Diagnostic and Therapeutic Advances in Blastic Plasmacytoid Dendritic Cell Neoplasm: A Focus on Hematopoietic Cell Transplantation

AbstractBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is an exceedingly rare disorder categorized under acute myeloid leukemia by the World Health Organization. Phenotypically, malignant cells coexpress CD4+ and CD56+ without coexpressing common lymphoid or myeloid lineage markers. BPDCN frequently expresses CD123, TCL1, BDCA-2, and CD2AP. Restriction of CD2AP expression to plasmacytoid dendritic cells makes it a useful tool to help confirm diagnosis. Clonal complex chromosome aberrations are described in two-thirds of cases. Eighty percent of BPDCN cases present with nonspecific dermatological manifestations, prompting inclusion in the differential diagnosis of atypical skin rashes refractory to standard treatment. Prognosis is poor, with a median survival of less than 18 months. No prospective randomized data exist to define the most optimal frontline chemotherapy. Current practice considers acute myeloid leukemia-like or acute lymphoblastic leukemia–like regimens acceptable for induction treatment. Unfortunately, responses are short-lived, with second remissions difficult to achieve, underscoring the need to consider hematopoietic cell transplantation early in the disease course. Allografting, especially if offered in first remission, can result in long-term remissions. Preclinical data suggest a potential role for immunomodulatory agents in BPCDN. However, further research efforts are needed to better understand BPDCN biology and to establish evidence-based treatment algorithms that might ultimately improve overall prognosis of this disease

Rituximab-containing reduced-intensity conditioning improves progression-free survival following allogeneic transplantation in B cell non-Hodgkin lymphoma

Background: In B cell non-Hodgkin lymphoma (B-NHL), rituximab-containing reduced-intensity conditioning regimens (R-RIC) have been shown to provide favorable outcomes in single-arm studies; however, large multicenter studies comparing R-RIC and non-rituximab-containing reduced-intensity conditioning regimens (nonR-RIC) have not been performed. Using the CIBMTR database, we report the outcomes of R-RIC versus nonR-RIC regimens in B-NHL. Methods: We evaluated 1401 adult B-NHL patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) who received nonR-RIC (n = 1022) or R-RIC (n = 379) regimens. Graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based approaches. Results: Median follow-up of survivors in the R-RIC and nonR-RIC groups was 47 and 37 months, respectively. On multivariate analysis, no difference was seen between the R-RIC and nonR-RIC cohorts in terms of acute GVHD grade II-IV (RR = 1.14, 95% CI = 0.83-1.56, p = 0.43) or grade III-IV (RR = 1.16, 95% CI = 0.72-1.89, p = 0.54), chronic GVHD (RR = 1.15, 95% CI = 0.92-1.46, p = 0.22), non-relapse mortality (RR = 0.90; 95% CI = 0.67-1.22; p = 0.51), relapse/progression (RR = 0.79; 95% CI = 0.63-1.01; p = 0.055), and mortality (RR = 0.84, 95% CI = 0.69-1.02, p = 0.08) risk. However, R-RIC was associated with a significantly improved progression-free survival (RR = 0.76; 95% CI 0.62-0.92; p = 0.006). On subgroup analysis, mortality benefit was noted in the R-RIC group patients not receiving busulfanbased RIC (RR = 0.76; 95% CI = 0.60-0.96; p = 0.02) and with the use of a higher cumulative rituximab dose (RR = 0.43; 95% CI = 0.21-0.90; p = 0.02). Conclusion: Our analysis shows that inclusion of rituximab in RIC regimens improves progression-free survival in patients with B cell NHL. These data supports the use of R-RIC in B-NHL patients undergoing allo-HCT

Maintenance Therapies for Hodgkin and Non-Hodgkin Lymphomas after Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT

Importance: Maintenance therapies are often considered as a therapeutic strategy in patients with lymphoma following autologous hematopoietic cell transplantation (auto-HCT) to mitigate the risk of disease relapse. With an evolving therapeutic landscape, where novel drugs are moving earlier in therapy lines, evidence relevant to contemporary practice is increasingly limited. The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) jointly convened an expert panel with diverse expertise and geographical representation to formulate consensus recommendations regarding the use of maintenance and/or consolidation therapies after auto-HCT in patients with lymphoma. Observations: The RAND-modified Delphi method was used to generate consensus statements where at least 75% vote in favor of a recommendation was considered as consensus. The process included 3 online surveys moderated by an independent methodological expert to ensure anonymity and an in-person meeting. The panel recommended restricting the histologic categories covered in this project to Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. On completion of the voting process, the panel generated 22 consensus statements regarding post auto-HCT maintenance and/or consolidation therapies. The grade A recommendations included endorsement of: (1) brentuximab vedotin (BV) maintenance and/or consolidation in BV-na\uefve high-risk HL, (2) rituximab maintenance in MCL undergoing auto-HCT after first-line therapy, (3) rituximab maintenance in rituximab-na\uefve FL, and (4) No post auto-HCT maintenance was recommended in DLBCL. The panel also developed consensus statements for important real-world clinical scenarios, where randomized data are lacking to guide clinical practice. Conclusions and Relevance: In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a rigorous framework for developing consensus recommendations for post auto-HCT maintenance and/or consolidation therapies in lymphoma.

Hispanics have the lowest stem cell transplant utilization rate for autologous hematopoietic cell transplantation for multiple myeloma in the United States: A CIBMTR report

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138212/1/cncr30747_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138212/2/cncr30747.pd

Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/133605/1/bjh14046.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/133605/2/bjh14046_am.pd

Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia

Optimal conditioning therapy for hematopoietic cell transplantation (HCT) in acute myelogenous leukemia (AML) remains undefined. We retrospectively compared outcomes of a consecutive series of 51 AML patients treated with oral busulfan (1 mg/kg every 6 hours for 4 days) and cyclophosphamide (60 mg/kg IV × 2 days) - (Bu/Cy) with 100 consecutive AML patients treated with pharmacokinetic targeted IV busulfan (AUC < 6000 μM/L*min per day × 4 days) and fludarabine (40 mg/m2 × 4 days) - (t-IV Bu/Flu). The Bu/Cy and t-IV Bu/Flu groups significantly differed according to donor relation, stem cell source, aGVHD prophylaxis, remission status, primary vs. secondary disease, median age, and % blasts prior to HCT (p < 0.01 for each). Conditioning with t-IV Bu/Flu reduced early toxicity including idiopathic pneumonia syndrome (IPS) and hepatic veno-occlusive disease (VOD). Additionally, the trajectory of early NRM (100 day: 16% vs. 3%, and1 year: 25% vs. 15% for Bu/Cy and t-IV Bu/Flu, respectively) favored t-IV Bu/Flu. Grade II-IV aGVHD (48% vs. 82%, p < 0.0001), as well as moderate/severe cGVHD (7% vs. 40%, p < 0.0001) differed between the Bu/Cy and t-IV Bu/Flu groups, due to the predominance of peripheral blood stem cells in the t-IV Bu/Flu group. Pharmacokinetic targeting of intravenous busulfan in combination with fludarabine is associated with reduced conditioning regimen related toxicity compared to oral busulfan and cyclophosphamide. However, multivariable analysis did not demonstrate significant differences in overall survival (p = 0.78) or non-relapse mortality (p = 0.6) according to conditioning regimen delivered

Allogeneic Transplantation Provides Durable Remission in a Subset of DLBCL Patients Relapsing after Autologous Transplantation

For diffuse large B-cell lymphoma (DLBCL) patients progressing after autologous haematopoietic cell transplantation (autoHCT), allogeneic HCT (alloHCT) is often considered, although limited information is available to guide patient selection. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 503 patients who underwent alloHCT after disease progression/relapse following a prior autoHCT. The 3-year probabilities of non-relapse mortality, progression/relapse, progression-free survival (PFS) and overall survival (OS) were 30, 38, 31 and 37% respectively. Factors associated with inferior PFS on multivariate analysis included Karnofsky performance status (KPS) <80, chemoresistance, autoHCT to alloHCT interval <1-year and myeloablative conditioning. Factors associated with worse OS on multivariate analysis included KPS<80, chemoresistance and myeloablative conditioning. Three adverse prognostic factors were used to construct a prognostic model for PFS, including KPS<80 (4 points), autoHCT to alloHCT interval <1-year (2 points) and chemoresistant disease at alloHCT (5 points). This CIBMTR prognostic model classified patients into four groups: low-risk (0 points), intermediate-risk (2-5 points), high-risk (6-9 points) or very high-risk (11 points), predicting 3-year PFS of 40, 32, 11 and 6%, respectively, with 3-year OS probabilities of 43, 39, 19 and 11% respectively. In conclusion, the CIBMTR prognostic model identifies a subgroup of DLBCL patients experiencing long-term survival with alloHCT after a failed prior autoHCT

Outcomes of Medicare-age eligible NHL patients receiving RIC allogeneic transplantation: a CIBMTR analysis

The application of allogeneic hematopoietic cell transplantation (allo-HCT) in non-Hodgkin lymphoma (NHL) patients ≥65 years in the United States is limited by lack of Medicare coverage for this indication. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report allo-HCT outcomes of NHL patients aged ≥65 years (older cohort; n = 446) compared with a cohort of younger NHL patients aged 55-64 years (n = 1183). We identified 1629 NHL patients undergoing a first reduced-intensity conditioning (RIC) or nonmyeloablative conditioning allo-HCT from 2008 to 2015 in the United States. Cord blood or haploidentical transplants were excluded. The median age was 68 years (range 65-77) for the older cohort vs 60 years (range 55-64) in the younger cohort. The 4-year adjusted probabilities of nonrelapse mortality (NRM), relapse/progression (R/P), progression-free survival (PFS), and overall survival (OS) of the younger and older groups were 24% vs 30% (P = .03), 41% vs 42% (P = .82), 37% vs 31% (P = .03), and 51% vs 46% (P = .07), respectively. Using multivariate analysis, compared with the younger group, the older cohort was associated with increased NRM, but there was no difference between the 2 cohorts in terms of R/P, PFS, or OS. The most common cause of death was disease relapse in both groups. In NHL patients eligible for allo-HCT, there was no difference in OS between the 2 cohorts. Age alone should not determine allo-HCT eligibility in NHL, and Medicare should expand allo-HCT coverage to older adults