Single‐agent venetoclax induces MRD‐negative response in relapsed primary plasma cell leukemia with t(11;14)
Authors: Tomas Jelinek, Jana Mihalyova, Michal Kascak, Juraj Duras, Tereza Popkova, Katerina Benkova, Petra Richterova, Hana Plonkova, Jana Zuchnicka, Lucie Broskevicova, Lucie Huvarova, Lucie Cerna, Katerina Growkova, Michal Simicek, Martin Havel, Jaromir Gumulec, Milan Navratil, Zdenek Koristek, Bruno Paiva, Roman Hajek
Journal: American Journal of Hematology (2018)

Plasma cell leukemia (PCL) is the most aggressive form of plasma cell dyscrasia. It is characterized by the presence of more than 20% and/or more than 2 × 109/L of circulating plasma cells (PCs). Primary plasma cell leukemia (pPCL) that presents de novo should be distinguished from secondary PCL, which corresponds to the leukemic transformation of pre-existing multiple myeloma (MM). Primary PCL is characterized by an increased frequency of adverse laboratory and clinical features as well as higher genetic instability than MM. Despite the introduction of novel agents into clinical practice, the prognosis of pPCL remains poor, with an estimated overall survival of 1-2 years in elderly patients and about 3 years in younger patients eligible for stem cell transplantation (SCT).1, 2 Venetoclax is a potent, highly selective Bcl-2 inhibitor, representative of the so-called BH3 mimetics. This novel group of agents targets the anti-apoptotic proteins, thus inducing tumor cell death. It has been demonstrated in vitro as well as in vivo that a subgroup of PCs is Bcl-2 dependent, and thus sensitive to venetoclax. This subset is restricted to those harboring t(11;14).3, 4 While translocation t(11;14) is only present in approximately 15-20% of MM patients, it is reported in up to 50% of pPCL patients, making venetoclax a very promising drug for such an aggressive disease.2 A 58-year old man with life-threatening acute renal failure (creatinine: 504 μmol/L; urea: 32.4 mmol/L, hyperkalemia of 6.4 mmol/L, and hypercalcemia of 3.45 mmol/L) was admitted to our intensive care unit in May 2017. The patient's blood count showed leukocytosis of 30.7 × 109/L with 35% of circulating PCs (Figure 1A) and anemia with hemoglobin level of 93 g/L. Bone marrow (BM) biopsy revealed 57% infiltration of lambda clonal PCs confirmed by flow cytometry. The paraprotein IgG lambda level was 8.9 g/L and the concentration of lambda free light chains (FLC) was 2348 mg/L with a pathological FLC ratio of 2134. Fluorescence in situ hybridization analysis revealed the presence of translocation t(11;14)(q13;q32) and subsequent translocation t(9;14)(p13;q32) (Figure 1B,C). A low dose CT (ldCT) scan demonstrated multiple osteolytic skeletal lesions. The diagnosis of pPCL was established based on these results and treatment with bortezomib and dexamethasone (VD) was immediately initiated. The treatment was intensified after 2 cycles with additional 2 cycles of hyperCVAD-VD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone). The patient's renal functions completely normalized after induction therapy and he subsequently underwent ASCT with a reduced dose of melphalan 140 mg/m2 in September 2017. This procedure was complicated by symptomatic dilated cardiomyopathy with a drop in left ventricle ejection fraction to 38% (EF of 65% at baseline). The hematological response after front-line therapy was very good partial response (VGPR) with the normalization of FLC ratio and persistent positive serum immunofixation. Due to the highly aggressive nature of pPCL, our patient was frequently followed-up. The first signs of relapse occurred in February 2018; 6 months after high dose therapy. The elevation of FLC lambda was accompanied by the deterioration of renal functions with rapidly increasing levels of serum creatinine. BM was infiltrated by 2% of PCs with 100% being lambda clonal. FDG-PET/CT demonstrated obvious progression compared with ldCT performed at the time of diagnosis. In the Czech Republic there is limited access to novel agents for treatment of pPCL. We took into account the fact that the patient harbors translocation t(11;14) and requested venetoclax free of charge from Abbvie as part of the pre-approval access program. Venetoclax as a single agent was administered orally once daily at the dose of 1200 mg in 21-day cycles. Venetoclax induced a very rapid decrease in FLC lambda levels, translating into the normalization of FLC ratio after the first cycle (Figure 1D). Treatment response was evaluated after 9 cycles of single-agent venetoclax. We performed next generation flow cytometry (NGF) for the evaluation of minimal residual disease (MRD) within BM according to EuroFlow recommendations. We confirmed flow MRD-negative response with a sensitivity level of 10−6 (Figure 1E,F) Moreover, we did FDG-PET/CT that demonstrated the disappearance of all previously reported pathological lesions (Figure 1G,H). The treatment has been well tolerated, no drug related serious adverse events have been observed and the only toxicity has been grade 1 thrombocytopenia. At the moment (October 2018) our patient is still receiving venetoclax monotherapy with no new safety signals. Primary PCL is one of the most aggressive blood cancers and the therapeutic outcomes of relapsed pPCL patients ineligible for SCT are especially poor. Our patient was not able to undergo SCT because of his cardiac co-morbidities, thus the treatment options remained very limited. Translocation t(11;14) is a routinely investigated cytogenetic abnormality that serves as a useful biomarker predicting sensitivity to venetoclax. This molecular subset is associated with high Bcl-2, and low Bcl-XL and Mcl-1 mRNA expression, resulting in higher sensitivity to Bcl-2 inhibition. In our case we also performed expression profiling of the anti-apoptotic proteins Bcl-1, Bcl-XL, and Mcl-1 to predict the sensitivity to venetoclax in vitro.5 We determined Bcl-2/Bcl-XL and Bcl-2/Mcl-1 mRNA ratio using quantitative polymerase chain reaction on FACS sorted PCs. The mRNA ratio of Bcl-2/Bcl-XL was 1.84 suggesting potential sensitivity to venetoclax and Bcl-2/Mcl-1 mRNA ratio was 0.18. In MM, venetoclax monotherapy was examined in a phase 1 trial in 66 relapsed/refractory MM patients with a median of 5 prior lines of therapy, with 46% (31/66) harboring t(11;14). The overall response rate (ORR) was 21% (14/66), and 15% achieved ≥VGPR. In the subgroup with t(11;14), ORR was 40% (27/66), with 27% of patients achieving ≥VGPR.4 The use of venetoclax has previously been reported also in refractory pPCL, but only as a part of combination treatment together with daratumumab, bortezomib and dexamethasone.6 Thus, it is complicated to draw any conclusion on the efficacy of venetoclax in this combination regimen. On the other hand, here we report indisputable evidence of venetoclax single-agent activity in the first relapse of pPCL with t(11;14) that induced MRD negative response confirmed by both - NGF and FDG-PET/CT. Venetoclax proved to be effective and safe, and represents a promising agent that can be successfully used in this setting. Nothing to report. The authors would like to thank to Shira Timilsina Godfrey, M.D. for editing the article, to Dr. Jiri Sobotka for providing FISH images and to Ladislav Vichanek for his help with graphic processing of the figure. This work was supported by the project "Cell Coolab Ostrava - Research and Development Center for Cell Therapy in Hematology and Oncology" (No. C.Z.02.1.01/0.0/0.0/17_049/0008440) supported by ERDF; and by The Ministry of Education, Youth and Sports (Specific university research of the Faculty of Medicine, University of Ostrava) project no. SGS01/LF2018-2019.