Transient Massive Lymphoid Bone Marrow Infiltrate Developing during Therapy with the Tyrosine Kinase Inhibitors Imatinib and Nilotinib: Report of 2 Patients.
Authors: Pungolino Ester , Cantoni Silvia , Del Curto Cecilia , Gargantini Livio , Caramella Marianna , Miqueleiz Sara , Tedeschi Alessandra , Draisci Michela , Gabutti Cristina , Paratore Simona , Lanza Karen , Ribera Sonia , Morra Enrica 
Published: November 2019

Abstract
Clinical use of tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) has highlighted uncommon side effects of this group of novel anti-cancer agents. One of these peculiar side effects observed with imatinib (IM) is the occurrence of a bone marrow (BM) polyclonal lymphoid (Ly) infiltrate, usually accounting for 15–30% of total BM cellularity, sometimes taking the form of mature lymphoid follicles. No such effect has so far been described with nilotinib (NIL). We report on 2 CP-CML pts, one on IM and the second one on NIL, who developed transient massive BM Ly infiltrate without any clinical modification and with stable disease. Case1 A 40 yr old male pt was started on IM 400 mg/day as first line therapy in July 2003. Complete Cytogenetic Response (CCyR) and complete molecular response (CMoR) were obtained at 3 and 12 mos respectively. Routine BM monitoring showed progressive increase of the Ly infiltrate coincident with CCyR, up to 30%. In March 2007, BM examination disclosed massive infiltration with mature lymphocytes accounting for 60% of total BM cellularity; cytogenetic and molecular monitoring for CML were negative and peripheral blood count (PBC) was normal. The BM examination repeated a month later showed a spontaneous regression of Ly infiltrate to 25%; the remaining lymphocytes were prevalently B, polyclonal by molecular biology; cariotype was normal; FISH showed non specific abnormality (18% of 45 nuclei positive for del 17p13). Subsequent follow up disclosed normal BM with stable lymphocyte infiltrate and persistent CCyR and CMoR. Case2 A 60 yr old female pt resistant to IM was switched to NIL on November 2005. CCyR were obtained at 12 mos. BM monitoring showed progressive increase of the Ly infiltrate coincident with CCyR, up to 25%. The pt was mildly leucopenic throughout treatment. In March 2007, BM examination disclosed a 50% infiltration of mature lymphocytes; cytogenetic, molecular analysis and PBC were invariate. BM examination was repeated and the Ly infiltrate had spontaneously regressed to 20%. Considering the paucity of residual lymphoid cells, no further analysis was performed. Subsequent follow up showed normal BM with stable Ly infiltrate and persistent CCyR. Discussion. Data from the literature support the correlation between clinical efficacy of IM and increased BM Ly infiltration. Such correlation has also been found in our pts receiving IM and NIL. What has not yet been described is the massive transient polyclonal Ly infiltrate observed in our pts with both IM and NIL. This finding are of uncertain clinical relevance: PBCs were unaffected and molecular studies did not disclose presence of other hematological disorders. However, the known possibility of chronic lymphoproliferative disorders developing during CML needs to be kept in mind. An environmental factor - e.g. a subclinical viral infection - can not be excluded considering that both pts developed the same BM changes concomitantly. The role of TKIs is still unclear, in this case, and the clinical relevance of this event is uncertain. However, the similar mechanism of action of IM and NIL may suggest that a similar mechanism underlies the development of the BM massive Ly infiltrate observed in our pts.