Uday Deotare

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: 10‐Color flow cytometry diagnosis and HyperCVAD therapy

Few studies describe the comprehensive immunophenotypic pattern of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in the bone marrow and its treatment. This retrospective analysis evaluates the diagnostic flow cytometry (FCM) pattern and outcome of nine patients diagnosed with BPDCN. A four‐tube 10‐color FCM panel used for diagnosis of acute leukemia (AL), showed cells in the blast gate (CD45dim/low SSC) and were positive for CD4(bright), CD33(dim), CD56(heterogenous), CD123(bright), CD36, CD38, HLA‐DR, CD71. Seven patients received front‐line induction therapy with HyperCVAD with an overall response rate of 86%. Five of six responders underwent planned allogeneic hematopoietic cell transplantation (allo‐HCT). For a median follow up of 13.3 months, the 1‐year disease free survival and overall survival were 56 and 67%, respectively. An accurate diagnosis of BPDCN can be made by 10‐color FCM using a four‐tube AL panel demonstrating a characteristic pattern of antigen expression. Front‐line induction chemotherapy with HyperCVAD can yield high remission rates, but allo‐HCT is required for long‐term durable remissions. Am. J. Hematol. 91:283–286, 2016.

Ponatinib in the therapy of chronic myeloid leukemia

ABSTRACT Introduction: Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder that has become the neoplastic poster child for understanding the disease biology of a malignant disease and targeting effective therapy. The targeted therapy of BCR-ABL inhibition by tyrosine kinase inhibitors (TKI) has provided the epitome for “Ehlrich’s magic bullet” postulated decades ago. Areas covered: Due to the therapy with these drugs, the survival of newly diagnosed patients with this disease now approaches that of age matched controls. Progression to advanced phases of CML had decreased over the years, though resistance has now been increasingly identified. Expert commentary: Ponatinib is a third generation TKI, which has shown to be effective in both early and advanced phases of CML and those bearing resistant mutations, specifically T315I. However, new side effect considerations need to be balanced with the efficacy, to establish the role of ponatinib in the therapy of CML.

Myeloablative versus Reduced-Intensity Conditioning in Patients with Myeloid Malignancies: A Propensity Score-Matched Analysis

Reduced-intensity conditioning (RIC) has been shown to have similar overall survival (OS) but higher relapse rates compared with myeloablative (MAC) regimens in patients with myeloid malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Using propensity score matching (PSM) analysis, well-balanced pairs of different variables can be compared effectively. We retrospectively compared allo-HSCT recipients with acute myeloid leukemia or myelodysplasia receiving a RIC regimen (FBT200; fludarabine 30 mg/m2/day for 4 days, busulfan 3.2 mg/kg/day for 2 days, and total body irradiation [TBI] 200 cGy) or MAC regimen (FBT400; fludarabine 50 mg/m2/day for 4 days, busulfan 3.2 mg/kg/day for 4 days, and TBI 400 cGy). A total of 248 patients (121 in the RIC group and 127 in the MAC group) were included in the analysis. No statistically significant difference was observed in 2-year OS (RIC group, 45.2 ± 5.0%; MAC group, 51.7 ± 5.2%; P = .541), nonrelapse mortality (NRM; RIC group, 28.7 ± 2.8% MAC group, 34.7 ± 4.6%; P = .368), and acute graft-versus-host disease (GVHD) (P = .171) or chronic GVHD (P = .605) at 1 year. The cumulative incidence of relapse (CIR) at 2 years was statistically significantly different between the 2 groups, however (RIC, 26.1 ± 2.6%; MAC, 14.2 ± 3.5%; P = .033). When PSM was applied to the study population, 42 case-control pairs were evenly matched. PSM analysis confirmed no statistically significant difference in 2-year OS (RIC, 49.0 ± 9.1%; MAC, 54.9 ± 7.7%; P = .718), NRM (RIC, 22.2 ± 2.3%; MAC, 33.3 ± 2.8%; P = .238), or CIR (RIC, 25.7 ± 2.6%; MAC, 9.5 ± 1.1%; P = .315) in the PSM pairs. Our findings demonstrate that after applying PSM, FBT 200 RIC conditioning has comparable OS, NRM, and CIR to FBT 400 MAC conditioning before allo-HSCT.

Haematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a North American multicentre collaborative study

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is incurable with conventional therapies. Limited retrospective data have shown durable remissions after haematopoietic cell transplantation (HCT) [allogeneic (allo) or autologous (auto)]. We conducted a multicentre retrospective study in BPDCN patients treated with allo‐HCT and auto‐HCT at 8 centres in the United States and Canada. Primary endpoint was overall survival (OS). The population consisted of 45 consecutive patients who received an allo‐HCT (n = 37) or an auto‐HCT (n = 8) regardless of age, pre‐transplant therapies, or remission status at transplantation. Allo‐HCT recipients were younger (50 (14–74) vs. 67 (45–72) years, P = 0·01) and had 1‐year and 3‐year OS of 68% [95% confidence interval (CI) = 49–81%] and 58% (95% CI = 38–75%), respectively. Allo‐HCT in first complete remission (CR1) yielded superior 3‐year OS (versus not in CR1) [74% (95% CI = 48–89%) vs. 0, P < 0·0001]. Allo‐HCT outcomes were not impacted by regimen intensity [3‐year OS for myeloablative conditioning = 61% (95% CI = 28–83%) vs. reduced‐intensity conditioning = 55% (95% CI = 28–76%)]. One‐year OS for auto‐HCT recipients was 11% (95% CI = 8–50%). These results demonstrate efficacy of allo‐HCT in BPDCN, especially in patients in CR1. Pertaining to auto‐HCT, our results suggest lack of efficacy against BPDCN, but this observation is limited by the small sample size. Larger prospective studies are needed to better define the role of HCT in BPDCN.

A critical review of treatment modalities for blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive tumor derived from the precursors of plasmacytoid dendritic cells. It is a rare disease presenting across all ages with either skin or both skin and bone marrow involvement often conferring a poor prognosis. Though localized radiation has been used before, acute leukemia based regimens, remains the treatment of choice for induction of remission. Hematopoietic stem cell transplant, either autologous or allogeneic, is further required for attaining sustained remissions. Recently, a number of targeted therapies and newer drugs have been used as the molecular and genetic understanding of the disease have improved.

Efficacy of Cidofovir in Treatment of BK Virus–Induced Hemorrhagic Cystitis in Allogeneic Hematopoietic Cell Transplant Recipients

BK virus-associated hemorrhagic cystitis (BK-HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HCT), with incidences up to 70%. Cidofovir is an antiviral agent with growing evidence as a therapeutic intervention. To assess the safety profile and efficacy of intravenous and intravesical cidofovir in allo-HCT patients with BK-HC, a retrospective study was undertaken of the allo-HCT cohort who received cidofovir for symptomatic BK-HC (hematuria with BK viruria or viremia) from January 2010 until March 2017 in a single transplant center in Ontario, Canada. The primary outcome measure was a reduction in BK-HC severity (graded from 1 to 4); secondary outcomes included overall survival, BK virus titers, and the onset of acute kidney injury. Twelve allo-HCT patients received cidofovir for BK-HC, with pretreatment clinical severity of 3 (50%) or 4 (50%). Cidofovir was administered via intravenous (33%), intravesical (58%), or both modalities (8%). After a median cumulative dose of 10 mg/kg (range, 1 to 37), mean BK-HC grade decreased significantly by 1.8 (3.5 precidofovir, 1.7 postcidofovir, P < .01). Sixty-six percent of patients had at least partial response to cidofovir, with similar response rates between intravenous (66%) and intravesical (62%) administration. Sixty-seven percent of patients died, and 33% of patients experienced renal toxicity, including 2 patients receiving intravesical therapy. In this retrospective series, there was a significant reduction in BK-HC severity after cidofovir administration; most patients achieved at least partial response after cidofovir administration. Even with intravesical instillation, acute kidney injury remains a potential complication of cidofovir. Although cidofovir may be an efficacious therapy for BK-HC, albeit with potential demonstrated toxicities, further prospective trials are needed.

Allogeneic Hematopoietic Stem Cell Transplantions in Blastic Plasmacytoid Dendritic Cell Neoplasm in first complete remission: an effective therapy for a rare disease

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive tumor derived from the precursors of plasmacytoid dendritic cells (pDC) with a high frequency of primary cutaneous involvement, and dissemination to bone marrow with disease progression.[1] Median age at presentation is 60 to 70 years with a male predominance (3:1). Most BPDCN patients present with skin lesions that include nodules, plaques, or bruise-like areas with lymphadenopathy or bone marrow Involvement.[2] BPDCN represents only 0.76% of cases presenting in the leukemic phase as acute leukemia.[3] Given the rarity of this hematologic malignancy, the optimal frontline therapy is unclear. Recent data suggest that BPDCN patients treated with acute lymphoblastic leukemia (ALL)-type regimens, with or without allogeneic hematopoietic cell transplant (alloHCT), may have a better outcome.[4] There are no published randomized controlled trials evaluating the role of autologous hematopoietic cell transplant (autoHCT) or allo-HCT in these patients. Our center had presented recently, excellent remission rates with HyperCVAD therapy.[5] Here we present the Allo-HCT data in this group of patients. Our retrospective analysis evaluates the outcome of 6 patients who were diagnosed with BPDCN and underwent allo-HCT at the Princess Margaret Cancer Centre. The study was approved by the Institutional Review Board of the hospital. All six patients were in leukemic phase at presentation, with five patients having skin involvement. All these patients were diagnosed by 10-color flow cytometry by using the panel published recently.[6] The basis for diagnosis was similar to that formulated by Garnache-Ottou et al.[7] with CD4, CD56 and CD123 positivity in all patients. Prior to transplant 5 out of 6 patients underwent HyperCVAD as the ALL-type chemotherapy for remission induction, one patient was treated with a combination of Fludarabine and L-Asparginase. All patients were transplanted in first Complete Remission (CR1) with median time of 4.5 months to undergo allo-HCT from achievement of CR1. The median age at transplant was 44 years (range, 25 to 70 years) with female preponderance (2M:4F). The myeloablative regimen (MAC) used was, Cyclophosphamide-60 mg/kg/day 2 days/Total Body Irradiation-200 cGy 6 doses (Cy/TBI) in patients with age 60 years (n1⁄4 3) and Fludarabine-30 mg/m/day 4 days/Busulphan-3.2 mg/kg/day 2 days/Total Body Irradiation-200 cGy 1 dose(FBT-200) was used as reduced intensity conditioning (RIC) in patients with age460 years (n1⁄4 3). Graft-versus-host disease (GVHD) prophylaxis was cyclosporine and mycophenolate in related donors with the addition of one dose of alemtuzumab to cyclosporine in unrelated donor transplantation. Two patients received stem cell transplants from sibling donors (6/6 HLA matched) and the remaining patients from matched unrelated donors (10/10 allelic HLA matched). The graft source was peripheral blood stem cells (PBSC) in all patients. The CD34 + cell dose varied from 3.7 to 37.86 with mean cell dose was 14.75 10/kg of recipient body weight. The median time for neutrophil and platelet engraftment was 13.5 (range, 11–17 days) and 13 days (range,

Outcome following second allogeneic hematopoietic cell transplantation: A single-center experience

Second allogeneic hematopoietic cell transplantation (HCT) may be indicated following relapse or graft failure following first HCT. Our retrospective single‐center study sought to investigate parameters that influence post‐second allogeneic HCT survival.

Reduction of severe acute graft-versus-host disease using a combination of pre transplant anti-thymocyte globulin and post-transplant cyclophosphamide in matched unrelated donor transplantation

Use of Post-transplant Cyclophosphamide (PTCy) has recently been introduced specifically in the haplo-identical transplant setting with promising results [1]. This intervention has also shown a significant reduction of acute graft versus host disease (aGVHD) and a trend towards improving chronic graft versus host disease (cGVHD) [2]. The efficacy of PTCy has mainly been demonstrated in patients with bone marrow (BM) as the stem cell source [3]; and has been associated with clinically significant acute and chronic GVHD in patients with peripheral blood as the stem cell source (PBSC) [4]. Anti-thymocyte globulin (ATG) has previously been shown to reduce the incidence of cGVHD at around 1 year post transplantation [5], without increasing the incidence of relapse [6]. The incidence of Gr III-IV aGVHD was 28% using ATG, cyclosporine and mycophenolate mofetil (ATG-CSA-MF), as the GVHD prophylaxis regimen, in the recently concluded randomized trial [7]. We hypothesized that a combination of both ATG and PTCy would reduce the incidence of both acute and chronic GVHD in our patient cohort; effectively reducing the morbidity and mortality associated with severe forms of GVHD. Here we present the preliminary outcome in our unrelated patients using this regimen. This is a retrospective study of the patient cohort treated from 1 October 2015 until 31 March 2016 in a single center. This study was approved by the institutional Research Ethics Board. This study cohort was compared to the earlier historical study cohort of patients who received pre transplant ATG as part of GVHD prophylaxis at our center [7]. Patients received transplant from HLAMatched (10/10) or mismatched (9/10) unrelated donors. The graft source was Filgrastim stimulated PBSC. The treatment schema initially for ages<60 years was a myeloablative regimen using the FBT400 protocol and for ages>60 years consisted of FBT200 as the reduced intensity conditioning (RIC) regimen [8]. The FBT400 regimen consisted of a combination of Fludarabine (50 mg/m2 on days −5,−4,−3,−2), Busulphan (once daily dose of 3.2 mg/kg on days −5,−4,−3,−2) along with 2 doses of total body irradiation (TBI) of 200 cGy on Day −1. The regimen of FBT200 comprised of reduced dose of Fludarabine at 30 mg/m2 on same days but with only 2 days of Busulphan (on days −2,−1) and only one dose of 200 cGy TBI on day −1 [9]. We subsequently decided to use FBT200 for all patients in view of increased liver and kidney toxicities observed with FBT400 regimen with post-transplant cyclophosphamide. The GVHD prophylaxis consisted of ATG (rabbit, Thymoglobulin; Genzyme-Sanofi, Lyon, France) on days −3, −2 and −1 with a total dose of 4.5 mg/kg. Patients additionally received 50 mg/kg/day IV cyclophosphamide on days +3 and +4 (PTCy), with the first dose starting 72 h after PBSC infusion. This was further followed by post transplant administration of IV cyclosporine (2.5 mg/kg twice daily) on day+ 5 onwards, with change to oral route when the patient was able to tolerate orally. Presented in part at the 58th American Society of Hematology Annual Meeting in San Diego, California, 2–6 December 2016 and at the American Society of Blood and Marrow Transplantation meeting at Orlando, Florida, 22–26 February 2017.

Extramedullary disease at diagnosis of AML does not influence outcome of patients undergoing allogeneic hematopoietic cell transplant in CR1

Extramedullary disease (EMD) at diagnosis of acute myeloid leukemia (AML) has been associated with increased risk of relapse and worse outcomes post‐chemotherapy. This study sought to investigate the association of EMD with outcomes following allogeneic hematopoietic cell transplantation (allo‐HCT).