Gemcitabine and docetaxel as a novel treatment regimen for blastic plasmacytoid dendritic cell neoplasm
Authors: Matthew L. Ulrickson, Akshjot Puri, Sarah Lindstrom, Ryan D. Cassaday, Nicolas De Padova, Pamela S. Becker
Journal: American Journal of Hematology (2017)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, clinically aggressive hematological malignancy derived from the precursors of plasmacytoid dendritic cells. It typically presents as cutaneous lesions, often with blood and bone marrow involvement as well. BPDCN has a male predominance and occurs with a median age of diagnosis in the sixth decade.1 It is characterized by co-expression of CD4, CD56, and CD123, which enable accurate identification of this entity. In fact, the consistent expression of CD123, the IL-3 receptor, has led to the study of an anti-IL3 diphtheria toxin conjugate, SL-401, and the antibody-drug conjugate, SGN-123a, in this patient population with encouraging early results.2 While BPDCN was previously categorized as a lymphoid malignancy, standard front-line regimens for lymphoma such as CHOP had poor efficacy in this patient population. Instead, now categorized with "acute myeloid leukemia (AML) and related precursor neoplasms," the literature demonstrates that responses are more favorable to leukemia-type regimens such as induction used for AML or acute lymphoblastic leukemia (ALL). In one retrospective series, ALL-based regimens such as hyper-CVAD appeared more effective than AML-based regimens for inducing remission in BPDCN.3 In the setting of response, autologous and allogeneic stem cell transplant (SCT) may be beneficial for appropriate candidates with durable responses seen many years following these therapies.4 However, even with these very aggressive approaches, the majority of patients relapse with a median overall survival of about 6 months.4 There is a significant need for additional treatment options for this patient population. Gemcitabine has demonstrated activity in a number of relapsed and refractory lymphoid malignancies with acceptable toxicity and a previous case report of gemcitabine monotherapy in an 80 year old with BPDCN suggested activity.5 Similarly, docetaxel was found to be cytotoxic to ALL cells in vitro and the combination had manageable toxicities in the treatment of other malignancies.6 Based on these experiences we evaluated the activity and tolerability of combination gemcitabine and docetaxel in relapsed BPDCN. This retrospective study identified patients treated for BPDCN diagnosed by WHO 2008 criteria at our institutions from January 1, 2013 to December 31, 2016 who received the gemcitabine/docetaxel regimen (gemcitabine 800 mg/m2 days 1, 8 and docetaxel 75 mg/m2 day 8 q3 weeks) by review of the electronic medical record. The study was reviewed and approved by the local IRB. Any patient with BPDCN that received gemcitabine/docetaxel during the study period was included. Responses were evaluated according to the International Working Group criteria for AML and mSWAT for skin-based disease. Overall survival (OS) and disease-free survival (DFS) were evaluated following receipt of the study regimen, as were therapy-associated toxicities. Three patients were identified during the study period. The median age was 68 (range 57–77), baseline ECOG performance status was 0–1 in all patients and the median number of prior regimens was 4.6 (range 4–6) as summarized in Table 1. Two of the patients had progressed after prior allogeneic transplant, both with a fully-matched unrelated peripheral blood stem cell graft; one patient experienced relapse three months following transplant and the other at seven months. Of note, the patient that did not undergo transplant paused his treatment on gemcitabine/docetaxel during ongoing response to participate in a clinical trial with SL-401. After two cycles on protocol, he had rapid skin progression to 95% BSA with spontaneous tumor lysis and lactate elevation to 10 mmol/L. However, with restart of gemcitabine/docetaxel complete response was once again obtained in the skin and marrow within two cycles with subsequent improvement in his performance status and lab parameters. Patient age (years) All three patients had complete skin response, with two patients having prior bone marrow involvement and they achieved complete marrow response as well. Median progression-free survival was 10.6 months (range 5–15 months), with one patient remaining in ongoing remission 15 months after treatment at the time of publication. The patient with 12-month progression-free survival was maintained on gemcitabine monotherapy for six months with stable disease control after initial response to support improved balance of efficacy and toxicity before returning to the combination after relapse while on separate clinical trial. After regaining complete response on gemcitabine/docetaxel, he relapsed in skin and marrow and died shortly thereafter. The final patient had CNS relapse during ongoing treatment with gemcitabine/docetaxel. Median overall survival after start of the regimen was 13.3 months (range 8–17 months) with one patient remaining alive and in remission 15 months after treatment, maintained on oral 6-mercaptopurine and methotrexate. The regimen was tolerated well overall, despite the advanced age of the cohort, with thrombocytopenia being the most common toxicity. Two of the three patients experienced grade 4 thrombocytopenia that led to dose-reduction, at the earliest during cycle three in a postallogeneic transplant patient. Two patients required GCSF support due to neutropenia, with one episode of febrile neutropenia reported. Nonhematologic toxicities were notable for one patient with hand-foot syndrome, grade 1–2 nausea, as well as fatigue and myalgias. Molecular evaluation was performed in an exploratory manner for one subject with a skin biopsy sample obtained just prior to initiation of gemcitabine/docetaxel. This identified mutations in NRAS (Q61K), TET2 (N752fs*59 and P1237fs*16), U2AF1 (S34F), RB1 (exon loss 3-27), and CPS1 (A347S). This was performed in the patient with 12 month PFS during initial treatment. BPDCN is an aggressive hematologic malignancy with limited treatment options. Gemcitabine in combination with docetaxel was well-tolerated and achieved significant and sustained responses in this small retrospective series. This regimen showed antineoplastic activity both following allogeneic transplant and in the multiply-relapsed setting. This regimen should be considered for patients with relapsed disease and for those who are unable to tolerate aggressive induction therapy or enroll in a clinical trial. Based on this experience, further study is warranted, although the rarity of this disorder does hinder prospective investigation. Molecular contributors to this disorder may help guide future therapy in this challenging population, and more consistent investigations of mutational burden and clonal development are needed. M.U, A.P. designed the study, collected data, analyzed data, and wrote the paper; S.L., N.D.P., analyzed the data and wrote/edited the paper; P.B., R.C., collected data, analyzed data and wrote the paper. The authors declare no competing financial interests.