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.

Clinical Efficacies of FLT3 Inhibitors in Patients with Acute Myeloid Leukemia.

FLT3 mutations are the most common genomic alteration detected in acute myeloid leukemia (AML) with a worse clinical prognosis. The highly frequent FLT3 mutations, together with the side effects associated with clinical prognosis, make FLT3 promising treatment targets and have provoked the advancement of FLT3 inhibitors. Recently, numerous FLT3 inhibitors were actively developed, and thus the outcomes of this aggressive subtype of AML were significantly improved. Recently, midostaurin and gilteritinib were approved as frontline treatment of AML and as therapeutic agents in the recurred disease by the United States Food and Drug Administration. Recently, numerous promising clinical trials attempted to seek appropriate management in frontline settings, in relapsed/refractory disease, or after stem cell transplantation in AML. This review follows numerous clinical trials about the usefulness of FLT3 inhibitors as frontline therapy, as relapsed/refractory conditioning, and as maintenance therapy of stem cell transplantation. The cumulative data of FLT3 inhibitors would be important clinical evidence for further management with FLT3 inhibitors in AML patients with FLT3 mutations.

Targeted Therapeutic Approach Based on Understanding of Aberrant Molecular Pathways Leading to Leukemic Proliferation in Patients with Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogenous hematopoietic neoplasm with various genetic abnormalities in myeloid stem cells leading to differentiation arrest and accumulation of leukemic cells in bone marrow (BM). The multiple genetic alterations identified in leukemic cells at diagnosis are the mainstay of World Health Organization classification for AML and have important prognostic implications. Recently, understanding of heterogeneous and complicated molecular abnormalities of the disease could lead to the development of novel targeted therapeutic agents. In the past years, gemtuzumab ozogamicin, BCL-2 inhibitors (venetovlax), IDH 1/2 inhibitors (ivosidenib and enasidenib) FLT3 inhibitors (midostaurin, gilteritinib, and enasidenib), and hedgehog signaling pathway inhibitors (gladegib) have received US Food and Drug Administration (FDA) approval for the treatment of AML. Especially, AML patients with elderly age and/or significant comorbidities are not currently suitable for intensive chemotherapy. Thus, novel therapeutic planning including the abovementioned target therapies could lead to improve clinical outcomes in the patients. In the review, we will present various important and frequent molecular abnormalities of AML and introduce the targeted agents of AML that received FDA approval based on the previous studies.

Clinical impact of lymphatic spread in patients with limited-stage upper aerodigestive tract NK/T cell lymphoma.

BACKGROUND: We investigated whether distancemax, that is, the degree of distance between the upper aerodigestive tract (UAT) mass and the farthest pathologic lymph node, was significantly associated with survival in patients with limited-stage UAT natural killer/T cell lymphoma (NKTCL). METHODS: A total of 157 patients who received chemotherapy (CTx) with/without radiotherapy (RTx) were enrolled. RESULTS: In the survival analysis, an elevated lactate dehydrogenase level [progression-free survival (PFS): hazard ratio (HR), 2.948; 95% confidence interval (CI), 1.606‒5.404; P <0.001; overall survival (OS): HR, 2.619; 95% CI, 1.594‒4.822; P =0.003], short distancemax (PFS: HR, 0.170; 95% CI, 0.071‒0.410; P <0.001; OS: HR, 0.142; 95% CI, 0.050‒0.402; P < 0.001), and CTx combined with RTx (HR, 0.168; 95%CI, 0.079‒0.380; P <0.001; OS: HR, 0.193; 95% CI, 0.087‒0.429; P <0.001) had an independent predictive value for PFS and OS. CONCLUSION: The evaluation of the degree of lymphatic spread and local control by CTx combined with RTx is essential in patients with limited-stage UAT NKTCL.

Clinical Impact of Extranodal Metabolic Tumor Volume in 240 Diffuse Large B cell Lymphoma Patients with Extranodal Involvement.

The present study is to investigate whether extranodal (EN) metabolic tumor volume (MTV) would have a specific clinical meaning for survival in EN diffuse large B cell lymphoma (DLBCL) patients. Two hundred forty DLBCL patients with EN involvement received 18F-fluorodeoxygenase (FDG) positron emission tomography/computed tomography (PET/CT) were enrolled. Survival analysis revealed that low EN MTV (PFS [progression-free survival], HR = 0.278, 95% CI = 0.127-0.807, p = 0.001; OS [overall survival], HR = 0.320, 95% CI = 0.145-0.703, p = 0.003), low total MTV (PFS, HR = 0.194, 95% CI = 0.085-0.445, p < 0.001; OS, HR = 0.213, 95% CI = 0.092-0.491, p < 0.007), and high National Cancer Center Network-International Prognostic Index score (PFS, HR = 3.152, 95% CI = 1.732-5.734, p < 0.001; OS, HR = 2.457, 95% CI = 1.363-4.430, p = 0.003) were independently associated with survivals in the patients. Our data showed that EN MTV is a useful and novel prognostic parameter for predicting survival in DLBCL patients with EN involvement.

Resistance Mechanisms to CAR T-Cell Therapy and Overcoming Strategy in B-Cell Hematologic Malignancies.

Chimeric antigen receptor (CAR) T-cell therapy has shown promising clinical impact against hematologic malignancies. CD19 is a marker on the surface of normal B cells as well as most B-cell malignancies, and thus has a role as an effective target for CAR T-cell therapy. In numerous clinical data, successes with cell therapy have provided anticancer therapy as a potential therapeutic option for patients who are resistant to standard chemotherapies. However, recent growing evidence showed the limitations of the treatment such as antigen-positive relapse due to poor CAR T-cell persistence and antigen-negative relapses associated with CAR-driven mutations, alternative splicing, epitope masking, low antigen density, and lineage switching. The understanding of the resistance mechanisms to the cell therapy has developed novel potential treatment strategies, including dual-targeting therapy (dual and tandem CAR), and armored and universal CAR T-cell therapies. In this review, we provide an overview of resistance mechanisms to CD19 CAR T-cell therapy in B-cell malignancies and also review therapeutic strategies to overcome these resistances.

Understanding Immune Evasion and Therapeutic Targeting Associated with PD-1/PD-L1 Pathway in Diffuse Large B-cell Lymphoma.

In tumor microenvironment, the programmed death 1 (PD-1) immune checkpoint has a crucial role of mechanism of T cell exhaustion leading to tumor evasion. Ligands of PD-1, programmed death ligand 1/2 (PD-L1/L2) are over-expressed in tumor cells and participate in prolonged tumor progression and survivals. Recently, clinical trials for patients who failed to obtain an optimal response prior to standardized chemotherapy in several solid cancers have been focused on targeting therapy against PD-1 to reduce disease progression rates and prolonged survivals. Since various inhibitors targeting the immune checkpoint in PD-1/PD-L1 pathway in solid cancers have been introduced, promising approach using anti-PD-1 antibodies were attempted in several types of hematologic malignances. In diffuse large B cell lymphoma (DLBCL) as the most common and aggressive B cell type of non-Hodgkin's lymphoma, anti-PD-1 and anti-PD-L1 antibodies were studies in various clinical trials. In this review, we summarized the results of several studies associated with PD-1/PD-L1 pathway as an immune evasion mechanism and described clinical trials about targeting therapy against PD-1/PD-L1 pathway in DLBCL.

Clinical impacts of inflammatory markers and clinical factors in patients with relapsed or refractory diffuse large B-cell lymphoma.

BACKGROUND: Systemic inflammatory response can be associated with the prognosis of diffuse large B cell lymphoma (DLBCL). We investigated the systemic factors significantly related to clinical outcome in relapsed/refractory DLBCL. METHODS: In 242 patients with DLBCL, several factors, including inflammatory markers were analyzed. We assessed for the correlation between the survivals [progression-free survival (PFS) and overall survival (OS)] and prognostic factors. RESULTS: In these patients, a high derived neutrophil/lymphocyte ratio (dNLR) (PFS, HR=2.452, P=0.002; OS, HR=2.542, P=0.005), high Glasgow Prognostic Score (GPS) (PFS, HR=2.435, P=0.002; OS, HR=2.621, P=0.002), and high NCCN-IPI (PFS, HR=2.836, P=0.003; OS, HR=2.928, P=0.003) were significantly associated with survival in multivariate analysis. Moreover, we proposed a risk stratification model based on dNLR, GPS, and NCCN-IPI, thereby distributing patients into 4 risk groups. There were significant differences in survival among the 4 risk groups (PFS, P<0.001; OS, P<0.001). CONCLUSION: In conclusion, dNLR, GPS, and NCCN-IPI appear to be excellent prognostic parameters for survival in relapsed/refractory DLBCL.

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

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

Understanding Splenomegaly in Myelofibrosis: Association with Molecular Pathogenesis.

Myelofibrosis (MF) is a clinical manifestation of chronic BCR-ABL1-negative chronic myeloproliferative neoplasms. Splenomegaly is one of the major clinical manifestations of MF and is directly linked to splenic extramedullary hematopoiesis (EMH). EMH is associated with abnormal trafficking patterns of clonal hematopoietic cells due to the dysregulated bone marrow (BM) microenvironment leading to progressive splenomegaly. Several recent data have emphasized the role of several cytokines for splenic EMH. Alteration of CXCL12/CXCR4 pathway could also lead to splenic EMH by migrated clonal hematopoietic cells from BM to the spleen. Moreover, low Gata1 expression was found to be significantly associated with the EMH. Several gene mutations were found to be associated with significant splenomegaly in MF. In recent data, JAK2V617F homozygous mutation was associated with a larger spleen size. In other data, CALR mutations in MF were signigicantly associated with longer larger splenomegaly-free survivals than others. In addition, MF patients with ≥1 mutations in AZXL1, EZH1 or IDH1/2 had significantly low spleen reduction response in ruxolitinib treatment. Developments of JAK inhibitors, such as ruxolitinib, pacritinib, momelotinib, and febratinib enabled the effective management in MF patients. Especially, significant spleen reduction responses of the drugs were demonstrated in several randomized clinical studies, although those could not eradicate allele burdens of MF.

Tumor necrosis and complete resection has significant impacts on survival in patients with limited-stage upper aerodigestive tract NK/T cell lymphoma.

Tumor necrosis (TN) is associated with worse prognosis in several solid cancers. Whether TN predicts poor outcome in natural killer cell / T cell lymphoma (NKTCL) is unclear. We investigated the clinical impact of TN on survival and other novel prognostic parameters in upper aero-digestive tract (UAT) NKTCL of 100 patients with limited stage. TN was significantly associated with poor performance status (p = 0.049), high Korean Prognostic Index score (p = 0.024), high C-reactive protein/albumin ratio (p = 0.003), higher maximum standard uptake value on positron emission tomography/computed tomography (PET/CT) (p = 0.008) and higher metabolic tumor volume (MTV) on PET/CT (p < 0.001). In univariate and multivariate analyses, progression-free survival and overall survival were independently associated with High MTV status (p = 0.001, p = 0.032), TN (p = 0.018, p = 0.009), local tumor invasiveness (p = 0.007, p = 0.035), complete resection (p = 0.020, p = 0.028) and regional lymph node involvement (p < 0.001, p < 0.001). TN and complete resection are concluded to be novel independent prognostic factors in patients with UAT NKTCL.

Would Lipophilic Statin Therapy as a Prognostic Factor Improve Survival in Patients With Uterine Cervical Cancer?

OBJECTIVES: In vitro studies showed that lipophilic statins inhibit cell growth, adhesion, and invasion and induce apoptosis in cancer cell lines. In uterine cervical cancer, several important factors including age, stage, anemia, lymphovascular invasion, lymph node metastases, and parametrial spread were known to significantly predict survival. We investigated whether statin therapy as a prognostic factor would significantly predict survival in cervical cancer. METHODS: Patients with stages IB to IV cervical cancer who received radical hysterectomy and/or para-aortic lymph node dissection were included. The statin-use group was identified as patients who were continuously prescribed with lipophilic statins from prediagnostic period of the cancer. RESULTS: The baseline characteristics of both statin-use group and control group were comparable. During a median follow-up of 36.6 months, progression-free survival and overall survival of the statin-use group were significantly higher than the control group (P < 0.001 and P = 0.004, respectively). In multivariate analysis, the statin-use group had an independent prognostic significance compared with other prognostic factors (progression-free survival: hazards ratio = 0.062, 95% confidence interval = 0.008-0.517, P = 0.010; overall survival: hazards ratio = 0.098, 95% confidence interval = 0.041-0.459, P = 0.032). CONCLUSIONS: In the present study, continuous lipophilic statin therapy from the prediagnostic period of uterine cervical cancer could reflect favorable outcome, independently.

A prospective, open-label, multicenter, observational study to evaluate the efficacy and safety of bortezomib-melphalan-prednisone as initial treatment for autologous stem cell transplantation-ineligible patients with multiple myeloma.

Bortezomib-melphalan-prednisone (VMP) showed superior efficacy versus MP as first-line treatment for transplantation-ineligible multiple myeloma (MM). This study investigated the efficacy of VMP for Korean patients with MM.Overall, 177 MM patients received 9 cycles of VMP in this prospective, multicenter, observational study. The primary endpoint was 2-year progression-free survival (PFS).Thirty-nine (22%) patients were aged ≥ 75 years and 83 (47.4%) patients had International Staging System stage III. A median of 5 cycles were delivered. Overall response rate (ORR) was 72.9%, and complete response (CR) rate was 20.3%. With a median follow-up of 11.9 months, median PFS was 17 months. The 2-year PFS and overall survival (OS) rates were 29.2% and 80.0%, respectively. Median OS was not reached. PFS was significantly different depending on performance status (Eastern Cooperative Oncology Group < 2 vs. ≥ 2; p = 0.0002), ß2-microglobulin level (< 5.5 vs. ≥ 5.5 mg/L; p = 0.0481), and cumulative dose of bortezomib (< 35.1 vs. ≥ 35.1 mg/m2; p < 0001). The common adverse events (AEs) were in line with the well-known toxicity profiles associated with VMP.In conclusion, VMP is a feasible and effective front-line treatment for transplant-ineligible older patients with MM in Korea. Continuing therapy with prompt adjustment of treatment according to AEs may be important to improve outcomes of elderly patients.

Tumor necrosis could reflect advanced disease status in patients with diffuse large B cell lymphoma treated with R-CHOP therapy.

Tumor necrosis (TN) can lower responsiveness to chemotherapy and confer basic resistance to anti-cancer therapy. We investigated the association of TN with poor clinical features and outcome in diffuse large B cell lymphoma (DLBCL). We examined the presence or absence of TN in 476 DLBCL patients of who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Eighty-nine (18.7 %) patients had TN at diagnosis. Patients with TN had a progression-free survival (PFS) and overall survival (OS) of 39.3 and 46.7 %, whereas patients without TN had a PFS and OS of 73.4 and 82.6 %. Adverse clinical factors of poor Eastern Cooperative Oncology Group performance status ≥ grade 2 (p = 0.005), elevated lactate dehydrogenase ratio >1 (p < 0.001), advanced Ann Arbor stage (p = 0.002), and bulky disease (p = 0.026) were more prevalent in the TN group than the non-TN group. Cox regression model analysis revealed TN as an independent prognostic factor for PFS and OS in DLBCL (PFS, hazard ratio [HR] = 1.967, 95 % confidence interval [CI] = 1.399-2.765, p < 0.001; OS, HR = 2.445, 95 % CI = 1.689-3.640, p < 0.001). The results indicate that TN could reflect adverse clinical features and worse prognosis in DLBCL patients receiving R-CHOP therapy.

Evaluation of prognostic factors in patients with relapsed AML: Clonal evolution versus residual disease.

BACKGROUND: It is widely known that the prognosis of acute myeloid leukemia (AML) depends on chromosomal abnormalities. The majority of AML patients relapse and experience a dismal disease course despite initial remission. METHODS: We reviewed the medical records and laboratory findings of 55 AML patients who had relapsed between 2004 and 2013 and who had been treated at the Division of Hematology of the Pusan National University Hospital. RESULTS: The event-free survival (EFS) was related to prognostic karyotype classification at the time of diagnosis and relapse (unfavorable vs. favorable or intermediate karyotypes at diagnosis, 8.2 vs. 11.9 mo, P=0.003; unfavorable vs. favorable or intermediate karyotypes at relapse, 8.2 vs. 11.9 mo, P=0.009). The overall survival (OS) was significantly correlated with karyotype classification only at diagnosis (unfavorable vs. favorable or intermediate vs. karyotypes at diagnosis, 8.5 vs. 21.8 mo, P=0.001; unfavorable vs. favorable or intermediate karyotypes at relapse, 8.5 vs. 21.2 mo, P=0.136). A change in karyotype between diagnosis and relapse, which is regarded as a factor of resistance against treatment, was not a significant prognostic factor for OS, EFS, and post-relapse survival (PRS). A Cox proportional hazards model showed that the combined use of fludarabine, cytosine arabinoside, and granulocyte colony-stimulating factor (FLAG) as a salvage regimen, was a significant prognostic factor for OS (hazard ratio=0.399, P=0.010) and the PRS (hazard ratio=0.447, P=0.031). CONCLUSION: The karyotype classification at diagnosis predicts survival including PRS in relapsed AML patients as well as in treatment-naïve patients. We suggest that presently, administration of salvage FLAG could be a better treatment option.

Clinical impact of induction treatment modalities and optimal timing of radiotherapy for the treatment of limited-stage NK/T cell lymphoma.

This study retrospectively investigated the optimal timing of radiotherapy (RT) in patients with limited-stage extranodal NK/T-cell lymphoma (ENTKL). Among 158 patients with newly diagnosed stage I/II ENKTL, 61 patients were treated with sequential chemotherapy followed by radiotherapy (SCRT), 55 with concurrent chemoradiotherapy followed by non-anthracycline-based chemotherapy (CCRT/CT), and 42 with chemotherapy (CT) only. The 5-year overall survival (OS) rate did not differ between SCRT (77.7±5.5%) and CCRT/CT (68.9±6.8%; p=0.234). In the SCRT group, 18 patients (29.5%) relapsed within the RT field and 6 (9.8%) at systemic sites, while in the CCRT/CT group, 9 patients (16.4%) relapsed at the primary site and 14 (25.5%) at systemic sites. The 5-year cumulative incidence of relapse (CIR) at primary sites was 26.3% and 19.2% after SCRT and CCRT/CT (p=0.308), while the 5-year CIR of systemic sites was 8.7% and 26.5% after SCRT and CCRT/CT, respectively (p=0.010). In the multivariate analysis, NK/T-cell Prognostic Index score and CR achievement were the most important prognostic factors for survival. Although up-front RT had limitations in systemic disease control and was associated with an increased risk of systemic relapse during RT compared to SCRT, timing of RT did not significantly affect survival outcomes.

Usefulness of spleen volume measured by computed tomography for predicting clinical outcome in primary myelofibrosis.

Although splenomegaly is major characteristic of primary myelofibrosis (PMF), splenomegaly has been devalued due to a less reliable method based on physical examination (PEx). We evaluated whether spleen volume (SV) on CT would accurately predict clinical outcomes in PMF. A total of 188 patients were enrolled. SV was quantitated by the automatic volume software. In ROC curve, the SV predicted prognosis more accurately than spleen length by PEx (p < 0.001). The ideal cut-off value was 378.1 cm(3) for SV, which was divided into high- and low-volume status. Patients with low SV status had superior leukemia-free survival and overall survival compared to high SV status (p < 0.001, p < 0.001) In the Cox analysis, old age ≥65 years (p = 0.004, p = 0.001), low Hemoglobin <10.0 g/dL (p = 0.023, p = 0.021), high WBC counts ≥25 × 10(9)/L (p = 0.003, p = 0.006), peripheral blasts ≥1 % (p = 0.029, p = 0.020), unfavorable cytogenetic abnormalities (p = 0.025, p = 0.028), and high SV status (p = 0.004, p = 0.003) were independently associated with survivals. SV measured by CT was important for predicting survival in patients with PMF.

High total metabolic tumor volume in PET/CT predicts worse prognosis in diffuse large B cell lymphoma patients with bone marrow involvement in rituximab era.

Bone marrow involvement (BMI) in diffuse large B cell lymphoma (DLBCL) was naively regarded as an adverse clinical factor. However, it has been unknown which factor would separate clinical outcomes in DLBCL patients with BMI. Recently, metabolic tumor volume (MTV) on positron emission tomography/computed tomography (PET/CT) was suggested to predict prognosis in several lymphoma types. Therefore, we investigated whether MTV would separate the outcomes in DLBCL patients with BMI. MTV on PET/CT was defined as an initial tumor burden as target lesion ≥ standard uptake value, 2.5 in 107 patients with BMI. Intramedullary (IM) MTV was defined as extent of BMI and total MTV was as whole tumor burden. 260.5 cm(3) and 601.2 cm(3) were ideal cut-off values for dividing high and low MTV status in the IM and total lymphoma lesions in Receiver Operating Curve analysis. High risk NCCN-IPI (p<0.001, p<0.001), bulky disease (p=0.011, p=0.005), concordant subtype (p=0.025, p=0.029), high IM MTV status (p<0.001, p<0.001), high total MTV status (p<0.001, p<0.001), and ≥ 2CAs in BM (p=0.037, p=0.033) were significantly associated with progression-free survival (PFS) and overall survival (OS) than other groups. In multivariate analysis, high risk NCCN-IPI (PFS, p=0.006; OS, p=0.013), concordant subtype (PFS, p=0.005; OS, p=0.007), and high total MTV status (PFS, p<0.001; OS, p<0.001) had independent clinical impacts. MTV had prognostic significances for survivals in DLBCL with BMI.