Venetoclax and hypomethylating agents in older/unfit patients with blastic plasmacytoid dendritic cell neoplasm
Authors: Naseema Gangat, Marina Konopleva, Mrinal M. Patnaik, Elias Jabbour, Courtney DiNardo, Aref Al‐Kali, James M. Foran, Ginna L. Granroth, Horatiu Olteanu, Tapan Kadia, Ayalew Tefferi, Naveen Pemmaraju
Journal: American Journal of Hematology (2021)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematological neoplasm predominantly afflicting older males (median age; 66–70 years), frequently characterized by a cutaneous, lymph node, bone marrow, and/or central nervous system (CNS) involvement with dismal outcomes.1, 2 Tagraxofusp, a CD123 directed antibody conjugate composed of human interleukin-3 (IL-3) and truncated diphtheria toxin, is an approved therapy for BPDCN, with high response rates of 90% and 67% among untreated patients and those with relapsed disease, respectively.3 Nonetheless, survival continues to be compromised with 24-month overall survival of 52% and median overall survival of 8.5 months in treatment naïve and relapsed patients, respectively.3 Moreover, treatment-induced toxicities are not uncommon with potential for fatality; hepatotoxicity (64%), hypoalbuminemia (55%), thrombocytopenia (49%), and capillary leak syndrome (19%).3 Notably, not all patients with BPDCN will be eligible for CD123-targeted therapy as in the setting of baseline severe hypoalbuminemia, cardiac co-morbidities, or renal insufficiency. Furthermore, the widespread availability of CD123-targeted agents beyond the US and EU is not common. Allogeneic stem cell transplantation (SCT) can result in long-term remissions for selected younger/fit patients with BPDCN but given the older median age and significant co-morbidities in many real-world patients with BPDCN, SCT is often not an option.4 Interestingly, in pre-clinical investigations, BPDCN cells depicted BCL-2 dependence,5 and epigenetic dysregulation6-9 and treatment with venetoclax have been administered as monotherapy or in combination with chemotherapy in small series of patients.10 Venetoclax (Ven), an oral BCL-2 inhibitor in combination with hypomethylating agents (HMA) is approved for elderly and/or unfit acute myeloid leukemia (AML).11-13 Accordingly, we share our experience with Ven and HMA in 10 patients (median age; 70 years [range; 22–82 years]) with BPDCN treated at the Mayo Clinic (Rochester, MN [n = 3], Arizona [n = 1], Florida [n = 1]), and MD Anderson Cancer Center (n = 5). Study patients were retrospectively recruited after respective institutional review board approval. Diagnosis was established by skin, lymph node, or bone marrow biopsy. In addition, all patients underwent positron emission tomography (PET) imaging and cerebrospinal fluid sampling to evaluate for nodal and CNS disease. Table 1 summarizes clinical characteristics including treatment details for all 10 BPDCN patients treated with Ven + HMA. Notably, the majority of patients had baseline co-morbidities, including renal failure, cardiac disease, hypoalbuminemia, hepato-biliary disease that limited upfront CD123-targeted and clinical trial-based therapy. It is, therefore, an urgent unmet medical need to investigate non-CD123-based and noncytotoxic chemotherapy regimens that can be safely delivered in the setting of extensive co-morbidities in older/unfit patients with BPDCN.14, 15 All patients in this case series that were offered treatment with HMA + VEN in the front-line or for relapsed disease responded to therapy, although responses were short-lived, two patients proceeded to allogeneic SCT, and transplant is forthcoming for another patient. A detailed overview of five patients treated at the Mayo Clinic is provided below. ASXL1 TET2 ZRSR2 Azacitidine 75 mg/m2 day 1–7 Ven 400 mg × 28 days 2 cycles Complete response after 2 cycles (14 months ongoing) Haploidentical transplant 4 months post-diagnosis Alive 17 months Post-diagnosis 13 months post-transplant ASXL1 VUS SH2B3 TERT TET2 Azacitidine 75 mg/m2 day 1–7 + Ven 400 mg × 28 days (cycle 1–2), Azacitidine 75 mg/m2 day 1–5 + Ven 100 mg × 14 days (cycle 3–5) Treatment interruption 3 months Azacitidine 75 mg/m2 day 1–7 + Ven 100 mg × 28 days (cycle 6) Complete response after 2 cycles (6 months) Cutaneous Relapse 6 months after achieving CR Prolonged Cytopenias Reactivation of tuberculosis Alive 10 months post-diagnosis Resumed Aza/Ven due to relapse Cutaneous, lymph node (cervical, axillary, inguinal, periportal, retroperitoneal) Bone marrow RUNX1 SF3B1 SRSF2 Azacitidine 75 mg/m2 day 1–7 + Ven 100 mg × 28 days (cycle 1) Azacitidine 75 mg/m2 day 1–7 + Ven 100 mg × 12 days (cycle 2) Tagraxofusp for cutaneous relapse Complete marrow response, Resolution of LN on PET post cycle 1, with major skin response (3 weeks) Cutaneous relapse during cycle 2 Dead 2 months post-diagnosis due to capillary leak syndrome 44,XY,add(1)(q21), der(4)t(1;4)(q21;q21), −9,-13[9]/46,XY [11] ASXL1 SRSF2 TET2 Decitabine 20 mg/m2 day 1–5, Ven 400 mg × 28 days (4 cycles) Complete response after cycle 2 tagraxofusp Cutaneous relapse after cycle 5 of tagraxofusp Major skin response after cycle 1 dec/ven (3 months) relapse after cycle 4 proceeded with Cladribine Death 10 months post-diagnosis due to progressive disease Hyper-CVAD 1A CLAG-M Re-induction, EC consolidation Bone marrow lymph nodes (axillary, mediastinal, retroperitoneal), spleen Decitabine 20 mg/m2, day 1–5, + Ven 400 mg × 28 days (6 cycles) Hyper-CVAD+ Ven 200 mg for second relapse post 2nd allo Complete response after 5 cycles proceeded to allogeneic transplant, relapsed 9 months post-transplant received tagraxofusp × 4 cycles proceeded to 2nd allogeneic transplant Death 12 months post 2nd allo due to sepsis and recurrent disease Overall survival- 36 months Cutaneous (chest, back, upper, and lower extremities), lymph nodes. Bone marrow TET2 JAK2 PHF6 SH2B3 Decitabine 20 mg/m2 X10 days +VEN 100 mg × 21 days #7 TET2 ETV6 NRAS TP53 U2AF1 ZRSR2 Decitabine 20 mg/m2 X10 days +VEN 100 mg × 21 days× 2 cycles Partial response- Bone marrow CNS➔ neg Hyper-CVAD alloSCT FLAG TET2 ASXL1 Decitabine 20 mg/m2 X10 days +VEN 100 mg × 21 days × 1 cycle Prior alloSCT Hyper-CVAD autoSCT Tagraxofusp TET2 MPL Decitabine 20 mg/m2 X10 days +VEN 100 mg × 21 days × 4 cycles TET2 ASXL1 KRAS NRAS Decitabine 20 mg/m2 X5 days +VEN 100 mg × 14 × 3 cycles days × 3 cycles Patient #1: A 67-year-old gentleman presented with a raised nodular skin rash involving the right lower flank region, which extended to involve the trunk, proximal thighs, and face. Skin biopsy confirmed BPDCN with neoplastic cells weakly positive for CD123 and CD56 with expression of CD4, CD43, and TCL1. Hemoglobin was 11.5 g/dL, white cell count 4.1 × 109/L, absolute neutrophil count (ANC) 2.3, 56% monocytes, and platelet count of 122 × 109/L. Bone marrow biopsy was noted to be 50% cellular with left-shifted granulopoiesis and 4% blasts, without morphological evidence for BPDCN. Karyotype was normal and ASXL1 p.Gly646TrpfsX12 (36%) mutation was noted, in addition to TET2 p.Try1255X (69%), p.Met804ArgfsX9 (13%) and two ZRSR2 variants, D185G, and in-frame exon 11 deletion. He initiated therapy with azacitidine 75 mg/m2 days 1–7 and Ven 400 mg for 28 days with dramatic improvement of cutaneous lesions after cycle one, achieving complete response after 2 cycles without treatment-emergent complications. He proceeded to a haplo-identical allogeneic transplant and remains disease-free 17 months after diagnosis. Patient #2: Sixty-six-year male presented with a 6-month history of progressively enlarging nodular lesion on his back and emergence of multiple lesions on his trunk and upper extremities. Left chest wall lesion biopsy was positive for CD56, CD123, CD303, TCL1A, and CD4. Hemoglobin was 13.5 g/dL, white count 3.8 × 109/L, 17% monocytes, and platelet count of 106 × 109/L. Bone marrow biopsy showed slight megakaryocytic atypia, slight increase in monocytes, and 3% blasts without morphologic evidence of BPDCN. Next-generation sequencing with ASXL1: c.1934dup; p.Gly646Trpfs*12 (29%) mutation and variants of unknown significance (VUS); SH2B3:c.107C>A; p.Ala36Glu (48%) TERT: c.1552G>T; p.Ala518Ser (50%) and TET2:c.3530T>G; and p.Ile1177Ser (58%). He received azacitidine 75 mg/m2 × 7 days, and Ven 400 mg daily, achieving a major cutaneous response after cycle 1. He developed prolonged cytopenias, and after cycle 5, had a treatment hiatus of 3 months due to reactivation of latent tuberculosis. During the latter phase, new skin lesions emerged after which sixth cycle of azacitidine for 7 days and Ven 100 mg × 28 days was administered with marked improvement in skin lesions. He is currently receiving cycle seven of azacitidine and Ven, awaiting a matched unrelated donor allogeneic SCT. Patient #3: A 65-year-old gentleman presented with a 2-week history of rash, fever, and weight loss. Hemoglobin was 7.2 g/dL, white count 1.2 × 109/L, ANC 0.39, and platelet count of 163 × 109/L. PET scan showed hypermetabolic lymphadenopathy, involving bilateral cervical, axillary, inguinal, periportal, and retroperitoneal nodes. Right shoulder skin biopsy was positive for CD4, CD123 consistent with BPDCN, and right axillary lymph node biopsy was also confirmatory. Bone marrow biopsy with 50% blasts, cytogenetics with trisomy 13, molecular studies revealed RUNX1: c.416G>A; p.Arg139Gln(15%), SF3B1: c.1998G>C; p.Lys666Asn(38%); and SRSF2: c.284C>G;p.Pro95Arg (34%) mutations. Due to transaminitis, he was initiated on azacitidine 75 mg/m2 × 7 days and Ven 100 mg daily × 28 days. Following cycle 1, complete marrow response with cytogenetic and molecular remission, near-complete resolution of adenopathy, and major skin response was achieved. However, new skin lesions emerged on day 12, cycle 2 of azacitidine and Ven, biopsy-proven to be relapsed disease. Hence, tagraxofusp was instituted, at 12 μg/kg daily × 3 doses, following which he developed fatal capillary leak syndrome. Patient #4: A 78-year-old gentleman presented with a 6-month history of a progressive skin rash; biopsy was positive for CD 45, BCL2, CD56, CD123, TCL1A, and CD33 consistent with BPDCN. White cell count was 4.4 × 109/L with 16% circulating blasts, platelets of 40 × 109/L, and hemoglobin of 12.2 g/dL. Bone marrow biopsy with 84% blasts consistent with BPDCN, with complex monosomal karyotype, and ASXL1: c.2324T>A; p.Leu775 (18%), SRSF2: c.284C>G; p.Pro95Arg (29%), TET2: c.4393C>T; p.Arg1465 (29%) mutations. PET/CT scan revealed involvement of lymph nodes in the neck, axillae, gastrohepatic, periportal regions, iliac chain, groin, and spleen. He initiated therapy with tagraxofusp, which was well-tolerated. Repeat PET imaging and bone marrow biopsy following cycle 2 of tagraxofusp demonstrated complete response with cytogenetic remission. In addition, skin lesions resolved but re-emerged after cycle 5 of tagraxofusp. He received cycle 1 of decitabine 20 mg/m2 × 5 days and Ven 400 mg × 28 days and attained a major skin response. During cycle 4, Ven was discontinued after 14 days due to cytopenias. Soon thereafter new skin lesions emerged after 3 months of achieving complete remission (CR). He received salvage therapy with one cycle of cladribine but unfortunately succumbed to progressive disease. Patient #5: A 22-year-old female presented with severe back pain. MRI spine without intramedullary or leptomeningeal enhancement but bone marrow was diffusely T1 hypodense. Blood counts on presentation were as follows; white count 27 × 109/L with 70% blasts, hemoglobin 9.5 g/dL, and platelet count 85 × 109/L. Peripheral blood flow cytometry revealed a distinct population expressing CD4, CD123, partial CD7 (dim), CD22, CD38 (low density), CD56, and HLA-DR. Bone marrow biopsy was consistent with BPDCN. PET imaging with bilateral axillary, mediastinal, retroperitoneal adenopathy, and mild splenomegaly. Initial therapy comprised of hyper fractioned cyclophosphamide, vincristine, adriamycin, dexamethasone (hyper-CVAD), which led to resolution of adenopathy, but persistent marrow disease. She received salvage cladribine, cytosine arabinoside, G-CSF, mitoxantrone, which led to CR, followed by consolidation with etoposide, cytosine arabinoside. Unfortunately, bone marrow biopsy after consolidation showed relapse for which she received decitabine 20 mg/m2 × 5 days and Ven 400 mg × 28 days for a total of 6 cycles, achieving remission after cycle 5, and proceeded with matched unrelated allogeneic transplant in CR2. Unfortunately, she relapsed 9 months post-transplant, was treated with tagraxofusp × 4 cycles, as a bridge to second matched related donor allogeneic transplant. She relapsed a year following second transplant, began salvage therapy with hyper-CVAD and Ven but died during cycle one as a result of sepsis and progressive disease. The literature on Ven plus HMA therapy for BPDCN is limited to a few patients treated with either Ven as a single agent, HMA alone, or as combination therapy. Ven monotherapy in two older patients with relapsed/refractory BPDCN, and cutaneous, nodal, and marrow involvement and prior therapies, including modified hyper-CVAD, IL-3 directed therapy, led to remarkable cutaneous response, partial nodal response but without marrow response at week 4 in patient one.5 Unfortunately, treatment was complicated by intracranial hemorrhage as a result of thrombocytopenia, which led to his demise.5 Similarly, a second patient also demonstrated a dramatic skin and nodal response, with partial marrow response at week 4, and continued on therapy for 12 weeks until disease progression.5 Notably, in a subsequent report of a 62-year female with cutaneous, nodal, and marrow involvement, previously received bortezomib and simvastatin, Ven treatment resulted in marrow response in 1 month, and complete nodal response at 6 months, which was ongoing at 9 months.16 With regard to azacitidine monotherapy, two elderly patients with BPDCN and concomitant myelodysplastic syndrome, achieved rapid improvement of skin lesions and stabilization of counts, but infectious complications resulted from neutropenia, after the fourth and fifth cycle of therapy, eventually leading to demise in both cases.17 In another series of three BPDCN patients that received azacitidine, similar short-lived responses were reported, with median overall survival of 17 months.18 Similarly, Ven + HMA or cytarabine in two heavily pretreated BPDCN patients, resulted in major nodal response, partial marrow response, and improvement in skin lesions in one patient; and the second patient achieved a major skin response.19 Two additional cases have since been reported, the first case with skin, lymph node, and marrow involvement and documented CR after hyper-CVAD (3 cycles), experienced cutaneous relapse, but achieved a rapid response by cycle 1 day 14 of Ven + azacitidine, which was durable at 8 months.20 Another patient with cutaneous relapse following tagraxofusp, achieved major skin response following 2 cycles of Ven and azacitidine, which is ongoing at cycle 5.21 In conclusion, the current series, which is one of the largest compilations of BPDCN patients treated with Ven + HMA off-protocol, confirms clinical efficacy and safety of the regimen, which may serve as a bridge to allogeneic transplant. As in older patients with AML that are unfit for cytotoxic chemotherapy, the HMA + VEN combination may be a feasible alternative to CD123-directed or cytotoxic chemotherapy in patients with BPDCN and extensive co-morbidities. For fit patients, results from ongoing clinical trials featuring combination therapies in doublets and triplets, evaluating Ven with decitabine, and Ven and azacitidine together with tagraxofusp in the relapsed setting are awaited.22-26 N. P. has been a consultant to, received honoraria or research support from Incyte, Novartis, Stemline, Cellectis, LFB, Affymetrix, SagerStrong Foundation, Abbvie, Celgene, Daiichi Sankyo, Plexxikon, Samus, MustangBio, ImmunoGen, CTI Biopharma, BMS, Pacylex, CareDX, and PharmEssentia. Data available by e-mail [email protected] and [email protected].