Clinical outcomes of etoposide and cytarabine as consolidation in elderly patients with primary CNS lymphoma.

BACKGROUND: A consolidation strategy has not been established for transplant-ineligible elderly patients with primary central nervous system lymphoma (PCNSL). In this study, we aimed to retrospectively evaluate the clinical outcomes of etoposide and cytarabine (EA) as consolidation chemotherapy for transplant-ineligible patients with PCNSL following high-dose methotrexate (MTX)-based induction chemotherapy. MATERIALS AND METHODS: Between 2015 and 2021, newly diagnosed transplant-ineligible patients with PCNSL with diffuse large B-cell lymphoma were consecutively enrolled. All enrolled patients were over 60 years old and received EA consolidation after achieving a complete or partial response following induction chemotherapy. RESULTS: Of the 85 patients who achieved a complete or partial response to MTX-based induction chemotherapy, 51 received EA consolidation chemotherapy. Among the 25 (49.0%, 25/51) patients in partial remission before EA consolidation, 56% (n = 14) achieved complete remission after EA consolidation. The median overall survival and progression-free survival were 43 and 13 months, respectively. Hematological toxicities were most common, and all patients experienced grade 4 neutropenia and thrombocytopenia. Forty-eight patients experienced febrile neutropenia during consolidation chemotherapy, and 4 patients died owing to treatment-related complications. CONCLUSION: EA consolidation chemotherapy for transplant-ineligible, elderly patients with PCNSL improved response rates but showed a high relapse rate and short progression-free survival. The incidences of treatment-related mortality caused by hematologic toxicities and severe infections were very high, even after dose modification. Therefore, the use of EA consolidation should be reconsidered in elderly patients with PCNSL.

Comprehensive insights into AML relapse: genetic mutations, clonal evolution, and clinical outcomes.

INTRODUCTION: Acute myeloid leukemia (AML) is a complex hematologic malignancy characterized by uncontrolled proliferation of myeloid precursor cells within bone marrow. Despite advances in understanding of its molecular underpinnings, AML remains a therapeutic challenge due to its high relapse rate and clonal evolution. METHODS: In this retrospective study, we analyzed data from 24 AML patients diagnosed at a single institution between January 2017 and August 2023. Comprehensive genetic analyses, including chromosomal karyotyping, next-generation sequencing, and gene fusion assays, were performed on bone marrow samples obtained at initial diagnosis and relapse. Clinical data, treatment regimens, and patient outcomes were also documented. RESULTS: Mutations in core genes of FLT3, NPM1, DNMT3A, and IDH2 were frequently discovered in diagnostic sample and remained in relapse sample. FLT3-ITD, TP53, KIT, RUNX1, and WT1 mutation were acquired at relapse in one patient each. Gene fusion assays revealed stable patterns, while chromosomal karyotype analyses indicated a greater diversity of mutations in relapsed patients. Clonal evolution patterns varied, with some cases showing linear or branching evolution and others exhibiting no substantial change in core mutations between diagnosis and relapse. CONCLUSIONS: Our study integrates karyotype, gene rearrangements, and gene mutation results to provide a further understanding of AML heterogeneity and evolution. We demonstrate the clinical relevance of specific mutations and clonal evolution patterns, emphasizing the need for personalized therapies and measurable residual disease monitoring in AML management. By bridging the gap between genetics and clinical outcome, we move closer to tailored AML therapies and improved patient prognoses.

Utility of Plasma Microbial Cell-Free DNA Whole-Genome Sequencing for Diagnosis of Invasive Aspergillosis in Patients With Hematologic Malignancy or COVID-19.

BACKGROUND: We evaluated the clinical accuracy and utility of whole-genome sequencing (WGS) of plasma microbial cell-free DNA (cfDNA) as a novel noninvasive method in diagnosing invasive aspergillosis (IA) in patients with hematologic malignancy (HM) or coronavirus disease 2019 (COVID-19). METHODS: Adults with HM or COVID-19 and suspected IA were recruited. IA cases were retrospectively diagnosed according to EORTC/MSG definitions and ECMM/ISHAM criteria for HM and COVID-19 patients, respectively. The results of cfDNA WGS were compared with the conventional diagnosis. RESULTS: Microbial cfDNA WGS was performed 53 times from 41 participants (19 from HM, 16 from COVID-19, and 7 from the control group). In participants with HM, Aspergillus cfDNA was detected in 100% of proven IA and 91.7% of probable IA cases. In participants with COVID-19, 50.0% of probable IA were positive for Aspergillus in cfDNA WGS. Concordance between Aspergillus cfDNA detection and proven/probable IA conventional diagnosis was significantly higher in participants with HM than in those with COVID-19. IA diagnosed using EORTC/MGS definitions showed significantly high concordance between Aspergillus cfDNA detection and proven/probable IA. CONCLUSIONS: Aspergillus cfDNA detection strongly correlated with proven/probable IA diagnosed using EORTC/MSG definitions and could be used as an additional diagnostic tool for IA.

Identification of MYC as an antinecroptotic protein that stifles RIPK1-RIPK3 complex formation.

The underlying mechanism of necroptosis in relation to cancer is still unclear. Here, MYC, a potent oncogene, is an antinecroptotic factor that directly suppresses the formation of the RIPK1-RIPK3 complex. Gene set enrichment analyses reveal that the MYC pathway is the most prominently down-regulated signaling pathway during necroptosis. Depletion or deletion of MYC promotes the RIPK1-RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. Interestingly, MYC binds to RIPK3 in the cytoplasm and inhibits the interaction between RIPK1 and RIPK3 in vitro. Furthermore, MYC-nick, a truncated form that is mainly localized in the cytoplasm, prevented TNF-induced necroptosis. Finally, down-regulation of MYC enhances necroptosis in leukemia cells and suppresses tumor growth in a xenograft model upon treatment with birinapant and emricasan. MYC-mediated suppression of necroptosis is a mechanism of necroptosis resistance in cancer, and approaches targeting MYC to induce necroptosis represent an attractive therapeutic strategy for cancer.

Real-world data on prognostic value of measurable residual disease assessment by fragment analysis or next-generation sequencing in multiple myeloma.

Measurable residual disease (MRD) negativity is a strong prognostic indicator in multiple myeloma (MM). However, the optimal use of MRD in daily clinical practice has been hampered by the limited feasibility of MRD testing. Therefore, we examined the clinical relevance of commercially available MRD modalities based on clonality assays by fragment analysis with IdentiClone® (n = 73 patients) and next-generation sequencing (NGS) with LymphoTrack® (n = 116 patients) in newly diagnosed patients with MM who received autologous stem cell transplantation (ASCT). MRD was assessed at the end of induction (pre-ASCT) and/or at 100 days after ASCT (post-ASCT). MRD could not predict survival when assessed by fragment analysis. However, NGS-based MRD negativity at pre- or post-ASCT was beneficial in terms of progression-free and overall survival. Moreover, NGS-based MRD negativity was independently associated with improved progression-free and overall survival, and MRD-positive patients both pre- and post-ASCT had worst outcome. Indeed, initial adverse prognostic features by high-risk cytogenetics could be mitigated upon achieving MRD negativity by NGS. We demonstrate the feasibility and clinical benefit of achieving MRD negativity by commercially available clonality-based MRD assays in MM and support incorporating NGS, but not fragment analysis, to tailor therapeutic strategies in real-world practice.

Detection of recurrent, rare, and novel gene fusions in patients with acute leukemia using next-generation sequencing approaches.

Identification of gene fusion is an essential part in the management of patients with acute leukemia, not only for diagnosis but also in predicting the treatment outcome and selecting appropriate treatment. Adopting next-generation sequencing (NGS) technology for identification of gene fusion in patients with acute leukemia can be a good alternative to conventional tests. In the present study, the NGS RNA fusion gene panel test was applied to diagnostic samples of patients with acute leukemia to identify fusion genes more efficiently. Among 134 patients with acute leukemia, 53 gene fusions were detected in 52 patients. In addition to the recurrent gene fusions specified in the WHO diagnostic criteria, 11 rare or novel gene fusions were identified. Of those, two were gene fusions associated with Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL), two were novel gene fusions, three were gene fusions with novel partner genes, and six were rare gene fusions from previous reports. We confirmed the clinical utility of the NGS test in identifying clinically significant gene fusions such as gene fusions involving KMT2A that has a large number of partners. Notably, Ph-like ALL-associated gene fusions could be easily identified despite the wide variety of genes involved. The results from the present study may contribute toward a better understanding of the genomic landscape of acute leukemia as well as patient management.

Serum albumin and C-reactive protein as significant predictors of non-relapse mortality in lower gastrointestinal graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) of the lower gastrointestinal (GI) tract is the major cause of non-relapse mortality (NRM) in allogeneic hematopoietic stem cell transplantation (alloHSCT). This study aimed to identify variables associated with corticosteroid response and NRM in patients who developed lower GI aGVHD. We retrospectively analyzed the clinical data of patients treated at Yonsei University Severance Hospital between 2008 and 2017. Among 244 recipients of alloHSCT, 48 (19.7%) were diagnosed as lower GI aGVHD at a median of 22 days after alloHSCT. In these cases, 20 (41.6%) patients were resistant to corticosteroid therapy. Corticosteroid resistance was associated with advanced stage of lower GI aGVHD (P = 0.019), low serum albumin (P = 0.006), and elevated CRP (P = 0.030) on day 7 after corticosteroid therapy. NRM rate was significantly higher in the corticosteroid-resistant group compared with the sensitive group (HR 5.339, P = 0.003). Multivariate analysis revealed serum albumin (P = 0.046), and CRP levels (P = 0.032) were independent prognostic factors for NRM. When the patients were classified into 3 groups according to Glasgow prognostic score (GPS), the rate of corticosteroid resistance was significantly higher in the high GPS group compared with the intermediate or low GPS group (83.3 vs. 27.2 and 15.3%, respectively, P < 0.001). We demonstrated that low serum albumin and elevated CRP level on day 7 after corticosteroid therapy are objective biomarkers of corticosteroid resistance and a significant predictor for higher NRM. These simple and practical parameters could be valuable information predicting response and prognosis in lower GI aGVHD.

Upfront autologous hematopoietic stem cell transplantation for high-risk patients with double-expressor diffuse large B cell lymphoma.

Although MYC and BCL2 co-expression in diffuse large B cell lymphoma (DLBCL) is associated with inferior prognosis, it remains uncertain whether upfront autologous hematopoietic stem cell transplantation (ASCT) is beneficial in this lymphoma. This study aimed to investigate whether ASCT consolidation could have a positive role for patients with MYC and BCL2 co-expression (double-expressor lymphoma, DEL). We retrospectively evaluated 67 DLBCL patients who underwent upfront ASCT following rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. The 5-year overall survival (OS) and progression-free survival (PFS) were 82.3% and 79.2%, respectively. There were 23 (34.3%) patients with DEL and 51 (76.1%) patients with non-germinal center B cell (GCB) subtype. The 5-year OS and PFS of patients with DEL were not different from those with non-DEL (P = 0.429 and P = 0.614, respectively). No survival difference for OS and PFS was also observed between GCB and non-GCB subtypes (P = 0.950 and P = 0.901, respectively). The OS and PFS were comparable for patients with DEL and non-DEL and both GCB and non-GCB subtypes. In conclusion, MYC and BCL2 co-expression did not have a poor prognostic impact among high-risk patients with DLBCL treated with upfront ASCT regardless of molecular classification. This preliminary study suggested that the role of consolidative ASCT is needed to be evaluated in a prospective randomized clinical trial.

Early Cytomegalovirus Reactivation and Expansion of CD56brightCD16dim/-DNAM1+ Natural Killer Cells Are Associated with Antileukemia Effect after Haploidentical Stem Cell Transplantation in Acute Leukemia.

Cytomegalovirus (CMV) infection is a major complication after allogeneic hematopoietic stem cell transplantation but is suggested to exert a strong antileukemia effect in part due to alterations in the composition of natural killer (NK) cells. We evaluated the impact of early CMV reactivation and changes in NK cell subset recovery on relapse rate and survival after haploidentical stem cell transplantation (haploSCT) for acute leukemia. Fifty patients with acute leukemia who received haploSCT were analyzed. Expression of T cells and specific receptors (NKG2A, NKG2D, DNAM1, and CD57) on circulating NK cells (CD56brightCD16dim/- or CD56dimCD16+ cells) was serially measured using multiparametric flow cytometry. CMV reactivation during the first 100 days was observed in 41 patients (82%) at a median of 23 days after haploSCT. The incidence of acute graft-versus-host disease (GVHD) and chronic GVHD tended to be higher in patients with CMV reactivation, although this difference was not statistically significant. Multivariate analysis showed that CMV reactivation (P = .011) and a dose of infused T cells > 3.2 × 108/kg (P = .027) were independent predictors of a reduced relapse risk and only CMV reactivation (P = .029) was an independent predictor of improved leukemia-free survival. CD56brightCD16dim/-DNAM1+NK cell counts increased from day 30 to 90 in patients with CMV reactivation but decreased after day 30 in patients without CMV reactivation. An increase in CD56brightCD16dim/-DNAM1+ NK cells was not associated with the occurrence of chronic GVHD but was associated with a reduced cumulative relapse rate (16.4% versus 58.0%, P = .019). Multivariate analysis indicates that an increase in the CD56brightCD16dim/-DNAM1+NK cell count was an independent predictor of reduced relapse risk. Our study demonstrates a significant correlation between low relapse rates and CMV reactivation as well as the recovery of CD56brightCD16dim/-DNAM1+ NK cells, providing valuable information for understanding the plausible immunologic mechanism of the graft-versus-leukemia effect.

Induction of apoptosis and differentiation by Na/H exchanger 1 modulation in acute myeloid leukemia cells.

We investigated the effect of the modulation of Na/H exchanger 1 (NHE1) on apoptosis, differentiation, and chemoresistance in acute myeloid leukemia (AML) cells to evaluate the possibility of NHE1 modulation as a novel therapeutic strategy for AML. The pHi of leukemia cell lines except KG1a was higher than that of normal bone marrow mononuclear cells (BM MNCs). Notably, in K562, cytarabine (AraC)-resistant OCI-AML2, and primary leukemia cells, pHi was significantly higher than that of normal BM MNCs. Western blotting and real-time quantitative PCR confirmed that the increased NHE1 expression was responsible for the higher pHi. Specifically, compared to CD34+CD38+ leukemia cells, the mean fluorescence intensity of NHE1 was significantly higher in CD34+CD38- leukemic stem cells. The out of range in pHi by treatment with an NHE inhibitor, the amiloride analogue 5-(N,N-hexamethylene) amiloride (HMA), or an NHE activator, phorbol 12-myristate 13-acetate (PMA), resulted in dose- and time-dependent inhibition of leukemia cell proliferation. PMA induced CD14+ differentiation of leukemia cells, whereas HMA induced cell cycle arrest at the G1 phase. HMA could induce apoptosis of leukemia cells even in AraC-resistant cells and showed an additive effect on apoptosis in AraC-sensitive cells. Our result revealed that AML cells prefer more alkalic intracellular moiety than normal BM MNCs following increased NHE1 expression and that NHE1 modulation can induce apoptosis and differentiation of AML cells. These findings imply that NHE1 is a potential target in cytotoxic or differentiation-induction treatment for AML.

Clinical implication of renal dysfunction during the clinical course in patients with paroxysmal nocturnal hemoglobinuria: a longitudinal analysis.

Although renal dysfunction at the time of diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) is a risk factor for mortality, subsequent renal events can occur. The objective of this study was to identify clinical implication of renal dysfunction occurring during the disease course in PNH patients. One hundred one patients with a granulocyte clone size of > 10% were enrolled. Renal events were observed in 55 (54.5%) patients during a median follow-up of 94.2 months. Median time to first renal event from diagnosis of PNH was 79.3 months. Thromboembolism (TE) event and recurrent TE events were observed in 25 (24.8%) and 8 (7.9%) patients, respectively. The rate of recurrent TE was significantly higher in patients with renal events ≥ 2 compared with that in patients with renal event ≤ 1 (18.8% vs. 2.9%; P = 0.012). The rate of recurrent TE was significantly higher in patients with chronic kidney disease (CKD) + acute kidney disease (AKD) compared with the rest of the patients (27.3% vs. 5.6%; P = 0.040). CKD+AKD was the only independent risk factor for OS in multivariate analysis (hazard ratio 7.95, 95% CI 1.24-51.15, P = 0.029). Therefore, close monitoring of renal events in PNH patients during the entire clinical course is essential.

Utility of allogeneic hematopoietic stem cell transplantation using international donors in a homogenous ethnic population: question in the era of various alternative donors.

The advent of various alternative donors in allogeneic hematopoietic stem cell transplantation (HSCT) raises the question of using international donors, especially in ethnically homogenous populations. We analyzed the clinical outcome and medical expense of human leukocyte antigen (HLA)-matched HSCT using domestic and international donors. We analyzed the patients who received allogeneic HSCT at five medical centers in Korea in the last 10 years. Using propensity-score matching, we compared overall survival (OS), relapse-free survival (RFS), and transplantation-related complications. Medical expense was analyzed based on National Health Insurance Service (NHIS) data. A total of 269 patients were analyzed after 3:1 (domestic/international) matching. There was no difference in OS (p = 0.395) and RFS (p = 0.604) between the domestic and international donor groups (5-year OS rate 42.9 and 37.8%, 5-year RFS rate 37.6 and 33.5% for domestic and international groups, respectively). No difference in chronic graft-versus-host disease (GVHD) incidence was observed (34.2% in domestic and 35.9% in international group, p = 0.804). Early infection was more frequent in the domestic group (55.0 vs. 35.8%, p = 0.007), whereas infection after 30 days was more frequent in the international group (28.7 vs. 49.3%, p = 0.001). Mean medical expense was far higher in the international group, by US $51,944 in the entire follow-up period (p < 0.001). We would expect similar outcomes for international and domestic donors in terms of survival and treatment-related complications with HLA-matched HSCT in other ethnically homogenous populations. These findings should be considered together with the high cost of using international donors in the era of various alternative donors.

Different prognostic effects of core-binding factor positive AML with Korean AML registry data.

Core-binding factor acute myeloid leukemia (CBF-AML) data in Asian countries has been rarely reported. We analyzed 392 patients with CBF-AML [281 with t(8;21), 111 with inv.(16)/t(16;16)] among data from 3041 patients with AML from the Korean AML Registry. Interestingly, del(9q) was less frequently detected in Korean than in German patients with t(8;21) (7.5% vs. 17%), and del(7q) was more frequently detected in Korean patients with inv(16). Overall survival (OS) was similar between patients in the first complete remission (CR) who received allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) for CBF-AML. OS of t(8;21) patients was poor when undergoing alloSCT in second/third CR, while OS of inv(16) patients in second/third CR was similar to that in first CR. Patients with > 3-log reduction of RUNX1/RUNX1T1 qPCR had improved 3-year event-free survival (EFS) than those without (73.2% vs. 50.3%). Patients with t(8;21) AML with D816 mutation of the c-Kit gene showed inferior EFS and OS. These poor outcomes might be overcome by alloSCT. Multivariate analysis for OS in patients with t(8;21) revealed older age, > 1 course of induction chemotherapy to achieve CR, loss of sex chromosome, del(7q), and second/third CR or not in CR before SCT as independent prognostic variables. Especially, del(7q) is the most powerful prediction factor of poor outcomes, especially in patients with t(8;21) (hazard ratio, 27.23; P < 0.001). Further study is needed to clarify the clinical effect of cytogenetics and gene mutation in patients with CBF-AML, between Asian and Western countries.

Platelet storage induces accelerated desialylation of platelets and increases hepatic thrombopoietin production.

BACKGROUND: Stored platelets undergo deleterious changes, referred to as platelet storage lesions (PSLs), which accelerate the desialylation of platelets and result in their phagocytosis and clearance by hepatic macrophages. Recent studies have reported that Ashwell-Morell receptor binds to desialylated platelets, thereby inducing hepatic thrombopoietin (TPO) production in a mouse model. Therefore, this study aimed to demonstrate these relationships between PSL and hepatic TPO production in human study. METHODS: Platelet concentrates (PCs) were obtained from 5 healthy volunteers and the remaining were discarded samples from the blood bank. PCs were divided into two halves, and stored either at 22 or 4 °C. Experiments were conducted using serial samples. Desialylation was assessed using flow cytometry, and structural changes were visualized using electron microscopy. Following co-culture of HepG2 cells (HB-8065, ATCC) with isolated platelets, hepatic TPO production was determined using real-time quantitative polymerase chain reaction and the supernatant TPO level was measured using a Luminex kit. RESULTS: For 5 days of storage duration, platelet counts were not influenced by the storage conditions, but the degree of desialylation was proportional to the storage duration. Significant changes in the platelet surface and structure according to storage conditions were noted in electron microscopy. HepG2 cells incubated with aged platelets expressed more TPO mRNA, and supernatant TPO levels were proportional to the storage duration. Refrigeration also influenced on the results of this study, but they were not statistically significant. CONCLUSIONS: This is the first study to demonstrate that, in vitro, aging and refrigeration affect the integrity of human platelets, resulting in induction of hepatic TPO mRNA and protein expression.

Epidemiology and Risk Factors for Invasive Fungal Diseases among Allogeneic Hematopoietic Stem Cell Transplant Recipients in Korea: Results of "RISK" Study.

Incidence, epidemiology, and risk factors of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients can vary from different cohorts and countries. Therefore, we performed a nationwide study to establish a proper antifungal prophylaxis strategies based on risk stratifications of IFDs after all-HSCT in Korea (RISK study). This was a multicenter, retrospective, and observational study in Korea. All consecutive adult patients who received allo-HSCT in 2013 were included. The 12-month cumulative incidence of proven/probable IFDs (PP-IFDs) was calculated during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT. Cox proportional hazard regression analysis was performed to identify risk factors for PP-IFDs at each phase. A total 521 allo-HSCT cases in 518 patients were analyzed. Overall cumulative incidence of PP-IFDs were 4.09% (95% confidence interval [CI], 2.38 to 5.81), 7.38% (95% CI, 5.09 to 9.67), and 15.36% (95% CI, 12.04 to 18.68) at the early, late and very phases, respectively. In multiple Cox regression analysis, variables were associated with PP-IFDs in each period were identified. Variables associated with early phase include underlying pulmonary diseases, underlying nonmalignant stable or chronic disease at allo-HSCT, unrelated or family mismatched donor, and prolonged neutropenia. Variables associated with the late phase include high ferritin level at the time point of allo-HSCT, use of secondary immunosuppressive agents due to refractory graft-versus-host disease (GVHD), and cytomegalovirus reactivation. For the very late phase, variables were secondary neutropenia, severe chronic GVHD, and use of TNF-alpha inhibitor for refractory GVHD. This study revealed the high cumulative incidence of IFDs in Korean allo-HSCT recipients, which have distinct risk factors in each phase after allo-HSCT. Our findings indicate that tailored antifungal prophylaxis is necessary for high-risk patients. Clinicians should consider using mold-active antifungal prophylaxis in allo-HSCT recipients who have high risks at different treatment period.

Clinical impact of early recovery of peripheral blood absolute lymphocyte count after frontline autologous stem cell transplantation for diffuse large B-cell lymphoma.

We conducted a retrospective study to evaluate the clinical impact of an early recovery of posttransplant absolute lymphocyte count (ALC) on the outcome of frontline autologous stem cell transplantation (ASCT) for diffuse large B-cell lymphoma (DLBCL). We reviewed 65 DLBCL patients who underwent frontline ASCT after primary chemotherapy based on cyclophosphamide, doxorubicin, vincristine, and prednisone. A receiver operating characteristic analysis was performed to determine the optimal cut point (0.4 × 109 /L) for an ALC at 15 days after ASCT (ALC-15). Both event-free survival and overall survival rates of the higher-ALC-15 group were significantly better than those of the lower-ALC-15 group (event-free survival, P = .008; overall survival, P = .013). The infused CD34+ cell count was significantly associated with the recovery of ALC-15 (>0.4 × 109 /L) after ASCT (P = .028). A multivariate analysis confirmed that a higher infused CD34+ cell dose (>5.0 × 106  cells/kg) was an independent factor affecting an early recovery of ALC after ASCT (odds ratio, 4.145; 95% confidence interval, 1.106-15.528; P = .035). In conclusion, an early recovery of ALC after ASCT can be regarded as a good prognostic marker in patients with DLBCL who have undergone frontline ASCT. We found that the infused CD34+ cell dose for ASCT was associated with the recovery of ALC.

The prognostic role of CD68 and FoxP3 expression in patients with primary central nervous system lymphoma.

The prognostic role of CD68 and FoxP3 in primary central nervous system lymphoma (PCNSL) has not been evaluated. Thus, we examined the prognostic significance of CD68 and FoxP3 expression in tumor samples of 76 newly diagnosed immunocompetent PCNSL patients. All patients were treated initially with high-dose methotrexate (HD-MTX)-based chemotherapy, and 16 (21.1%) patients received upfront autologous stem cell transplantation (ASCT) consolidation. High expression of CD68 (>55 cells/high-power field) or FoxP3 (>15 cells/high-power field) was observed in 10 patients, respectively. High CD68 expression was associated with inferior overall survival (OS) and progression-free survival (PFS) in multivariate analysis (P = 0.023 and P = 0.021, respectively). In addition, we performed subgroup analysis based on upfront ASCT. High CD68 expression was also associated with inferior OS and PFS in multivariate analysis (P = 0.013 and P < 0.001, respectively) among patients who did not receive upfront ASCT (n = 60), but not in patients who received upfront ASCT. The expression of FoxP3 was not significantly associated with survival. Therefore, we identified a prognostic significance of high CD68 expression in PCNSL, which suggests a need for further clinical trials and biological studies on the role of PCNSL tumor microenvironment.

Salvage therapy for acute chemorefractory leukemia by allogeneic stem cell transplantation: the Korean experience.

Little is known about the characteristics that make patients with acute leukemia suitable for undergoing salvage therapy by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we analyzed the clinical outcomes of 223 patients with acute leukemia who underwent allo-HSCT while not in complete remission (CR). The primary end points were overall survival (OS) and CR rate. CR was achieved in 79.8% of patients after allo-HSCT. Acute graft-versus-host disease (GVHD) was significantly associated with CR (P = 0.045). During a median follow-up of 30.1 months, the median OS was 6.1 months. OS was significantly longer in patients with good or standard risk cytogenetic characteristics than in those with poor risk cytogenetic characteristics (P = 0.029, P = 0.030, respectively). Patients who received allo-HSCT from a matched sibling donor had better survival than those with unrelated donors (P = 0.015). Primary chemorefractoriness was not associated with poor survival (P = 0.071). The number of chemotherapies before allo-HSCT was significantly correlated with outcome (P = 0.006). Chronic GVHD was a strong predictor of a longer OS (P = 0.025). In conclusion, survival of patients with primary chemorefractory acute leukemia is not lower when treated upfront with allo-HSCT. Hence, allo-HSCT should be actively considered in such patients. Acute and chronic GVHD is associated with better outcomes patients with acute leukemia who have undergone allo-HSCT and not achieved CR.

The role of upfront autologous stem cell transplantation in high-risk younger patients with primary central nervous system lymphoma.

Upfront autologous stem cell transplantation (ASCT) has shown favourable outcome in patients with primary central nervous system lymphoma (PCNSL), but the role of risk-adapted upfront ASCT consolidation has not been evaluated in PCNSL. As PCNSL patients with the International Extranodal Lymphoma Study Group (IELSG) prognostic score ≥2 or those who did not achieve complete response after two courses of induction chemotherapy (non-CR1) have shown inferior outcomes, we retrospectively analysed the role of upfront ASCT in 66 high-risk (IELSG ≥2 and/or non-CR1) younger (age <65 years) immunocompetent PCNSL patients who achieved at least partial response after initial high-dose methotrexate-based chemotherapy. Nineteen patients who received upfront ASCT exhibited significantly better overall survival (OS, P = 0·021) and progression-free survival (PFS, P = 0·005) compared to 47 patients who did not. In univariate and multivariate analyses, upfront ASCT was associated with better OS (P = 0·037 and P = 0·025, respectively) and PFS (P = 0·009 and P = 0·007, respectively). In a propensity score-matched cohort (n = 36), patients who received upfront ASCT also showed better outcome (P = 0·037 for OS, P = 0·001 for PFS). Our results suggest that upfront ASCT consolidation might be especially beneficial for high-risk PCNSL patients.

Risk factors associated with early mortality in patients with multiple myeloma who were treated upfront with a novel agents containing regimen.

BACKGROUND: Although the introduction of novel agents improved the survival outcomes in patients with multiple myeloma (MM), some patients died within one year (early mortality, EM) following diagnosis. In this study, we evaluated the EM rate, and investigated the risk factors associated with EM in MM patients. METHODS: Retrospective data from 542 patients who were initially treated with a novel agent-containing regimen were analyzed. RESULTS: The median overall survival (OS) for the entire cohort was 56.5 months. The median OS in the 2010-2014 group was longer than in the 2002-2009 group (59.2 months vs. 49.1 months, P = 0.054). The rate of EM was 13.8 %, and the most common causes of EM were infection and comorbidity. In multivariate analysis, the age-adjusted Charlson comorbidity index (ACCI ≥ 4), low body mass index (BMI < 20 kg/m(2)), thrombocytopenia, and renal failure were significantly associated with EM. The presence of none, 1, or ≥ 2 factors was associated with a 4.1 %, 14.3 %, or 27.4 % risk of EM (P < 0.001), respectively. The median OS times were significantly different depending on the presence of factors associated with EM (P < 0.001). CONCLUSIONS: In conclusion, the ACCI (≥ 4), low BMI, thrombocytopenia and renal failure were strong predictors for EM in the novel agent era. The results of this study will help to identify patients at high risk for EM, and may be helpful to more accurately predict prognosis of MM patients in the novel-agent era.