To the editor:
Dasatinib is a tyrosine kinase inhibitor licensed in the treatment of chronic myeloid leukemia (CML) known to exert immunomodulatory effects in vitro and in vivo.1 We report on 9 chronic phase CML patients who developed follicular lymphoid hyperplasia (FLH) apparently caused by dasatinib, an unreported adverse event related to this drug.
Patients received dasatinib at 100 mg (n = 7), at 80 mg (n = 1), or at 50 mg (n = 1) daily for chronic phase CML, either frontline as part of the Optimized Tyrosine kinase Inhibitors Monotherapy (OPTIM) dasatinib trial (EudraCT number 2008-006854-17)2 (n = 2) or after intolerance (n = 2), or suboptimal response/resistance (n = 5) to imatinib. From our first line patients included in the prospective academic OPTIM dasatinib trial, the estimated order of frequency of FLH might be 0.7% (2 of 291). Sex ratio of female to male was 3:6. Sokal scores were low (n = 2), intermediate (n = 1), and high (n = 6). Median age at FLH diagnosis was 52 years (range, 24-69 years).
All patients presented with progressive cervical lymph node enlargement after median treatment duration of 20 months (range, 9 to 35 months). One patient presented additionally inguinal lymph node enlargement. At the time of discovery, 8 patients were in complete cytogenetic response associated with a major molecular response (n = 3) or with a complete molecular response (n = 3).
Clinical examination revealed no local or systemic infectious disease. Toxoplasmosis, viral and autoimmune disorders assessments failed to show any active disease. Tomodensitometry confirmed absence of additional localization. In 1 patient, nodes enlargement was associated with peripheral lymphocytosis related to an increase of natural killer cells and CD8+ T-cells, but not to B-cells, as previously described.1 All patients underwent a lymph node biopsy that revealed an FLH (Figure 1A), and an extramedullary blastic transformation of CML was ruled out. Lymph node immunostaining showed a follicular reactive phenotype CD10+ Bcl2− (see Figure 1B). Cytogenetic analysis of lymph node revealed in 1 patient as clonal abnormality (Figure 1C) without IGH/BCL2 rearrangement detected by standard fluorescence in situ hybridization (data not shown) and clonality assessment showed a DJ-JH rearrangement (Figure 1D). However, the frequency of rearrangement could be underestimated because clonality was searched only in some patients, but not all, according to availability of material and techniques in each hospital. Philadelphia chromosome was undetectable, ruling out a localized lymphoid blast crisis of CML.
![Figure 1. Example of follicular hyperplasia features in a patient. (A) At low power examination, the lymph node architecture is preserved with florid follicular hyperplasia. Large follicles show irregular borders, a prominent germinal center, and sometimes enlarged mantle zone (original magnification ×2.5). (B) Reactive germinal centers show a bcl2−/bcl6+/CD10+ immunostaining pattern (original magnification ×2.5). (C) The karyotype of lymphadenopathy after G-banding was as follows: 46,XY,add(1)(q41),der(14)t(1;14)(q24;q32)[8]/46XY[12]. Derivative chromosomes are marked by arrows. (D) Polymerase chain reaction heteroduplex analysis of incomplete Ig heavy chain (IGH) DH-JH rearrangement: detection of a slight homoduplex band (280 bp).](https://ash.silverchair-cdn.com/ash/content_public/journal/blood/122/17/10.1182_blood-2013-07-513879/4/m_3082f1.jpeg?Expires=1735832532&Signature=gvfT9ww0iD4NPxy8-WF0dEkqPiQY7jonzPHeGeSVAZTmaFCzYoZp2Ksk2JY6EEj7jiwpA-CWzWmTStU5~HM8GckBTi9Tu7n~G-U28UAjqPRhvpvR6yv6zdXKvRdTvwUrTGxOfVGkaNvC7~2cq7HyQEnMPlE8GNZ4lxuZz6cWWpPyGu7I1v~AIaQSI-1-XBb36l3uw74dX7Rndbv91N1S2d7leBqRLsSNaWT2OepS7XOi4OyeBWjjo4BzoBJtgbrPeMQQNriyN54pavlw~oBLpvOkLFnYJMW4KAujzZz6vd2t1AqgXjMvWYFVIEJxk62N7CP5wWnHSX5wadHZ06bBtw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Example of follicular hyperplasia features in a patient. (A) At low power examination, the lymph node architecture is preserved with florid follicular hyperplasia. Large follicles show irregular borders, a prominent germinal center, and sometimes enlarged mantle zone (original magnification ×2.5). (B) Reactive germinal centers show a bcl2−/bcl6+/CD10+ immunostaining pattern (original magnification ×2.5). (C) The karyotype of lymphadenopathy after G-banding was as follows: 46,XY,add(1)(q41),der(14)t(1;14)(q24;q32)[8]/46XY[12]. Derivative chromosomes are marked by arrows. (D) Polymerase chain reaction heteroduplex analysis of incomplete Ig heavy chain (IGH) DH-JH rearrangement: detection of a slight homoduplex band (280 bp).
Example of follicular hyperplasia features in a patient. (A) At low power examination, the lymph node architecture is preserved with florid follicular hyperplasia. Large follicles show irregular borders, a prominent germinal center, and sometimes enlarged mantle zone (original magnification ×2.5). (B) Reactive germinal centers show a bcl2−/bcl6+/CD10+ immunostaining pattern (original magnification ×2.5). (C) The karyotype of lymphadenopathy after G-banding was as follows: 46,XY,add(1)(q41),der(14)t(1;14)(q24;q32)[8]/46XY[12]. Derivative chromosomes are marked by arrows. (D) Polymerase chain reaction heteroduplex analysis of incomplete Ig heavy chain (IGH) DH-JH rearrangement: detection of a slight homoduplex band (280 bp).
Dasatinib was discontinued in all patients, leading to a complete disappearance of node enlargement within a median time of 1 month (range, 15 days to 2 months). The majority of patients were challenged with nilotinib (n = 6), with 2 patients who remained free of tyrosine kinase inhibitor because of a long-lasting complete molecular response and 1 patient who underwent an allogeneic stem cell transplantation.
FLH is characterized with follicular centers hyperplasia related to B lymphocytesstimulation. Dasatinib is an inhibitor of the SRC family kinase.3 Lyn, an Src family protein, is expressed in B lymphocytes and is a regulator of B-cell antigen receptor via Atk/PKB signaling, contributing to B-cell activation.4,5 Thus, the impact of dasatinib on SRC kinases and on Akt/PKB pathway could contribute to the FLH initiation. Moreover, chronic active B-cell antigen receptor signaling was identified as a new mechanism in lymphoma6 and Akt/PKB overexpression was associated with progression of tumor in humans.3 Considering cytogenetic clonal abnormalities observed in 1 patient, malignant transformation into lymphoma cannot be eliminated. We recommend a systematic search for lymph node enlargement by physical examination in patients treated with dasatinib. A diagnosis of FLH should trigger dasatinib discontinuation.
Authorship
L.L. and P.R. contributed equally to this study.
Acknowledgments: We would like to thank Pierre-Simon Rohrlich, from Service d’Hématologie Clinique, Hôpital Archet 1, Nice, France for critical reading of the manuscript.
Contribution: C.R. and L.L. performed data analysis and wrote the paper; P.R. is the OPTIM Dasatinib study coordinator, and reviewed and approved the final version of the report; L.L., F.E.N., D.R., M.N., L.M., M.T., S.G., and A.T. followed the patients, provided the data, critically reviewed the manuscript, and approved it in its final version; C.C.C. and F.B. performed extensive lymph node immunopathological and clonal analysis and prepared the figures; and I.T. performed cytogenetic analysis of the lymph node and provided the karyotyping analysis picture presented here.
Conflict-of-interest disclosure: F.E.N. has given lectures for BMS, Novartis, Ariad, and Teva; was involved in advisory boards of BMS, Ariad, Novartis, Pfizer, and Teva; is consultant for Novartis; and is an investigator of the OPTIM Dasatinib trial. D.R. received honoraria from Novartis, BMS, Pfizer, and TEVA, and is an investigator of the OPTIM Dasatinib trial. L.L. was involved in advisory boards of BMS, Novartis, and Pfizer; and is an investigator of the OPTIM Dasatinib trial. G.M. is investigator of the OPTIM trial; is a consultant for Novartis, BMS, Pfizer, and Ariad; and had research support from BMS. A.T. received research support from Novartis and BMS, and is consultant for BMS. S.G. received a research grant from Novartis; and has received honoraria from BMS and Novartis. The remaining authors declare no competing financial interests.
Correspondence: Laurence Legros, Service d'Hématologie Clinique, Hôpital Archet 1, 151, Route de Saint Antoine de Ginestière, BP 3079, 06202 Nice Cedex 2, France; e-mail: legros@unice.fr.
