Int J Clin Exp Pathol 2014;7(5):2683-2689 www.ijcep.com /ISSN:1936-2625/IJCEP1402007 Case Report A rare case of acute lymphoblastic leukemia in a patient with light chain (AL) amyloidosis treated with lenalidomide Ranjit Nair1, Shereen Gheith2, Dan Popescu3, Nicole M Agostino3 1Department of Internal Medicine, Lehigh Valley Hospital and Health Network, Allentown, PA 18105, USA; 2Depart- ment of Pathology, Lehigh Valley Hospital and Health Network, Allentown, PA 18105, USA; 3Department of Hema- tology/Oncology, Lehigh Valley Hospital and Health Network, Allentown, PA 18105, USA Received February 3, 2014; Accepted April 3, 2014; Epub April 15, 2014; Published May 1, 2014 Abstract: Lenalidomide belongs to a novel class of drugs called Immunomodulators which are now being used for the treatment of plasma cell dyscrasias with variable degrees of efficacy and toxicity. Though Second Primary Malignancies (SPM) have been a concern with its use, the benefits of the treatment outweigh the risks. The leuke- mogenic risk seems to be potentiated especially when combined with alkylating agents and the SPMs documented are predominantly myeloblastic. To date there are no reported cases of new lymphocytic leukemias in AL amyloido- sis, regardless of whether undergone treatment or not. We present a case of AL amylodosis who was treated with lenalidomide and subsequently developed acute lymphoblastic leukemia. Keywords: Second primary malignancy, acute lymphoblastic leukemia, AL amyloidosis, lenalidomide Introduction Case Plasma cell neoplasms are characterized by A 73 year old female presented to our institu- clonal proliferation of plasma cells in the bone tion in the fall of 2007 with 3 month history of marrow leading to the production of monoclo- lower extremity edema. A routine complete nal immunoglobulins. They are sometimes blood count at the time of presentation showed accompanied by tissue deposition of monoclo- hemoglobin of 11.5 g/dL, normal WBC count, nal immunoglobulins or their components. and platelets 319,000/μL. Serum and urine Amyloidosis refers to a distinct group of tissue protein electrophoresis with immunofixation deposition disorders among which light-chain detected lambda light chains. A kidney biopsy (AL) amyloidosis is the most common type. The was obtained and showed multiple glomeruli with moderate to severe diffuse mesangial introduction of lenalidomide and other immu- expansion with accumulations of acellular, nomodulators (IMiDs) as a treatment modality weakly PAS positive material that shows red- for amyloidosis was a significant breakthrough green birefringence staining with Congo red in this disease. Multiple trials are ongoing with when examined under polarized light microsco- IMiDs in combination with other drugs for the py consistent with amyloid deposition (Figure treatment of AL amyloidosis [1]. There have 1). Immunofluorescent studies demonstrated been rare cases in which plasma cell neo- smudgy lambda light chain deposition in the plasms treated with lenalidomide develop interstitium and vessel walls. Kappa light chain acute leukemia post lenalidomide treatment was negative. The diagnosis of renal amyloido- and these cases were predominantly myelo- sis, AL lambda type involving glomeruli, intersti- blastic. We describe a rare incidence of tium and vessels was rendered. Bone marrow B-lymphoblastic leukemia in a patient with AL studies demonstrated a population of lambda amylodosis who received lenalidomide and light chain restricted plasma cells by flow dexamethasone for 56 months. cytometry. The bone marrow aspirate smears Acute leukemia in a lenalidomide treated amyloidosis patient g/dL. Review of peripheral blood smear showed numerous blasts. Bone marrow studies demonstrat- ed a markedly hypercellular mar- row with sheets of medium sized blast (Figure 2B). Flow cytometric studies showed an expanded B- lymphoblast population with dim CD45+, bright CD38, dim-moder- ate CD19, CD20, CD10, dim TdT, moderate CD34, variable CD33 and moderate-bright HLA-DR expr- ession, all consistent with a diag- nosis of B-lymphoblastic leukemia. FISH analysis showed copy gain of MYC and IGH in 13% of the nuclei, deletion of p53 gene in 76% of the cells, deletion of ABL gene in 79% Figure 1. Renal Biopsy with insert demonstrating amyloid deposits of the cells and low levels of copy showing birefringence on polarizing microscopy after Congo red stain- ing. gain for BCR (6.5%) and MLL genes (9%), monosomy 7 (79.5% of the cells), deletion of 20q (79.5% of showed trilineage hematopoiesis and with a the cells), tetrasomy 8 and copy gains for population of plasma cells, 5-8% of the total 5p/5q. There were no rearrangements for any cellularity (Figure 2A). Congo red stain was pos- studied probe set. Cytogenetic studies demon- itive for amyloid deposition. Cytogenetic and strated a normal karyotype: 46 XX. FISH (fluorescent in-situ hybridization) panel for multiple myeloma were within normal limits. The patient began induction chemotherapy These findings were compatible with lambda with daunorubicin, vincristine and prednisone light chain amyloidosis. and achieved a complete remission. Phase 2 of induction chemotherapy included cytoxan, Lenalidomide was started at 15 mg daily for 21 cytarabine, 6-mercaptopurine and intrathecal days, followed by 7 days off, for a 28 day total methotrexate [2]. Consolidation chemotherapy cycle. Dexamethasone was given at a dose of with high dose methotrexate was administered 20 mg weekly. She received aspirin for throm- and was complicated by an admission for infec- boembolic prophylaxis. At the initiation of treat- tion and bleeding. A few months after the com- ment, her serum lambda light chain level was pletion of consolidation chemotherapy, the 60 mg/dL. There was initially a flare in her patient unfortunately relapsed. Salvage chemo- lambda light chains to 101 mg/dL then the lev- therapy was attempted with vincristine and els started to improve. The patient achieved dexamethasone. Due to complications of her partial hematologic response with more than disease and treatment, she eventually devel- 50% reduction in the level of the serum mono- oped multi-organ failure and was put on com- clonal protein in less than 2 months and a com- fort measures. plete hematologic response with complete dis- appearance of the monoclonal protein in the Discussion serum in 7 months. The patient continued to be on the same regimen for a total duration of 56 It is estimated that more than 12 million cancer months. survivors are currently alive in the United States. Increasing survivorship has led to focus In November 2012, she presented with gener- on the long-term outcome of malignancies and alized weakness, lightheadedness and easy chemotherapy complications [3]. Lenalidomide bruising. On complete blood count the patient which is a less toxic and more potent derivative was found to have severe thrombocytopenia at of its parent drug, thalidomide, has renewed 16,000/μL. Her WBC count was normal at interest in the treatment of plasma cell dyscra- 5,600 cells/μL and the hemoglobin was 12.0 sias due to its significant therapeutic activity. 2684 Int J Clin Exp Pathol 2014;7(5):2683-2689 Acute leukemia in a lenalidomide treated amyloidosis patient Figure 2. A: Core bone marrow biopsy showing prominence of plasma cells consistent with AL amyloidosis. B: Bone marrow aspirate showing Acute Lymphoblastic Leukemia. Lenalidomide was examined in multiple phase with multiple myeloma who were treated with 2 studies for the treatment of AL amyloidosis in lenalidomide. However, the increased risk of a combination with other drugs. These trials SPM with lenalidomide was noted when the demonstrated favorable hematologic and drug was used in combination with alkylating organ response rates, manageable toxicity and agents. The hematologic malignancies found in no reported cases of second primary malignan- association with multiple myeloma were pre- cy (SPM) [4-9]. Lenalidomide, along with other dominantly acute myeloid leukemia or myelo- new targeted agents has dramatically improved dysplastic syndromes and a limited number of the overall median survival of patients with cases of B cell malignancies including acute amyloidosis to greater than 3 years [6, 9]. There lymphoblastic leukemia, Hodgkin and non- is a growing concern about an increasing num- Hodgkin lymphoma (NHL) [11, 12, 26]. ber of cases of SPMs associated with the use of lenalidomide in newly diagnosed and In a prospective double blind study by McCarthy relapsed multiple myeloma [10-12]. Though et al which compared the use of lenalidomide there are no reported cases of SPM in untreat- versus placebo for maintenance therapy after ed primary amyloidosis except for the limited autologous hematopoietic stem-cell transplan- number of cases reported of its delayed pro- tation in multiple myeloma, 8 cases of SPMs gression to multiple myeloma, it could be were reported in the lenalidomide group, two of debated that patients with untreated amyloido- which were NHL and ALL [12]. It is unclear as to sis do not survive long enough for other can- whether these 2 patients had received an alkyl- cers to develop [13]. We describe a patient with ating agent during the treatment course. The AL amylodosis who was treated with lenalido- rest of the malignancies were non-lymphoid in mide and dexamethasone. After 56 months of origin. A phase 3 placebo-controlled trial for treatment, she developed B-lymphoblastic leu- multiple myeloma by M. Attal et al, studied kemia. After thorough review of the literature, patients under the age of 65 years with non- we found no reports of B-cell acute lymphoblas- progressive disease who received consolida- tic leukemia occurring after a diagnosis of AL tion treatment with lenalidomide within six amyloidosis. months of autologous stem-cell transplanta- tion [11]. At a median follow-up of 34 months Before the advent of immunomodulators there from randomization and 44 months from diag- have been numerous cases of SPMs in multiple nosis, there were 32 SPMs in 26 patients myeloma, MGUS and Waldenström’s macro- reported in the lenalidomide group versus 12 globulinemia, but were predominantly of non SPMs in 11 patients in the placebo group.