Expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model.

The development of new treatment agents in recent decades has significantly improved the survival of patients with multiple myeloma (MM). Nonetheless, MM remains an incurable disease; therefore, novel combination therapies are required. Natural killer (NK) cells are one of the safest immunotherapeutic options. In this study, we found that the anti-myeloma activity of expanded NK cells (eNKs) was improved by daratumumab, lenalidomide, and dexamethasone (DRd) in an MM xenograft mouse model. NK cells expanded from peripheral blood mononuclear cells collected from MM patients were highly cytotoxic against DRd pretreated tumor cells in vitro. To mimic the clinical protocol, a human MM xenograft model was developed using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγnull (NSG) mice. MM bearing mice were randomly divided into six groups: no treatment, eNK, Rd, Rd + eNKs, DRd, and DRd + eNKs. DRd significantly enhanced the cytotoxicity of eNKs by upregulating NK cell activation ligands and effector function. DRd in combination with eNKs significantly reduced the serum M-protein level and prolonged mouse survival. In addition, DRd significantly increased the persistence of eNK and homing to MM sites. These results show that the anti-myeloma activity of ex vivo-expanded and activated NK cells is augmented by the immunomodulatory effect of DRd in MM-bearing mice, suggesting the therapeutic potential of this combination for MM patients.

Clonal hematopoiesis in the donor does not adversely affect long-term outcomes following allogeneic hematopoietic stem cell transplantation: result from a 13-year follow-up.

Donor clonal hematopoiesis may be transferred to the recipient through allogeneic hematopoietic stem cell transplantation (HSCT), but the potential for adverse long-term impact on transplant outcomes remains unknown. A total of 744 samples from 372 recipients who received HSCT and the corresponding donors were included. Bar-coded error-corrected sequencing using a modified molecular inversion probe capture protocol was performed, which targeted 33 genes covering mutations involved in clonal hematopoiesis with indeterminate potential (CHIP) and other acute myeloid leukemia-related mutations. A total of 30 mutations were detected from 25 donors (6.7%): the most frequently mutated gene was TET2 (n=7, 28%), followed by DNMT3A (n=4, 16%), SMC3 (n=3, 12%) and SF3B1 (n=3, 12%). With a median follow-up duration of 13 years among survivors, the presence of CHIP in the donor was not associated with recipient overall survival (P=0.969), relapse incidence (P=0.600) or non-relapse mortality (P=0.570). Donor CHIP did not impair neutrophil (P=0.460) or platelet (P=0.250) engraftment, the rates of acute (P=0.490), or chronic graft-versus-host disease (P=0.220). No significant difference was noted for secondary malignancy following HSCT between the two groups. The present study suggests that the presence of CHIP in allogeneic stem donors does not adversely affect transplant outcomes after HSCT. Accordingly, further study is warranted to reach a clearer conclusion on whether molecular profiling to determine the presence of CHIP mutations is necessary for the pretransplant evaluation of donors prior to stem cell donation.

Diagnostic Accuracy and Prognostic Relevance of Immunoglobulin Heavy Chain Rearrangement and 18F-FDG-PET/CT Compared With Unilateral Bone Marrow Trephination for Detecting Bone Marrow Involvement in Patients With Diffuse Large B-Cell Lymphoma.

BACKGROUND: In diffuse large B-cell lymphoma (DLBCL), bone marrow involvement (BMI) has an important clinical implication as a component of staging and International Prognostic Index. This study aimed to determine whether molecular analysis of immunoglobulin heavy chain (IgH) genes and positron emission tomography-computed tomography (PET/CT) could overcome the limitation of defining morphologic BMI by trephination biopsy and could increase the diagnostic accuracy or prognostic prediction. METHODS: A total of 94 de novo patients with DLBCL underwent PET/CT, polymerase chain reaction (PCR) test for detection of IgH gene rearrangement, and unilateral bone marrow (BM) trephination at diagnosis. RESULTS: A total of 9 patients (9.6%) were confirmed to present morphologic BMI (mBMI) based on trephination biopsy. On the other hand, 21 patients (22.3%) were confirmed to have IgH clonality (IgH BMI), while 16 (17.0%) were classified with BMI based on the assessment of PET/CT (PET BMI). Each IgH rearrangement PCR and PET/CT showed the high negative predictive value of detecting the BMI. However, the combined assessment of IgH rearrangement and PET/CT could increase the diagnostic accuracy and specificity with 87.2% and 97.0%, respectively. The survival outcome of patients with double positive PET BMI and IgH BMI was significantly worse than that with either single positive PET BMI or IgH BMI, and even less than patients with neither PET BMI nor IgH BMI (3-year PFS: 50.0% vs. 75.4% vs. 97.9%, P = 0.007, 3-year OS: 50.0% vs. 75.6% vs. 80.1%, P = 0.035, respectively). CONCLUSION: This study suggests that the combined evaluation of PET/CT and IgH rearrangement could give additional information for predicting therapeutic outcomes in patients with negative morphologic BMI as an important part of the prognosis.

Next-generation sequencing-based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse.

Next-generation sequencing (NGS) has been applied to define clinically relevant somatic mutations and classify subtypes in acute myeloid leukemia (AML). Persistent allelic burden after chemotherapy is associated with higher relapse incidence, but presence of allelic burden in AML patients after receiving allogeneic hematopoietic cell transplantation (HCT) has not been examined longitudinally. As such, we aimed to assess the feasibility of NGS in monitoring AML patients receiving HCT. Using a targeted gene panel, we performed NGS in 104 AML patients receiving HCT using samples collected at diagnosis, pre-HCT, and post-HCT at day 21 (post-HCTD21). NGS detected 256 mutations in 90 of 104 patients at diagnosis, which showed stepwise clearances after chemotherapy and HCT. In a subset of patients, mutations were still detectable pre-HCT and post-HCT. Most post-HCT mutations originate from mutations initially detected at diagnosis. Post-HCTD21 allelic burdens in relapsed patients were higher than in nonrelapsed patients. Post-HCTD21 mutations in relapsed patients all expanded at relapse. Assessment of variant allele frequency (VAF) revealed that overall VAF post-HCTD21 (VAF0.2%-post-HCTD21) is associated with an increased risk of relapse (56.2% vs 16.0% at 3 years; P < .001) and worse overall survival (OS; 36.5% vs 67.0% at 3 years; P = .006). Multivariate analyses confirmed that VAF0.2%-post-HCTD21 is an adverse prognostic factor for OS (hazard ratio [HR], 3.07; P = .003) and relapse incidence (HR, 4.75; P < .001), independent of the revised European LeukemiaNet risk groups. Overall, current study demonstrates that NGS-based posttransplant monitoring in AML patients is feasible and can distinguish high-risk patients for relapse.

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.

Prognostic significance of FDG-PET/CT in determining upfront autologous stem cell transplantation for the treatment of peripheral T cell lymphomas.

This observational study aimed to evaluate the prognostic significance of interim and final 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET/CT) responses to upfront autologous stem cell transplantation (ASCT) in patients with peripheral T cell lymphomas (PTCLs). A total of 118 patients, from two independent institutions, with newly diagnosed PTCLs were enrolled, and 96 of them were evaluated. PET/CT was assessed at diagnosis, and during and after the primary treatment. Clinical outcomes of interim and final PET/CT were compared between transplanted and non-transplanted patients. The responses of PET/CT were assessed based on visual analysis using the Deauville five-point scale (5-PS). Clinicopathological features of transplanted patients (n = 37) were similar to those of non-transplanted patients (n = 59). After a median follow-up of 60.8 months, only final PET/CT response based on 5-PS was the independent prognostic factor of survival outcome (P < 0.001; HR 8.215; 95% C.I. 2.97-22.72) in multivariate analysis. Interim PET/CT response did not have a differential potential for predicting progression-free survival (PFS). In 59 patients, with score 1 or 2 in final PET/CT, the PFS rate was not significantly different between transplanted and non-transplanted patients (P = 0.970). Moreover, among the 37 patients with final PET/CT response score of 3-4, the PFS rate was equally poor in both transplanted and non-transplanted patients (P = 0.178). Final PET/CT assessment, based on 5-PS, was an important prognostic parameter for primary treatment of PTCLs, regardless of upfront ASCT. Interim PET/CT response could not be an indicator to determine the requirement for upfront ASCT.

Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy.

Somatic mutations commonly detected in a variety of myeloid neoplasms have not been systematically investigated in chronic myeloid leukemia (CML). We performed targeted deep sequencing on a total of 300 serial samples from 100 CML patients; 37 patients carried mutations. Sixteen of these had evidence of mutations originating from preleukemic clones. Using unsupervised hierarchical clustering, we identified 5 distinct patterns of mutation dynamics arising following tyrosine kinase inhibitor (TKI) therapy. This study demonstrates that patterns of mutation acquisition, persistence, and clearance vary but have a number of interesting correlations with clinical outcomes. Mutation burden often persisted despite successful TKI response (pattern 1), providing indirect evidence that these mutations also originated from preleukemic mutations, whereas patients exhibiting mutation clearance (pattern 3) showed mixed clinical outcomes. Unsurprisingly, patients acquiring new mutations during treatment failed TKI therapy (pattern 2). These patterns show that CML mutation dynamics following TKI therapy are markedly distinct from other myeloid neoplasms. In summary, clinical implications of mutation profiles and dynamics in CML should be interpreted with caution.

18F-FDG PET/CT is useful for determining survival outcomes of patients with multiple myeloma classified as stage II and III with the Revised International Staging System.

PURPOSE: This study evaluated the prognostic role of 18F-FDG PET/CT at baseline in patients with newly diagnosed multiple myeloa (MM) and evaluated the prognostic relevance of 18F-FDG PET/CT for each stage according to the Revised International Staging System (R-ISS). METHOD: We retrospectively analyzed the records of 167 patients with newly diagnosed MM. 18F-FDG PET/CT was performed prior to induction therapy in patients with newly diagnosed MM. RESULTS: In the total cohort, the presence of more than three hypermetabolic focal lesions (FLs) or extramedullary disease (EMD) on baseline PET/CT was associated with significantly inferior progression-free survival (PFS) and overall survival (OS) than other patients. Because most patients (91%) with EMD had more than three FLs, PET/CT positivity was defined as the presence of more than three FLs or the presence of EMD. In multivariate analyses, PET/CT positivity was an independent predictor of PFS and OS in all patients. Fifty-five patients (46.1%) with R-ISS II were PET/CT-positive at baseline and had significantly shorter PFS and OS. PET/CT positivity was also correlated with poor PFS and OS in patients with R-ISS III. CONCLUSION: 18F-FDG PET/CT was an independent predictor of survival outcomes in patients with newly diagnosed MM. In addition, performing 18F- FDG PET/CT at diagnosis may be useful for determining the survival outcomes of MM patients with R-ISS II and III.

Optimal chemo-mobilization for the collection of peripheral blood stem cells in patients with multiple myeloma.

BACKGROUND: For successful autologous stem cell transplantation, the collection of a sufficient number of hematopoietic stem cells after induction therapy is essential for transplant candidates with multiple myeloma (MM). METHODS: In this study, we compared the efficacy and safety of stem cell mobilization using cyclophosphamide (CY; 3.0 g/m2 on day 1) or etoposide (VP-16; 375 mg/m2 on days 1 and 2) in patients with MM. Granulocyte-colony stimulating factor (G-CSF, 10 µg/kg/day, subcutaneously) was administered from the onset of neutropenia to the final day of collection. RESULTS: Sixty-five patients were mobilized with a combination of CY and G-CSF, and 63 were mobilized with a combination of VP-16 and G-CSF. All patients were mobilized within 7 months of beginning frontline treatment. The median number of CD34+ cells collected was significantly higher in the VP-16 mobilization group than in the CY mobilization group (27.6 ×  106 CD34+/kg vs. 9.6 × 106 CD34+/kg, P <  0.001). The rate of mobilization failure, defined as < 2.0 × 106 CD34+/kg collected in three apheresis procedures, was lower in the VP-16 group than in the CY group (1.6% vs. 10.8%, P = 0.062). Severe infections during the mobilization period were more frequent in the CY group than in the VP-16 group (18.5% vs. 7.9%, P = 0.117). CONCLUSION: In conclusion, an intermediate dose of VP-16 with G-CSF appears to be an effective and tolerable chemo-mobilization method compared to CY and G-CSF, particularly in cases where use plerixafor in MM is difficult.

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.

Clinical response and pharmacokinetics of bendamustine as a component of salvage R-B(O)AD therapy for the treatment of primary central nervous system lymphoma (PCNSL).

BACKGROUND: A relatively high proportion of patients diagnosed with primary CNS lymphoma will experience recurrent disease, yet therapy options are limited in salvage therapy. This is the first study to evaluate a bendamustine-based combination regimen for the treatment of relapsed/refractory PCNSL and to characterize bendamustine pharmacokinetics in the human CSF. METHODS: Patients received bendamustine 75 mg/m2 for two days as part of R-B(O)AD administered intravenously every 4 weeks for up to 4 cycles. Response and adverse events of the regimen were assessed. A sparse sampling strategy and population based modeling approach was utilized for evaluation of plasma and CSF levels of bendamustine. RESULTS: Ten patients were enrolled into study of whom 70% were of refractory disease and with high IELSG prognostic risk scores. The ORR of R-BOAD was 50% (95% CI, 0.24 to 0.76) with one patient achieving CR and four PR. Primary toxicity of the regimen was reversible myelosuppression, mostly grade 3 or 4 neutropenia. The Cmax mean for plasma and CSF were 2669 ng/mL and 0.397 ng/mL, respectively, and patients with response at deep tumor sites displayed higher trends in peak exposure. Pharmacokinetic data was best described by a four-compartment model with first-order elimination of drug from central plasma and CSF compartments. CONCLUSIONS: R-BOAD is an effective salvage option for PCNSL, but with significant hematologic toxicity. Bendamustine CSF levels are minimal; however correspond to plasma exposure and response. TRIAL REGISTRATION: ClinicalTrials.gov NCT03392714 ; retrospectively registered January 8, 2018.

Genome-wide genotype-based risk model for survival in core binding factor acute myeloid leukemia patients.

The present study attempted to build a single nucleotide polymorphism (SNP)-based risk model for predicting overall survival (OS) and event-free survival (EFS) in patients with core binding factor acute myeloid leukemia (CBF-AML). Adopting genome-wide SNP array using Affymetrix SNP array 6.0, we analyzed 868,157 SNPs with respect to OS and EFS in 104 patients with CBF-AML. Significant SNPs were identified from single SNP analysis. The risk model was constructed with incorporation of six SNPs and three clinical factors (age, c-kit exon 17 mutation, and LDH) for OS and six SNPs and three clinical factors (age, WBC, and LDH) for EFS. The model was further defined into low- and high-risk groups based on risk scores. The median age was 39 years, and the subgroup of t(8;21) and inv(16) or t(16;16) was assessed in 68 (65.4%) and 36 patients (34.6%). Finally, six SNPs per each OS (rs4353685, rs4908185, rs7709207, rs12034, rs1554844, and rs17241868) and EFS (rs13385610, rs11210617, rs11169282, rs7709207, rs4438401, and rs16894846) were incorporated into the risk model. OS was significantly different in favor of the low risk group (80.4 ± 8.4%) compared to the high-risk group (22.0 ± 7.3% at 3 years; p = 8.75 × 10- 13; HR 8.67). For EFS, there was also a significant difference between the low- (75.0 ± 5.8%) versus high-risk group (17.1 ± 6.3% at 3 years; p = 5.95 × 10- 13; HR 7.67). A genome-wide SNP-based risk model can stratify CBF-AML patients according to their OS and EFS in 104 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.

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.

DNMT3A R882 Mutation with FLT3-ITD Positivity Is an Extremely Poor Prognostic Factor in Patients with Normal-Karyotype Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation.

The prognostic relevance of epigenetic modifying genes (DNMT3A, TET2, and IDH1/2) in patients with acute myeloid leukemia (AML) has been investigated extensively. However, the prognostic implications of these mutations after allogeneic hematopoietic cell transplantation (HCT) have not been evaluated comprehensively in patients with normal-karyotype (NK)-AML. A total of 115 patients who received allogeneic HCT for NK-AML were retrospectively evaluated for the FLT3-ITD, NPM1, CEBPA, DNMT3A, TET2, IDH1/2, WT1, NRAS, ASXL2, FAT1, DNAH11, and GATA2 mutations in diagnostic samples and analyzed for long-term outcomes after allogeneic HCT. The prevalence rates for the mutations were as follows: FLT3-ITD positivity (FLT3-ITD(pos)) (32.2%), NPM1 mutation (43.5%), CEBPA mutation (double) (24.6%), DNMT3A mutation (DNMT3A(mut)) (31.3%), DNMT3A R882(mut) (18.3%), TET2 mutation (8.7%), and IDH1/2 mutation (16.5%). The 5-year overall survival (OS) and event-free survival (EFS) rates were 57.3% and 58.1%, respectively. A multivariate analysis revealed that FLT3-ITD(pos) (hazard ratio, [HR], 2.23; P = .006) and DNMT3A R882(mut) (HR, 2.74; P = .002) were unfavorable prognostic factors for OS. In addition, both mutations were significant risk factors for EFS and relapse. People with DNMT3A R882(mut) accompanied by FLT3-ITD(pos) had worse OS and EFS, and higher relapse rates than those with the other mutations, which were confirmed in a propensity score 1:2 matching analysis. These results suggest that DNMT3A R882(mut), particularly when accompanied by FLT3-ITD(pos), is a significant prognostic factor for inferior transplantation survival outcome by increasing relapse risk, even after allogeneic HCT.

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.

Prognostic value of the inverse platelet to lymphocyte ratio (iPLR) in patients with multiple myeloma who were treated up front with a novel agent-containing regimen.

Recently, reactive thrombosis or platelet to lymphocyte ratio has been reported as a strong predictor of poor prognosis in various types of cancer. However, a study investigating the relationship between platelet counts and thrombopoietic cytokines suggested that low platelet could be important in multiple myeloma (MM), which means platelet count decreased in advanced International Staging System (ISS) stage. Therefore, we developed inverse platelet to lymphocyte ratio (iPLR) and assessed the prognostic value of iPLR in patients with MM. We retrospectively analyzed 283 patients who were treated up front with a novel agent-containing regimen. Patients were classified into three groups based on hazard ratio (HR) according to iPLR: low iPLR (group 1), middle iPLR (group 2), and high iPLR (group 3). Over a median follow-up of 34.8 months, staging by iPLR group had predictive value for progression-free survival (PFS) and overall survival (OS). In addition, staging by iPLR group was a reliable method to predict for survival in patients who presented with renal failure (eGFR<60 mL/min/1.73 m2) and in elderly patients. Multivariate analyses demonstrated that staging by iPLR group was associated with PFS and OS in patients with MM. In conclusion, this study suggested that iPLR is a simple and reliable inflammatory prognostic factor in the era of novel agents.

Thalidomide-based induction regimens are as effective as bortezomib-based regimens in elderly patients with multiple myeloma with cereblon expression.

Cereblon (CRBN) has been identified as a primary target of immunomodulatory drugs and is considered a biomarker for the prediction of outcomes after thalidomide- or lenalidomide-based treatments. In this study, we evaluated CRBN expression in bone marrow (BM) tissue at diagnosis and investigated the relationship between CRBN expression and treatment outcomes after thalidomide- or bortezomib-based front-line therapies in 89 elderly patients with multiple myeloma (MM). CRBN expression at the time of diagnosis was evaluated with immunohistochemical (IHC) staining for myeloma cells in paraffin wax-embedded BM tissue. CRBN-immunostained slides were scored by intensity and diffuseness, and a total score of >6 was defined as CRBN-positive (CRBN(+)). Thirty-eight patients (45.2 %) were CRBN(+). Among patients treated with thalidomide-based regimens, CRBN(+) patients showed a better treatment response than did CRBN-negative patients (35.0 vs. 11.8 % complete response rate, respectively; HR = 4.038, P = 0.137). During a median follow-up of 31.8 months, patients treated with bortezomib-based regimens had a longer time to progression (TTP) than did patients treated with thalidomide-based regimens (15.6 vs. 13.2 months, respectively; P = 0.047), but early mortality occurred frequently in patients treated with bortezomib-based regimens. Additionally, there was no significant difference in survival outcomes between thalidomide- and bortezomib-based regimens in CRBN(+) patients (median TTP, 13.8 vs. 15.6 months, respectively; P = 0.842 and median OS, 39.3 vs. 30.1 months, respectively; P = 0.074). These data suggest that thalidomide-based regimens are as effective as bortezomib-based regimens in elderly patients with MM who are CRBN(+). Thus, CRBN positivity, by IHC staining, may be useful in deciding appropriate treatment options in elderly patients with MM.

Transplant outcomes of the triple-negative NPM1/FLT3-ITD/CEBPA mutation subgroup are equivalent to those of the favourable ELN risk group, but significantly better than the intermediate-I risk group after allogeneic transplant in normal-karyotype AML.

The prognostic significance of molecular mutations (FLT3-ITD, NPM1, and CEBPA mutations) was examined in patients with normal-karyotype acute myeloid leukaemia (NK-AML) after allogeneic haematopoietic cell transplantation (HCT). In total, 115 patients received allogeneic HCT for NK-AML and were evaluated for FLT3-ITD, NPM1, and CEBPA mutations in diagnostic samples and for long-term outcomes following HCT, retrospectively. The prevalences of FLT3-ITD(pos), NPM1 (mut), and CEBPA (dm) (double mutations) were 32.2, 43.5, and 24.6 %, respectively. The triple-negative group (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)) showed a similar transplant outcome to those in the favourable European LeukemiaNet (ELN) risk group for overall survival (OS) (60.9 vs. 63.7 %; p = 0.810), but a more favourable OS than others in the intermediate-I risk group (40.0 %; p = 0.034). Also, the triple-negative group showed a similar relapse rate at 5 years compared with those in the favourable risk group (9.7 vs. 15.5 %; p = 0.499), but a lower rate of relapse than the others in the intermediate-I risk group (15.5 vs. 48.6 %; p = 0.004). The 5-year relapse incidences were 4.0 % (NPM1 (mut)/FLT3-ITD(neg)), 14.7 % (CEBPA (dm)), 15.5 % (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)), 39.1 % (NPM1 (mut)/FLT3-ITD(pos)/non-CEBPA (dm)), and 66.7 % (NPM1 (wild)/FLT3-ITD(pos)/non-CEBPA (dm)). Thus, the triple-negative (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)) group showed favourable long-term outcomes after allogeneic HCT in NK-AML, similar to those of the favourable risk group by the ELN risk classification.

Report on outcomes of hypomethylating therapy for analyzing prognostic value of Revised International Prognostic Scoring System for patients with lower-risk myelodysplastic syndromes.

The outcomes for patients with lower-risk myelodysplastic syndromes (LR-MDS) by the International Prognostic Scoring System (IPSS) vary widely. For more precise prognostication, this study evaluates the prognostic value of revised IPSS with the response to hypomethylating therapy (HMT). Using the Korean MDS Working Party database, treatment outcomes for 236 patients with HMT were retrospectively evaluated. The patients were then reclassified into very low/low (VL/L), intermediate (INT), and high (H) risk groups according to IPSS-R. According to the HMT response, the 3-year overall survival (OS) did not differ between the response group (37.9 ± 9.1 %) and the stable group (52.9 ± 6.6 %, p = 0. 782). When reclassifying according to IPSS-R, 42 patients (20.8 %) were reclassified into the H risk group. Most of them did not have benefit from continued HMT and progressed to secondary failure. The median OS was 59.0 months (range, 40.0-77.9 months) for the VL/L risk group, 31 months (range, 22.7-439.3 months) for the INT risk group, and 20.0 months (range, 15.9-24.1 months) for the H risk group (p < 0.001). In the multivariate analysis, the following factors were associated with survival: age ≥ 65 (HR = 1.515, p = 0.023), ECOG ≥ 2 (HR = 2.968, p < 0.001), H risk group according to IPSS-R (HR = 3.054, p < 0.001), P/VP cytogenetic risk according to IPSS-R (HR = 4.912, p = 0.003), and transformation to AML (HR = 2.158, p = 0.002). If IPSS-R reclassifies LR-MDS patients as H risk, these patients should be considered for early allo-HCT, regardless of the current benefits from HMT.