12Centro di Biostatistica per l’epidemiologia clinica, Department of Health Sciences, University of Milano-Bicocca, Monza, Italy. E-mail: elena.elli@libero.it
Keywords: iron chelation therapy, deferasirox, myelofibrosis
First published online 20 May 2019 doi: 10.1111/bjh.15964
Supporting Information
Additional supporting information may be found online in the Supporting Information section at the end of the article.
Fig S1. Median ferritin levels during iron chelation ther-apy (ICT) according to iron chelation response (ICR).
Table SI. Clinical and laboratory features of patients at baseline of iron chelation therapy (ICT) (n= 45).
Table SII. Treatment-related toxicity.
Data S1. Inclusion criteria and methods for the assess-ment of IOL at baseline and during iron chelation therapy (ICT).
Data S2. Erythroid response to DFX. Data S3. Statistical analysis.
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Cheson, B.D., Greenberg, P.L., Bennett, J.M., Lowenberg, B., Wijermans, P.W., Nimer, S.D., Pinto, A., Beran, M., De Witte, T.M., Stone, R.M., Mittelman, M., Sanz, G.F., Gore, S.D., Schiffer, C.A. & Kantarjian, H. (2006) Clinical application and proposal for modification of the International Working Group (IWG) response criteria for myelodysplasia. Blood, 108, 419–425.
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Piol-telli, P. & Pogliani, E.M. (2014) Iron chelation
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Characterisation of a new clinical presentation of chronic
lym-phocytic leukaemia: symptomatic bronchial involvement, a
study from the FILO group
Patients with chronic lymphocytic leukaemia (CLL) fre-quently present with pulmonary injuries (Khanijo et al, 2017), such as infections that include bacterial and pneumo-cystis pneumonia or invasive aspergillosis (Henn et al, 2014). Lungs may also be the site of leukaemic pulmonary infiltra-tion – an extra-nodal development of the disease – in the pulmonary parenchyma (Hill et al, 2012; Carmier et al, 2013). Although a few cases of symptomatic bronchial involvement (SBi) associated with CLL (CLL SBi) have been reported, they were mostly from the pre-rituximab era (Chernoff et al, 1984; Palosaari & Colby, 1986; Desjardins et al, 1990; Maw et al, 2015). To date, SBi has not been studied with use of recent diagnostic assays, such as
high-resolution computed tomography (HRCT) scans of the chest and molecular biology. The present study aimed to further characterise CLL SBi, to better manage these cases.
We collected data retrospectively from 19 CLL patients who presented with SBi at several centres of the French Inno-vative Leukaemia Organization (FILO). The diagnosis of CLL SBi was confirmed by clinical, radiological, pathological (based on histopathological analysis of bronchial biopsies) and functional (based on tests of pulmonary function) data. In particular, we systematically excluded diagnoses of viral, bacterial or fungal infection. Patients with unexplained and persistent bronchial symptomatology first received appropri-ate antibiotics treatment (such as amoxicillin/clavulanic acid);
e126 ª 2019 British Society for Haematology and John Wiley & Sons Ltd
following this, infection was definitively ruled out by analys-ing bronchoscopy-associated microbiology. HRCT chest scans were generated, with (n= 16) or without (n = 5) injection of a contrast agent, and all images were re-analysed by two spe-cialised chest radiologists. As a control, we analysed a cohort of 10 CLL patients without clinical bronchial symptoms. Results of pulmonary function tests were also collected when-ever they were available. Airflow obstruction was confirmed when the ratio of forced expiratory volume in one-second (FEV1) to forced volume capacity (FEV1/FVC) was less than 07. We also collected biological data on lymphocytosis, fluo-rescence in situ hybridisation (FISH) and the mutational
status of the immunoglobulin heavy chain variable gene (IGHV), together with therapeutic data and results of a next generation sequencing (NGS) gene panel, which included TP53 (exons 2–11), NOTCH1 (exon 34), BIRC3 (exons 6–9), ATM (exons 1–62), FBXW7 (exons 8–11), SF3B1 (exons 14– 16), POT1 (exons 5–10), BTK (exon 15), PLCG2 (exons 19, 20, 24) and RPS15 (exon 4). The criteria for a pulmonary response to CLL treatment were defined in consultation with pulmonologists, and were based on an improvement of symp-toms, and on results of imaging and lung functional tests.
Patient characteristics are summarised in Table I. HRCT scans of the lungs of all CLL SBi patients showed a much Table I. Key features from 19 patients presenting with symptomatic bronchial involvement (SBi)
All patients (n = 19)
n %
Median age, years (range) 63 (52–80)
Sex
Female 4 21
Male 15 79
Smoker
Yes/no 7/12 37/63
Lymphocyte count,9109/l (range) 63 (59–220)
Binet classification A/B/C 6/11/2 32/58/10 FISH (n = 17) Normal 4 24 Deletion 13q 4 24 Deletion 17p 1 6 Trisomy 12 7 41 del11q 2 11
IGHV mutation status (n = 14)
Mutated/unmutated 4/10 29/71
Lung function test (n = 15)
Air flow obstruction (FEV1/FVC< 07)
Yes/no 8/7 53/47 Histological evidence Yes/no 17/2 89/11 Type of treatment (n = 18) Rituximab-chemotherapy 11 61 Chemotherapy 2 11 Alemtuzumab-chemotherapy 1 6 BCR inhibitors 3 17 BCL2 inhibitors 1 6
Bronchial involvement: impact on a treatment line initiation (n = 18)
Yes/no 13/5 72/28
Bronchial involvement: only criterion to start the treatment line (n = 18)
Yes/no 9/9 50/50
Bronchial improvement after treatment Clinical (n = 17)
Yes/no 14/3 82/18
Radiological (n = 12)
Yes/no 11/1 92/8
On lung function tests (n = 7)
Yes/no 5/2 71/29
higher frequency of anomalies of small airways and peripheral bronchi (P= 0001). Typical anomalies were endobronchial nodules (8 patients, 62%) and tree-in-bud pattern (10 patients, 77%; examples in Fig 1A, B). Analyses of pulmonary function tests revealed airflow obstruction in 54% of patients. Median FEV1 was 222 l (range 089–301) and 76%, when expressed as a percentage of predicted values (range 30–129). The median FEV1/FVC ratio was 06 (range 035–096). All patients underwent bronchoscopy. Endobronchial nodules were macroscopically visible in 4 patients. Bronchial spur biopsy was performed in 17 patients, and each revealed a
diffuse mucosal infiltration by small B-lymphocytes, which had a phenotype consistent with CLL (Fig 1C, D). We thus assumed that the airway obstruction was the result either of a diffuse narrowing by CLL cells, or of focal polypoid deposits of CLL cells. We did not find an obvious clinical or biological profile of SBi in patients, including Binet stage, therapeutic data, FISH and IGHV mutational status, as well as NGS muta-tional data. Based on cytogenetic and molecular data, we observed that our patients had CLL with an intermediate or poor prognosis. The frequencies of active and passive smoking in our population were consistent with the data for smoking
(A) (B)
(C) (D)
(E) (F)
Fig 1. (A, B) Examples of chest high-resolution computed tomography (HRCT). (A) Small airways lesions called “tree-in-bud pattern” and cen-trolobular micronodules. (B) Endobronchial nodules in a lobar bronchus (black arrow). (C, D) Example of bronchial biopsy showing a diffuse infiltrate of the mucosa by small lymphocytes with round nuclei consistent with chronic lymphocytic leukaemia (hematoxylin and eosin stain); at medium magnification 9200 (C), expressing CD20 (D). (E) Cumulative incidence of symptomatic bronchial involvement from diagnosis of chronic lymphocytic leukaemia (CLL) and (F) progression-free survival (PFS) from the beginning of treatment indicated for symptomatic bron-chial involvement.
in the French public aged 65–75 years (Pasquereau et al, 2017). The median time for diagnosis of SBi (from the time of CLL diagnosis) was 61 months (range 0–288) (Fig 1E). Eighteen patients received at least one line of treatment. Only one patient was untreated; she presented with a moderate cough, which did not affect her daily life. Therapy was hetero-geneous and included chemotherapy either with (n = 11) or without rituximab (n= 2), or with alemtuzumab (n = 1), ibrutinib (n= 3) or venetoclax (n = 1). First line therapy was started at the time of SBi for 11 patients (61%). A diagnosis of SBi was the only criterion for treating 9 of the patients (50%). Improvement in respiration was observed mostly after treatment at the clinical, radiological, or functional levels, with an improvement noted in 82%, 92% and 71% of patients respectively. At a median follow-up of 36 months (range 6– 128), the median progression-free survival (PFS) after treat-ment of CLL SBi was 33 months (Fig 1F).
In summary, we report here on the largest cohort of CLL patients with symptomatic and specific bronchial tree infil-tration. Our findings document that SBi is a manifestation of CLL that should be considered along with CLL history when a patient presents with an unexplained obstructive respira-tory condition. A major objective of our study was to estab-lish criteria for the differential diagnosis of SBi. We conclude that the first step is to rule out symptomatic bronchial infec-tions of viral, bacterial or fungal aetiology. A diagnosis of SBi should be considered only if bronchial symptoms persist despite appropriate management of potential infectious aeti-ologies. HRCT scans plus pulmonary function tests are mandatory prerequisites for supporting the diagnosis of SBi. The strongest diagnostic criterion is bronchial spur biopsy. Given that SBi is an unusual condition, we suggest that treat-ment should be discussed in consultation with pulmonolo-gists, in order to evaluate the response properly. Finally, although our study is limited in that it is retrospective and because of the small sample size, it nevertheless has identified three key diagnostic elements of SBi: bronchial symptoms in the absence of infection, endobronchial nodules revealed in a lung scan, and positive bronchial spur biopsy. Our findings strongly suggest that SBi is a full-fledged entity that requires specific management.
Author contributions
C.H., M.N., F.C. and F.M. contributed to the overall design and participated in the research, collected, analysed, and interpreted data, and prepared and wrote the manuscript; F.B.M., S.P. and F.C. performed the molecular analysis;
H.Da. analysed the CT scans, L.W. and F.W. analysed the lung data; J.B.B. did the statistical analysis; R.D. undertook the histopathological analysis; J.D., K.L., J.O.B., C.T., B.D., S.L., H.De. and M.W. collected clinical data; C.H. and M.N. provided final review of the manuscript. All authors critically reviewed and approved the final version of the manuscript. Morgane Nudel1 Fanny Baran-Marszak2 Jean-Baptiste Bossard1 Romain Dubois3 Helo€ıse Dapvril4 Jehan Dupuis5 Kamel Laribi6 Jacques-Olivier Bay7 Cecile Tomowiak8 Brigitte Dreyfus8 Stephane Lepretre9 Helene Demarquette1 Frederic Wallyn10 Lidwine Wemeau10 Mathieu Wemeau11 Stephanie Poulain12 Franck Morschhauser1 Florence Cymbalista2 Charles Herbaux1
1Hematologie Clinique, Centre Hospitalier Regional Universitaire de Lille, Lille, France,2Bobigny: Hematologie, CHU Avicennes, Bobigny, 3Anatomopathologie, Centre Hospitalier Regional Universitaire de Lille, Lille, France,4Radiologie Thoracique, Centre Hospitalier Regional Universitaire de Lille, Lille, France,5Hematologie Clinique, CHU Henri Mondor, Creteil,6Hematologie Clinique, Centre Hospitalier Le Mans, Le Mans,7Hematologie Clinique, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont Ferrand,8Hematologie Clinique, Centre Hospitalier Universitaire Poitiers, Poitiers,9Hematologie Clinique, Centre Hospitalier Universitaire Rouen, Rouen,10Pneumologie, Centre Hospitalier Regional Universitaire de Lille, Lille, France,11Hematologie Clinique, Centre Hospitalier de Roubaix, Roubaix and12Laboratoire D’Hematologie, Centre Hospitalier Regional Universitaire de Lille, Lille, France.
E-mail: charles.herbaux@chru-lille.fr
Keywords: chronic lymphocytic leukaemia, symptomatic bronchial involvement, endobronchial nodules, extramedullary involvement, treatment criterion
First published online 22 May 2019 doi: 10.1111/bjh.15966
References
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bronchopulmonary involvement due to chronic lymphocytic leukaemia. European Respiratory Review, 22, 416–419.
Chernoff, A., Rymuza, J. & Lippmann, M.L. (1984) Endobronchial lymphocytic infiltration.
Unusual manifestation of chronic lymphocytic leukemia. The American Journal of Medicine, 77, 755–759.
Desjardins, A., Ostiguy, G., Cousineau, S. & Gyger, M. (1990) Recurrent localised
pneumonia due to bronchial infiltration in a patient with chronic lymphocytic leukaemia. Thorax, 45, 570.
Henn, A., Mellon, G., Beno^ıt, H., Roos-Weil, D., Jaureguiberry, S., Mordant, P., Fekkar, A. & Caumes, E. (2014) Disseminated cryptococcosis, invasive aspergillosis, and mucormycosis in a patient treated with alemtuzumab for chronic lymphocytic leukaemia. Scandinavian Journal of Infectious Diseases, 46, 231–234.
Hill, B.T., Weil, A.C., Kalaycio, M. & Cook, J.R. (2012) Pulmonary involvement by chronic
lymphocytic leukemia/small lymphocytic lym-phoma is a specific pathologic finding indepen-dent of inflammatory infiltration. Leukemia & Lymphoma, 53, 589–595.
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obstruction. Respirology Case Reports, 3, 41–43.
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Impact of ruxolitinib on myelofibrosis patients post allogeneic
stem cell transplant
—a pilot study
For most patients with intermediate or high-risk diseases, allo-geneic haematopoietic stem cell transplantation (SCT) is potentially the only curative treatment, although it is associ-ated with a risk of transplant-relassoci-ated mortality (Kr€oger et al, 2015; Shantzer et al, 2017). Ruxolitinib, a potent JAK1/JAK2 inhibitor, is recommended for the relief of constitutional symptoms and splenomegaly in patients who are ineligible for allogeneic SCT (Marchetti et al, 2017). Ongoing studies fur-ther demonstrated improved allogeneic SCT outcomes in patients who were previously treated with ruxolitinib (Gupta et al, 2019). However, the role of ruxolitinib in post-SCT maintenance has not been illustrated. We report the data from a retrospective study that evaluated the feasibility and toxicity of ruxolitinib as both pre-SCT treatment and post-transplant maintenance regimens in allogeneic SCT for myelofibrosis.
The patients were grouped into 3 cohorts (A, B, C): 3 patients in Cohort A never received ruxolitinib, 9 Patients in Cohort B only received pre-SCT ruxolitinib and 4 patients in Cohort C received both pre-SCT and post-SCT ruxolitinib. All patients had constitutional symptoms and splenomegaly at diagnosis, except for 1 patient who had prior splenectomy. The median post-SCT follow-up time was 365 months (range: 18–72 months). Pre-SCT ruxolitinib doses were titrated from 10 to 20 mg twice daily and tapered off from 5 days before starting conditioning. The post-SCT dose was 5 mg twice daily, starting after the absolute neutrophil count (ANC) reached 05 9 109/l for 3 consecutive days. The
med-ian duration of ruxolitinib treatment pre-SCT was 8 months (range 5–20), whilst that of ruxolitinib maintenance post-SCT was 20 months (range 4–32).
Of 16 patients, 10 received SCT from a matched unrelated donor, 5 received SCT from a matched sibling donor and 1 received a haplo-identical SCT. Detailed conditioning regi-men information is available in the Appendix S1. Patient characteristics are summarized in Table I.
Table I. Patient characteristics
Baseline characteristics
Cohort
A (n = 3) B (n = 9) C (n = 4)
Mean age at SCT (years) 543 63 578
Gender (n) Male 3 5 3 Female 0 4 1 ECOG PS at diagnosis (n) 0 2 5 0 1 1 4 1 2 0 0 1 3 0 0 2 Medical comorbidities (n) 0 1 1 1 1–3 1 4 2 >3 1 4 1 Cytogenetic abnormalities (n) Trisomy 8 0 0 1 Del(12p) 0 0 1 Del(13q) 0 1 0 Trisomy 1q 0 1 0 Complex karyotype 1 1 0 JAK2 V617F mutated 3 7 3 Prior treatment (n) Hydroxycarbamide 0 2 0 Lenalidomide + prednisone 2 0 0 Sirolimus 0 0 1 Eltrombopag 0 0 1 SCT conditioning regimen (n) Flu/Bu 2 8 4 Flu/Bu/TBI 0 1 0 Bu/Cy 1 0 0
Bu, busulfan; Cy, cyclophosphamide; ECOG PS, Eastern Cooperative Oncology Group performance status; Flu, fludarabine; n, number of patients; SCT, stem cell transplantation; TBI, total body irradiation.
