Risk factors of early disease progression and decreased survival for multiple myeloma patients after upfront autologous stem cell transplantation.

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post-ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08-3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53-4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31-0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32-0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05-4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03-7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45-34.59), post-ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09-28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23-6.17) experienced shorter OS. In contrast, post-ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17-0.79) and post-ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24-0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post-ASCT outcome prediction beyond clinical trials.

Surface TREM2 on circulating M-MDSCs as a novel prognostic factor for adults with treatment-naïve diffuse large B-cell lymphoma.

INTRODUCTION: Circulating monocytic myeloid-derived suppressive cells (M-MDSCs) are implicated as a poor prognostic factor and cause CAR T-cell failure in diffuse large B-cell lymphoma (DLBCL). Triggering receptors expressed on myeloid cells 2 (TREM2) are a transmembrane glycoprotein that polarize macrophages to anti-inflammation phenotype but have never been explored on M-MDSCs. This study aims to elucidate the expression and clinical impact of surface TREM2 on circulating M-MDSCs derived from DLBCL adults. METHODS: This prospective, observational study enrolled 100 adults with newly diagnosed and treatment-naïve DLBCL from May 2019 to October 2021. Human circulating M-MDSCs were obtained from freshly isolated peripheral blood, and each patient's surface-TREM2 level on M-MDSCs was normalized via a healthy control at the same performance of flow-cytometry analysis. Murine MDSCs derived from bone marrow (BM-MDSCs) were adopted to assess the link between Trem2 and cytotoxic T lymphocytes. RESULTS: More circulating M-MDSCs at diagnosis of DLBCL predicted worse progression-free (PFS) and overall survival (OS). Patients with higher IPI scores, bone marrow involvement, or lower absolute counts of CD4+ or CD8+ T cells in PB had significantly higher normalized TREM2 levels on M-MDSCs. Additionally, normalized TREM2 levels on M-MDSCs could be grouped into low (< 2%), medium (2-44%), or high (> 44%) levels, and a high normalized TREM2 level on M-MDSCs was proven as an independent prognostic factor for both PFS and OS via multivariate Cox regression analysis and associated with worst PFS and OS. Interestingly, normalized levels of surface TREM2 on M-MDSCs were negatively associated with absolute counts of PB CD8+ T cells and positively correlated with levels of intracellular arginase 1 (ARG1) within M-MDSCs. Wild-type BM-MDSCs had significantly higher mRNA levels of Arg1 and showed more prominent ability to suppress the proliferation of co-cultured CD8+ T cells than BM-MDSCs from Trem2 knockout mice, and the suppressive ability could be impaired by adding Arg1 inhibitors (CB1158) or supplementing L-arginine. CONCLUSION: In treatment-naïve DLBCL adults, a high surface-TREM2 level on circulating M-MDSCs is a poor prognostic factor for both PFS and OS and warrants further investigation for its potential as a novel target in immunotherapy.

Risk Factors and Outcomes of Stem Cell Mobilization Failure in Multiple Myeloma Patients.

Introduction: Autologous hematopoietic stem cell transplantation (ASCT) is a well-established treatment for patients with multiple myeloma (MM), and adequate stem cell collection must be assured before ASCT. However, prediction of poor mobilizers (PMs) is still difficult despite several risk factors for mobilization failure having been identified. Methods: We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan who underwent stem cell collection between October 2006 and August 2020. A CD34+ cell collection of <1 × 106 cells/kg was defined as a mobilization failure. The primary endpoint was mobilization failure. The secondary endpoint was overall survival (OS). Odds ratios (ORs) and 95% confidence intervals (CIs) for mobilization failure were calculated using a logistic regression model. The cumulative incidence of mortality was estimated using the Kaplan-Meier method. Results: In the multivariate analysis, absolute monocyte count <500/µL (adjusted OR 10.75, 95% CI: 1.82-63.57, p = 0.009), platelet count <150,000/µL (adjusted OR 12.49, 95% CI: 2.65-58.89, p = 0.001) before mobilization, and time interval from diagnosis to stem cell harvest ≥180 days (adjusted OR 7.69, 95% CI: 1.61-36.87, p = 0.011) were risk factors for PMs. PM patients had poorer OS compared to patients with successful stem cell collection in the univariate analysis (log-rank test p = 0.027). The predicted probability of PMs was estimated by the multiple logistic regression model with a sensitivity of 84.6% and a specificity of 84.0%. Conclusion: Absolute monocyte count <500/µL, platelet count <150,000/µL, and treatment duration more than 180 days before stem cell mobilization are risk factors for unsuccessful stem cell collection. Our prediction models have high sensitivity and specificity for mobilization failure prediction and allow for early interventions for possible PMs.

Long-term outcomes of frontline intensification in primary CNS lymphoma: A real-world single-center experience.

BACKGROUND: Frontline intensification (including consolidative whole-brain radiotherapy or high-dose chemotherapy with autologous stem-cell transplantation after induction therapy) has been proposed to treat primary central nervous system lymphoma (PCNSL). However, no prospective randomized trials have answered whether frontline intensification can offer a survival benefit to PCNSL patients. We aim to clarify the outcomes and survival influence of frontline intensification on real-world patients with different risk-stratified PCNSLs. METHODS: Between January 2003 and December 2016, 110 PCNSL adults were retrospectively included, and 76 patients achieved at least PR after induction therapy, including 38 patients who received frontline intensification. The median follow-up with the 31 survivors was 7.52 years. RESULTS: Of the 38 induction-completed patients who had not received frontline intensification, 95% achieved post-induction therapy CR/CRu; however, all inevitably recurred. In the 38 who received frontline intensification, CR/CRu improved from 45% (pre-frontline intensification) to 84% (post-frontline intensification), and they achieved significantly better PFS (non-reach vs. 522 days, p < 0.001) and OS (non-reach vs. 899 days, p < 0.001). Additionally, patients had similar PFS and OS rates when receiving HDC-ASCT and/or WBRT as frontline intensification. Frontline intensification significantly improved PFS and OS survival in higher-risk patients (intermediate/high IELSG risk, MSKCC group 2/3, or Nottingham/Barcelona score ≥ 2 points) but did not improve OS in lower-risk patients. Among the 38 patients who received frontline intensification, two had treatment-related mortality; 14 recurred after frontline intensification. MTX-based chemotherapy was the main salvage modality, and the median OS was 295 days after recurrence. Progressive disease and infection (especially pneumonia) are two major causes of mortality in patients who receive frontline intensification. CONCLUSIONS: When achieving CR/CRu/PR after induction chemotherapy, frontline intensification should be adopted to improve PFS and OS in real-world PCNSL patients, especially higher-risk patients.

Darinaparsin in patients with relapsed or refractory peripheral T-cell lymphoma: results of an Asian phase 2 study.

Darinaparsin is a novel organic arsenical compound of dimethylated arsenic conjugated to glutathione, with antitumor activity and a mechanism of action markedly different from other available agents. This phase 2, nonrandomized, single-arm, open-label study evaluated the efficacy and safety of intravenous darinaparsin (300 mg/m2 over 1 hour, once daily for 5 consecutive days, per 21-day cycle) and its pharmacokinetics at multiple doses in 65 Asian patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). The primary end point was the overall response rate (ORR). The ORR based on central assessment was 19.3% (90% confidence interval, 11.2-29.9), which was significantly higher than the predefined threshold of 10% (P = .024). The ORR was 16.2% in patients with PTCL-not otherwise specified and 29.4% in patients with angioimmunoblastic T-cell lymphoma. Tumor size decreased in 62.3% of patients. Treatment-emergent adverse events (TEAEs) were observed in 98.5% of patients. Grade ≥3 TEAEs with an incidence rate of ≥5% included anemia (15.4%), thrombocytopenia (13.8%), neutropenia (12.3%), leukopenia (9.2%), lymphopenia (9.2%), and hypertension (6.2%). Darinaparsin is effective and well tolerated, with TEAEs that were clinically acceptable and manageable with symptomatic treatment and dose reductions. This trial was registered at www.clinicaltrials.gov as #NCT02653976.

Prognostic factors in patients with bone marrow hemophagocytosis and its association with hematologic malignancies.

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous group of hyperinflammatory statuses that are difficult to diagnose and can be life-threatening. Bone marrow (BM) hemophagocytosis is one of the diagnostic criteria according to HLH 2004 diagnostic criteria and HS score. Limited studies have focused on the prognostic factors of BM hemophagocytosis and its association with hematologic malignancies. We aimed to analyze the clinical significance of BM hemophagocytosis. Patients with BM hemophagocytosis, either by cytology or pathology, were enrolled at Taipei Veterans General Hospital from January 2002 to July 2021. Relevant clinical and laboratory data were extracted from medical records. Of 119 patients with BM hemophagocytosis, 57 were diagnosed with hematologic malignancies. The median age of the patients was 58, ranging from 21 to 90. Splenomegaly (adjusted odds ratio [aOR] 2.96; 95% confidence interval [CI] 1.13-7.79) was a risk factor for hematologic malignancies, while autoimmune disease (aOR 0.07; 95% CI 0.01-0.39) and increased D-dimer (aOR 0.25; 95% CI 0.07-0.92) were protective factors. Risk factors for mortality in patients with BM hemophagocytosis were hematologic malignancies (adjusted hazard ratio [aHR] 2.34; 95% CI 1.24-4.44), Eastern Cooperative Oncology Group score ≥3 (aHR 2.42; 95% CI 1.20-4.89) and thrombocytopenia (aHR 3.09; 95% CI 1.04-9.16). In conclusion, among patients with BM hemophagocytosis, splenomegaly was a predictor of hematologic malignancies. Patients with hematologic malignancies, poor performance status, or thrombocytopenia had a higher mortality risk. Further validation studies are warranted.

Herpes zoster prophylaxis: Essential for treating newly diagnosed multiple myeloma patients.

BACKGROUND: Multiple myeloma (MM) is known for its immune disturbance and patients suffering from MM are thus vulnerable to opportunistic infections, including herpes zoster (HZ). As HZ infection remarkably affects patients' quality of life and poses huge economic burdens on the health system, we aim to identify the risk factors of HZ infection and evaluate the effects of different dosages, types, and durations of anti-HZ prophylaxis drugs to prevent HZ infection. METHODS: 551 MM patients at Taipei Veterans General Hospital in Taiwan between January 1, 2009 and August 31, 2021 were restrospectively analyzed. The patients' baseline characteristics were recorded. The primary endpoint of the study was the incidence of HZ infection among the studied patient population. Due to the lack of cost coverage from Taiwanese public health insurance on HZ prophylaxis drugs, the use of anti-HZ drugs mainly depends on physicians' preferences and patients' choices. RESULTS: In our study, prophylaxis was given to 283 of the patients. In the multivariate analysis, we included non-prophylaxis, age ≥ 60, corrected serum calcium ≥12 mg/dl, serum creatinine ≥2 mg/dl, serum ß2-microglobulin ≥5500 mg/L, autologous stem cell transplant (SCT), and allogeneic SCT for analysis. Our results demonstrated that the non-prophylaxis group (HR: 2.37, 95% CI 1.57-3.57) and patients receiving autologous SCT (HR: 2.22, 95% CI 1.28-3.86) and allogeneic SCT (HR: 5.12, 95% CI 1.13-23.22) had higher risk of HZ infection. The difference in dosage and types of anti-HZ drugs showed similar protective effects. In patients who stopped anti-HZ prophylaxis before active cancer-related treatment, a higher risk of getting HZ infection compared to the corresponding group was also observed (adjusted HR 3.09, 95% CI 1.35-7.07, p = 0.008). CONCLUSIONS: We concluded that MM patients should receive HZ prophylaxis drugs while receiving active cancer-related treatment. Patients receiving SCT are also at high risk of getting HZ infection, even under prophylaxis.

A clinical trial with valproic acid and hydralazine in combination with gemcitabine and cisplatin followed by doxorubicin and dacarbazine for advanced hepatocellular carcinoma.

BACKGROUND: Survival benefit from chemotherapy in advanced hepatocellular carcinoma (HCC) was limited till now. New chemoregimens with cytotoxicity modulators were explored to improve efficacy. Chemotherapy modulated with valproic acid (VA) as a deacetylation inhibitor of histone and DNA damage response proteins, and hydralazine (HZ) as a DNA hypomethylating agent, hypothetically suppressing DNA repair, were used in phase II trial here for advanced HCC. METHODS: Between July 2008 and March 2016, patients with chemo-naive advanced HCC, regardless of previous sorafenib treatment, not amenable to local therapy and with Child Pugh score ≤7, were treated with VA (200 mg thrice per day) and HZ (12.5 mg twice per day) in conjunction with gemcitabine and cisplatin (GCGG): gemcitabine (1000 mg/m2 , D1; 800 mg/m2 D8, 15) and cisplatin (70 mg/m2 , D1) every 28 days till disease progression and then with Dox-DTIC: doxorubicin (45 mg/m2 ) and dacarbazine (450 mg/m2 ) every 28 days. The primary endpoint was overall survival (OS); the secondary endpoints were safety, progression-free survival (PFS) and response rate (RR). RESULTS: Thirty-seven patients with 16 sorafenib-experienced, underwent GCGG treatment, and 30 of them underwent the following Dox-DTIC treatment. The median OS was 14.6 months (95% confidence interval: 6.0-23.1). The median PFSs for patients treated with VA- and HZ-combined GCGG and Dox-DTIC were 3.7 and 4.2 months, respectively; the RRs were 10/37 (27.0%) and 7/30 (23.3%); and grade 3/4 neutropenia were 54% and 51%. However, there were no chemotherapy-related deaths. CONCLUSION: VA- and HZ-combined sequential chemotherapy was effective in advanced HCC with manageable toxicities.

Carfilzomib, dexamethasone, and daratumumab in Asian patients with relapsed or refractory multiple myeloma: post hoc subgroup analysis of the phase 3 CANDOR trial.

BACKGROUND: Due to increasing use of frontline lenalidomide, effective and safe lenalidomide-free therapies for relapsed/refractory multiple myeloma (RRMM) are needed in Asia. This subgroup analysis of phase 3 CANDOR study evaluated efficacy and safety of KdD vs Kd in Asian patients with RRMM. METHODS: Self-identified Asian patients with RRMM (KdD = 46; Kd = 20) with 1‒3 prior therapies were included. The primary endpoint of progression-free survival was estimated by stratified Cox regression. RESULTS: Baseline demographics and patient characteristics were balanced in both arms. KdD reduced the risk of progression or death by 25% vs Kd [hazard ratio (HR) = 0.75; 95% CI 0.259, 2.168] in the Asian subgroup, compared with 37% vs Kd (0.63; 0.464, 0.854) in the overall CANDOR population. Percentage of patients who reported grade ≥ 3 treatment-emergent adverse events (TEAEs) in the KdD and Kd arms was 95.7 and 90.0%, respectively. Serious AEs were observed in 58.7 and 40.0% of patients in the KdD and Kd arms, respectively. There were two (4.3%) fatal TEAEs in the KdD arm due to infections. CONCLUSIONS: There was a trend toward better efficacy and a favorable benefit-risk profile for KdD vs Kd in Asian patients with RRMM. Cautious interpretation is warranted due to small patient size.

Underweight as a risk factor of mortality in patients with newly diagnosed multiple myeloma.

PURPOSE: Multiple myeloma (MM), a clonal plasma cell malignancy, composes around 10% of hematologic malignancies. Though recent advances in treatment have dramatically improved MM survival, some aggressive courses of disease and dismal outcomes still exist. Low body weight, undernutrition, and cachexia are noted at MM diagnosis. We aim to evaluate the impact of low body mass index (BMI) and undernutrition in MM patients. METHODS: We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan between January 1, 2006 and October 31, 2018. Being underweight is defined as having a BMI of under 18.5 kg/m2. The patient's baseline characteristics, including BMI, serum albumin level, and comorbidities, etc., were recorded. The primary endpoint of the study was all-cause mortality. A Cox regression model was used to estimate the risk factors of mortality. RESULTS: A total of 378 newly diagnosed MM patients were enrolled in this study. The median age of the patients was 69. Thirty patients (7.9%) were underweight at diagnosis. The median overall survival was 1.3 years (95% CI 0.3-5.7) and 5.0 years (95% CI 3.1-5.9) for patients with low BMI and for patients with normal or higher BMI, respectively. In the multivariate analysis, low BMI (95% CI 1.07-4.44), ECOG ≥2 (95% CI 1.02-2.89), hypoalbuminemia (95% CI 1.21-4.01), high LDH (95% CI 1.22-3.49), and light chain ratio > 100 (95% CI 1.06-2.77) were independent risk factors of mortality. CONCLUSION: MM patients who were underweight, with hypoalbuminemia, poor performance status, higher LDH, and light chain ratio > 100 were associated with poor overall survival.

Risk and impact of invasive fungal infections in patients with multiple myeloma.

Infection is associated with great morbidity and mortality in patients with multiple myeloma (MM), but evidence for invasive fungal infections (IFIs) is lacking. We aimed to investigate risk factors for IFI in MM patients and to determine its impact on patients' survival. We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan between January 2002 and October 2018. MM was diagnosed according to the International Myeloma Working Group criteria. IFI was defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. All risk factors of IFI in MM patients were estimated using Cox regression models in the univariate and multivariate analyses. Of the 623 patients recruited, 22 (3.5%) were diagnosed with proven or probable IFI. Light chain disease (adjusted hazard ratio [HR] 6.74, 95% confidence interval [CI] 2.10-21.66), hemoglobin less than 8 g/dl (adjusted HR 3.34, 95% CI 1.32-8.42), serum albumin < 3.5 g/dl (adjusted HR 3.24, 95% CI 1.09-9.68), and having received allogeneic stem cell transplantation (allo-SCT) (adjusted HR 5.98, 95% CI 1.62-22.03) were significantly associated with IFI in the multivariate analysis. Contracting IFI was in turn associated with early mortality (adjusted HR 11.60, 95% CI 1.26-106.74). Light chain disease, anemia, hypoalbuminemia, and receiving allo-SCT were independent predictors of IFI in MM patients. The early mortality risk is much higher in those encountering IFI. Physicians must be aware of the rare but potentially lethal infections.

Difference in thrombotic microangiopathy between concurrently and previously diagnosed systemic lupus erythematosus.

BACKGROUND: Thrombotic microangiopathy (TMA) syndromes are potentially life-threatening complications and are defined as integrated syndromes of microangiopathic hemolytic anemia, thrombocytopenia, and organ injury. Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect various organs, including the hematopoietic system. SLE can complicate with TMA and can be categorized into two distinct groups by chronological association: TMA occurring as the initial presentation and leading to a diagnosis of SLE concurrently (TMA-cSLE) or TMA developing in patients previously diagnosed as having SLE (TMA-pSLE). We examined the differences in clinical characteristics, treatment responses, and clinical outcomes between these groups. METHODS: We reviewed data of patients diagnosed as having TMA and SLE at Taipei Veterans General Hospital between 2002 and 2013. We included 29 patients: 8 and 21 in TMA-cSLE and TMA-pSLE groups, respectively. All underwent plasma exchange. Patients' demographic and clinical characteristics, disease activity, and treatment modality were summarized. RESULTS: Overall survival (OS) from SLE or TMA diagnosis was poor for the TMA-cSLE group. Median OS from SLE diagnosis was 2.9 months in the TMA-cSLE group and 103.5 months in the TMA-pSLE group (p < 0.001). Median OS from TMA diagnosis was 2.9 months in the TMA-cSLE group and 10.7 months in the TMA-pSLE group (p = 0.58). Time to TMA remission after treatment appeared longer in the TMA-cSLE group (38.00 vs 10.76 days). Multivariate Cox analysis revealed TMA-cSLE and anti-RNP positivity were independent risk factors for mortality in SLE patients with TMA. CONCLUSION: The occurrence of TMA with SLE is rare, and its vigorous course results in high mortality and morbidity rates. In patients without a history of autoimmune disease, early suspicion of TMA and working-up for SLE under this condition are vital. Early recognition of TMA-cSLE and prompt plasma exchange with upfront immunosuppressive therapies for TMA-cSLE patients or anti-RNP-positive patients may improve their prognosis.

Pralatrexate as a bridge to allogeneic hematopoietic stem cell transplantation in a patient with advanced-stage extranodal nasal-type natural killer/T cell lymphoma refractory to first-line chemotherapy: a case report.

BACKGROUND: Extranodal natural killer/T cell lymphoma, nasal type, is one of the more common subtypes of mature T cell lymphoma, especially in the Far East Asian population. This aggressive histologic subtype of peripheral T cell lymphomas is frequently susceptible to exposure of Epstein-Barr virus infection. The optimal treatment is not well elucidated. For stage IV disseminated extranodal natural killer/T cell lymphoma, induction chemotherapy with consolidative autologus or allogeneic hematopoietic stem cell transplantation is recommended as the major first-line treatment. However, there is controversy over which type of chemotherapy is most appropriate and effective as a bridge to autologus or allogeneic hematopoietic stem cell transplantation in patients with newly diagnosed disseminated advanced-stage or relapsed extranodal natural killer/T cell lymphoma because of cancer chemoresistance or associated complications. Pralatrexate is the first US Food and Drug Administration-approved novel agent for the treatment of refractory/recurrent peripheral T cell lymphomas. In our case, pralatrexate was used as a successful bridge to allogeneic hematopoietic stem cell transplantation in a patient with advanced-stage disseminated extranodal natural killer/T cell lymphoma refractory to first-line chemotherapy. CASE PRESENTATION: We presented a case report of a 29-year-old Asian man diagnosed as having stage IV disseminated extranodal natural killer/T cell lymphoma, nasal type, with skin and bone marrow involvement, whose disease was primary refractory to first-line dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide chemotherapy, but obviously responded to treatment with two cycles of single-agent pralatrexate treatment. Monitoring Epstein-Barr virus viremia revealed dramatic downregulation. In addition to complete remission of the involvement of bone marrow and nasal cavity, skin involvement also obtained partial remission. The extranodal natural killer/T cell lymphoma successfully achieved complete remission after a bridge to allogeneic hematopoietic stem cell transplantation. CONCLUSIONS: This is the first study to present pralatrexate as a successful bridge to allogeneic hematopoietic stem cell transplantation in a 29-year-old Asian male patient with advanced-stage extranodal natural killer/T cell lymphoma refractory to first-line dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide chemotherapy. This case provides a novel treatment opinion for extranodal natural killer/T cell lymphoma, especially for the Far East Asian population.

The landscape of BCR-ABL mutations in patients with Philadelphia chromosome-positive leukaemias in the era of second-generation tyrosine kinase inhibitors.

BCR-ABL mutations are associated with resistance to tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome-positive leukaemia. The emergence of these mutations in the era of second-generation TKIs, such as dasatinib and nilotinib, remains an evolving field. We conducted a retrospective study to quantitatively characterize the BCR-ABL transcript and mutation status during treatment with first-generation and second-generation TKI therapies. BCR-ABL mutations were detected by direct sequencing for patients with Philadelphia chromosome-positive leukaemia receiving TKI therapies. The efficacy of TKI therapy was quantitatively assessed by calculating the log reduction of BCR-ABL transcripts, which was measured using real-time quantitative polymerase chain reaction. Fisher's exact test was performed to analyse the associations of log reduction <3 and mutation status. We found 35 patients harbouring 55 mutations of 43 different types, of which 30% occurred in patients receiving imatinib, 27% in nilotinib, and 43% in dasatinib. We found a novel germline mutation, N336 N (AAC➔AAT), and two novel frameshift mutations, Asn358Thr fs*14 and Gly251Ala fs*16. T315I was the most common missense mutation, followed by V299L and F317L. Intron 8 35-bp insertion was the most frequent frameshift mutation. Both missense and multiple BCR-ABL mutations were significantly associated with worse molecular response compared with the molecular response of patients without mutation. Missense mutations, rather than frameshift, were associated with less log reduction, while the T315I, F317L, and T315A mutations were significantly correlated with poor log reduction. Collectively, amino acid substitutions at T315I, F317L, and T315A accounted for the majority of missense mutations and the loss of major molecular response. Mutation analysis is essential for patients receiving TKI therapy who exhibit an unfavourable response. The present study provided a landscape of BCR-ABL mutations in the era of second-generation TKIs.

A new prognostic score for disease progression and mortality in patients with newly diagnosed primary CNS lymphoma.

BACKGROUND: Although various prognostic models for primary central nervous system lymphoma (PCNSL) have been developed, there is no consensus regarding the optimal prognostic index. We aimed to evaluate potential prognostic factors and construct a novel predictive model for PCNSL patients. METHODS: We enrolled newly diagnosed PCNSL patients between 2003 and 2015. The primary endpoint was progression-free survival (PFS), and the secondary endpoint was overall survival (OS). The prognostic factors identified using multivariate Cox proportional hazards models were used to develop a predictive model. We subsequently validated the prognostic model in an independent cohort. We also evaluated the validity of the existing scores: the International Extranodal Lymphoma Study Group (IELSG), the Nottingham/Barcelona (NB), and the Memorial Sloan-Kettering Cancer Center models (MSKCC). RESULTS: We identified 101 patients with newly diagnosed PCNSL at our center. Multivariate analysis showed that age ≥80, deep brain lesions, and ECOG ≥2 were independent risk factors of PFS. Assigning one point for each factor, we constructed a novel prognostic model, the Taipei Score, with four distinct risk groups (0-3 points). The performances of the Taipei Score in discriminating both PFS and OS in the training cohort were significant, and the score was validated in the external validation cohort. The IELSG, NB and MSKCC models had insufficient discriminative ability for either PFS or OS in both cohorts. CONCLUSION: The Taipei Score is a simple model that discriminates PFS and OS for PCNSL patients. The score may offer disease risk stratification and facilitate clinical decision-making.

European Group for Blood and Marrow Transplantation score correlates with outcomes of older patients undergoing allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are hematological diseases predominantly occurring in older patients. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the curative therapy for refractory AML or high-risk MDS, old age is often a hurdle to the procedure. We conducted a retrospective study to analyze the prognostic factors predicting outcomes of older patients undergoing allo-HSCT for acute leukemia and MDS. METHODS: We collected data from patients diagnosed with acute leukemia or MDS, who underwent allo-HSCT at >50 years of age and reviewed clinical characteristics, including age, sex, underlying disease, European Group for Blood and Bone Marrow Transplantation (EBMT) risk score, and presence of acute graft-versus-host disease (aGVHD) or chronic GVHD (cGVHD). The Cox proportional hazard model was adopted to explore the independent prognostic factors for overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM). RESULTS: A total of 85 older patients were included, with the median age at allo-HSCT being 55 years. The significant prognostic factors for worse OS or PFS were an EBMT risk score > 3 and grade III-IV aGVHD, while patients with moderate to severe cGVHD would have better OS or PFS. Interestingly, it is not cGVHD but grade III-IV aGVHD that significantly correlated with NRM. CONCLUSION: This cohort study suggests that an EBMT risk score >3 and grade III-IV aGVHD predict poor outcomes, and careful management of GVHD may allow better survival for older patients undergoing allo-HSCT.

The risk of early mortality in elderly patients with newly diagnosed acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a common hematologic neoplasm with high incidence and mortality in the elderly. Our aims were to explore risk factors for early mortality in elderly AML patients and develop a new prognostic score. METHODS: We enrolled newly diagnosed AML patients age 60 and above at Taipei Veterans General Hospital between July 2008 and May 2017. The primary endpoint was early mortality, defined as death within two months after AML diagnosis. A multivariate Cox proportional hazards model was used to build a risk-scoring system incorporating significant risk factors for AML. RESULTS: The final cohort included 277 elderly AML patients. The median age was 74 (range 60-96), and 61.7% were male. The two-month mortality rate was 29.9%. Age ≥ 80 (adjusted HR 1.88), myocardial infarction (adjusted HR 1.87), ECOG ≥ 2 (adjusted HR 2.10), complex karyotype (adjusted HR 3.21), bone marrow blasts ≥ 70% (adjusted HR 1.88), WBC ≥ 100 × 109 /L (adjusted HR 3.31), and estimated glomerular filtration rate (eGFR) < 45 (adjusted HR 2.60) were identified as independent predictors for early mortality in the multivariate analysis. A simplified score incorporating the seven factors was developed with good predictive ability measured by Harrell's C statistic [0.72 (95% CI 0.66-0.78)]. CONCLUSIONS: We identified seven potential risk factors for early mortality and built up a new prognostic score for elderly AML patients. The new score may help clinicians stratify patients and initiate appropriate management. Further validation of our findings on other cohorts is warranted.

Mycobacterial infections in adult recipients of allogeneic hematopoietic stem cell transplantation: A cohort study in a high endemic area.

BACKGROUND: Mycobacterial infections are important and potentially life-threatening complications after organ transplantations. Notably, for the recipients of allogeneic hematopoietic stem cell transplantation (HSCT), there are a few supporting results to explore post-transplant mycobacterial infections. Taiwan is a high endemic area of the infection. We aim to investigate the incidence, risk factors, and survival of post-transplant mycobacterial infections, including mycobacterium tuberculosis (MTB) and non-tuberculous mycobacterium (NTM). METHODS: We included 422 adult patients undergoing allogeneic HSCT at an Asian tertiary medical center between January 2003 and December 2014. A total 26 subjects developed post-transplant mycobacterial infections. Risk factors, clinical features, and survival for post-transplant mycobacterial infections were collected and analyzed. RESULTS: Post-transplant mycobacterial infections occurred in 26 (6.2%) of 422 HSCT patients. Two-year cumulative incidences in MTB and NTM were 1.4% and 5.4%. In the multivariate analysis, being age >45 years (adjusted HR 2.21, 95% CI 1.01-4.83) and extensive chronic graft-versus-host disease (cGVHD) (adjusted HR 4.95, 95% CI 2.14-11.46) were identified as independent risk factors of infections. There was a trend as a risk factors in relapsed patients (P = 0.088). For patients with cGVHD, there was a significant difference of post-transplant survival between mycobacterial infections and none (P = 0.036). Pneumonia contributed most to mortality (n = 11, 42.3%). CONCLUSION: Mycobacterial infections are worth to note in a high endemic area. Once a high-risk group is identified, much effort is required to target new approaches for prevention, early detection and treatment of infections.

Risk Prediction for Early Mortality in Patients with Newly Diagnosed Primary CNS Lymphoma.

Background: Overall survival of patients with primary CNS lymphoma (PCNSL) has improved since the introduction of immunochemotherapy. However, up to 10-15% of PCNSL patients still die shortly after diagnosis. In the present study, we aimed to investigate the risk factors of early mortality (death within 60 days after diagnosis) in patients with PCNSL. Methods: We included newly diagnosed PCNSL patients in a tertiary medical center in Taiwan between January 1, 2002 and May 31, 2018. Clinical risk factors were collected and compared between PCNSL patients who had and did not have early mortality. Results: A total of 133 consecutive patients with PCNSL were included in this study. Approximately 9.8% of the PCNSL patients had early mortality. In multivariate analysis, age ≥ 80 (adjusted hazard ratio [HR] 3.34, 95% confidence interval [CI] 1.01-11.04, p = 0.048) and involvement of the basal ganglia (adjusted HR 4.85, 95% CI 1.47-15.95, p = 0.009) were identified as independent risk factors of early mortality. Use of MTX-based chemotherapy served as an independent protective factor for early mortality (adjusted HR 0.19, 95% CI 0.05-0.67, p = 0.010). Infection and tumor-associated mass effect contributed most to early mortality. Conclusion: Early mortality is not uncommon in patients with PCNSL. Identification of patients with higher risk may help clinicians with initiating appropriate surveillance and management.

Risk factors and clinical features for post-transplant thoracic air-leak syndrome in adult patients receiving allogeneic haematopoietic stem cell transplantation.

Post-transplant thoracic air-leak syndrome (ALS) is rare but potentially life-threatening in patients receiving allogeneic haematopoietic stem cell transplantation (HSCT). Nevertheless, papers on thoracic ALS are limited, and this complication remains largely unknown. We reviewed 423 adult patients undergoing allogeneic HSCT from 2003 to 2014. Risk factors, clinical features and survival for thoracic ALS were collected and analysed. Thirteen out of 423 patients (3.1%) developed post-transplant thoracic ALS, including two ALS patients in the early phase. The median age at HSCT was 33 years among 13 patients with thoracic ALS. Male patients were predominant (69%). The median onset time was 253 days (range: 40-2680) after HSCT. Multivariate analysis revealed that grade III-IV acute graft-versus-host disease (GVHD) (p = 0.017), extensive chronic GVHD (cGVHD) (p = 0.019) and prior history of pulmonary invasive fungal infection (p = 0.007) were significant risk factors for thoracic ALS. In patients with cGVHD, those with thoracic ALS had a significantly worse survival than those without thoracic ALS (p = 0.04). Currently, published data analysing and exploring post-transplant thoracic ALS are limited. Our study employed a large patient cohort and determined the risk factors and clinical features for post-transplant thoracic ALS.