Plasma Cell Leukemia with Successful Upfront Venetoclax in Combination with Allogeneic Transplantation

Background

Plasma cell leukemia is an aggressive and highly fatal form of plasma cell neoplasm in which clonal plasma cells constitute >20% of the total leukocytes in the blood or an absolute count of >2.0×109/L [1]. A new revised consensus criterion of ≥5% circulating plasma cells has recently been published by the International Myeloma Working Group (IMWG) [2]. However, little is known about this rare condition. To date, only a few case reports and case series have been published. The median overall survival (OS) was 4–6 months prior to the introduction of novel therapeutics. Despite the advent of these novel options, for instance, immunomodulatory agents, proteosome inhibitors, and stem cell transplant, the long-term OS remained disappointing [3]. Here, we report the first case of primary plasma cell leukemia successfully treated with up-front novel agents consisting of Venetoclax and daratumumab in combination with intensive chemotherapy and allogeneic stem cell transplantation.

Case Report

A 59-year-old woman presented with a 2-week history of sudden epistaxis, unprovoked prolonged gum bleeding, blurred vision, and mild headache. There was no significant medical or surgical history. She was also progressively symptomatic of anemia with reduced effort tolerance and intermittent chest pain. No constitutional symptoms were observed. No traditional medications, supplements, or recreational drugs were used.

There was no significant personal or family history of bleeding disorder. On examination, the patient appeared pale with no jaundice. The liver was palpable 3 cm below the right costal margin. Multiple petechiae were observed on the trunk and limbs. Clinically, no lymphadenopathy was observed. Detailed funduscopic examination with direct and indirect binocular ophthalmoscopy revealed bilateral hemorrhages and choroiditis spots.

Laboratory investigations revealed bicytopenia (haemoglobin, 4.3 g/dL, platelet count, 90 x109/L) and leukocytosis (31×109/L). The coagulation profile revealed a slightly prolonged prothrombin time/PT (17seconds; reference 11.2–14.6 seconds) and activated partial thromboplastin time/aPTT (44.5 seconds; reference 30–42 seconds) with low fibrinogen (1.4 g/L). Elevated total protein (117 g/L) with increased globulin (95 g/L) and corrected calcium (2.72 mmol/L) levels were found. Liver enzymes, renal function, lactate dehydrogenase, and urinalysis results were normal. Peripheral blood film (Figure 1) showed the presence of many lymphoplasmacytic cells and background rouleaux formation. We performed von Willebrand studies, which showed a von Willebrand factor antigen (vWF: Ag) level of 81.5% and von Willebrand factor ristocetin cofactor (vWF: Rco) of 29.1%, with a reduced vWF: RCo to vWF: Ag ratio of 0.36, indicating type II von Willebrand disease. In our patient, this was most likely acquired. Serum protein electrophoresis and immunofixation demonstrated the presence of IgG lambda paraprotein (85.2 g/L) with an abnormal serum-free light chain kappa to lambda ratio of 0.074. A skeletal survey using conventional radiography revealed several lytic lesions over the bilateral femoral heads with sparing of other parts. Bone marrow aspiration and trephine biopsy (Figure 1) confirmed the presence of lambda-light-chain-restricted clonal plasma cells. There were 65% of total analyzed cells identified as circulating plasma cells in the peripheral blood. These plasma cells (Figure 2) were found in a SSC low/ CD45 dim-negative gate, expressing strong CD38 and CD138. Interestingly, these cells also expressed CD19 and surface lambda. While most of the plasma cell population were negative for CD20 and CD56, some plasma cells exhibited dim CD20 and CD56. There was no expression of CD117 on the plasma cells. The remaining small population of mature B lymphocytes did not show any clonality.

The karyotyping sample was suboptimal for analysis. Dual-color dual-fusion fluorescence in-situ hybridization (FISH) detected t(11;14) – IGH/CCND1 fusion in 87% of the 100 cells analyzed. FISH analysis of c-MYC using break-apart probes did not detect MYC rearrangement. However, 3 copies of c-MYC were observed in 69.5% of the 200 cells analyzed, indicating trisomy 8. A deletion of 17p13.1 at the TP53 locus was detected in 87% of the 200 cells analyzed. No abnormal rearrangement involving the BCL2 gene was detected using the BCL2 break-apart probe. The MYD88 L265P mutation, which was detected using polymerase chain reaction (PCR), was tested as one of the differential diagnoses based on initial morphological features in peripheral blood film showed increased circulating lymphoplasmacytic cells. We concluded that this patient had primary de novo plasma cell leukemia based on all the investigations performed.

The patient received 1 cycle of bortezomib, cyclophosphamide, and dexamethasone (VCD), followed by 5 cycles of subcutaneous bortezomib (1.3 mg/m2), continuous infusion of conventional doxorubicin (36 mg/m2 over 4 days), dexamethasone (40 mg daily for 4 days) and Venetoclax (100 mg/day). Throughout the therapy, the patient was covered with antimicrobial prophylaxis including acyclovir, itraconazole, and cotrimoxazole.

GCSF-induced peripheral blood stem cell (PBSC) mobilization was attempted after 4 cycles of chemotherapy, but was unsuccessful. Her disease achieved a very good partial response with residual 2.0 g/L IgG lambda paraprotein with no immunoparesis. The serum-free light chain kappa-to-lambda ratio was within normal range (0.267). She then received 1 cycle of Dara-VRD (daratumumab 16 mg/kg weekly for 2 weeks, bortezomib, lenalidomide 25 mg OD for 2 weeks, and dexamethasone) with the aim of measurable residual disease (MRD) eradication prior to transplantation. No serum monoclonal paraprotein was detectable following the chemotherapy. Fortunately, she did not develop any opportunistic infections despite multiple therapies.

She was scheduled for consolidation with allogeneic transplantation because of her high-risk disease profile. She underwent an HLA-matched sibling donor (MSD) allogeneic stem cell transplant (gender mismatch, same cytomegalovirus/CMV-positivity, and same blood group A Rh(D) positive) with myeloablative conditioning (MAC) using fludarabine 120 mg/m2 and melphalan 180 mg/m2. The donor source was peripheral blood with a stem cell dose of 5.01×106/kg. She was started on cyclosporin/mycophenolate mofetil immunosuppression as graft-versus-host disease (GvHD) prophylaxis. Cyclosporin was subsequently switched to oral tacrolimus due to cyclosporin intolerance (nausea, vomiting, and diarrhea). Her white cell and platelet engrafted on Day+9 and Day+10, respectively. Post-transplant marrow assessment showed disease in remission with 100% donor FISH chimerism and absence of t(11;14) and 17p deletion by FISH. She received 3-monthly pamidronate and alternate-day lenalidomide maintenance. She remained clinically well with a good performance status and no active GvHD 18 months after transplant.

Discussion

Primary plasma cell leukemia (PCL), which is characterized by the proliferation of clonal plasma cells from the bone marrow or plasma cell expansion from the extramedullary compartment, is a rare and aggressive form of plasma cell dyscrasia. In recent years, the incidence of secondary PCL has increased, possibly because of improved overall survival (OS) of patients with multiple myeloma (MM). This could be explained by the advent of a vast variety of targeted therapies with improved supportive measures. More patients with MM receive several lines of treatment, potentially resulting in evolutionary selective pressure on the MM tumor microenvironment [4]. Patients with primary PCL present a decade earlier than secondary PCL, with a median age at diagnosis of 55 years for the former [5]. To date, there is a lack of consensus on the classification of extramedullary disease (EMD) of MM, which is defined by the presence of clonal plasma cells outside the bone marrow. PCL was identified as one of the EMD subtypes by Kumar et al [6].

The new consensus definition of PCL by IMWG was based on the evidence that the presence of ≥5% circulating plasma cells in patients with MM demonstrated an adverse prognostic outcome identical to the previously defined PCL [1,2]. By adopting the new diagnostic criteria, more patients could be diagnosed with primary PCL with subsequent treatment adaptation. This may result in earlier diagnosis and prompt initiation of therapy.

PCL is often associated with asthenia and renal insufficiency. Hepatosplenomegaly can occur. Some typical symptoms of MM can be seen in PCL, such as skeletal changes, including osteolytic lesions and bone pain. Hypercalcemia may not be present in all patients but has been shown to be a poor prognostic factor in PCL [7]. In this rare case, the patient initially presented with hyperviscosity symptoms (bleeding and blurring of vision) with laboratory confirmation of acquired Von Willebrand syndrome (AvWS). This phenomenon is not uncommon in monoclonal gammopathies and lymphoproliferative disorders such as MM and lymphomas [8]. The relationship between AvWS and PCL has rarely been reported. One study proposed the interference of the paraprotein with VWF binding to platelet glycoprotein (GP1b) as a pathogenic mechanism [9].

A full workup on the treatment-naive blood and marrow samplings is imperative for identification of unique signatures of the neoplastic clone that can be used for treatment selection and disease monitoring. It is important to examine the detailed molecular genetic information of the neoplastic cells such as FISH at the time of initial diagnosis and to look at the effect of treatment at a detailed level, such as MRD.

FISH plays a crucial role in risk stratification and treatment of PCL. The prevalence of t(11;14) is high in PCL, with a frequency ranging from 25% to 70% in comparison to approximately 10–20% in MM [10]. Venetoclax, a potent and highly selective Bcl-2 inhibitor, targets anti-apoptotic proteins, thus inducing tumor cell death. A subgroup of plasma cells is Bcl-2-dependent, which is restricted to those harboring t(11;14), and hence, sensitive to Venetoclax [11]. Several case reports have shown favorable results using Venetoclax as part of therapy, even in the setting of refractory PCL [10,12]. Deletion of 17p13.1 was observed in up to 50% of primary PCL and 75% of secondary PCL. Due to the aggressive nature and poor prognosis of PCL, early detection of these mutations using molecular FISH is paramount to guide the commencement of targeted treatment, potentially resulting in a much deeper MRD-negative remission. MYC rearrangement was reported in 13.3% of primary PCL [13], whereas abnormalities in chromosome 8 (translocations, 1 copy gain, small deletions, duplications, and increased levels of MYC mRNA) were detected in 92% by others [14]. Our patient had 1 copy gain on chromosome 8, without MYC rearrangement. MYC abnormalities, which lead to increased MYC expression, have been reported to be associated with higher incidence of PCL, extramedullary disease, and an adverse outcome [15]. Hence, more intensified upfront chemotherapy, novel agents, and/or tandem autologous/allogeneic transplantation might be a reasonable consideration.

High frequencies of MYD88 L265P mutations have been reported in lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia and extranodal diffuse large B cell lymphoma [16]. To the best of our knowledge, this is the first report on the unique existence of this mutation. Further studies are warranted to determine the clinicopathological significance of the molecular data in PCL.

The rational basis for combination therapy in our case is based on the fact that there is a synergistic in-vitro anti-tumor effect between bortezomib and genotoxic chemotherapy, for instance, doxorubicin in myeloma cell lines [17]. Venetoclax has been shown to be effective in relapsed/refractory PCL setting [10,12]. Due to the aggressive nature of our patient’s disease, Venetoclax was combined with chemotherapeutic agents in the front-line setting with the aim to achieve deeper disease remission.

Daratumumab, a monoclonal antibody targeting the CD38 glycoprotein that induces apoptosis, has demonstrated impressive OS when used with PI and immunomodulatory agents in relapsed or refractory MM. A case series gathering data from the Mayo Clinic Cancer Center from January 2012 to June 2019 concluded that Dara-based regimens showed a rapid and high overall response rate (ORR) in patients with PCL who received a median of 2 prior lines of therapy [18]. The rationale and potential of adding daratumumab to front-line therapy remain elusive.

The cornerstone of treatment in PCL is extrapolated from myeloma trials, which comprise combination therapy incorporating a proteasome inhibitor (PI), an immunomodulatory agent, steroids, and/or anthracyclines and alkylators as part of intensive chemotherapy, followed by consolidative autologous hematopoietic stem cell transplantation (auto-HSCT) in eligible patients, followed by maintenance therapy [19]. The adoption of auto-HSCT following standard myeloma-like induction regimens has been advocated by several prospective clinical trials with moderate evidence [20,21]. Some studies have shown a superior OS among patients who underwent tandem compared to single ASCT [19,22]. Peripheral blood stem cell (PBSC) mobilization failed in our patient, possibly because it was attempted after a long course of treatment. It remains unknown whether front-line novel agents like Venetoclax interfere with stem cell mobilization. The efficacy and safety of allo-HSCT in PCL are largely inconclusive due to the rarity of the disease, which lead to difficulties in recruiting patients to randomized control trials. Despite the possibility of cure, allo-HSCT has been shown to have no OS benefit when compared to auto-HSCT, and disease relapse remains the major cause of death in these patients [23]. However, the same study demonstrated longer 12-month progression-free survival (PFS) after allo-HSCT [23]. Due to the high-risk disease profile of our patient, consolidative allo-HSCT with deeper remission was performed to reduce the relapse rate after transplantation. Our case was a successful example highlighting that the use of Venetoclax prior to transplantation can be a successful strategy and allo-HSCT can be a possible option in PCL.

Conclusions

Our systematic literature review failed to find any publications on incorporation of Venetoclax and daratumumab in the front-line treatment of PCL followed by allo-HSCT. The success of our patient remaining in complete remission 18 months after allo-HSCT has highlighted the efficacy and safety of Venetoclax in the upfront management of PCL, particularly in those harboring targeted or high-risk mutations. Further studies, particularly randomized clinical trials, are warranted, with the ultimate goal of improving overall survival of these patients.