Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive hairy cell leukemia

BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation–positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation–positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation–positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.</p

Series of Hairy Cell Leukemia Patients with Co-Existent Plasma Cell Disorders

Abstract Despite a reported increased incidence of secondary hematologic malignancies and plasma cell disorders in the literature, the specific co-existence of hairy cell leukemia (HCL) and monoclonal gammopathies of unknown significance (MGUS) or plasma cell multiple myeloma (MM) has been based on a few case reports. In the following report, we compile clinico-pathologic data on a series of hairy cell leukemia patients with myeloma precursor diseases using immunohistochemistry, molecular polymerase chain reaction (PCR) and multi-parametric flow cytometry (MFC) techniques with an aim to deep sequence these parallel lymphoid processes in the future. Between 2004 and 2014, 6 HCL patients followed at the National Institutes of Health were identified with associated plasma cell disorders, based on presence of increased clonal plasmacytosis in bone marrow and abnormal serum and/or urine protein electrophoresis/immunofixation. Immunohistochemical (IHC) staining for CD20, TRAP, CD138, cyclin D1, kappa and lambda light chains was performed on bone marrow biopsies. MFC using a panel of B-cell antibodies and PCR clonality studies targeting immunoglobulin heavy and light chain loci were performed prior to treatment to confirm the presence of malignant lymphoid clonal processes. Among the 6 hairy cell leukemia patients with associated plasma cell disorders, there were 5 males and one female. Median age was 67 (range, 47-74). Patients prior to treatment showed bone marrow involvement by HCL with 5-90% infiltration. Hairy cells in all patients tested were TRAP positive, Cyclin D1 was positive in 5, and BRAF V600E was detected in 5 of 5 patients tested. All patients were diagnosed as classic HCL, although 1 patient had an additional population consistent with HCL variant. In addition, 3/6 patients (50%) showed mild increase in marrow plasma cells (5-10%) and the other 3 patients (50%) had over 10% of plasma cells in the core biopsy. The mean plasma cell percentage was 10% (3-25%), mean monoclonal protein concentration was 1.3 g/dL, and isotypes included: 4 IgG, 1 IgA, and 1 free kappa only. 3 patients were classified as MGUS and 3 as smoldering MM (SMM). Interestingly, three out of 6 (50%) patients had positive cyclin D1 expression by IHC in both plasma cells and hairy cells. Several patients had evidence of multiple clonal rearrangements by PCR studies. In addition, two patients demonstrated evidence of monoclonal B-cell lymphocytosis (MBL) on MFC. So far, 3 patients achieved complete remission without minimal residual disease (MRD) using moxetumomab pasudotox in one multiply relapsed case, and first line cladribine plus rituximab in 2 newly diagnosed HCL cases, without significant progression to MM. No patients demonstrated end organ damage due to MGUS/SMM after a median follow-up of 4.6 (range 0.9-10.1) years. By using serum studies, IHC staining, PCR and MFC tools, we identified a group of HCL patients with evidence of additional precursor malignant lymphoid disease states, including MGUS/SMM and MBL. Underlying mechanisms of these parallel malignant processes may include global lymphoid dysregulation through common lymphocyte ancestry pathways; or, it could be due to post-immune HCL therapy exposure, or a combination. Currently, we are conducting deep sequencing of these samples with the aim to uncover mechanisms of pathogenesis. Treatments capable of eliminating HCL MRD, including addition of rituximab to first-line cladribine, or single-agent moxetumomab pasudotox for multiply relapsed HCL, might be advantageous for patients who may need treatment for MM in the future. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare

Evidence of canonical somatic hypermutation in hairy cell leukemia

To compare hairy cell leukemia (HCL) with chronic lymphocytic leukemia (CLL) and normal B cells with respect to their B-cell receptors, somatic hypermutation (SHM) features in HCL were examined in a series of 130 immunoglobulin gene heavy chain rearrangements, including 102 from 100 classic (HCLc) and 28 from 26 variant (HCLv) patients. The frequency of unmutated rearrangements in HCLc was much lower than that in HCLv (17% vs 54%, P < .001) or historically in CLL (17% vs 46%, P < .001), but HCLv and CLL were similar (P = .45). As previously reported for CLL, evidence of canonical SHM was observed in HCLc rearrangements, including: (1) a higher ratio of replacement to silent mutations in the complementarity determining regions than in the framework regions (2.83 vs 1.41, P < .001), (2) higher transition to transversion ratio than would be expected if mutations were random (1.49 vs 0.5, P < .001), and (3) higher than expected concentration of mutations within RGYW hot spots (13.92% vs 3.33%, P < .001). HCLv met these 3 criteria of canonical SHM to a lesser extent. These data suggest that, whereas HCLc cells may recognize antigen-like CLL and normal B cells before malignant transformation, HCLv cells from some patients may originate differently, possibly without undergoing antigen recognition