Acquired Whim Syndrome: A Possible New Side Effect Of Dasatinib!
Authors: Yadav Satya Prakash , Ramzan Mohammed , Chopra Yogi Raj , Dhingra Nivedita , Sachdeva Anupam 
Published: October 2019

Abstract

Introduction
WHIM (Warts, Hypogammaglobulinemia, Infections and Myelokathexis) syndrome is a hereditary disorder caused by activating mutation in CXCR4 receptor. CXCR4 receptor is expressed in many cells including myeloid and lymphoid cells. Dasatanib is aTKI inhibitor and very effective drug in treating Ph+ve acute lymphoblastic leukaemia (Ph+ALL). Dasatinib has many off target effects which are not completely known as yet. Dasatinib effect on CXCR4 is not well described. In Chronic myeloid leukaemia it causes reacquisition CXCR4 activation leading to hiding of myeloid leukaemia cells inside the bone marrow. However some work has been done on effects of Dasatinib on mature neutrophil indicates adhesion defect and inhibition of pro-inflammatory effect. Here we describe two children who developed acquired WHIM syndrome like features while on Dasatinib therapy.

Methods
Two girls aged 9 and 11 year old with Ph+ALL were treated initially as per BFM95 protocol and Imatinib 375 mg/m2 daily. Both went in remission and later achieved complete molecular remission. However during maintenance therapy first patient at 19 months from diagnosis and second at 12 months from diagnosis started having rising value of quantitative BCR-ABL values. As both children had no siblings and no matched unrelated donor was available so in both Imatinib was stopped and after taking informed consent of parents Dasatinib was started at a dose of 100/mg/m2/day in two divided doses and maintenance therapy of oral 6-Mercaptopurine (6-MP) and Methotrexate (MTX) was continued. They both achieved reduction in BCR-ABL quantitative PCR after 3 months and molecular remission at 6 and 9 months respectively after starting Dasatinib.

Results
During therapy with dasatinib and oral 6-MP and MTX both children started having recurrent respiratory tract infections with neutropenia and warts appeared on face and body. Serum immunoglobulin G levels were lower than 200 mg/dl in both. We felt that these symptoms resembled WHIM syndrome and possibly could be due to Dasatinib. So we gave Intravenous immunoglobulin to both the children and IV antibiotics and stopped both Dasatinib and chemotherapy for a week. Neutropenia recovered within 72 hr after stopping of dasatinib. However, we did not perform bone marrow examination in both the cases to prove myelokathexis. Both children did well when Dasatinib was restarted at a lower dose of 50 mg/m2/day once daily and oral 6-MP and MTX. Warts disappeared over next 4-6 months and did not have any further episodes of fever or febrile neutropenia needing IV antibiotics. Their repeat serum immunoglobulin G levels stayed normal over next 6-12 months.

Conclusion
Both our children on dasatinib developed WHIM syndrome like features which resolved on reducing dose of Dasatinib. Dasatinib possibly mediates this side effect through CXCR4 receptor or downstream pathway. More data are needed to prove this association.

Disclosures:
No relevant conflicts of interest to declare.