Kumar, Ambuj

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease listed as a separate entity in the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours. It is a clinically aggressive hematologic malignancy derived from precursors of plasmacytoid dendritic cells. Traditionally, therapeutic options for BPDCN consisted of conventional antineoplastic chemotherapy, adopted from regimens used to treat acute leukemia (myeloid or lymphoblastic, or lymphomas. Tagraxofusp, a CD123 directed antibody conjugate composed of human interleukin-3 (IL-3) and truncated diphtheria toxin, is also approved for treatment of BPDCN. Unfortunately, none of these are curative options of this disease. Allogeneic (Allo) hematopoietic cell transplantation (HCT) is an established treatment modality for patients with BPDCN with reported encouraging survival, whereas reported data on autologous (auto) HCT are limited. Methods: We conducted a systematic review and meta-analysis (SR/MA) to assess the totality of evidence on the role of allo- and auto-HCT in patients with BPDCN. We performed a comprehensive search of EMBASE and PUBMED/MEDLINE, on April 25, 2024. To be eligible for inclusion in this SR/MA, studies must have included ≥10 patients; be published in full manuscript or letter to editor and have evaluated the use of an allo-HCT and/or auto-HCT for treating BPDCN. Pertaining to benefits, we extracted data based on complete remission (CR), progression-free survival (PFS) (substituted with disease-free survival (DFS) if PFS missing), and overall survival (OS). For harms, we extracted data on non-relapse mortality (NRM) and relapse. Data were pooled under a random effects model. Results: Initial search identified 692 references, of which, 10 met our inclusion criteria. For allo-HCT, 10 studies were included; and for auto-HCT, there were 3 studies. For allo-HCT, pooled rates for CR, PFS/DFS and OS were 69% (2 studies, 91 patients (pts)), 49% (10 studies, 561 pts), and 55% (9 studies, 531 pts), respectively. Pooled rates for NRM and relapse were 24% (8 studies, 470 pts) and 24% (10 studies, 561 pts). Tests of heterogeneity were as follows: for CR analysis (I2=97.04%), PFS/DFS (I2=79.57%), OS (I2=33.18%), NRM (I2=0) and relapse (I2=55.55%). For auto-HCT, only one study reported CR=100%. Pooled rates of PFS/DFS and OS were 68% (3 studies, 43 pts), and 66% (3 studies, 43 pts), respectively. Pooled rates for NRM and relapse were 3% (2 studies, 27 pts) and 25% (3 studies, 43 pts). Tests of heterogeneity were as follows: for CR analysis (I2=not applicable), PFS/DFS (I2=0), OS (I2=27.90%), NRM (I2=0) and relapse (I2=0). A subgroup analysis for allo-HCT recipients in CR1 showed pooled rates of PFS and OS of 60% (5 studies, 76 pts) and 69% (5 studies, 76 pts), respectively. Tests of heterogeneity for PFS and OS for the allo-HCT in CR1 were I2=51.99% and I2=0, respectively. Conclusion: Results of this SR/MA demonstrate that both allo-HCT and auto-HCT are effective treatments for patients with BPDCN, although data supporting the latter are scarce. Allo-HCT in CR1 is associated with a higher pooled rate of OS (69%). Efforts should focus on prompt referral of BPDCN patients for an allo-HCT in CR1, whenever possible, to optimize survival outcomes.

AbstractIntroductionLenalidomide maintenance, commonly prescribed in the postautologous transplantation (AHCT) setting for multiple myeloma (MM), is associated with development of secondary primary malignancies (SPM). Proteasome inhibitor maintenance (PIM) has also been evaluated in MM. We conduct a systematic review/meta‐analysis to assess the efficacy of PIM in MM.MethodsPerforming a comprehensive search of the medical literature using PubMed/Medline and EMBASE on September 11, 2019, we extracted data on clinical outcomes related to benefits (OS, PFS, and depth of hematologic response [DOHR]) and harms (SPM and adverse events). 2144 references were identified; three studies were eligible for inclusion.ResultsA total of 1760 patients were included in the analysis; 507 patients received bortezomib and 395 received ixazomib maintenance. Control arms were either placebo (n = 261) or thalidomide (n = 358). PIM did not improve OS (HR 0.88, 95% CI 0.73‐1.05, P = .15) but improved PFS (HR 0.77, 95% CI 0.69‐0.86, P ≤ .00001) and DOHR (HR 0.88, 95% CI 0.79‐0.98, P = .02) compared with control. There were no significant differences between PIM and control regarding SPM (p = NS) and ≥grade 3 peripheral neuropathy (PN) (p = NS).ConclusionsPIM following AHCT in MM improves PFS and DOHR without an increase in development of SPM or severe PN compared with placebo/thalidomide.

Background: Sickle cell disease (SCD) is an inherited hemoglobinopathy which affects over 300,000 children born each year worldwide. In spite of improvement in supportive care in recent years, there is still a lack of effective treatment options. SCD leads to debilitating and cyclic episodes of erythrocyte sickling with progressive organ injury, contributing to lifetime morbidity and shortened life expectancy. Allogeneic HCT (allo-HCT) is a potentially curative therapy for SCD because engraftment is associated with resolution of the clinical phenotype of the disease and abrogation of its complications. Medical literature on allo-HCT for SCD is largely limited to children. Recent studies have evaluated the efficacy of allo-HCT in the adult population. Here, we conduct a systematic review/meta-analysis to assess the totality of evidence pertaining to the efficacy (or lack thereof) of allo-HCT in children and adults. Materials and methods: We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE and Cochrane library on July 3rd, 2019. We extracted data on clinical outcomes related to benefits (overall [OS] and disease free/event free survival [EFS/DFS]) and harms (non-relapse mortality [NRM] and graft failure [GF]), independently by two authors. Our search strategy identified 1001 references but only 30 studies (n= 1995 patients) were included in this systematic review/meta-analysis. We also performed a sub analysis on clinical outcomes for studies that included only pediatric patients (defined as <18 years) and those in patients ≥18 years of age. Results: Median age for patients enrolled in all the studies was at 10 years. Recurrent veno-occlusive crises represented the most common indication for allo-HCT followed by acute chest syndrome and stroke; nevertheless, most patients had more than one indication. Matched related donors (MRD) were the most common donor source (93%). Bone marrow was the most common source of hematopoietic stem cells (77%). Majority of patients underwent conditioning with myeloablative regimens (77%). Pooled OS rates (n=29 studies, 1681 patients) after allogeneic HCT was 95% (95%CI=93-96%) with low heterogeneity (I2=6.4%) among included studies (Figure 1). Pooled EFS/DFS rates (n=29 studies, 1894 patients) post-allografting was 90% (95%CI=87-93%) with moderate heterogeneity (I2=54%). Pooled NRM rates from 30 studies (1995 patients) was 4% (95%CI=2-6%) with low heterogeneity (I2=29.4%). Pooled GF rates from 28 studies (1851 patients) was 4% (95%CI=2-6%) with moderate heterogeneity (I2=55%). A subset analysis specifically for pediatric patients (n= 11 studies, 1009 patients, median age at 9.7 years) showed a pooled OS rate of 96% (95%CI=94-97%) with low heterogeneity (I2=0%); and for adult patients (n=3 studies, 51 patients, median age at 33.4 years) the pooled OS was 94% (95%CI=80-100%) with moderate heterogeneity (I2=52%). Pooled EFS/DFS for pediatric patients (n= 11 studies, 1009 patients) was at 89 %( 95%CI=84-93%) with moderate heterogeneity (I2=55.1%); and for adult patients (n=2 studies, 30 patients) was at 95% (95%CI=83-100%) with high heterogeneity (I2=96.5%). Pooled NRM from 10 studies with pediatric patients (281 patients) was at 6 % (95%CI=3-10%) with low heterogeneity (I2=0%); and from 3 studies with adult patients (51 patients) was at 1% (95%CI=0-7%) with low heterogeneity (I2=15.1%). Pooled GF from 10 studies with pediatric patients (281 patients) was at 3 % (95%CI=1-7%) with moderate heterogeneity (I2=40%); and from 2 studies with adult patients (30 patients) was at 5% (95%CI=0-17%) with high heterogeneity (I2=95.4%). Conclusions: The results of our systematic review/meta-analysis show excellent OS, EFS/DFS in children and adults undergoing allo-HCT with pooled OS rates exceeding 90%. The main limitation to offering an allo-HCT in SCD remains the availability of a suitable donor as 85% of patients meeting criteria do not have a MRD. We anticipate that with emergence of haploidentical transplantation the number of allo-HCT will increase in the future. GF remains a significant concern in this population and future studies should focus on novel immune suppression strategies to help reduce GF. Disclosures Kharfan-Dabaja: Pharmacyclics: Consultancy; Daiichi Sankyo: Consultancy.

BackgroundThe outcomes for patients with diffuse large B‐cell lymphoma (DLBCL) with adverse clinical prognostic factors such as a high age‐adjusted International Prognostic Index (aaIPI) are not optimal. In the current study, the authors performed a systematic review and meta‐analysis to assess the totality of evidence pertaining to the efficacy of autologous hematopoietic stem cell transplantation (auto‐HCT) consolidation for patients with DLBCL in first remission.MethodsThe authors searched the Cochrane and MEDLINE/PubMed databases through December 1, 2018, for studies comparing conventional chemotherapy with rituximab (R‐chemo) versus R‐chemo and auto‐HCT. Two authors independently reviewed all references for study inclusion and extracted data related to benefits (overall survival, progression‐free survival, and response rates) and harms (treatment‐related mortality and adverse events).ResultsFour studies (1173 patients) met the inclusion criteria and were included in the current analysis. The median duration of follow‐up ranged from 42 to 76 months. There was no difference noted with regard to the overall survival (hazard ratio, 1.01; 95% CI, 0.74‐1.37), progression‐free survival (hazard ratio, 0.77; 95% CI, 0.58‐1.04), or response rates (risk ratio, 0.98; 95% CI, 0.92‐1.04) between patients who received R‐chemo and auto‐HCT and those who received R‐chemo alone. The risk of mortality and therapy failure was not found to be different when the analysis was limited to high aaIPI between the 2 groups. Although there was no difference noted with regard to the risk of treatment‐related mortality, there was a significantly higher incidence of CTCAE grade 3 or 4 adverse events in patients who received R‐chemo and auto‐HCT compared with patients treated with R‐chemo alone.ConclusionsThe findings from what to the authors' knowledge is the first meta‐analysis performed in the rituximab era demonstrated no beneficial effect of upfront auto‐HCT consolidation in patients with aggressive B‐cell non‐Hodgkin lymphoma, including high‐risk clinical groups (high aaIPI).