Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: Results of the multicenter KMMWP2201 study.

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed at investigating this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age: 63 years). The overall response rate was 90% in responseevaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, highrisk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2 to 3 months prior to start of KRd treatment significantly decreased PFS and overall survival (OS) in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e.delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AEs) were observed in 56% of the patients, and non-fatal or fatal AE's that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.

Relapse with plasmacytoma after upfront autologous stem cell transplantation in multiple myeloma.

Plasmacytoma has been reported to be associated with a poor prognosis in patients with multiple myeloma (MM). In this study, we evaluated the incidence of relapse with plasmacytoma and survival outcomes after upfront autologous stem cell transplantation (ASCT). This study retrospectively analyzed the data of 303 patients with MM who underwent upfront ASCT between April 2000 and April 2018 at eight institutes in the Republic of Korea. In total, 52 patients (17.1%) had plasmacytoma at MM relapse after upfront ASCT, of whom, 27 had paramedullary plasmacytoma (PMD) and 25 had extramedullary plasmacytoma (EMD). Patients with initial plasmacytoma were more likely to have plasmacytoma at MM relapse than those without initial plasmacytoma (37.1% vs. 11.2%). Over a median follow-up of 66.0 months, patients with plasmacytoma at relapse had significantly inferior overall survival (OS) than those without plasmacytoma (43.9 vs. 100.7 months, P < 0.001), but the OS did not significantly differ between patients with EMD and those with PMD (42.2 vs. 56.6 months, P = 0.464). After MM relapse, all patients received salvage therapy, and progression-free survival after relapse was significantly shorter in patients with plasmacytoma than in those without (6.4 vs. 12.4 months, P = 0.007). This study showed that plasmacytoma frequently developed at MM relapse after upfront ASCT in patients with plasmacytoma at the time of diagnosis. Plasmacytoma at relapse was significantly associated with a poor prognosis.

Early transplantation-related mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia.

BACKGROUND: Transplantation-related mortality (TRM) is a major obstacle in allogeneic hematopoietic cell transplantation (allo-HCT). Approximately 60-80% of TRM occurs early, within 100 days of transplantation. METHODS: This was a nationwide population cohort study involving 5395 patients with acute leukemia who underwent allo-HCT between 2003 and 2015. Patient data were collected from the Korean National Health Insurance Service database. We investigated the cumulative incidence rates (CIRs) of early TRM at 50 and 100 days. RESULTS: The CIRs of early TRM at 50 and 100 days were 2.9 and 8.3%, respectively. There was no decrease in the CIRs of early TRM over time. The early mortality was significantly higher in patients with more than 9 months between the diagnosis and transplantation (CIRs of TRM at 50, 100 days; 6.0, 13.2%), previous transplantations (CIRs of TRM at 50, 100 days; 9.4, 17.2%), and cord blood transplantation (CIRs of TRM at 50, 100 days; 6.1, 8.3%). The early TRM was significantly lower in patients who received iron chelation before transplantation (CIRs of TRM at 50, 100 days; 0.3, 1.8%). CONCLUSIONS: In conclusion, the overall CIR of early TRM was less than 10%. The predictable factors for early TRM included age, time from diagnosis to transplantation, the number of prior transplantations, the graft source, and previous iron chelation therapy.

Carfilzomib in addition to lenalidomide and dexamethasone in Asian patients with RRMM outside of a clinical trial.

Carfilzomib, lenalidomide, and dexamethasone (KRd) effectively improve survival in patients with relapsed and refractory multiple myeloma (RRMM). However, the outcome of KRd treatment in Asian patients reflecting a general RRMM population outside of a clinical trial has not been reported. Fifty-five RRMM patients who were treated with carfilzomib in combination with Rd from the time of the first approval of KRd in the Republic of Korea were analyzed. The median age was 61 years. The percentage of patients with an ECOG performance status ≥ 3, creatinine clearance < 50 mL/min, high-risk cytogenetics, and ≥ 4 lines of prior treatment were 9%, 22%, 31%, and 27%, respectively. Forty-one patients started treatment with KRd, whereas the remaining 14 patients (25%) were added carfilzomib during the Rd treatment. In the whole cohort, the overall response rate was 73% and progression-free survival was 8.8 months. The addition of carfilzomib in patients who were refractory or had disease progression during Rd treatment reattained a response in half of the patients. The advantage of carfilzomib with Rd was significant in patients in the first relapse. Toxicity profile was acceptable, excluding severe infections. Carfilzomib in combination with Rd is effective and has a reasonable adverse event rate in Asian patients with RRMM.

Incidence, prevalence, mortality, and causes of death in Waldenström macroglobulinemia: a nationwide, population-based cohort study.

BACKGROUND: The epidemiological features of Waldenström macroglobulinemia (WM) have seldom been investigated at a national level, particularly in East Asia. The goal of our study is to present the incidence, prevalence, mortality, survival with competing risks, and causes of death of patients with WM. METHODS: We used a national population-based database, operated by the Health Insurance Review and Assessment Service of the Korean government. This data includes information on all WM patients diagnosed according to uniform criteria, between 2003 and 2016. RESULTS: The total number of patients newly diagnosed with WM during the study period was 427, with a male-to-female ratio of 3.2:1. The incidence increased from 0.03 to 0.10 per 105 between 2003 and 2016, and the prevalence was 0.42 per 105 in 2016. A total of 217 patients with WM died during the study period (standardized mortality ratio = 7.57), and the overall survival (OS) of WM patients was 47.5%. On multivariate analysis, older age was associated with worse OS (P <  0.0001). WM was the most common cause of death (n = 102, 48.6%), followed by other malignant neoplasms (n = 82, 39.0%). CONCLUSIONS: The national incidence of WM in Korea, a racially homogeneous country in Asia, was lower than that in previous reports from other countries, reflecting ethnic disparities. However, the incidence increased, and mortality was the highest ever reported. The main cause of death was WM in itself. This study reflects the need for greater awareness of WM, particularly in Asian countries.

Endothelial activation and stress index (EASIX) is a reliable predictor for overall survival in patients with multiple myeloma.

BACKGROUND: Recently, the endothelial Activation and Stress Index (EASIX) score has been reported to predict overall survival (OS) after allogeneic stem cell transplantation. This study evaluated the prognostic role of EASIX score in patients with newly diagnosed multiple myeloma (MM). METHODS: This retrospective study analyzed the records of 1177 patients with newly diagnosed MM between February 2003 and December 2017 from three institutions in the Republic of Korea. Serum lactate dehydrogenase (LDH), creatinine, and platelet count at diagnosis were measured in all included patients. EASIX scores were calculated using the formula-LDH (U/L) × Creatinine (mg/dL) / platelet count (109/L) and were evaluated based on log2 transformed values. RESULTS: The median age of patients was 63 years (range, 22-92), and 495 patients (42.1%) underwent autologous stem cell transplantation (ASCT). The median log2 EASIX score at diagnosis was 1.1 (IQR 0.3-2.3). Using maximally selected log-rank statistics, the optimal EASIX cutoff value for OS was 1.87 on the log2 scale (95% CI 0.562-0.619, p < 0.001). After median follow-up for 50.0 months (range, 0.3-184.1), the median OS was 58.2 months (95% CI 53.644-62.674). Overall, 372 patients (31.6%) showed high EASIX scores at diagnosis, and had significantly inferior OS compared to those with low EASIX (log2 EASIX ≤1.87) (39.1 months vs. 67.2 months, p < 0.001). In multivariate Cox analysis, high EASIX was significantly associated with poor OS (HR 1.444, 95% CI 1.170-1.780, p = 0.001). In the subgroup analysis of patients who underwent ASCT, patients with high EASIX showed significantly inferior OS compared to those with low EASIX (52.8 months vs. 87.0 months, p < 0.001). In addition, in each group of ISS I, II, and III, high EASIX was associated with significantly inferior OS (ISS 1, 45.2 months vs. 76.0 months, p = 0.001; ISS 2, 42.3 months vs. 66.5 months, p = 0.002; ISS 3, 36.8 months vs. 55.1 months, p = 0.001). CONCLUSION: EASIX score at diagnosis is a simple and strong predictor for OS in patients with newly diagnosed MM.

Clinical features and treatment outcomes of limited-stage mantle cell lymphoma: Consortium for Improving Survival of Lymphoma report.

Limited-stage (Ann Arbor stage I or II) mantle cell lymphoma (MCL) is an extremely rare disease. Thus, there is little data on the clinical features and treatment outcomes of patients with early-stage MCL. We examined consecutive stage I or II MCL 41 cases diagnosed between 2000 and 2016 in 16 institutions of the Consortium for Improving Survival of Lymphoma group. All cases were pathologically confirmed and systemic evaluation was performed for staging. The clinical features were reviewed, and the treatment outcomes were analyzed. The median age of patients was 66 years (range 19-85 years); there were more men (n = 31, 75.6%) than women. Most patients (n = 28, 68.3%) had stage 2 disease, and 29 (70.7%) were symptomatic. The elevation of lactate dehydrogenase (n = 2, 4.9%) was not common; thus, 39 patients (95.1%) had a low-risk score (0 or 1) for the International Prognostic Index, and 28 (68.3%) had a low-risk score (1-3) for the MCL International Prognostic Index. Most patients (n = 37, 90.1%) received chemotherapy as the first therapeutic strategy, while some received radiotherapy (n = 2), surgical resection (n = 1), or no treatment (n = 1). Of the patients who received chemotherapy, 23 (56.9%) received a rituximab-containing regimen, and R-CHOP (n = 17) and R-bendamustine (n = 5) were commonly used. The best response was noted in 97.4% (n = 38) of patients, including 32 who showed a complete response (78%). With a median follow-up duration of 40.6 months, the 42 months relapse-free survival was 59.1%, and the 5-year overall survival rate was 80.4%. Limited-state MCL showed indolent clinical and low-risk prognostic features. Chemotherapy could be effective for controlling localized MCL lesions, with high complete response rates.

The effectiveness and safety of lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma in real-world clinical practice: a study of the Korean Multiple Myeloma Working Party (KMMWP-151 study).

Although lenalidomide plus dexamethasone (RD) is a therapeutic option for relapsed/refractory multiple myeloma (RRMM), limited real-world clinical data exist. The purpose of this study was to estimate efficacy and safety of RD in RRMM patients of the clinical practice. Data from patients at 25 university hospitals in South Korea between October 2009 and December 2016 were collected retrospectively. We report the effectiveness and safety of RD in 546 RRMM patients in routine clinical practice in South Korea. Patients (median age, 65 years) typically received median 7 cycles of RD, and 184 (33.7%) patients were treated with 10 or more cycles of RD. Patients with renal impairment (CLCr < 40 mL/min; 10.4%), comorbid conditions (≥ 2; 12.0%), and poor performance status (≥ 2; 25.1%) were included. The overall response rate was 64.2%: complete response (13.1%), very good partial response (VGPR 19.9%). With median follow-up duration of 18.6 months, median PFS and OS were 11.2 months and 25.2 months, respectively. In multivariate analysis, less than 2 comorbid conditions, normal LDH, failed one chemotherapy prior to RD, and ≥ 10 cycles of RD therapy had significantly prolonged PFS (P = 0.007, P = 0.011, P = 0.007, and P < 0.001, respectively). Adverse events were acceptable. RD is effective and safe in real-life clinical practice, including patients with comorbidities. RD is an effective and safe treatment in a real clinical setting which includes patients with comorbidities. Early and continual use of RD treatment may improve RRMM survival outcomes.

Pomalidomide, cyclophosphamide, and dexamethasone for elderly patients with relapsed and refractory multiple myeloma: A study of the Korean Multiple Myeloma Working Party (KMMWP-164 study).

Patients with transplant-ineligible relapsed and refractory multiple myeloma (RRMM) have a short life expectancy, especially when they have failed both the proteasome inhibitor and immunomodulator therapies. This study aimed to assess the efficacy and safety of pomalidomide, cyclophosphamide, and dexamethasone (PCd) in elderly patients with RRMM. This phase 2 clinical trial recruited 55 elderly patients with RRMM. The patients underwent a 28-day treatment cycle: pomalidomide (4 mg/day on days 1-21, administered orally) and cyclophosphamide (400 mg/day on days 1, 8, and 15; administered orally) plus dexamethasone. The median (range) age of the patients was 73.3 (64-86) years, and 8 (14.5%) patients who were ≥ 80 years old. Eight (14.5%) and 31 (56.4%) patients exhibited stage III (revised international staging system) and frail status (simplified frailty scale), respectively. The overall response rate (ORR) and clinical benefit rate (CBR) of PCd therapy were 58.2% and 72.7%, respectively. The median PFS and median overall survival (OS) were 6.90 months (95% CI, 4.7-9.0) and 18.48 months (95% CI, 9.4-27.6), respectively. The incidence rate of grade ≥ 3 non-hematological toxicities was 70.8%. In particular, the incidence rate of primary infection was 45.4%, including 21.8% for pneumonia, 9.0% for sepsis, and 14.6% for febrile neutropenia. In conclusion, PCd is an effective regimen for elderly patients with RRMM who had failed both bortezomib and lenalidomide treatments, but in whom the treatment-associated infection is the main cause of morbidity and mortality.

Treatment with intravenous busulfan, melphalan, and etoposide followed by autologous stem cell transplantation in patients with non-Hodgkin's lymphoma: a multicenter study from the consortium for improving survival of lymphoma.

Several high-dose therapy (HDT) conditioning regimens have been used to treat non-Hodgkin's lymphoma (NHL), such as bis-chloroethylnitrosourea (BCNU)/etoposide/cytosine arabinoside/melphalan (BEAM), BCNU/etoposide/cytosine arabinoside/cyclophosphamide (BEAC), and cyclophosphamide/BCNU/etoposide (CBV). BCNU is an active drug in HDT of NHL, but the supply is limited in some countries, including Korea. Busulfan has been used in allogeneic and autologous stem cell transplantation (ASCT). This phase II study evaluated the efficacy of busulfan/melphalan/etoposide (BuME) as a conditioning regimen for HDT in relapsed or high-risk NHL. The regimen consisted of intravenous busulfan (3.2 mg/kg/day) on days -8, -7, and -6, etoposide (400 mg/m2 /day) on days -5 and -4, and melphalan (50 mg/m2 /day) on days -3 and -2. A total of 46 patients were included in the study, with 36 (78.3%) achieving a complete response after ASCT. The 2-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 46.7% (95% CI, 31.8-60.4%) and 63.7% (95% CI, 47.7-76.0%), respectively. There was no development of veno-occlusive disease and no treatment-related deaths within 100 days after ASCT. These results indicate that a BuME regimen is well-tolerated and effective for patients with relapsed or high-risk NHL, and may be comparable to some previously used regimens. This regimen may be useful as a substitute for BCNU-containing regimens.

The effects of erythropoiesis-stimulating agents on the management of chemotherapy-induced anemia and tumor growth in diffuse large B-cell lymphoma patients.

Erythropoiesis-stimulating agents (ESAs), such as erythropoietin (EPO) and darbepoetin, may alleviate anemia in diffuse large B-cell lymphoma (DLBCL) patients. However, many cancer cells express EPO receptors (EPOR), through which exogenously administered ESAs potentially promote cancer cell growth. We conducted preclinical/phase II studies to investigate the safety and efficacy of ESAs for managing chemotherapy-related anemia in DLBCL patients. We examined EPOR expression in germinal center B-cell (GCB)- and activated B-cell (ABC)-DLBCL cell lines, and investigated the effects of ESAs on cell proliferation, and rituximab-mediated complement-dependent cytotoxicity (CDC). The clinical study enrolled 50 histologically confirmed DLBCL patients receiving rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP) who had hemoglobin levels <10.0 g/dl after a maximum of three R-CHOP cycles and received ≥4 doses of fixed-dose darbepoetin (360 µg) once every 3 weeks. EPOR mRNA was detected in all GCB-DLBCL cell lines, but little/none was detected in ABC-DLBCL cell lines. GCB-DLBCL and ABC-DLBCL cell proliferation was unaffected by EPO or darbepoetin. Rituximab-mediated CDC of DLBCL cell lines with/without EPOR expression was not affected adversely by EPO. In the clinical study, baseline mean hemoglobin was 9.19 g/dl; the overall mean change in hemoglobin was 1.59 ± 1.3 g/dl (16 weeks). Forty-eight percent of enrolled patients achieved a hematopoietic response. Our study shows that ESAs do not affect the growth of DLBCL cells or rituximab-mediated CDC under the experimental conditions that we used, and the appropriate use of ESAs may be effective and safe for DLBCL patients with anemia after R-CHOP.

Ruxolitinib shows activity against Hodgkin lymphoma but not primary mediastinal large B-cell lymphoma.

BACKGROUND: The upregulated expression of the JAK/STAT pathway promotes tumor growth in Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL). Based on the hypothesis that JAK2 is a therapeutic target, we performed a prospective pilot study using ruxolitinib. METHODS: Relapsed or refractory patients with HL or PMBCL were eligible for this study, and JAK2 amplification was assessed by fluorescence in situ hybridization. Ruxolitinib was administered orally at a dose of 20 mg twice daily for a 28-day cycle. Treatment was continued for up to 16 cycles or until progressive disease or intolerability. The primary objective was to assess the overall disease control rate comprising complete response (CR), partial response (PR), or stable disease (SD). RESULTS: We analyzed 13 HL patients and six PMBCL patients. All responders (one CR, five PR, and one SD) had HL whereas all cases of PMBCL progressed after first or second cycle. The disease control rate for HL was 54% (7/13) with median response duration of 5.6 months. JAK2 amplification was present in six of nine patients tested (four HL, two PMBCL), and three of these HL patients showed PR (n = 2) or SD (n = 1). None of the three HL patients shown to not have JAK2 amplification responded to ruxolitinib. Most treatment-related adverse events were grade 1 or 2 and manageable. CONCLUSIONS: Ruxolitinib has single-agent activity against HL but does not act against PMBCL with or without JAK2 amplification. TRIAL REGISTRATION: The study population was patients who had relapsed or refractory HL or PMBCL, and patients were registered for our pilot study after providing written informed consent between November 2013 and November 2015 (CilinicalTrials.gov: NCT01965119).

Echinochrome A Promotes Ex Vivo Expansion of Peripheral Blood-Derived CD34+ Cells, Potentially through Downregulation of ROS Production and Activation of the Src-Lyn-p110δ Pathway.

Intracellular reactive oxygen species (ROS) play an important role in the proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs). HSPCs are difficult to be expanded ex vivo while maintaining their stemness when they are exposed to oxidative damage after being released from the bone marrow. There have been efforts to overcome this limitation by using various cytokine cocktails and antioxidants. In this study, we investigated the effects of echinochrome A (Ech A)-a well-established and non-toxic antioxidant-on the ex vivo expansion of HSPCs by analyzing a CD34+ cell population and their biological functions. We observed that Ech A-induced suppression of ROS generation and p38-MAPK/JNK phosphorylation causes increased expansion of CD34+ cells. Moreover, p38-MAPK/JNK inhibitors SB203580 and SP600125 promoted ex vivo expansion of CD34+ cells. We also demonstrated that the activation of Lyn kinase and p110δ is a novel mechanism for Ech A to enhance ex vivo expansion of CD34+ cells. Ech A upregulated phospho-Src, phospho-Lyn, and p110δ expression. Furthermore, the Ech A-induced ex vivo expansion of CD34+ cells was inhibited by pretreatment with the Src family inhibitor PP1 and p110δ inhibitor CAL-101; PP1 blocked p110δ upregulation and PI3K/Akt activation, whereas CAL-101 and PI3K/Akt pathway inhibitor LY294002 did not block Src/Lyn activation. These results suggest that Ech A initially induces Src/Lyn activation, upregulates p110δ expression, and finally activates the PI3K/Akt pathway. CD34+ cells expanded in the presence of Ech A produced equal or more hematopoietic colony-forming cells than unexpanded CD34+ cells. In conclusion, Ech A promotes the ex vivo expansion of CD34+ cells through Src/Lyn-mediated p110δ expression, suppression of ROS generation, and p38-MAPK/JNK activation. Hence, Ech A is a potential candidate modality for the ex vivo, and possibly in vivo, expansion of CD34+ cells.

Phase 2 Study of an Intravenous Busulfan and Melphalan Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma (KMM150).

This prospective study evaluated the efficacy and toxicity of intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). A total of 99 patients with MM, enrolled between January 2013 and March 2016, received intravenous busulfan (9.6 mg/kg) and melphalan (140 mg/m2) before ASCT. The median time to transplant was 6.2 months, and 90 (90.9%) patients underwent ASCT within 12 months of the diagnosis. The overall response rate after ASCT was 94.0%, including 43.5% with a stringent complete response/complete response, 27.3% with very good partial response, and 23.2% with partial response. The most common severe nonhematologic toxicity (grade 3 to 4) was infection (26.3%) and stomatitis (15.2%). Three (3.2%) patients developed veno-occlusive disease. No treatment-related mortality was observed. After a median follow-up of 26.1 months, the median progression-free survival was 27.2 months (range, 13.0 to 41.4 months) and median overall survival was not reached. In conclusion, a conditioning regimen of intravenous busulfan and melphalan was effective and tolerable. ClinicalTrials.gov. number: NCT01923935.

Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: a multicenter retrospective analysis.

Bendamustine plus rituximab (BR) showed efficacy and safety in indolent lymphomas and mantle cell lymphoma. However, there were limited experiences of real-world practice of BR in diffuse large B cell lymphoma (DLBCL). In this study, we report the Korean experiences with BR in relapsed or refractory DLBCL who are not eligible for intensive chemotherapy and autologous stem cell transplantation. This is an observational, multicenter, retrospective analysis. Between December 2011 and December 2015, a total of 58 patients with relapsed or refractory DLBCL were treated with BR in 11 tertiary hospitals in Korea. Patients received an intravenous (IV) infusion of rituximab at a dose of 375 mg/m2 on day 1. On days 2 and 3, patients received an IV infusion of bendamustine at doses of 120 or 90 mg/m2. Median age was 69 (range 18-86), 74.1% had stage III or IV disease, and 67.2% showed high-intermediate or high International Prognostic Index scores at diagnosis. In an intention-to-treat analysis, 18 patients (31.0%) showed a complete response and 14 (24.1%) showed a partial response, resulting in an overall response rate of 55.1%. The median duration of the response was 3.7 months (range 1.0-47.2 months). The median progression-free survival was 3.9 months (95% confidence interval [CI], 2.4-5.4 months), and the median overall survival was 6.7 months (95% CI, 4.7-8.7 months). The most common grade 3/4 adverse event was neutropenia (n = 40; 68.9%). Febrile neutropenia was observed in 11 patients (18.9%). Grade 3/4 thrombocytopenia was observed in 34 patients (58.6%). Our study confirmed the high efficacy and acceptable toxicity profile of BR in relapsed or refractory DLBCL patients. However, we need to closely observe the higher tendency of grade 3/4 hematological toxicities in Korean patients.

Response to hypomethylating agents improves long-term outcomes for lower-risk patients with myelodysplastic syndrome in case-matched cohorts.

Predictive factors for initiating hypomethylating agents' (HMAs) treatment and the survival benefit of HMAs for lower-risk myelodysplastic syndrome (LR-MDS) are still unknown. This study evaluated the factors affecting the use of HMAs and compared long-term outcomes between best supportive care (BSC) and HMA groups after matching baseline clinical factors. Data of 353 patients diagnosed with LR-MDS by International Prognostic Scoring System between October 1992 and July 2013 were retrospectively analyzed. HMAs were administered continuously until a clinical response or progression. HMAs were administered to 243 patients with median 45 days (range 0-7078 days) after diagnosis, while 110 patients were treated with BSC. HMAs were administered over a median of 5 cycles and overall response was achieved in 104 patients (42.8%). The cumulative incidence of HMA treatment increased in higher-risk groups by other risk scoring systems. Three-year overall survival (OS) rate was higher in BSC group (69.1%) than HMA responders (47.4%, p = 0.065) or HMA non-responders (46.3%, p = 0.005). Among 162 case-matched cohorts, 3-year OS rates were comparable between the BSC group (67.1%) and HMA responders (58.1%, p = 0.914), while that of HMA non-responder was low (32.2%, p < 0.001). In the case-matched cohorts, HMA non-responder were associated with inferior OS rate in the multivariate analysis (hazard ratio 3.01, p = 0.001). Higher-risk groups by other clinical risk scoring systems among IPSS lower-risk patients showed an increased incidence of using HMAs. The OS rate of HMA responders among case-matched cohorts showed an improved OS rate similar to the BSC group.

The Derived Neutrophil-to-Lymphocyte Ratio Is an Independent Prognostic Factor in Transplantation Ineligible Patients with Multiple Myeloma.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is an independent prognostic marker in solid and hematological cancers. While the derived NLR (dNLR) was shown to be non-inferior to the NLR in large cohorts of patients with different cancer types, it has not been validated as a prognostic marker for multiple myeloma (MM) to date. METHODS: Between May 22, 2011 and May 29, 2014, 176 patients with MM from 38 centers who were ineligible for autologous stem cell transplantation were analyzed. The dNLR was calculated using complete blood count differential data. The optimal dNLR cut-off value according to receiver operating characteristic analysis of overall survival (OS) was 1.51. All patients were treated with melphalan and prednisone combined with bortezomib. RESULTS: The complete response rate was lower in the high dNLR group compared to the low dNLR group (7 vs. 26.1%, respectively; p = 0.0148); the corresponding 2-year OS rates were 72.2 and 84.7%, respectively (p = 0.0354). A high dNLR was an independent poor prognostic factor for OS (hazard ratio 2.217, 95% CI 1.015-4.842; p = 0.0458). CONCLUSION: The dNLR is a readily available and cheaply obtained parameter in clinical studies, and shows considerable potential as a new prognostic marker for transplantation-ineligible patients with MM.

Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia.

We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios ≤10(-3) and MR5 for ratios <10(-5). Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P = .004) or 6.3 times (P = .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298.