A 41-year-old woman presented in December 2005 with fatigue, headache, tinnitus, nausea, and early satiety and was found to have abnormal blood counts. A bone marrow (BM) biopsy reportedly revealed undifferentiated acute leukemia (uAL). The patient was induced with a lymphoblastic AL regimen and was reported to be in remission at discharge in February 2006. She received no other chemotherapy until January 2007 when she presented again with leukopenia and recurrent leukemia. She first received 5 cycles of HyperCVAD. HyperCVAD consists of cyclophosphamide, vincristine, adriamycin, and dexamethasone alternating every 21-28 days with methotrexate and cytarabine along with intrathecal CNS prophylaxis. Each set of drugs is given four times for a total of eight cycles followed by maintenance. She then developed thrombocytopenia and then received 6-mercaptopurine and methotrexate (Linker maintenance) for 10 months before her leukemia recurred in June 2008, with a BM biopsy again reported as uAL (WBC count = 0.8 x 109/L, hemoglobin 7.6 g/dL, platelet count = 8 x 109/L). She received induction chemotherapy and was referred to Cedars-Sinai Medical Center for transplantation consultation, after a BM biopsy in July 2008 showed no definitive evidence of residual leukemia. At Cedars-Sinai, she received 1 more cycle of HyperCVAD and underwent an HLA-matched sibling transplant in October 2008. In May 2009, a liver biopsy confirmed graft versus host disease (GVHD) and she received prednisone. She remained in remission until June 2010 when she again became cytopenic and BM biopsy showed relapsed uAL. Her immunosuppressive therapy was stopped, and she received Linker's cycle 1A and then high-dose Ara-C and mitoxantrone (HAM) to achieve remission. The Linker regimen consists of seven courses of therapy followed by maintenance. Its chemotherapy differs from HyperCVAD in that prednisone is used instead of decadron, asparaginase is used, and 6-mercaptopurine is used in the courses of therapy as cyclophosphamide is not. She received a donor lymphocyte infusion (DLI) in August 2010. The cells for the DLI were obtained from the patient's sister on her initial stem cell harvesting and were stored at our hospital. There were three such additional bags stored. The first bag to be thawed and infused consisted of 1.12 x 108 CD3 cells/kg, and the entire bag was given as a DLI. She was well for over 4 months with normal blood counts, apart from increased liver function tests (LFTs) suspected to be due to GVHD.
In late December 2010, she became thrombocytopenic, with normal LFTs, and showed circulating leukemic cells. The BM biopsy sections (Figure 1) showed tightly packed, variably sized, leukemic blasts with irregular nuclear contours or nuclear folds, finely dispersed chromatin, small, usually multiple nucleoli, and scant cytoplasm. The Wright-Giemsa-stained aspirate smears (Figure 2) showed blasts with irregular nuclear contours or nuclear folds, finely distributed chromatin, small nucleoli, and variably abundant, lightly basophilic, agranular cytoplasm with microvacuoles at the periphery of the cell (arrow in Figure 2). The leukemic cells were cytochemically negative for alpha naphthyl butyrate esterase. By flow cytometry, the leukemic cells were TdT+, bright CD56+, HLA-Dr+, dim CD45+, dim CD7+, dim CD38+, dim CD117+, CD3-, CD4-, CD5-, CD8-, CD10-, CD13-, CD14-, CD19-, CD20-, CD22-, CD23-, CD33-, CD34-, CD64-, kappa -, lambda -, cytoplasmic CD79a-, cytoplasmic CD3-, and cytoplasmic myeloperoxidase-. This immunophenotype was similar to the previous flow cytometric immunophenotype of the relapsed leukemia in June 2010. Immunohistochemical stains showed CD43+, TdT+ (Figure 3), CD56+ (Figure 4), CD123+ (Figure 5), and TCL-1+ (Figure 6) leukemic cells. T-cell receptor (TCR) Tgamma, IgH and Igkappa gene rearrangement (RA) showed several small clonal peaks likely representing the few admixed small T- and B-lymphocytes also detected by flow cytometry, similar to previous reports, while TCR Tbeta gene RA was negative. Karyotypic analysis could not be performed. NPM1 exon 12 mutation, FLT3 ITD and FLT3 D835 mutation by PCR were negative. The above morphologic, immunophenotypic, and molecular findings led to a diagnosis of plasmacytoid dendritic cell (PDC) leukemia, as per the current WHO classification, wherein, before rendering a diagnosis of uAL, rare entities including PDC leukemia must be excluded. By cytomorphology, although no feature is considered specific for BPDCN, the blasts in this case are reminiscent of lymphoblasts with overlapping monocytic features and show peripherally situated microvacuoles, as typically described in this entity. By immunophenotype, to diagnose by immunohistochemistry, the expression of at least 1 of 5 BPDCN-associated markers in a CD56+, CD4+-, TdT+, lineage-negative neoplasm is considered minimal. In this case, the leukemic cells were positive for 2 of 5 BPDCN-associated markers, CD123 and TCL-1.
The patient received cyclophosphamide, etoposide, and clofarabine (CEC) on 12/23/2010 for reinduction, and then received a DLI (containing 0.56 x 108 CD3 cells/kg) on 12/29/10. Her blood counts normalized and her LFTs rose. She received an additional DLI on 2/21/2011 in order to maintain her graft-versus-leukemia effect. This was the third and final saved bag from the donor's original collection and contained 0.56 x 108 CD3 cell/kg. Six weeks later, her blood counts dropped, LFTs normalized, and a BM biopsy confirmed relapsed PDC leukemia involving 50% of a 40% cellular marrow, with morphology and immunophenotype similar to the prior biopsy in December 2010. The patient received her 4th DLI on 5/6/11 (this one obtained from a recollection of the donor and containing 0.10 x 108 CD3 cells/kg) after receiving CEC for reinduction.