Effect of BCR::ABL1 transcript type and droplet digital polymerase chain reaction on successful treatment-free remission in chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitor.

Background: Droplet digital polymerase chain reaction (ddPCR) is an exact method of measurement. Objectives: We conducted this study to identify the prognostic factors for successful treatment-free remission in patients with chronic-phase chronic myeloid leukemia who discontinued tyrosine kinase inhibitors (TKIs). We also aimed to validate ddPCR for predicting molecular relapse. Design: This is a prospective, multicenter study. Methods: We enrolled patients treated with TKIs for at least 3 years with a confirmed sustained deep molecular response (DMR) for at least 1 year. TKI was re-administered in patients who experienced the loss of major molecular response (MMR). Results: A total of 66 patients from five institutions in South Korea were enrolled. During a median follow-up period of 16.5 months, 29/66 (43.9%) patients experienced molecular relapse; the probability of molecular relapse-free survival (RFS) at 6 or 12 months after TKI discontinuation was 65.6% or 57.8%, respectively, with most molecular relapses occurring within the first 7 months. All patients who lost MMR were re-treated with TKI, and all re-achieved MMR at a median of 2.8 months. E14a2 transcript type (p = 0.005) and longer DMR duration (⩾48 months) prior to TKI discontinuation (p = 0.002) were associated with prolonged molecular RFS and with sustained DMR. Patients with both e13a2 transcript type and detectable BCR::ABL1 (⩾MR5.0) by ddPCR at the time of TKI discontinuation showed shorter duration of molecular RFS (p = 0.015). Conclusion: Our data suggest that transcript type and BCR::ABL1 transcript levels on ddPCR should be taken into consideration when deciding whether to discontinue TKI therapy.

A multi-center and non-interventional registry of brentuximab vedotin in patients with relapsed or refractory CD30-positive lymphoma: the CISL1803/BRAVO study.

Background: Brentuximab vedotin (BV), a potent antibody-drug conjugate, targets the CD30 antigen. In Korea, BV has been approved for the treatment of relapsed or refractory Hodgkin lymphoma (HL), anaplastic large-cell lymphoma (ALCL), and cutaneous T-cell lymphomas, including mycosis fungoides (MF). However, there are limited data reflecting real-world experiences with BV treatment for HL, ALCL, and MF. Methods: This was a multicenter, non-interventional registry study of the efficacy and safety of BV in patients with relapsed or refractory CD30-positive lymphoma (CISL1803/BRAVO). Outcomes were determined based on the occurrence of relapse or progression and overall survival after BV treatment. Results: A total of 85 patients were enrolled in this study. The median number of BV cycles was 10 (range, 2‒16) in the patients with HL. The objective response rate (ORR) of patients with HL to BV was 85.4% (41/48), comprising 27 complete responses (CRs) and 14 partial responses (PRs). The ORR of ALCL was 88% (22/25), consisting of 17 CRs and five PRs, whereas the ORR of MF was 92% (11/12). At the median follow-up of 44.6 months after BV treatment, the median post-BV progression-free survival of HL, ALCL, and MF patients was 23.6 months, 29.0 months, and 16.7 months, respectively (P=0.641). The most common side effect of BV was peripheral neuropathy; 22 patients (25.9%, 22/85) experienced peripheral neuropathy (all grades). Conclusion: The treatment outcomes of patients with relapsed or refractory CD30-positive lymphoma improved with BV treatment, and the safety profile was manageable.

Long-Term Efficacy and Safety of Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria and High Disease Burden: Real-World Data From Korea.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled terminal complement activation. Eculizumab, a monoclonal antibody C5 inhibitor was introduced in Korea in 2009 and has been the standard treatment option for PNH. METHODS: This study assessed the long-term efficacy/safety of eculizumab in PNH using real-world data from the Korean Health Insurance Review and Assessment Service. Eighty patients who initiated eculizumab from 2009-2020 were enrolled. RESULTS: At eculizumab initiation, the median age was 51.5 years, lactate dehydrogenase (LDH) 6.8 × upper limit of normal, and granulocyte clone size 93.0%. All patients had at least one PNH-related complication before eculizumab initiation, including renal failure (n = 36), smooth muscle spasm (n = 24), thromboembolism (n = 20), and pulmonary hypertension (n = 15). The median (range) duration of eculizumab treatment was 52.7 (1.0, 127.3) months (338.6 total treated patient-years). Despite high disease activity in the study population before treatment initiation, overall survival was 96.2% and LDH levels were stabilized in most patients during treatment. PNH-related complications at treatment initiation were resolved in 44.4% of patients with renal failure, 95.8% with smooth muscle spasm, 70.0% with thromboembolism, and 26.7% with pulmonary hypertension. Extravascular hemolysis occurred in 28.8% of patients (n = 23; 0.09 per patient-year) and breakthrough hemolysis in 18.8% (n = 15; 0.06 per patient-year). No treatment discontinuation cases related to eculizumab were observed. CONCLUSION: These data provided evidence for the long-term efficacy and safety of eculizumab in Korean PNH patients with high disease burdens.

Comparison of first-line treatment with CHOP versus ICED in patients with peripheral T-cell lymphoma eligible for upfront autologous stem cell transplantation.

Introduction: Upfront autologous stem cell transplantation (ASCT) has been recommended for patients who are newly diagnosed with peripheral T-cell lymphoma (PTCL), and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), an anthracycline-based chemotherapy has been the frontline chemotherapy for PTCL. However, it is not clear whether anthracycline-based chemotherapies such as CHOP could be standard induction therapy for PTCL. Methods: We conducted a randomized phase II study to compare CHOP with fractionated ifosfamide, carboplatin, etoposide, and dexamethasone (ICED) for patients eligible for ASCT. The primary endpoint was progression-free survival (PFS) and secondary endpoints included objective response rate, overall survival (OS), and safety profiles. Results: Patients were randomized into either CHOP (n = 69) or ICED (n = 66), and the characteristics of both arms were not different. PTCL-not otherwise specified (NOS, n = 60) and angioimmunoblastic T-cell lymphoma (AITL, n = 53) were dominant. The objective response rate was not different between CHOP (59.4%) and ICED (56.1%), and the 3-year PFS was not different between CHOP (36.7%) and ICED (33.1%). In AITL patients, CHOP was favored over ICED whereas ICED was associated with more cytopenia and reduced dose intensity. Patients who received upfront ASCT after achieving complete response to CHOP or ICED showed 80% of 3-year OS. Discussion: In summary, our study showed no therapeutic difference between CHOP and ICED in terms of response and PFS. Thus, CHOP might remain the reference regimen especially for AITL based on its better outcome in AITL, and upfront ASCT could be recommended as a consolidation of complete response in patients with PTCL.

Dose-escalated radiotherapy for clinically localized and locally advanced prostate cancer.

BACKGROUND: Treatments for clinically localized prostate cancer include radical prostatectomy, external beam radiation therapy, brachytherapy, active surveillance, hormonal therapy, and watchful waiting. For external beam radiation therapy, oncological outcomes may be expected to improve as the dose of radiotherapy (RT) increases. However, radiation-mediated side effects on surrounding critical organs may also increase. OBJECTIVES: To assess the effects of dose-escalated RT in comparison with conventional dose RT for curative treatment of clinically localized and locally advanced prostate cancer. SEARCH METHODS: We performed a comprehensive search using multiple databases including trial registries and other sources of grey literature, up until 20 July 2022. We applied no restrictions on publication language or status. SELECTION CRITERIA: We included parallel-arm randomized controlled trials (RCTs) of definitive RT in men with clinically localized and locally advanced prostate adenocarcinoma. RT was dose-escalated RT (equivalent dose in 2 Gy [EQD2] ≥ 74 Gy, lesser than 2.5 Gy per fraction) versus conventional RT (EQD2 < 74 Gy, 1.8 Gy or 2.0 Gy per fraction). Two review authors independently classified studies for inclusion or exclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data from the included studies. We performed statistical analyses by using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of the evidence of RCTs. MAIN RESULTS: We included nine studies with 5437 men in an analysis comparing dose-escalated RT versus conventional dose RT for the treatment of prostate cancer. The mean participant age ranged from 67 to 71 years. Almost all men had localized prostate cancer (cT1-3N0M0). Primary outcomes Dose-escalated RT probably results in little to no difference in time to death from prostate cancer (hazard ratio [HR] 0.83, 95% CI 0.66 to 1.04; I2 = 0%; 8 studies; 5231 participants; moderate-certainty evidence). Assuming a risk of death from prostate cancer of 4 per 1000 at 10 years in the conventional dose RT group, this corresponds to 1 fewer men per 1000 (1 fewer to 0 more) dying of prostate cancer in the dose-escalated RT group. Dose-escalated RT probably results in little to no difference in severe RT toxicity of grade 3 or higher late gastrointestinal (GI) toxicity (RR 1.72, 95% CI 1.32 to 2.25; I2 = 0%; 8 studies; 4992 participants; moderate-certainty evidence); 23 more men per 1000 (10 more to 40 more) in the dose-escalated RT group assuming severe late GI toxicity as 32 per 1000 in the conventional dose RT group. Dose-escalated RT probably results in little to no difference in severe late genitourinary (GU) toxicity (RR 1.25, 95% CI 0.95 to 1.63; I2 = 0%; 8 studies; 4962 participants; moderate-certainty evidence); 9 more men per 1000 (2 fewer to 23 more) in the dose-escalated RT group assuming severe late GU toxicity as 37 per 1000 in the conventional dose RT group. Secondary outcomes Dose-escalated RT probably results in little to no difference in time to death from any cause (HR 0.98, 95% CI 0.89 to 1.09; I2 = 0%; 9 studies; 5437 participants; moderate-certainty evidence). Assuming a risk of death from any cause of 101 per 1000 at 10 years in the conventional dose RT group, this corresponds to 2 fewer men per 1000 (11 fewer to 9 more) in the dose-escalated RT group dying of any cause. Dose-escalated RT probably results in little to no difference in time to distant metastasis (HR 0.83, 95% CI 0.57 to 1.22; I2 = 45%; 7 studies; 3499 participants; moderate-certainty evidence). Assuming a risk of distant metastasis of 29 per 1000 in the conventional dose RT group at 10 years, this corresponds to 5 fewer men per 1000 (12 fewer to 6 more) in the dose-escalated RT group developing distant metastases. Dose-escalated RT may increase overall late GI toxicity (RR 1.27, 95% CI 1.04 to 1.55; I2 = 85%; 7 studies; 4328 participants; low-certainty evidence); 92 more men per 1000 (14 more to 188 more) in the dose-escalated RT group assuming overall late GI toxicity as 342 per 1000 in the conventional dose RT group. However, dose-escalated RT may result in little to no difference in overall late GU toxicity (RR 1.12, 95% CI 0.97 to 1.29; I2 = 51%; 7 studies; 4298 participants; low-certainty evidence); 34 more men per 1000 (9 fewer to 82 more) in the dose-escalated RT group assuming overall late GU toxicity as 283 per 1000 in the conventional dose RT group. Based on long-term follow-up (up to 36 months), dose-escalated RT may result or probably results in little to no difference in the quality of life using 36-Item Short Form Survey; physical health (MD -3.9, 95% CI -12.78 to 4.98; 1 study; 300 participants; moderate-certainty evidence) and mental health (MD -3.6, 95% CI -83.85 to 76.65; 1 study; 300 participants; low-certainty evidence), respectively. AUTHORS' CONCLUSIONS: Compared to conventional dose RT, dose-escalated RT probably results in little to no difference in time to death from prostate cancer, time to death from any cause, time to distant metastasis, and RT toxicities (except overall late GI toxicity). While dose-escalated RT may increase overall late GI toxicity, it may result, or probably results, in little to no difference in physical and mental quality of life, respectively.

Radioimmunotherapy with 131 I-rituximab for patients with relapsed or refractory follicular or mantle cell lymphoma.

AIM: This study aimed to evaluate the safety and efficacy of 131 I-rituximab in patients with relapsed or refractory follicular or mantle cell lymphoma. METHODS: Twenty-four patients with relapsed or refractory follicular or mantle cell lymphoma were administered unlabeled rituximab (70 mg) immediately before receiving a therapeutic dose of 131 I-rituximab. Contrast-enhanced 18F-fluorodeoxyglucose positron emission tomography/computed tomography was used a month later to assess tumor response. RESULTS: This study enrolled 24 patients between June 2012 and 2022. Depending on how they responded to radioimmunotherapy (RIT), 131 I-rituximab was administered one to five times. Of the 24 patients, 9 achieved complete response after RIT and 8 achieved partial response. The median progression-free and overall survival was 5.9 and 37.9 months, respectively. During the follow-up period of 64.2 months, three patients were diagnosed with a secondary malignancy. Among treatment-related adverse events, hematologic toxicities were common, and grade 3-4 thrombocytopenia and neutropenia were reported in 66.6% of cases. CONCLUSION: 131 I-rituximab has an effective and favorable safety profile in patients with relapsed or refractory follicular lymphoma and mantle cell lymphoma. This suggests that RIT may also be considered a treatment option for patients with relapsed or refractory follicular lymphoma and mantle cell lymphoma.

A non-interventional, post-marketing surveillance study evaluating the safety and effectiveness of biosimilar rituximab (CT-P10) during routine clinical practice in the Republic of Korea.

BACKGROUND: CT-P10 was the first licensed rituximab biosimilar. This Korean post-marketing surveillance study evaluated CT-P10 safety and effectiveness in approved indications. RESEARCH DESIGN AND METHODS: This prospective, open-label, observational, phase 4 study collected routine clinical practice data across 27 centers in the Republic of Korea. Patients received their first CT-P10 treatment, per prescribing information, for non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA) during the surveillance period (16 November 2016-15 November 2020). Safety (including adverse events [AEs] and adverse drug reactions [ADRs]) and disease-specific clinical response (by best overall response [NHL/CLL], Disease Activity Score in 28-joints [RA], or Birmingham Vasculitis Activity Score for Wegener's Granulomatosis [GPA/MPA]) were assessed for ≤1 year (NHL/CLL) or ≤24 weeks (RA/GPA/MPA). RESULTS: The safety population comprised 677 patients (604 NHL, 16 CLL, 42 RA, 7 GPA, 8 MPA). AEs/ADRs were reported for 68.4%/27.7% (NHL/CLL), 31.0%/14.3% (RA), and 86.7%/13.3% (GPA/MPA) of patients. Serious AEs and unexpected ADRs did not raise new safety signals. Pneumonia was the most frequent serious ADR overall. Positive effectiveness outcomes were observed. CONCLUSIONS: Findings were consistent with the known CT-P10/reference rituximab safety profile, with high effectiveness observed in NHL/CLL and RA.

Busulfan, Melphalan, and Etoposide (BuME) Showed an Equivalent Effect to Busulfan, Cyclophosphamide, and Etoposide (BuCE) as Conditioning Therapy for Autologous Stem Cell Transplantation in Patients with Relapsed or High-Risk Non-Hodgkin's Lymphoma: A Multicenter Randomized Phase II Study bythe Consortium for Improving Survival of Lymphoma (CISL).

PURPOSE: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard management for relapsed or high-risk non-Hodgkin's lymphoma (NHL). We reported the busulfan, melphalan, and etoposide (BuME) conditioning regimen was effective in patients with relapsed or high-risk NHL. Moreover, the busulfan, cyclophosphamide, and etoposide (BuCE) conditioning regimen has been used widely in ASCT for NHL. Therefore, based on these encouraging results, this randomized phase II multicenter trial compared the outcomes of BuME and BuCE as conditioning therapies for ASCT in patients with NHL. MATERIALS AND METHODS: Patients were randomly assigned to receive either BuME (n=36) or BuCE (n=39). The BuME regimen was comprised of busulfan (3.2 mg/kg/day, intravenously) administered on days -7, -6, and -5, etoposide (400 mg/m2 intravenously) on days -5 and -4, and melphalan (50 mg/m2/day intravenously) on days -3 and -2. The BuCE regimen was comprised of busulfan (3.2 mg/kg/day intravenously) on days -7, -6, and -5, etoposide (400 mg/m2/day intravenously) on days -5 and -4, and cyclophosphamide (50 mg/kg/day intravenously) on days -3 and -2. The primary endpoint was 2-year progression-free survival (PFS). RESULTS: Seventy-five patients were enrolled. Eleven patients (30.5%) in the BuME group and 13 patients (33.3%) in the BuCE group had disease progression or died. The 2-year PFS rate was 65.4% in the BuME group and 60.6% in the BuCE group (p=0.746). There were no non-relapse mortalities within 100 days after transplantation. CONCLUSION: There were no significant differences in PFS between the two groups. Therefore, busulfan-based conditioning regimens, BuME and BuCE, may be important treatment substitutes for the BCNU-containing regimens.

Survival impact of adherence to tyrosine kinase inhibitor in chronic myeloid leukemia.

BACKGROUND/AIMS: Adherence to tyrosine kinase inhibitors (TKIs) has become a critical aspect of care in chronic myeloid leukemia (CML). We aimed to examine the association of TKI adherence with overall survival (OS) outcomes in Korean patients diagnosed with CML and treated with TKIs using data from the National Health Information Database. METHODS: This study included 2,870 CML patients diagnosed between 2005 and 2013. Drug adherence was evaluated according to the medication possession ratio (MPR) and classified as high adherence (i.e., MPR ≥ 0.95 [upper 50%]), moderate adherence (i.e., MPR ≥ 0.68 and < 0.95 [middle 25%]), and low adherence (i.e., MPR < 0.68 [lower 25%]). RESULTS: The median MPR was 0.95 (range, 0 to 4.67). Male sex (p = 0.003), age < 70 years (p < 0.001), high income (≥ 30%, p < 0.001), and maintaining frontline TKI (< 0.001) were associated with better adherence. Adherence to dasatinib was the lowest (vs. imatinib or nilotinib, p < 0.001). Compared with high MPR patients, those with moderate MPR (hazard ratio [HR], 4.90; 95% confidence interval [CI], 3.87 to 6.19; p < 0.001) and low MPR (HR, 11.6; 95% CI, 9.35 to 14.42; p < 0.001) had poorer OS. CONCLUSION: Adherence to TKI treatment is an important factor predicting survival outcomes in Korean CML patients. Male sex, age < 70 years, high income, and maintaining frontline TKI are associated with high adherence to TKI. Thus, those without these characteristics should be closely monitored for treatment adherence.

Multicenter retrospective analysis of patients with chronic lymphocytic leukemia in Korea.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in Western countries but is rare in the East Asian countries. Due to its rarity and the lack of feasible novel agents and laboratory prognostic tools, there are limited data on the clinical outcomes of this disease in Asia. To clarify the current treatment status, we performed a multicenter retrospective analysis of patients with CLL in Korea. METHODS: The medical records of 192 eligible patients between 2008 and 2019 were reviewed for clinical characteristics, treatment courses, and outcomes. The first-line treatment regimens of the patients included in this analysis were as follows: fludarabine/cyclophosphamide/ rituximab (FCR) (N=117, 52.7%), obinutuzumab plus chlorambucil (GC) (N=30, 13.5%), and chlorambucil monotherapy (N=24, 10.8%). RESULTS: The median progression-free survival (PFS) was 55.6 months, and the average 2-year PFS rate was 80.3%. PFS was not significantly different between the patients receiving FCR and those receiving GC; however, chlorambucil treatment was associated with significantly inferior PFS (P <0.001). The median overall survival was 136.3 months, and the average 5- and 10-year OS rates were 82.0% and 57.4%, respectively. CONCLUSION: This is one of the largest studies involving Korean patients with CLL. Although the patients had been treated with less favored treatment regimens, the outcomes were not different from those reported in Western studies.

Treatment-free remission of chronic myeloid leukemia in real-world practice by the detection limit of MR4.3.

BACKGROUND: Molecular response (MR) 4.0 or 4.3 remains an indicator of treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) in countries that accept it as the criterion of undetectable minimal residual disease (UMRD) in clinical practice. We retrospectively analyzed the TFR outcomes to identify the clinical efficacy of MR4.0/4.3 as the UMRD criterion. PATIENTS AND METHODS: CML patients treated with tyrosine kinase inhibitors (TKIs) between March 2001 and May 2015 for >3 years and treatment cessation for over 6 months were included. TFR was analyzed using MR3.0 loss and UMRD loss as criteria. TFR failure-free survival was defined as the time from cessation of TKI therapy to MR loss or restarting TKI, and overall survival as the time from TKI cessation to death. The probability of regaining the MR was evaluated. RESULTS: In the 93 participants, the median duration of follow-up and TKI therapy were 17.3 (3.9-92.0) months and 7.4 (3.1-16.9) years, respectively. TFR at 5 years was 47.9 % and 44.4 %, for MR3.0 loss and UMRD loss, respectively. Among the 42 patients who restarted TKI, 41 regained MR3.0 (97.6 %). In multivariate analysis, the time to UMRD was ≤12 months, and the absence of prior TKI treatment (P = 0.018 and 0.044 in UMRD loss, respectively) was significantly correlated with TFR failure-free survival. CONCLUSION: Clinical outcomes were comparable to those of clinical trials. Our results suggest that the detection limit of MR4.3 can be used in clinical practice for TKI treatment cessation for TFR in CML patients.

Immunosuppressive role of CD11b+ CD33+ HLA-DR- myeloid-derived suppressor cells-like blast subpopulation in acute myeloid leukemia.

OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) facilitate tumor growth and development by suppressing T cell function; however, their role in acute myeloid leukemia (AML) remains unclear. Here, we investigated the immunosuppressive role and prognostic value of blasts with an MDSC-like phenotype. METHODS: CD11b+ CD33+ HLA-DR- MDSC-like blasts from bone marrow mononuclear cells of patients with AML were analyzed. To investigate their T cell-suppressing function, MDSC-like blasts were isolated using flow cytometry and co-cultured with CD8+ cytotoxic T cells and NB4 leukemic cells. Treatment outcomes were then compared between the MDSC-like blasts low (≤9.76%) and high (>9.76%) groups to identify clinical significance. RESULTS: MDSC-like blasts showed higher expression of arginase-1 and inducible nitric oxide synthase. Isolated MDSC-like blasts significantly suppressed CD8+ T cell proliferation induced by phytohemagglutinin A. NB4 cell proliferation was significantly suppressed upon co-culture with CD8+ cytotoxic T cells and partially restored upon co-culture with MDSC-like blasts. Patients with high MDSC-like blasts at diagnosis showed substantially shorter overall survival and leukemia-free survival relative to low MDSC-like blasts patients, with subgroup analysis showing statistically significant differences in patients not receiving allogeneic hematopoietic stem cell transplantation. CONCLUSION: We demonstrated that MDSC-like blasts drive AML-specific immune-escape mechanisms by suppressing T cell proliferation and restoring T cell-suppressed NB4 cell proliferation, with clinically higher fractions of MDSC-like blasts at diagnosis resulting in poor prognosis.

Outcomes of Chronic Phase Chronic Myeloid Leukemia after Treatment with Multiple Tyrosine Kinase Inhibitors.

We sought to evaluate the outcomes of chronic phase (CP) chronic myeloid leukemia (CML) in an era where five tyrosine kinase inhibitors (TKIs) are commercially available for the treatment of CML. Records of patients diagnosed with CP CML, treated with TKIs and referred to our center were reviewed. Between January 2005 and April 2016, 206 patients were followed for a median of 48.8 (1.4-190.1) months. A total of 76 (37%) patients received one TKI, 73 (35%) received two TKIs and 57 (28%) were exposed to >3 TKIs (3 TKIs, n = 33; 4 TKIs, n = 17; 5 TKIs, n = 7). Nineteen (9.2%) patients progressed to advanced phases of CML (accelerated phase, n = 6; myeloid blastic phase, n = 4; lymphoid blastic phase, n = 9). One third (n = 69) achieved complete molecular response (CMR) at first-line treatment. An additional 55 patients achieved CMR after second-line treatment. Twenty-five patients (12.1%) attempted TKI discontinuation and 14 (6.8%) stopped TKIs for a median of 6.3 months (range 1-53.4). The 10-year progression-free survival and overall survival (OS) rates were 81% and 87%, respectively. OS after 10-years, based on TKI exposure, was 100% (1 TKI), 82% (2 TKIs), 87% (3 TKIs), 75% (4 TKIs) and 55% (5 TKIs). The best OS was observed in patients tolerating and responding to first line TKI, but multiple TKIs led patients to gain treatment-free remission.

Adipose Tissue-Derived Mesenchymal Stem Cells Suppress Growth of Huh7 Hepatocellular Carcinoma Cells via Interferon (IFN)-ß-Mediated JAK/STAT1 Pathway in vitro.

Interferon (IFN)-ß and/or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) secreted by adipose tissue-derived mesenchymal stem cells (ASCs) have been proposed as key mechanistic factors in anti-cancer efficacy in lung cancer and breast cancer cells, where they act through paracrine signaling. We hypothesized that IFN-ß and TRAIL produced by ASCs suppress proliferation of hepatocellular carcinoma cells (HCCs). The present study evaluated the anti-cancer effects of ASCs on HCCs in vitro. We found that indirect co-culture with ASCs diminished growth of Huh7 hepatocellular carcinoma cells with increased protein levels of p53/p21 and phosphorylated STAT1 (pSTAT1), without apoptosis. Treatment with ASC-conditioned medium (ASC-CM) also decreased growth of Huh7 cells through elevated p53/p21 and pSTAT1 signaling. ASC-CM-mediated inhibition of cell growth was neutralized in Huh7 cells treated with anti-IFN-ß antibody compared to that in ASC-CM-treated Huh7 cells incubated with an anti-TRAIL antibody. Treatment with JAK1/JAK2 inhibitors recovered inhibition of growth in Huh7 cells incubated in ASC-CM or IFN-ß via down-regulation of pSTAT1/p53/p21. However, treatment of IFN-ß resulted in no alterations in resistance of Huh7 cells to TRAIL. Our findings suggest that ASCs decrease growth through activated STAT1-mediated p53/p21 by IFN-ß, but not TRAIL, in Huh7 cells.

Long-term data from a phase 3 study of radotinib versus imatinib in patients with newly diagnosed, chronic myeloid leukaemia in the chronic phase (RERISE).

In the phase 3 study RERISE, patients with newly diagnosed chronic myeloid leukaemia in chronic phase demonstrated significantly faster and higher rates of major molecular response (MMR) with twice-daily radotinib 300 mg (n = 79) or 400 mg (n = 81) than with once-daily imatinib 400 mg (n = 81) after 12 months. With ≥48 months' follow-up, MMR was higher with radotinib 300 mg (86%) or 400 mg (83%) than with imatinib (75%). Among patients with BCR-ABL1 ≤ 10% at three months, MMR and molecular response 4·5 (MR4·5 ) were achieved within 48 months by more radotinib-treated patients (300 mg: 84% and 52%, respectively; 400 mg: 74% and 44%, respectively) than imatinib-treated patients (71% and 44%, respectively). Estimated overall and progression-free survival rates at 48 months were not significantly different between imatinib (94% and 94%, respectively) and radotinib 300 mg (99% and 97%, respectively) or 400 mg (95% and 93%, respectively). The treatment failure rate was significantly higher with imatinib (19%) than with radotinib 300 mg (6%; P = 0·0197) or 400 mg (5%; P = 0·0072). Safety profiles were consistent with previous reports; most adverse events occurred within 12 months. Radotinib continues to demonstrate robust, deep molecular responses, suggesting that treatment-free remission may be attainable.

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).

Phase II study of R-CVP followed by rituximab maintenance therapy for patients with advanced marginal zone lymphoma: consortium for improving survival of lymphoma (CISL) study.

BACKGROUND: The response rate and survival improvement for rituximab, a CD20-targeting monoclonal antibody, have been demonstrated in marginal zone lymphoma (MZL) as monotherapy and in combination with chemotherapeutic regimens, yet relapses still occur despite treatment completion. Thus, extending the period of remission in MZL patients remains an essential goal. This multicenter, single-arm, open-label phase II study evaluated the survival efficacy of 2 years of rituximab-maintenance therapy in patients with stage III-IV CD20-positive MZL who had responded to first-line R-CVP (rituximab, cyclophosphamide, vincristine, and prednisolone). The objective of this study was to determine whether rituximab maintenance following R-CVP warrants further investigation. METHODS: Prior to rituximab-maintenance therapy, patients received 6-8 cycles of first-line R-CVP therapy for stage III-IV MZL. Rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), and vincristine (1.4 mg/m2; maximum 2 mg) were administered via an intravenous infusion on day 1 of each 3-week cycle, while oral prednisolone (100 mg) was given on days 1-5 of each 3-week cycle. The patients who achieved complete response (CR), partial response (PR), or stable disease (SD) to R-CVP treatment, were prescribed rituximab-maintenance therapy which was administered intravenously at a dose of 375 mg/m2 every 8 weeks for up to 12 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and treatment safety. RESULTS: 47 patients were enrolled, of whom, 45 (96%) received rituximab-maintenance treatment. Fifteen (33%) patients had nodal MZL. Following R-CVP first-line therapy, 20 (44%), 22 (49%), and 3 (7%) patients achieved CR, PR, and SD, respectively. After a median follow-up of 38.2 months, their observed 3-year PFS rate was 81%. During the rituximab-maintenance, 6 PR and 1 SD patients achieved CR following the administration of R-CVP. Elevated LDH and the presence of B symptoms were found to be significant prognostic factors for PFS (P = 0.003) and demonstrated a 3-year OS rate of 90%. Rituximab-maintenance therapy was well tolerated, and the common treatment-emergent adverse events were sensory neuropathy (18%), myalgia (13%), fatigue (9%), and neutropenia (9%). CONCLUSION: Rituximab-maintenance therapy following first-line R-CVP demonstrated good PFS in patients with stage III-IV MZL, in addition to a favorable toxicity profile. Trial registration clinicaltrials.gov: NCT01213095.

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

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