Response to Ibrutinib of a Refractory IgA Lymphoplasmacytic Lymphoma Carrying the MYD88 L265P Gene Mutation
1 Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
2 Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.
3 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Received: June 19, 2019
Accepted: August 16, 2019
Mediterr J Hematol Infect Dis 2019, 11(1): e2019057 DOI 10.4084/MJHID.2019.057
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2014 a 66-year-old woman presented with anemia and an IgAk monoclonal
spike. Bone marrow (BM) biopsy showed 80% lymphocytes and
lymphoplasmacytoid cells. Computed Tomography (CT) scan documented
neither adenopathy nor splenomegaly. Diagnosis of IgA lymphoplasmacytic
lymphoma was made. After three lines of treatment, progressive disease
with adenopathies, splenomegaly, and ascites were documented on a CT
scan. Our patient developed thrombocytopenia, transfusion-dependent
anemia, and clinical deterioration. We performed genetic studies of
peripheral blood lymphocytes with the NGS approach. Given the
identification of MYD88 L265P mutation, in February 2018 our patient
started ibrutinib off-label. Hb and PLT improved from day +35. In July
2018 no ascites and 50% reduction of adenopathies and spleen were shown
on a CT scan. In April 2019 the patient was still on ibrutinib with
transfusion independence and good performance status.
MYD88 L265P triggers survival signaling through BTK and HCK, and MYD88 L265P expressing cell lines undergo apoptosis in response to ibrutinib, which targets both of these kinases. Moreover, Ibrutinib has demonstrated significant activity in patients with relapsed/refractory B-Cell malignancies.[12,13] In 2015, the FDA and the EMA approved ibrutinib for the treatment of symptomatic WM but not for LPL, based on a clinical trial in previously treated patients. The patients with LPL not fulfilling the diagnostic criteria of WM were excluded from WM trials and should be treated as the other indolent lymphoproliferative neoplasms, while recent guidelines[14-17] included recommendations on the usage of ibrutinib specifically for WM. For these reasons, the use of ibrutinib in non-IgM LPL has not yet been reported. We present here the first report of a patient with MYD88-mutated IgA LPL who underwent salvage therapy with ibrutinib.
The patient was treated with rituximab-cyclophosphamide-dexamethasone (RCD regimen) with Partial Response (PR) (Figure 1). Eighteen months later the patient, who presented with progressive disease (PD) (Hb 8 g/dl, lymphocytes 3.56 x 109/L with 80% lymphoplamacytic cells, IgAk monoclonal spike 1.9 g/dl), was treated with bendamustine. In January 2017, after five cycles, the BM aspirate showed 90% lymphoid cells and adenopathies, splenomegaly and ascites were noted on a CT scan. Thus, cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) was started and, after three cycles, the patient developed thrombocytopenia (Platelets, PLT: 30 x 10^9/L), transfusion-dependent anemia (Hb 7.7 g/dl), persistent lymphocytosis (Lymphocytes: 7.15 x 109/L) in the peripheral blood (PB) and clinical deterioration (Figure 1). We performed genetic studies of PB lymphocytes (after separation over a Ficoll gradient, yielding >80% clonal B lymphocytes) with a targeted NGS approach detecting mutations in 20 genes frequently mutated in CLL (ATM, BIRC3, BRAF, CDKN2A, PTEN, CDH2, DDX3X, FBXW7, KIT, KLHL6, KRAS, MYD88, NOTCH1, NRAS, PIK3CA, POT1, SF3B1, TP53, XPO1, ZMYM3). The MYD88 L265P mutation was identified in 65.7% of the reads. Given the identification of MYD88 L265P in the peripheral blood, ibrutinib appeared a reasonable option. In February 2018, our patient started ibrutinib off-label, 420 mg once daily (Figure 1). Hb and PLT improved from day +35 (Hb 10-12 g/dl, PLT > 100 x 10^9/L). In July 2018 no ascites and 50% reduction of adenopathies and spleen were shown on a CT scan. In April 2019, the patient was still on full dose ibrutinib with transfusion independence and good performance status.
This patient is unique in that it represents - to the best of our knowledge - the first reported case of response to ibrutinib in symptomatic aggressive IgA secreting LPL with MYD88 mutation refractory to multiple lines of treatment. Guidelines for treatment of WM pose indication for ibrutinib in relapsed or untreated patients who are not candidates for chemoimmunotherapy.[14-17] Our case clearly indicates that ibrutinib may represent a valuable therapeutic option for chemorefractory LPL not fulfilling the diagnostic criteria of WM. Our patient had previously been exposed to alkylators, immunomodulators, anti-CD20 monoclonal antibodies and steroids. Her therapeutic options at the time of her most recent relapse were limited and given the identification of the MYD88 L265P mutation in the peripheral blood, ibrutinib appeared as a reasonable option. In our patient, ibrutinib produced a response within 4–6 weeks, that is a typical time-frame during a response is usually observed. The partial response has been sustained for approximately 15 months at the time of this report. The kynetics of response in different disease compartments (blood, nodal, extranodal, spleen) were similar to those observed in WM patients[15,19] and CLL patients on single-agent ibrutinib with few treatment emergent adverse events consisting in grade 1 bruising, arthralgias and diarrhea, which improved and resolved with continued treatment.
In conclusion, we present the case of a heavily pretreated patient with MYD88-mutated IgA LPL, who has obtained a partial response to ibrutinib that is ongoing after more than one year of therapy. This observation suggests that ibrutinib appears to be potentially effective in this difficult-to-treat-condition.
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