Clinical Lymphoma Myeloma and Leukemia

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ISSN / EISSN : 2152-2650 / 2152-2669
Published by: Elsevier BV (10.1016)
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Anagha Inguva,
Clinical Lymphoma Myeloma and Leukemia; doi:10.1016/j.clml.2021.07.012

Abstract:
SUMMARY The use of venetoclax in combination with hypomethylating agents (HMA) has changed the paradigm for the treatment of acute myeloid leukemia (AML) in elderly patients and those unfit for intensive chemotherapy. A phase 3 study has shown superior response rates and improved overall survival for patients treated with venetoclax + azacitidine compared with the previous standard of care, azacitidine alone. This success has led to multiple exciting follow-up studies, including investigations related to the discovery of predictors of response, relapse and the mechanism of action of this therapy. While venetoclax + HMA has shown significant benefit in elderly patients unfit for chemotherapy, further questions remain as to how this therapy can be expanded into other populations including relapsed or refractory patients and younger newly diagnosed patients with adverse risk features. In this article, we discuss the clinical outcomes of AML with venetoclax + HMA, established and potential predictors of response to this regimen, its mechanisms of action, and speculate on the future of venetoclax + HMA therapy in AML.
Clinical Lymphoma Myeloma and Leukemia; doi:10.1016/j.clml.2021.07.008

Abstract:
Background Hypomethylating agents (HMAs) is one of recommended treatment for elderly patients with acute myeloid leukemia (AML); however, their high cost precludes their general use, especially in developing countries. Therefore, the fixed-dose HMAs approach was adopted to reduce the expenses. This study focuses on the clinical outcome of various treatment protocols, including intensive chemotherapy, fixed-dose HMAs, and palliative treatment in Thai elderly patients with AML. Fixed-dose HMAs include 5-azacitidine given at 100 mg per day for seven days and decitabine given at 30 mg per day for five days. Patients and Methods: We conducted a 10-year cohort study focused on elderly AML patients aged over 60 years. The exclusion criteria were acute promyelocytic leukemia. Results A total of 243 AML patients were enrolled. Comparing three groups of treatment regimens (intensive chemotherapy, fixed-dose HMAs, and palliative treatment), the proportions of patients in each category accounted for 23.5%, 21.4%, and 55.1%, respectively. The median overall survival (OS) in each therapeutic option was 7.7, 11, and 2.5 months, respectively. From multivariate analysis, palliative treatment was significantly inferior OS comparing to the fixed-dose HMAs and intensive treatment (HR: 0.42; 95%CI: 0.29-0.60; P-value < 0.001 and HR: 0.41; 95%CI: 0.28-0.61; P-value < 0.001, respectively). Nevertheless, the OS outcome in patients with fixed-dose HMAs was comparable to those who received intensive treatment. Conclusion Our study demonstrates that the fixed-dose regimen of HMAs is the reasonable treatment for these patients, and this approach is not inferior to intensive therapy. Thai Clinical Trials Registry identifier: TCTR20210514007. Micro-Abstract Hypomethylating agents (HMAs) is an effective treatment for elderly AML patients. To reduce expenses, the fixed-dose HMAs are commonly used in our institute, instead of a weight-adjusted dose. Patients receiving fixed-dose HMAs had significantly superior OS comparing to those receiving palliative treatment. Moreover, the survival outcome of the fixed-dose HMAs arm was comparable to intensive chemotherapy arm.
, C Belli, L Bassolli, L Ferri, Ma Perusini, A Enrico, Tdm Pereira, Wfs Junior, V Buccheri, Rf Pinheiro, et al.
Clinical Lymphoma Myeloma and Leukemia; doi:10.1016/j.clml.2021.07.026

Abstract:
Micro This study analyzed the overall survival (OS) of patients with Myelodysplastic Syndrome (MDS) with isolated deletion 5q in South America. Age >75 years, ECOG ≥2 and BM blasts >2% at diagnosis are independently associated with worse OS. Lenalidomide treatment is the only factor that improves the OS. Background: Myelodysplastic Syndrome (MDS) with isolated deletion 5q is associated with a low risk to leukemic evolution and long overall survival (OS); it comprises 3-4.5% of MDS cases in Latin America classified according to the WHO 2008. This study aims to describe clinical, laboratory and the outcome of patients according to the newest WHO 2016 proposal. Methods: We retrospectively reviewed patients from four Brazilian (BR) and four Argentinean (AR) centers diagnosed between 1999 and 2019. Results: The 58 patients (16-AR and 42-BR) presented a median age of 67 (IQR 61-75) years old, female predominance (70.7%) and transfusion dependency (62.5%) at diagnosis. Median hemoglobin level was 8.1g/dL, 27.5% and 44.4% presented thrombocytosis and neutropenia, respectively. Bone marrow (BM) was predominantly hypercellular (43.1%) with 66% showing dysplasia >1 lineage and 37.9% with >2% of blasts. Deletion 5q was mostly isolated (79.3%) and a variety of abnormalities were observed in remaining cases. Most patients were treated with erythropoietin-stimulating agents (ESA), 18 with lenalidomide and 15 with thalidomide. Median follow-up was 7.6 years, with a median OS of 3.5 years and an 8-years leukemic evolution rate of 18.4%. Multivariate analysis showed that age >75 years (HR 2.19), ECOG ≥2 (HR 5.76), BM blasts >2% (HR 2.92) and lenalidomide treatment (HR 0.25) independently influenced the OS. Conclusion: Older age, worse performance status and higher percentage of blasts, that can be easily assessed, were associated to a worse prognosis. Also, our results corroborate the protective influence of lenalidomide in terms of OS in this South American series.
David Bomze, Eli Sprecher, Ilan Goldberg, Liat Samuelov,
Clinical Lymphoma Myeloma and Leukemia; doi:10.1016/j.clml.2021.07.021

Abstract:
Background. Although primary cutaneous B-cell lymphomas (PCBCL) comprise 25% of all cutaneous lymphomas, their incidence in the pediatric population is unknown, and the information on pediatric PCBCL has mostly been gathered from individual case reports or series from single centers. Patients and Methods. This was a population-based, retrospective cohort study of patients in 18 cancer registries in the United States diagnosed between 2000 to 2016 through the Surveillance, Epidemiology, and End Results (SEER) program. Age-adjusted incidence rates were calculated for PCBCL in pediatric (<20 years) and adult (≥20 years) populations. Demographic, clinical, and pathological characteristics of PCBCL were compared between the two groups. Results. A total of 48 pediatric and 5128 adult PCBCL cases were included. Median age at diagnosis was 16.5 years and 65 years in the two groups, respectively. The major histologic subtypes of pediatric cases were marginal zone lymphoma (77.1%), followed by diffuse large B-cell lymphoma (12.5%) and follicle center lymphoma (10.4%), which were equally distributed in adults. The age-adjusted pediatric PCBCL incidence rate (per 1,000,000 person‐years) was 0.12 (95% CI 0.09-0.16). The incidence in the adult population was approximately 40-fold higher than the one observed in the pediatric group (IRR 41.4, 95% CI 31.2-56.2). All 48 pediatric cases were alive during a median follow-up time of 48 months. Conclusions. Pediatric PCBCL is a very rare disease affecting mostly adolescents of both sexes. The major histologic subtype is marginal zone lymphoma, and the prognosis is favorable.
Justin Shaya, Kristen Pettit, Malathi Kandarpa, Dale Bixby, Jessica Mercer,
Clinical Lymphoma Myeloma and Leukemia; doi:10.1016/j.clml.2021.07.001

Abstract:
Background The introduction of tyrosine kinase inhibitor (TKI) therapy has dramatically improved outcomes for patients with chronic myeloid leukemia (CML); however, the prognosis for those who do not meet treatment milestones remains guarded. Here, we report our experience of patients with CML treated at a single center who did not achieve a complete cytogenetic response (CCyR) at 24 months. Methods We retrospectively evaluated 305 patients who were diagnosed with CML at the University of Michigan between 2001 and 2014 and were treated with TKIs. We assessed rates of CCyR at 24 months correlated to clinical outcomes. Results The majority of patients (79%) achieved CCyR at 24 months and were classified as responders. At a median follow-up of 8.1 years from TKI initiation, overall survival among responders was significantly greater than non-responders (93% vs. 85%, p<0.001). Progression to blast phase was more common in non-responders (1.9% vs. 10.4%, p=0.004). However, 34% of non-responders (at 24 months) went on to achieve CCyR with continued TKI therapy. Conclusion Here, we re-demonstrate the importance of early CCyR in predicting survival and prevention of progression to blast phase. In addition, late CCyR appears to have prognostic implications, and continued TKI therapy with the goal of achieving a later CCyR may be a reasonable strategy in patients with limited alternate treatment options.
, Pavel Khaustov, Elena Ribakovsy, Ohad Benjamini, Abraham Avigdor
Clinical Lymphoma Myeloma and Leukemia; doi:10.1016/j.clml.2021.07.006

Abstract:
Background : Brentuximab-vedotin (BV) monotherapy has shown high efficacy in heavily pre-treated patients with relapsed or refractory Hodgkin lymphoma (HL) after high-dose chemotherapy or autologous stem cell transplantation (ASCT). We retrospectively analyzed the outcomes of treatment with BV of HL patients and examined the predictive ability of PET-CT for response in this setting. Patients & methods : Records of 49 HL patients (median age, 39 years, 55% male) treated with BV for relapse (71.4%) or consolidation (28.6%) post-ASCT were analyzed. Patients who did not reach complete response (CR) on PET/CT after 4 cycles (non-responders) discontinued BV and received the next treatment line. Overall survival (OS) and progression-free survival (PFS) were compared between responders and non-responders. Results : After a median follow-up of 19.1 months, all consolidation patients were alive and none progressed. Median OS in 23 relapsed patients that did not achieve CR after 4 cycles and continued to the next treatment was 55.0 months, while all those in CR (n=24) were alive (p=0.0120). No statistically significant differences in OS were observed between responders and non-responders with relapsed HL (p=0.1072). Median PFS evaluated after four BV cycles was significantly longer in responders compared to non-responders (47.9 vs. 1.5 months, p<0.0001). Neuropathy and neutropenia were the main toxicities observed. Conclusions : HL patients treated with BV for relapse or consolidation who achieved CR by PET-CT after 4 cycles showed improved PFS and OS compared to non-responders. Non-responders treated for relapsed HL who proceeded to the next treatment line demonstrated comparable OS to responders.
Wael Harb, Nehal J. Lakhani, Richard Messmann, , Ayad M. Al-Katib
Clinical Lymphoma Myeloma and Leukemia; doi:10.1016/j.clml.2021.07.016

Abstract:
Background PNT2258 consists of a native, chemically unmodified, 24-base DNA oligonucleotide designed to target the regulatory region upstream of the BCL2 gene, delivered in a protective liposome. Derangement of BCL2-regulated control mechanisms is a defining characteristic of certain malignancies, and it was hypothesized that the oligonucleotide would promote anticancer activity via suppression of BCL2 transcription. Methods PNT2258 was evaluated in this, multicenter, non-randomized, open-label Phase 2 study in 13 subjects with relapsed/refractory B-cell malignancies to investigate potential antitumor activity and safety. Subjects with follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, or chronic lymphocytic leukemia received intravenous PNT2258 120 mg/m2 on Days 1–5 of a 21-day cycle for up to 8 cycles, followed by 100 mg/m2 on Days 1–2 of a 28-day cycle until study withdrawal. Results All 13 subjects were treated with PNT2258 monotherapy and evaluable for response and safety and tolerability. The overall response rate was 53.8% [7/13; 95% confidence interval (CI): 25.1%–80.8%]. Median duration of response was 23.4 months (range: 3, 31.5). The disease control rate of subjects with stable disease or better was 84.6% [95% CI: 54.6%–98.1%]. The most frequently (≥ 50%) observed adverse events (AEs) were nausea, chills, diarrhea, fatigue, headache, vomiting, and back pain. Hypertension (30.8%) and diarrhea (23.1%) were the most frequent grade ≥ 3 AEs. No deaths were observed. Conclusions Clinically meaningful and durable activity with an acceptable safety profile was observed in subjects with relapsed/refractory B-cell malignancies who received single-agent PNT2258. Trial registration NCT01733238, first posted 26-Nov-2012. https://clinicaltrials.gov/ct2/show/NCT01733238
, Ozgur Mehtap, Gözde Daglıoz Gorur, Elif Birtas Atesoglu, Ayfer Geduk, Serkan Unal, Pınar Tarkun, Abdullah Hacıhanefioglu
Clinical Lymphoma Myeloma and Leukemia; doi:10.1016/j.clml.2021.06.016

Abstract:
Structured Abstract Abstract Diffuse large B cell lymphoma is an aggressive lymphoma which fails to cure in first line almost in one third of patients. Earlier risk assessment and tailoring therapy with interim PET will select a group of patients having high risk to relapse. Although interim PET guided therapy has been established in Hodgkin Lymphoma; the role of interim PET in non-Hodgkin lymphomas is debated.In this study ve searched the association of interim PET on survival in 103 DLBCL patients .Interim PET assessed by 5 point Deauville Score predicts PFS and OS with a PPV of 65.4% and a NPV of 77.9 %. BACKGROUND Diffuse large B cell lymphoma is the most frequent aggressive non-Hodgkin lymphoma.Predicting response and estimating prognosis earlier makes management of this heterogenous lymphoma more satisfying.Interim PET response is established in Hodgkin Lymphoma to tailor the therapy but results for non-Hodgkin Lymphoma is unconvincing.In the current study evaluation of interim PET and survival outcomes of 103 DLBCL patients is performed. PATIENTS AND METHODS 103 Patients with DLBCL followed up in a single center between 2009-2019 were enrolled the study. All patients received R-CHOP chemoimmunotherapy at first line. Interim PET was performed after at least one or more cycles. All PET scans were performed with 18F-FDG isotope as PET/CT. PET scoring results were evaluated according to the 5-Point Deauville Scoring system defined in the National Comprehensive Cancer Network clinical guidelines for iPET and eotPET . 5-P DS of scores of 1–3 were defined as negative scans, and scores of 4–5 were considered to be positive scans. RESULTS 46 (44.7%) Female and 57 (55.3%) male aged between 25 and 83 (median 57) years newly diagnosed DLBCL patients were enrolled in the study. Median PFS was 21 (IQR 8,5-53,7) months and median OS was 33,5 (IQR 12,5-62,9) months for the total cohort. Positive predictive value of interim PET according to Deauville scoring system was 65.4 % and negative predictive value was 77.9 %. CONCLUSION Our study showed that according to Deauville 5 point scale (D 5PS) scoring system, interim PET- positive patients have shorter both PFS and OS than iPET -negative patients.
Clinical Lymphoma Myeloma and Leukemia, Volume 21; doi:10.1016/s2152-2650(21)00233-0

B.V. Biderman, E.B. Likold, S.Yu. Smirnova, E.A. Nikitin, D.A. Koroleva, E.E. Zvonkov, L.S. Al-Radi, , A.B. Sudarikov
Clinical Lymphoma Myeloma and Leukemia; doi:10.1016/j.clml.2021.07.005

Abstract:
Introduction IGHV repertoire narrowing could be an evidence for the involvement of a limited set of antigens in the development of lymphomas. For CLL the existence of more than 200 subgroups of tumor IGHV antigen-binding sites, so called "stereotypical" antigen receptors (SAR) has been shown. For others lymphomas the possibility of SARs is also suggested. The aim of this study is to compare the tumor IGHVs and possible SARs in various B-cell malignancies in Russia and other countries. Materials and methods The study included samples of 1800 CLL patients, 52 patients with mantle cell lymphoma, 48 patients with hairy cell lymphoma and 37 patients with splenic marginal cell lymphoma. The nucleotide sequences of the IGHV genes were determined according to ERIC protocol. Results In CLL most common IGHV genes were IGHV1-69, IGHV1-2, IGHV3-30 and IGHV4-34. The most common SARs were CLL#1, CLL#6, CLL#2, CLL#3. In MCL the most common genes were IGHV4-34, IGHV3-21, IGHV3-23. In 5 MCL patients CDR3 sequences were identified matching definitions of a stereotyped. In the half of SMZL patients was identified gene IGHV1-2. Other IGHV genes were much less common. Two pairs of SMZL patients have motives similar to each other. In HCL IGHV repertoire was the most variable, no trends for antigen receptor stereotypy were observed. It was found that SARs are highly disease-specific both at the level of nucleotide and amino acid sequences. Conclusion Our results suggest that antigens crucial for the pathogenesis of B-cell malignancies could be disease-specific. Further studies on extended samples of non-CLL patients concerning the role of SARs in pathogenesis of these diseases may also contribute to the development of new diagnostic and prognostic markers. MICROABSTRACT The narrowing of the immunoglobulin heavy chain variable region (IGHV) gene repertoire is a feature of chronic lymphocytic leukemia (CLL) and several other B-cell malignancies. In this study we examined the IGHV gene sequences of 1937 patients with the most common B-cell lymphomas. We present a detailed comparison of B-cell receptor gene repertoires between CLL and other malignancies in patients from Russia and other populations.
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