ABSTRACT
Primary mediastinal B-cell lymphoma (PMBCL) is the only non-Hodgkin's lymphoma variant responding to immune checkpoint inhibitor (ICI) therapy, approximately in half of the cases; however, no molecular markers predicting a response to ICI therapy in PMBCL have been described so far. In this study, we assessed the incidence of the loss of heterozygosity (LOH), elevated microsatellite alteration at selected tetranucleotides (EMAST), and microsatellite instability (MSI) in the tumor genomes of 72 patients with PMBCL undergoing high-dose chemotherapy treatment at the National Research Center for Hematology (Moscow, Russia). Tumor DNA was isolated from biopsy samples taken at diagnosis. Control DNA was isolated from the blood of patients in complete remission or from buccal epithelium. STR-profiles for LOH and EMAST were assessed by PCR with COrDIS Plus multiplex kit (Gordiz Ltd., Moscow, Russia). LOH was detected in 37 of 72 patients (51.4%). EMAST was found in 40 patients (55.5%); 24 had a combination of EMAST with LOH. MSI-high was not found, while MSI-low was detected only in one patient. The association of certain genetic lesions with the clinical outcome in patients receiving treatment according to the standard clinical protocol R-Da-EPOCH-21 has been estimated (58 patients out of 72) and no associations with the worst overall or event-free survival were found.
Subject(s)
Colorectal Neoplasms , Lymphoma, B-Cell , Colorectal Neoplasms/pathology , Humans , Lymphoma, B-Cell/genetics , Microsatellite Instability , Microsatellite RepeatsABSTRACT
Despite the introduction of new technologies in molecular diagnostics, one should not underestimate the traditional routine methods for studying tumor DNA. Here we present the evidence that short tandem repeat (STR) profiling of tumor DNA relative to DNA from healthy cells might identify chromosomal aberrations affecting therapy outcome. Tumor STR profiles of 87 adult patients with de novo Ph-negative ALL (40 B-ALL, 43 T-ALL, 4 mixed phenotype acute leukemia (MPAL)) treated according to the "RALL-2016" regimen were analyzed. DNA of tumor cells was isolated from patient bone marrow samples taken at diagnosis. Control DNA samples were taken from the buccal swab or the blood of patients in complete remission. Overall survival (OS) analysis was used to assess the independent impact of the LOH as a risk factor. Of the 87 patients, 21 were found with LOH in various STR loci (24%). For B-ALL patients, LOH (except 12p LOH) was an independent risk factor (OS hazard ratio 3.89, log-rank p-value 0.0395). In contrast, for T-ALL patients, the OS hazard ratio was 0.59 (log-rank p-value 0.62). LOH in particular STR loci measured at the onset of the disease could be used as a prognostic factor for poor outcome in B-ALL, but not in T-ALL.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Chromosome Aberrations , DNA, Neoplasm , Humans , Loss of Heterozygosity/geneticsABSTRACT
INTRODUCTION: Immunoglobulin heavy chain variable region (IGHV) repertoire narrowing could be an evidence for the involvement of a limited set of antigens in the development of lymphomas. For chronic lymphocytic leukemia (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.
Subject(s)
Genes, Immunoglobulin Heavy Chain , Immunoglobulin Variable Region , Leukemia, Lymphocytic, Chronic, B-Cell , Amino Acid Sequence , B-Lymphocytes , Humans , Immunoglobulin Variable Region/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/geneticsABSTRACT
Standard therapy in hairy cell leukemia (HCL) is often impossible at the time of deep neutropenia/agranulocytosis with or without infectious complications; it is thus a complex therapeutic problem. Vemurafenib has been used to treat resistant HCL since 2012. Because vemurafenib does not have a myelotoxic effect, we thought that it could be used to treat HCL associated with deep neutropenia/agranulocytosis with or without the development of infectious complications as a preliminary stage before treatment with cladribine. We conducted a retrospective analysis of treatment with vemurafenib followed by a standard course of cladribine provided to 22 patients with deep neutropenia/agranulocytosis with or without infectious complications at diagnosis. Vemurafenib was provided to 22 patients with HCL. The response to therapy was evaluated by complete blood cell count (absolute neutrophil count [ANC], hemoglobin concentration, platelet count, absence of hairy cells), spleen size (assessed by ultrasound), and reduce infectious complications. After that, a standard course of cladribine was provided. Among the 22 patients, the male/female sex ratio was 2:1, and median (range) age was 52 (24-78) years. There were 7 patients with severe infectious manifestations admitted to the intensive care unit, including 1 patient during extracorporeal membrane oxygenation. The median (range) ANC at diagnosis was 0.3 (0.04-0.7) × 109/L. Vemurafenib was provided at a dosage of 240 mg 1 or 2 times a day. In 20 patients, vemurafenib was provided for 3 months or more. In 1 case, the effect was not obtained during 1 month of treatment, and the patient died from severe infectious complications during prolonged agranulocytosis. In 21 patients treated with vemurafenib, an increase of ANC was observed and the infectious complications resolved, thus allowing the application of cladribine therapy. After a standard course (0.1 mg/kg per day for 7 days) of cladribine chemotherapy, 18 patients (90%) experienced complete clinical remission and 2 patients (10%) experienced partial remission with residual splenomegaly. In 1 patient, vemurafenib therapy was still ongoing 2 months after initiating therapy. In cases of proven BRAFV600E mutation, vemurafenib can be successfully used as an effective preliminary therapy in patients with deep neutropenia/agranulocytosis with or without infectious complications before standard therapy with purine analogs.
Subject(s)
Infections/drug therapy , Leukemia, Hairy Cell/drug therapy , Neutropenia/drug therapy , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Adult , Aged , Female , Humans , Infections/genetics , Infections/immunology , Infections/mortality , Leukemia, Hairy Cell/complications , Leukemia, Hairy Cell/genetics , Leukemia, Hairy Cell/mortality , Male , Middle Aged , Neutropenia/genetics , Neutropenia/immunology , Neutropenia/mortality , Progression-Free Survival , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Retrospective Studies , Vemurafenib/pharmacology , Vemurafenib/therapeutic use , Young AdultSubject(s)
Antigens, Neoplasm/immunology , B-Lymphocytes/immunology , Immune Checkpoint Proteins/immunology , Immunological Synapses/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Lymphoma, B-Cell, Marginal Zone/immunology , Lymphoma, Mantle-Cell/immunology , Splenic Neoplasms/immunology , Antigens, CD/blood , Antigens, CD/immunology , Antigens, Neoplasm/blood , B7-H1 Antigen/blood , B7-H1 Antigen/immunology , Cluster Analysis , Female , Humans , Male , Middle AgedABSTRACT
INTRODUCTION: Russia took part in the multicenter population-based study (Europe) and included 6.8% adult patients with newly diagnosed chronic myeloid leukemia (CML). The objective of this study was to analyze the mortality in the Russian cohort of patients with newly diagnosed CML in the EUTOS PBS observational study. PATIENTS AND METHODS: The analyzed cohort consisted of 197 patients (>18 years) with Ph+/BCR-ABL1+ CML diagnosed in the period from October 1, 2009 through December 31, 2012 from 6 regions of Russia. The distribution of the phases of CML were: chronic phase (CP), 93.4% and accelerated phase (AP) + blast crisis (BC), 6% + 0.6%. The median age was 50 years (range, 18-82 years); the male/female ratio was equal. RESULTS: The overall survival (OS) at 5, 6, and 7 years was 80% (95% confidence interval [CI], 72%-86%), 78% (95% CI, 65%-80%), and 73% (95% CI, 65%-80%), respectively (P < .001). The 5-year OS in patients with AP and BC was 39%. In Russia, the study was prolonged, with a median follow-up of 77 months (range, 0.7-108 months): 141 (71.5%) patients were alive, 47 (24%) patients died, and the status of 9 (4.5%) patients is was unknown. Forty-seven (23.8%) patients died during the follow-up period. The largest number of deaths was observed in the first year after the CML diagnosis: 17 (36%) of 47 cases, 3 of 17 died refusing the CML treatment. At the seventh year of CML therapy, 1 patient died after allogenic hematopoietic stem cell transplantation. The causes of death were: (1) progression of CML to AP/BC in 20 (43%) patients; (2) death in remission in 5 (11%) patients with complete cytogenetic response (CCyR) and/or major molecular response; and (3) death without progression to AP/BC but with signs of leukemia in 22 (46%) patients. The 5-year cumulative incidence of death from all reasons was 20%; the cumulative incidence of CML-related and non-CML-related death at the fifth year was 18% and 11%, respectively. CONCLUSION: In general, the results of treatment in the Russian population sample of non-selected patients with CML were comparable with the data of the total European cohort. The CML-related deaths prevailed in the first year of CML therapy. The appropriate monitoring and therapy interventions during the first year of CML treatment are apparently important for the long-term treatment results.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Disease-Free Survival , Follow-Up Studies , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Philadelphia Chromosome , Prospective Studies , Russia/epidemiology , Survival RateABSTRACT
We aimed to characterize withdrawal syndrome (WS) and evaluate factors associated with its development in the prospective clinical study RU-SKI in patients with chronic myeloid leukemia with deep molecular response who discontinued tyrosine kinase inhibitor (TKI) therapy. In total, 98 adult patients with chronic myeloid leukemia chronic phase, TKI therapy ≥ 3 years, and deep molecular response (BCR-ABL ≤ 0.01%) ≥ 2 years were enrolled and observed without treatment. WS was defined as newly observed or worsening musculoskeletal pain after TKI cessation. WS symptoms were found in 41 (42%) of 98 patients with a median time of observation of 25 months (range, 12-42 months). WS grades 1 to 2 and grade 3 were observed in 39 (95%) and in 2 (5%) patients, respectively. The median duration of WS was 5 months (range, 1-25 months). WS was resolved in 37 (90%) patients. Anti-inflammatory therapy was used in 21 (51%) patients. Older age (P = .039) and longer TKI therapy (P = .001) were associated with WS. The 2-month landmark analysis found no association of WS development and the rate of molecular relapses. In total, 42% of the patients experienced WS after TKI therapy discontinuation in the RU-SKI study. Physicians should be warned about the possibility of WS development, and patients of older age and with longer TKI treatment need special attention.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors/administration & dosage , Substance Withdrawal Syndrome , Adult , Aged , Aged, 80 and over , Female , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/physiopathology , Male , Middle Aged , Prospective Studies , Recurrence , Russia , Substance Withdrawal Syndrome/metabolism , Substance Withdrawal Syndrome/pathology , Substance Withdrawal Syndrome/physiopathologyABSTRACT
Polymerase chain reaction (PCR) analysis of rearranged T-cell receptor (TCR) genes is a valuable diagnostic tool for differential diagnosis of T-cell large granular lymphocytic (T-LGL) leukemia and reactive lymphocytosis. Age-related narrowing of T-cells repertoire and expansion of immune or autoimmune clones may lead to false-positive results. The objective of this study was to evaluate the specificity and positive predictive value of PCR-based clonality assessment for a differential diagnostics of T-LGL leukemia. Rearrangements of TCRG and TCRB genes using the BIOMED-2 protocol were assessed in healthy individuals including the elderly (n = 62) and patients with rheumatic diseases (n = 14), transitory reactive CD8+ lymphocytosis (n = 17), and T-LGL leukemia (n = 42). Monoclonal TCRG/TCRB rearrangements in blood were identified in 11.3%/4.8% (7/3 of 62) of healthy individuals; 21.4%/14.3% (3/2 of 14) of patients with rheumatic diseases, and 17.6%/11.8% (3/2 of 17) of patients with reactive lymphocytosis. Immunomagnetic selection of lymphocytes in healthy individuals (31 of 33) revealed that clonal T-cells belong to CD8+ and CD57+ population. No clonal Vß-Jß TCRB rearrangements were found in the control group, only Dß-Jß TCRB and TCRG. Given the high detectability (96.7%) of Vß-Jß TCRB monoclonal rearrangements in patients with αß-T-LGL leukemia, this marker had the greatest specificity and positive predictive value (100%; 99.2%). The presence of clonal CD8+CD57+ cells in blood is common for healthy individuals and patients with reactive conditions and may not associate with any malignancy. Different specificity of TCRG/ Dß-Jß TRB/ Vß-Jß TCRB PCR reactions should be taken into account for T-cell clonality data interpretation.
Subject(s)
CD8-Positive T-Lymphocytes/metabolism , Cell Proliferation , Gene Rearrangement, beta-Chain T-Cell Antigen Receptor , Hematologic Neoplasms , Polymerase Chain Reaction , Adolescent , Adult , Aged , CD8-Positive T-Lymphocytes/pathology , Diagnosis, Differential , Female , Follow-Up Studies , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/genetics , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/pathology , Humans , Male , Middle Aged , Prospective Studies , Retrospective StudiesABSTRACT
Castleman disease (CD) is rare lymphoproliferative disorder with local lesionsor with multiple lessions (multicentric CD [MCD]-usually with plasma cell or mix cell morphology). Patients with human herpesvirus (HHV) type 8-positive MCD were included in a separate group owing to its extremely aggressive course and the high risk of transformation into HHV8(+) plasmablastic lymphoma. At our hematologic center, from 1996 to the present, the clinical and morphologic features of 87 patients with CD were analyzed. Immunohistochemical examination revealed DNA HHV8(+) lymph node tissue in patients with plasma cell and mixed cell morphology. In 45 patients, plasma cell or mixed cell variant CD was diagnosed. In 21 patients (8%), the manifestation of CD was local and in 29 (9%), it was multicentric. HHV8 was identified in only 6 cases (23.1%) of MCD (5 men and 1 woman, with a median age of 48.2 years; range, 36-77 years). The median follow-up point was 39.2 months. In 4 patients, the mixed cell variant was diagnosed and in 2, the plasma cell variant was diagnosed. In all the patients, constitutional symptoms, generalized lymphadenopathy, and hepatosplenomegaly were detected. Various laboratory changes were observed, but the most significant were anemia, thrombocytopenia, hypergammaglobulinemia, M-component, increased erythrocyte sedimentation rate, and circulating immune complexes. In 2 cases of HHV8(+) CD, MCD was combined with autoimmune hemolytic anemia and in 2 cases with non-Hodgkin lymphoma. At the last follow-up point, 2 patients were still alive after CHOP (cyclophosphamide, prednisone, Adriamycin, vincristine) and R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate [Oncovin], prednisone) therapy with rituximab maintenance. HHV8(+) MCD results in aggressive multiorgan lesions and pronounced changes in laboratory test results. It is characterized by an unfavorable prognosis with a high risk of transformation to plasmablastic lymphoma and a lethal outcome. Timely chemotherapy for patients with HHV8(+) MCD can result in remission and prolong life.
Subject(s)
Castleman Disease/diagnosis , Castleman Disease/etiology , Herpesviridae Infections/complications , Herpesvirus 8, Human , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers , Castleman Disease/therapy , Child , Child, Preschool , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Female , Follow-Up Studies , Hepatomegaly , Herpesviridae Infections/virology , Humans , Immunohistochemistry , Immunosuppressive Agents/therapeutic use , Liver Function Tests , Lymph Nodes/pathology , Male , Middle Aged , Prednisone/therapeutic use , Splenomegaly , Treatment Outcome , Vincristine/therapeutic use , Young AdultABSTRACT
The World Health Organization 2008 classification highlighted a new nosology-splenic diffuse red pulp lymphoma (SDRPL) with clinical and laboratory features similar to both splenic marginal zone lymphoma and hairy cell leukemia (HCL) and variant form of HCL. Experience of hematologists on the diagnosis and differential diagnosis of SDRPL is extremely limited. The aim of our report was to characterize the clinical and immunomorphologic features of SDRPL on our own observations. During 2013-2014, in National Research Center for Hematology, 87 spleen specimens removed from various B-cell lymphomas were analyzed. In four (4.6%) cases, the diagnosis SDRPL was made based on morphologic, immunohistochemical, immunophenotypic, molecular examination of spleen biopsies, blood and bone marrow samples. In all cases of SDRPL were observed significant splenomegaly, lymphocytosis from 56% to 94% (in two cases with leukocytosis 55.000 and 75.000 109/l). The circulating "villous" lymphocytes phenotype was CD20+ (bright), CD11c+/±, CD103 (weakly)+/±, LAIR-1+, CD25-, CD5-, CD10-, and CD23-. Mutation BRAFV600E was not detected. Bone marrow with minor lymphoid CD20+, CD25-, Annexin1-, Cyclin D1- cell infiltration. The average weight of the spleen was 3900 g (1450-9500 g), and morphologically, there was revealed lymphoid infiltration of red pulp with phenotype CD20+, DBA.44+, CD25-, Annexin1-, Cyclin D1-, CD103-, CD123-, CD27-, focal SD11c± and TRAP±. Now patients are observed in remission: two patients after splenectomy, two after splenectomy and cladribine+rituximab chemotherapy. SRDPL-a rare lymphoma that is suspected in the cases with significant splenomegaly and lymphocytosis with villous lymphocytes forms that have only a part of the classic markers HCL, with minor bone marrow infiltration. The standard diagnosis and treatment is splenectomy. Differential diagnosis of SMZL and HCL has clear criteria, but criteria of differentiation with variant HCL are still unknown.