are summarized in Table 1. Accordingly, to the real-life setting, median age was 70 years (35% aged75 years), 92.9% had advanced Binet stage B/C, and 45.1% of patients had either del17p and/or TP53 mutation. At baseline, 54.2% of patients had at least one significant comorbidity. The most common were vascular disorders (24.5%, with 21% having arterial hypertension),
metabolism and nutrition disorders (16.6%), cardiac disorders (11.2%), and/or neoplasms (11%). As a consequence, 14% of patients were tak-ing an anti-thrombotic drug at the time of ibrutinib exposure.
In total, 372 patients had several points of follow-up during the first months of therapy, and were therefore suitable for ORR/safety evaluations. Among them, 54 had permanent treatment discontinua-tions, included 8 due to disease progression (Supporting Information Figure 1). Median follow-up was 3 months (1-10 months). Due to age, comorbidities, and number of previous therapies, many of these patients wouldn’t have been recruited in a clinical trial. The best overall response rate was 88.5%, including 37.9% of partial response and 44.1% of partial response1 lymphocytosis. Some patients were reported in complete response by physicians but without confirmation by bone marrow biopsy. About 10% had stable disease and 1.5% showed disease progression.
Safety was also evaluated, 73.4% patients experienced1 adverse event (AE) of mild-to-moderate severity, but 33.2% experienced1 seri-ous adverse event (SAE) (34% if aged>75y), mostly ibrutinib-related. A summary of selected adverse events of interest with ibrutinib is pre-sented in the Supporting Information Table 2. Twenty-five patients died during follow-up. Despite the short follow-up inherent to the 11-months inclusion period of the ATU, the findings are consistent with ibrutinib registration studies,1,2confirming the good safety and efficacy of ibruti-nib in a real-world setting.
At initiation of treatment, concomitant antithrombotic therapy included anti platelet in 36, heparin in 13, and others (vitamine K antag-onists, direct oral coagulants) in 10 patients. The frequency of serious hemorrhagic events was low, occurring in 1.6% of patients overall and 2.6% of patients who were receiving concomitant antithrombotic therapy during ibrutinib treatment (n5 78). As shown in Supporting Information Figure 2, these data are in concordance with those from published clinical trials in the R/R setting.3
The data presented in this article represent the largest real-life cohort obtained through the French ATU program of 428 CLL patients treated with ibrutinib, physicians being from both public and private practice. The response rates are consistent with those observed in the clinical trial RESONATE (ibrutinib vs ofatumumab). In this phase 3 study randomizing ibrutinib versus ofatumumab, 2% of participants had a complete response, 68% had a partial response, 15% had a partial response with lymphocytosis (resulting in an 85% response rate), 11% had stable disease, and 1% showed disease progression in the ibrutinib arm based on investigator assessment.2As a comparison, evaluation of the ATU of ofatumumab in France has yielded disappointing results.4
In a very similar cohort of 95 ibrutinib treated patients in a Swedish compassionate use program (median age 69 years, 65% with del17p/ TP53 mutations, same profile of previous therapies), response rate was 84% and PFS was 77% at a median follow-up of 10.2 months. These response rates and survivals obtained in hundreds of real-life patients (from compassionate use programs in France, UK, and Sweden) favor-ably compare with the results claimed from clinical trials.
Previous reports claimed that CLL patients treated with chemo-immunotherapy or ofatumumab alone may benefit from similar outcomes
T A B L E 1 Characteristics of the patients at baseline Characteristics
Demography n5 428
Male, n (%) 287 (67.1)
Female, n (%) 141 (32.9)
Age (years), median (min–max) 70 (33-93)
Aged75 years, n (%) 150 (35.0)
Relapsed/refractory patients, n (%) 417 (97.4) Concomitant anti-thrombotic at baseline, n (%) 59 (13.8)
Platelet aggregation inhibitors 36 (8.4)
Heparin 13 (3.0)
Others 10 (2.3)
Disease duration (years) n5424
Median (min–max) 8.1 (0.0-40.5)
Other n5 381
Del17p and/or TP53 mutation, n (%) 172 (45.1)
Binet stage A, n (%) 27 (7.1)
Binet stage B, n (%) 138 (36.2)
Binet stage C, n (%) 216 (56.7)
Lymph nodes n5 379
Lymph nodes5 cm, n (%) 191 (50.4)
Number of previous treatments n5 426
Median (min-max) 3 (0-10)
Principal previous treatments n5 415
Fludarabine/cyclophosphamide/rituximab, n (%) 264 (63.6) R-bendamustine, n (%) 248 (59.8) Chlorambucil6 steroids 6 R, n (%) 148 (35.7) Alemtuzumab6 steroids, n (%) 112 (27.0) R-CHOP, R-mini-CHOP, n (%) 108 (26.0) Ofatumumab, n (%) 52 (12.5) Transplant, n (%) 37 (8.9) Allogenic transplantation, n (%) 22 (5.3) Autologous transplantation, n (%) 15 (3.6) Hematology Lymphocytes n5 384 >100 giga/L, n (%) 57 (14.8) Neutrophils n5 396 <0.75 giga/L, n (%) 4 (1.0) Platelets n5 400 <50 giga/L, n (%) 19 (4.8) Hemoglobin n5 388
n5 number of patients (note that number of patients included for each assessment may not be equivalent as not all assessments performed for all patients).
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in real life, but experience more side effects than reported in trials, due to the burden of comorbidities (especially renal impairment), or reduced rela-tive dose-intensity. In our series, ibrutinib was well tolerated including in the elderly population, with no unexpected AE, except more cardiac dis-orders including atrial fibrillation (AF) (6.5% in all population, and 9.3% above 75 years). Data pooled from clinical trials showed that 6.5% of 756 patients receiving ibrutinib for CLL and mantle cell lymphoma had atrial fibrillation.5Our experience in patients
>75 years suggests that chronic, medically treated atrial fibrillation before initiation of therapy does not impact on outcomes with ibrutinib, but that patients with peripheral arteriopathy/myocardial infarction and taking anticoagulants should be managed more carefully.6
Overall, despite inherent limitations of a real-world analysis (eg, the declarative nature of data collection and the absence of data monitoring), the findings from data collected in this ATU confirm and extend previous reports on ibrutinib safety and efficacy in the context of controlled studies after a short follow-up.
A C K N O W L E D G E M E N T S
Authors would like to acknowledge all physicians and patients for their participation. All the co-authors collected the clinical data. Andrew Lane (Lane Medical Writing) drafted the initial version and was funded by Janssen France. The final manuscript was prepared by the authors.
C O N F L I C T O F I N T E R E S T
LY: Roche, Abbivie, Gilead, Janssen. TA: Janssen, Gilead, Roche, Abbvie. CD: Janssen, Mundipharma, Gilead. MSD: Roche, Janssen, Gilead, Abbvie. PF: Janssen. ASM: no. OT: Janssen, Gilead, Mundi-pharma, Roche. JD: Abbvie, Celgene. FC: Janssen, Gilead, Abbvie, Roche. PS and CA are employees of Janssen-Cilag.
Loic Ysebaert1, Therèse Aurran-Schleinitz2, Caroline Dartigeas3, Marie-Sarah Dilhuydy4, Pierre Feugier5, Anne-Sophie Michallet6, Olivier Tournilhac7, Jehan Dupuis8, Pierre Sinet9, Claire Albrecht9, Florence Cymbalista10 1
IUC Toulouse-Oncopole, Toulouse, France 2Institut Paoli-Calmettes, Boulevard de Sainte-Marguerite, Marseille, France 3H^opital Bretonneau, Tours, France 4
CHU de Bordeaux, Bordeaux, France 5CHU de Nancy, Nancy, France
6
CHU Lyon Sud, Lyon, France 7CHU Estaing, Clermont-Ferrand, France 8H^opital Henri Mondor, Creteil, France 9Janssen-Cilag, Issy-les-Moulineaux, France 10H^opital Avicenne, Bobigny, France
Correspondence
Loïc Ysebaert MD, Service d’Hematologie Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France.
Email: ysebaert.loic@iuct-oncopole.fr Funding information Janssen France
R E F E R E N C E S
[1] Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42. [2] 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):213–223. 17
[3] Jones J, Hillmen P, Coutre S, et al. Pattern of use of anticoagulation and/ or antiplatelet agents in patients with chronic lymphocytic leukemia treated with single-agent ibrutinib. In 56th ASH Annual Meeting and Exposition. San Francisco, CA, USA, 6-9 December 2014 (Abstract 1990). [4] Dupuis J, Brice P, François S, et al. Ofatumumab in refractory chronic lymphocytic leukemia: experience through the French early access pro-gram. Clin Lymphoma Myeloma Leuk. 2015;15(2):e43–e46.
[5] Brown JR, O’brien S, Moslehi J, et al. Pooled analysis of atrial fibrilla-tion adverse events in ibrutinib randomized controlled registrafibrilla-tion trial. Poster 30 presented at the 2016 ASH Meeting on Hematologic Malignancies, Chicago, September 16-17, 2016.
[6] Michallet AS, Campidelli A, Lequeu H, et al. Ibrutinib in very elderly patients with relapsed/refractory chronic lymphocytic leukemia: a real-world experience of 71 patients treated in France A study from the French Innovative Leukemia Organization (FILO) group. Am J Hematol. 2017. doi: 10.1002/ajh.24773. [Epub ahead of print]
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 supporting information tab for this article.
FIGURE S1 Reasons for drug permanent discontinuation in 54/372 patients. FIGURE S2 Frequency of serious hemorrhagic events.
TABLE S2 Summary of selected adverse events of interest with ibrutinib.
Received: 19 April 2017
|
Accepted: 22 April 2017 DOI 10.1002/ajh.24776Validation of the 2016
revisions to the WHO
classification in lower-risk
myelodysplastic syndrome
To the Editor:
“Lower-risk” (LR) myelodysplastic syndrome (MDS) is defined as low and intermediate-1 risk by International Prognostic Scoring System (IPSS). Currently available prognostic models lack the ability to identify LR-MDS patients with poor outcome who may benefit from early ther-apy.1 These models, unlike WHO-based systems, do not incorporate morphologic parameters such as lineage dysplasia and percentage (%) of ring sideroblasts (RS).
The recent 2016 World Health Organization (WHO) revisions for MDS classification attempts to create biologically homogeneous sub-groups by refining morphologic criteria and incorporating genetic infor-mation. These include emphasis on the number of dysplastic lineage(s),
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