Outcomes in Refractory Diffuse Large B-Cell Lymphoma: Results from Two Prospective Korean Cohorts / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy worldwide. Although substantial improvement has been achieved by the frontline rituximab-based chemoimmunotherapy, up to 40%-50% of patients will eventually have relapsed or refractory disease, whose prognosis is extremely dismal. @*Materials and Methods@#We have carried out two prospective cohort studies that include over 1,500 DLBCL patients treated with rituximab plus CHOP (#NCT01202448 and #NCT02474550). In the current report, we describe the outcomes of refractory DLBCL patients. Patients were defined to have refractory DLBCL if they met one of the followings, not achieving at least partial response after 4 or more cycles of R-CHOP; not achieving at least partial response after 2 or more cycles of salvage therapy; progressive disease within 12 months after autologous stem cell transplantation. @*Results@#Among 1,581 patients, a total of 260 patients met the criteria for the refractory disease after a median time to progression of 9.1 months. The objective response rate of salvage treatment was 26.4%, and the complete response rate was 9.6%. The median overall survival (OS) was 7.5 months (95% confidence interval, 6.4 to 8.6), and the 2-year survival rate was 22.1%±2.8%. The median OS for each refractory category was not significantly different (p=0.529). @*Conclusion@#In line with the previous studies, the outcomes of refractory DLBCL patients were extremely poor, which necessitates novel approaches for this population.

Current Treatment Patterns and the Role of Upfront Autologous Stem Cell Transplantation in Patients with Peripheral T-Cell Lymphoma: A Korean Nationwide, Multicenter Prospective Registry Study (CISL 1404) / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#We conducted a nationwide, multicenter, prospective registry study for newly diagnosed patients with peripheral T-cell lymphoma (PTCL) to better define the clinical characteristics, treatment patterns, survival outcomes, and the role of upfront autologous stem cell transplantation (ASCT) in these patients. @*Materials and Methods@#Patients with PTCL receiving chemotherapy with curative intent were registered and prospectively monitored. All patients were pathologically diagnosed with PTCL. @*Results@#A total of 191 patients with PTCL were enrolled in this prospective registry study. PTCL, not otherwise specified (PTCL-NOS) was the most common pathologic subtype (n=80, 41.9%), followed by angioimmunoblastic T-cell lymphoma (AITL) (n=60, 31.4%). With a median follow-up duration of 3.9 years, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 39.5% and 60.4%, respectively. The role of upfront ASCT was evaluated in patients who were considered transplant-eligible (n=59). ASCT was performed as an upfront consolidative treatment in 32 (54.2%) of these patients. There were no significant differences in PFS and OS between the ASCT and non-ASCT groups for all patients (n=59) and for patients with PTCL-NOS (n=26). However, in patients with AITL, the ASCT group was associated with significantly better PFS than the non-ASCT group, although there was no significant difference in OS. @*Conclusion@#The current study demonstrated that the survival outcomes with the current treatment options remain poor for patients with PTCL-NOS. Upfront ASCT may provide a survival benefit for patients with AITL, but not PTCL-NOS.

Advantage of achieving deep response following frontline daratumumab-VTd compared to VRd in transplant-eligible multiple myeloma: multicenter study

Background@#The goal of induction therapy for multiple myeloma (MM) is to achieve adequate disease control. Current guidelines favor triplet (bortezomib-lenalidomide-dexamethasone;VRd) or quadruplet regimens (daratumumab, bortezomib-thalidomide-dexamethasone;D-VTd). In the absence of a direct comparison between two treatment regimens, we conducted this study to compare the outcomes and safety of VRd and D-VTd. @*Methods@#Newly diagnosed MM patients aged ＞18 years who underwent induction therapy followed by autologous stem cell transplantation (ASCT) between November 2020 and December 2021 were identified. Finally, patients with VRd (N=37) and those with D-VTd (N=43) were enrolled. @*Results@#After induction, 10.8% of the VRd group showed stringent complete remission (sCR), 21.6% showed complete response (CR), 35.1% showed very good partial response (VGPR), and 32.4% showed partial response (PR). Of the D-VTd group, 9.3% showed sCR, 34.9% CR, 48.8% VGPR, and 4.2% PR (VGPR or better: 67.6% in VRd vs. 93% in D-VTd, P =0.004). After ASCT, 68.6% of the VRd group showed CR or sCR, while 90.5% of the D-VTd group showed CR or sCR (P=0.016). VRd was associated with an increased incidence of skin rash (P=0.044). Other than rashes, there were no significant differences in terms of adverse events between the two groups. @*Conclusion@#Our study supports the use of a front-line quadruplet induction regimen containing a CD38 monoclonal antibody for transplant-eligible patients with newly diagnosed MM.

Reduced-intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for patients with myelofibrosis

Background@#Allogeneic hematopoietic stem cell transplantation (alloSCT) is the sole curative option for myelofibrosis (MF). However, it is unknown as to which of the two, myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), is a better preconditioning regimen. @*Methods@#Twenty-five patients with MF were treated with alloSCT, 12 of whom underwent RIC.Baseline characteristics, response to alloSCT, adverse events, including graft-versus-host disease (GVHD), and survival outcomes were reviewed. @*Results@#There was no difference in the neutrophil engraftment rate and time to engraftment between MAC vs. RIC. The time to platelet engraftment was significantly longer in the MAC group (median, 112.8 vs. 28.8 days for MAC vs. RIC, respectively, P =0.049). RIC was more advantageous in terms of achieving complete chimerism (38.5% vs. 83.3%, P =0.041). The incidence of acute GVHD was 84.6% (11 of 13) and 58.3% (7 of 12) in the MAC and RIC groups, respectively. The cumulative incidence of grade III‒IV acute GVHD was significantly higher in the MAC group than in the RIC group (P =0.03). No significant differences were observed in progression-free and overall survival. The 17-month probability of progression-free survival was 38.4% [95% confidence interval (CI), 19.3‒76.5] vs. 47.6% (95% CI, 25.7‒88.2) (P =0.21), and that of overall survival was 53.8% (95% CI, 32.5‒89.1) vs. 48.6% (95% CI, 26.8‒88.3) (P =0.85) for MAC vs. RIC, respectively. @*Conclusion@#RIC offers a significant advantage over MAC, even in younger patients with MF undergoing alloSCT, in terms of cell engraftment, rate of complete chimerism achievement, and incidence of acute GVHD.

IDH1/2 mutations in acute myeloid leukemia

The mutational and epigenetic landscape of acute myeloid leukemia (AML) has become increasingly well understood in recent years, informing on biological targets for precision medicine. Among the most notable findings was the recognition of mutational hot-spots in the isocitrate dehydrogenase (IDH) genes. In this review, we provide an overview on the IDH1/2 mutation landscape in Korean AML patients, and compare it with available public data. We also discuss the role of IDH1/2 mutations as biomarkers and drug targets.Taken together, occurrence of IDH1/2 mutations is becoming increasingly important in AML treatment, thus requiring thorough examination and follow-up throughout the clinical course of the disease.

Eltrombopag for Post-Transplant Poor Graft Function in East Asian Patients

Poor graft function (PGF) is a serious, potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Eltrombopag has shown multilineage responses in patients with refractory severe aplastic anemia, supporting the idea that it may improve cytopenia in patients with PGF. This retrospective, single center analysis included 8 Korean patients receiving eltrombopag for PGF. Median interval between transplant and eltrombopag treatment was 73 days, and the median duration treatment was 3.5 weeks.With median maximum daily dose of 50 mg, the time to best response was 93 days. Median hemoglobin increased from 8.2 g/dL to 10.9 g/dL, platelet from 18.5 × 109 /L to 54 × 109 /L, and absolute neutrophil count from 1.25 × 109 /L to 3.32 × 109 /L. In conclusion, eltrombopag is a good option for PGF in Korean patients, even at a lower dose compared to western patients.

The Presence of Clonal Hematopoiesis Is Negatively Associated with Diabetic Peripheral Neuropathy in Type 2 Diabetes

Background@#Clonal hematopoiesis of indeterminate potential (CHIP) has been reported to be associated with increased cardiovascular disease, aging and insulin resistance. Despite the debate of causal contribution of CHIP on metabolic diseases, we want to explore whether CHIP is related to diabetic peripheral neuropathy (DPN). @*Methods@#This study analyzed the prevalence of CHIP in patients with type 2 diabetes classified according to DPN status. Logistic regression analysis was used to evaluate the association between CHIP and DPN. @*Results@#CHIP was more prevalent in subjects without DPN than those with DPN (19.9% vs. 8.8%, respectively; P=0.013). Individuals having any CHIP, or DNA methyltransferase 3A (DNMT3A) CHIP were less likely to have any abnormality shown in DPN test; the adjusted odds ratio were 0.85 (95% confidence interval [CI], 0.73 to 1.00) and 0.70 (95% CI, 0.56 to 0.89), respectively. Interestingly, DNMT3A CHIP showed the negative association, but Tet methylcytosine dioxygenase 2 (TET2) CHIP showed the positive association with abnormal feet electrochemical skin conductance level. @*Conclusion@#On the contrary to expectations, CHIP was negatively associated with DPN. Functional linking between the mutation in hematopoietic cells and DPN, and the opposite role of DNMT3A and TET2 should be investigated.

Clinical and immunological signatures of severe COVID-19 in previously healthy patients with clonal hematopoiesis

Identifying additional risk factors for COVID-19 severity in numerous previously healthy patients without canonical clinical risk factors remains challenging. In this study, we investigate whether clonal hematopoiesis of indeterminate potential (CHIP), a common aging-related process that predisposes various inflammatory responses, may exert COVID-19 severity. We examine the clinical impact of CHIP in 143 laboratory-confirmed COVID-19 patients. Both stratified analyses and logistic regression including the interaction between canonical risk factors and CHIP show that CHIP is an independent risk factor for severe COVID-19, especially in previously healthy patients. Analyses of 60,310 single-cell immune transcriptome profiles identify distinct immunological signatures for CHIP (+) severe COVID-19 patients, particularly in classical monocytes, with a marked increase in pro-inflammatory cytokine responses and potent IFN-{gamma} mediated hyperinflammation signature. We further demonstrate that the enhanced expression of CHIP (+) specific IFN-{gamma} response genes is attributed to the CHIP mutation-dependent epigenetic reprogramming of poised or bivalent cis-regulatory elements. Our results highlight a unique immunopathogenic mechanism of CHIP in the progression of severe COVID-19, which could be extended to elucidate how CHIP contributes to a variety of human infectious diseases.

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.

Recent Clinical Update of Acute Myeloid Leukemia: Focus on Epigenetic Therapies

Acute myeloid leukemia (AML) is a complicated disease characterized by genetic heterogeneity and simultaneous alterations in multiple genes. For decades, its only curative method has been intensive induction chemotherapy with or without allogeneic hematopoietic stem cell transplantation, and this approach cannot be applied to elderly patients, who make up more than 50% of AML patients. Recent advances in genomics facilitated the elucidation of various mutations related to AML, and the most frequent mutations were discovered in epigenetic regulators. Alterations to epigenetic modifications that are essential for normal cell biology, including DNA methylation and histone acetylation, have been identified. As epigenetic dysregulation is an important carcinogenic mechanism and some epigenetic changes are reversible, these epigenetic alterations have become targets for novel drug development against AML. This review summarizes the recent advances in epigenetic therapies for AML and discusses future research directions.

Genomics of diffuse large B cell lymphoma

Next generation sequencing (NGS) technology has revealed the heterogeneity of diffuse large B-cell lymphoma (DLBCL) from a mutation perspective. Accordingly, the conventional cell of origin-based classification of DLBCL has changed to a mutation-based classification. Mutation analysis delineates that B-cell receptor pathway activation, EZH2 mutation, and NOTCH mutations are distinctive drivers of DLBCL. Moreover, the combination of RNA expression data and DNA mutation results suggests similarity between DLBCL subtypes and other non-Hodgkin lymphomas. NGS-based dissection of DLBCL would be the cornerstone for precision treatment in this heterogeneous disease in the near future.

Recent Clinical Update of Acute Myeloid Leukemia: Focus on Epigenetic Therapies

Acute myeloid leukemia (AML) is a complicated disease characterized by genetic heterogeneity and simultaneous alterations in multiple genes. For decades, its only curative method has been intensive induction chemotherapy with or without allogeneic hematopoietic stem cell transplantation, and this approach cannot be applied to elderly patients, who make up more than 50% of AML patients. Recent advances in genomics facilitated the elucidation of various mutations related to AML, and the most frequent mutations were discovered in epigenetic regulators. Alterations to epigenetic modifications that are essential for normal cell biology, including DNA methylation and histone acetylation, have been identified. As epigenetic dysregulation is an important carcinogenic mechanism and some epigenetic changes are reversible, these epigenetic alterations have become targets for novel drug development against AML. This review summarizes the recent advances in epigenetic therapies for AML and discusses future research directions.

Genomics of diffuse large B cell lymphoma

Next generation sequencing (NGS) technology has revealed the heterogeneity of diffuse large B-cell lymphoma (DLBCL) from a mutation perspective. Accordingly, the conventional cell of origin-based classification of DLBCL has changed to a mutation-based classification. Mutation analysis delineates that B-cell receptor pathway activation, EZH2 mutation, and NOTCH mutations are distinctive drivers of DLBCL. Moreover, the combination of RNA expression data and DNA mutation results suggests similarity between DLBCL subtypes and other non-Hodgkin lymphomas. NGS-based dissection of DLBCL would be the cornerstone for precision treatment in this heterogeneous disease in the near future.

Pediatric-inspired regimen with late intensification and increased dose of L-asparaginase for adult acute lymphoblastic leukemia: the KALLA 1406/1407 study

Background/Aims@#The objective of this study was to evaluate the efficacy and feasibility of the pediatric-inspired regimen of the adult acute lymphoblastic leukemia (ALL) Working Party, the Korean Society of Hematology. @*Methods@#Data of 99 patients with newly diagnosed ALL, who were treated with the KALLA 1406/1407 protocol, were retrospectively analyzed. All patients equally received age-adjusted daunorubicin, vincristine, and prednisolone. L-asparaginase was additionally administered to Philadelphia (Ph)-negative patients according to age, whereas Ph-positive patients received 600 mg/day of imatinib. @*Results@#A total of 99 patients were enrolled in this study, of whom 62 (62.6%) were diagnosed with Ph-negative ALL and 37 (37.3%) were diagnosed with Ph-positive ALL. The median age of patients in the Ph-negative ALL group was 46 years, and that of patients in the Ph-positive ALL group was 49 years. In patients with Ph-negative ALL, 57 (92%) patients achieved complete remission (CR) and CR with incomplete hematologic recovery (CRi). Disease-free survival (DFS) and overall survival (OS) rates at 2 years were estimated to be 42% and 63%, respectively. In patients with Ph-positive ALL, 32 (86%) patients achieved CR/CRi, and 2-year DFS and OS were 31.2% and 49.1%, respectively. Patients who were able to proceed to the allogeneic hematopoietic cell transplantation and younger patients showed significantly superior survival in both Ph-negative ALL and Ph-positive ALL. Neutropenic fever and bacterial infection were the most common and severe adverse events. @*Conclusions@#The KALLA 1406/1407 protocol showed tolerable toxicities in adult ALL patients. Especially, younger patients had more survival benefits with KALLA 1406/1407 protocol.

Leukemic stem cell phenotype is associated with mutational profile in acute myeloid leukemia

Background/Aims@#Understanding leukemic stem cell (LSC) is important for acute myeloid leukemia (AML) treatment. However, association of LSC with patient prognosis and genetic information in AML patients is unclear. @*Methods@#Here we investigated the associations between genetic information and the various LSC phenotypes, namely multipotent progenitor (MPP)-like, lymphoid primed multipotent progenitor (LMPP)-like and granulocyte-macrophage progenitors (GMP)-like LSC in 52 AML patients. @*Results@#In secondary AML patients, MPP-like LSC was significantly higher than de novo AML (p = 0.0037). The proportion of MPP-like LSC was especially high in post-myeloproliferative neoplasm AML (p = 0.0485). There was no correlation between age and LSC phenotype. Mutations of KRAS and NRAS were observed in MPP-like LSC dominant patients, TP53 and ASXL1 mutations in LMPP-like LSC dominant patients, and CEBPA, DNMT3A and IDH1 mutations in GMP-like LSC dominant patients. Furthermore, KRAS mutation was significantly associated with MPP-like LSC expression (p = 0.0540), and TP53 mutation with LMPP-like LSC expression (p = 0.0276). When the patients were separated according to the combined risk including next generation sequencing data, the poorer the prognosis, the higher the LMPP-like LSC expression (p = 0.0052). This suggests that the dominant phenotype of LSC is one of the important factors in predicting the prognosis and treatment of AML. @*Conclusions@#LSC phenotype in AML is closely associated with the recurrent mutations which has prognostic implication. Further research to confirm the meaning of LSC phenotype in the context of genetic aberration is warranted.

Clonal hematopoiesis is associated with risk of severe Covid-19

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival.1-4 These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH.2,5,6 A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19.7,8 Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of Clostridium Difficile (HR=2.0, 95% CI: 1.2-3.3, p=6x10-3) and Streptococcus/Enterococcus infections (HR=1.5, 95% CI=1.1-2.1, p=5x10-3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

High Cell-Free DNA Levels in Cerebrospinal Fluid Predict Leptomeningeal Seeding of Hematologic Malignancy

Background@#and Purpose: The main difficulty when diagnosing leptomeningeal metastases (LMSs) is the low sensitivity of cytology. Cancer cells release cell-free DNA (cfDNA) during proliferation and apoptosis, and so we analyzed the cfDNA level as a biomarker for LMSs in hematologic malignancy. @*Methods@#This study prospectively enrolled 20 patients with hematologic malignancy who underwent cerebrospinal fluid (CSF) analysis. LMS was diagnosed based on both CSF cytology and clinical findings. @*Results@#The CSF level of cfDNA was higher in patients with LMSs (108.17±84.84 ng/mL, mean±standard deviation) than in non-LMS patients (14.23±2.78 ng/mL). The sensitivity of cfDNA was higher than that of cytology (100% vs. 87%). @*Conclusions@#The cfDNA level in the CSF can be used as a supplemental marker for diagnosing LMS in hematologic malignancy patients.

Reduced-Intensity Conditioning with Busulfan and Fludarabine for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Lymphoblastic Leukemia

Purpose@#Allogeneic hematopoietic stem cell transplantation (HSCT) with optimal conditioning has helped better long-term survival in acute lymphoblastic leukemia (ALL). This study investigated the efficacy and safety of reduced-intensity conditioning (RIC) with busulfan and fludarabine in adult ALL patients unfit for myeloablation. @*Materials and Methods@#Records of 78 patients who underwent HSCT with RIC consisting of 3.2 mg/kg/day of busulfan for 2 or 3 days and 30 mg/m2/day of fludarabine for 5 or 6 days were analyzed. @*Results@#The median age at diagnosis was 49 years. Over a median follow-up of 22 months, 2-year estimates of relapse-free survival (RFS) and overall survival were 57.4% and 68.7%, respectively. Multivariate analysis showed a trend of improved RFS in patients with chronic graft-versus-host disease (GVHD) (hazard ratio, 0.53; 95% confidence interval, 0.26–1.08; p=0.080). The cumulative incidences of relapse and non-relapse mortality were 42.9% and 19.6%, respectively and one case of central nervous system relapse was noted. No hepatic veno-occlusive disease was reported. Grade II–IV acute GVHD and any grade chronic GVHD occurred in 21.1% and 41.7%, respectively. @*Conclusion@#RIC with busulfan and fludarabine is an effective and safe conditioning regimen for adult ALL patients unfit for myeloablation.

Strong association between herpes simplex virus-1 and chemotherapy-induced oral mucositisin patients with hematologic malignancies

Background/Aims@#A link between oral cavity infections and chemotherapy-induced oral mucositis (CIOM) in patients with hematological malignancies (HMs) undergoing intensive chemotherapy (IC) or hematopoietic stem cell transplantation (HSCT) has been suggested. However, conclusive data are lacking, and there are no current guidelines for the prophylactic use of antimicrobials to prevent CIOM in these populations. @*Methods@#The relationships between herpes simplex virus (HSV) reactivation and Candida colonization in the oral cavity and CIOM in patients with HMs undergoing IC or HSCT were evaluated. Patients aged ≥ 19 years with HMs undergoing IC or HSCT were enrolled. Each patient was evaluated for HSV and Candida in the oral cavity along with CIOM at baseline and during the 2nd, 3rd, and 4th weeks. @*Results@#Seventy presentations among 56 patients were analyzed. CIOM was observed in 23 presentations (32.9%), with a higher incidence associated with HSCT (17 of 35 presentations, 48.6%) than with IC (six of 35 presentations, 8.6%). The reactivation of HSV-1 was significantly associated with an increased incidence of CIOM after adjusting for age, sex, type of disease, and treatment stage. A higher HSV-1 viral load was associated with an increased incidence of CIOM. The presence of Candida was not associated with CIOM. @*Conclusions@#HSV-1 reactivation in the oral cavity was highly associated with CIOM in patients with HMs undergoing high-dose chemotherapy.

AL amyloidosis: advances in diagnosis and management

Light chain (AL) amyloidosis is a disease in which malignant plasma cell clones affect multiple organs including the heart and kidney. The mechanism for organ function deterioration in AL amyloidosis differs from multiple myeloma. Thus, not all agents used to treat multiple myeloma shows similar efficacy in AL amyloidosis. In AL amyloidosis, both hematologic and organ responses after treatment are important to improve the clinical outcome. Especially, improving heart function is one of the key aspects in the treatment of AL amyloidosis. With recent advances in the understanding of the pathophysiologic mechanism of AL amyloidosis, novel treatment methods are under active trial. In this article, I have reviewed the advances in pathophysiology, diagnosis, risk stratification, and treatment of AL amyloidosis.