ABSTRACT
Introduction. Primary mediastinal lymphoma (PML) is an aggressive lymphoid tumor treatment success of which is determined by induction therapy. To date, none of the standard chemotherapy regimens (CT) have demonstrated an advantage in efficacy. Intensive therapy programs are associated with high toxicity. Aim - to evaluate the efficacy and toxicity of two pilot prospective treatment protocols PML-16 and PML-19 as well as the possibility of using the analysis of freely circulating tumor DNA (ctDNA) to assess MRD in patients with PML. Materials and methods. From January 2016 to January 2022, 34 previously untreated PML patients were included in the study;average age - 32;stage > I - in 60 %;extramediastinal lesions - in 14.7 %;bulky disease - in 73.5 % of patients. Positron emission tomography combined with computed tomography (PET-CT) was performed;ctDNA was determined to assess the completeness of remission. Results. Eighteen patients received treatment according to the PML-16 protocol (6 courses of chemotherapy;2 blocks of RmNHL-BFM-90 + 4 courses of R-EPOCH). After the end of therapy, all 18 patients achieved PET-negative remission. The next 16 patients received treatment according to the PML-19 protocol (4 courses of chemotherapy;2 blocks of R-mNHL-BFM-90 + 2 courses of R-EPOCH) in combination with lenalidomide. After the end of therapy, 9 (56 %) patients achieved PET-negative remission;7 (44 %) retained pathological activity (D4-5 points). After 3 and 6 months 15 (94 %) patients achieved normalization of metabolic activity. Considering the high frequency of false-positive results in patients with PML, a ctDNA study was performed to determine the depth of remission in 15 patients. After the end of therapy, all 15 patients had complete elimination of ctDNA. Of these, 5 (33 %) remained PET-positive at the end of treatment. During further observation, after 3-6 months, in 4 patients the level of metabolic activity decreased to physiological without the use of consolidating therapy. After the end of therapy, one patient suffered the new coronavirus infection, COVID-19. A month later, residual formation of SUVmax 14.2 remained in the mediastinum. The patient is currently under observation. With a median follow-up of 36 months (9 to 76 months) all 34 patients are in remission. Conclusion. The effectiveness of PML-16 made it possible to abandon the consolidation therapy and refuted the idea of the need for 6 courses of CT. The combination of programs based on the application of the principle of high-dose short-pulse induction of remission (R-mNHL-BFM-90) in combination with the prolonged administration of medium doses (R-EPOCH) was crucial in achieving a successful result. The inclusion of lenalidomide in the "PML-19" program made it possible to achieve complete remission in 100 % of cases after 4 courses. The possibility of using DNA analysis to assess MRD in patients with PML was shown.Copyright © 2022 Izdatel'stvo Meditsina. All rights reserved.
ABSTRACT
Introduction. Primary mediastinal lymphoma (PML) is an aggressive lymphoid tumor treatment success of which is determined by induction therapy. To date, none of the standard chemotherapy regimens (CT) have demonstrated an advantage in efficacy. Intensive therapy programs are associated with high toxicity. Aim - to evaluate the efficacy and toxicity of two pilot prospective treatment protocols PML-16 and PML-19 as well as the possibility of using the analysis of freely circulating tumor DNA (ctDNA) to assess MRD in patients with PML. Materials and methods. From January 2016 to January 2022, 34 previously untreated PML patients were included in the study;average age - 32;stage > I - in 60 %;extramediastinal lesions - in 14.7 %;bulky disease - in 73.5 % of patients. Positron emission tomography combined with computed tomography (PET-CT) was performed;ctDNA was determined to assess the completeness of remission. Results. Eighteen patients received treatment according to the PML-16 protocol (6 courses of chemotherapy;2 blocks of RmNHL-BFM-90 + 4 courses of R-EPOCH). After the end of therapy, all 18 patients achieved PET-negative remission. The next 16 patients received treatment according to the PML-19 protocol (4 courses of chemotherapy;2 blocks of R-mNHL-BFM-90 + 2 courses of R-EPOCH) in combination with lenalidomide. After the end of therapy, 9 (56 %) patients achieved PET-negative remission;7 (44 %) retained pathological activity (D4-5 points). After 3 and 6 months 15 (94 %) patients achieved normalization of metabolic activity. Considering the high frequency of false-positive results in patients with PML, a ctDNA study was performed to determine the depth of remission in 15 patients. After the end of therapy, all 15 patients had complete elimination of ctDNA. Of these, 5 (33 %) remained PET-positive at the end of treatment. During further observation, after 3-6 months, in 4 patients the level of metabolic activity decreased to physiological without the use of consolidating therapy. After the end of therapy, one patient suffered the new coronavirus infection, COVID-19. A month later, residual formation of SUVmax 14.2 remained in the mediastinum. The patient is currently under observation. With a median follow-up of 36 months (9 to 76 months) all 34 patients are in remission. Conclusion. The effectiveness of PML-16 made it possible to abandon the consolidation therapy and refuted the idea of the need for 6 courses of CT. The combination of programs based on the application of the principle of high-dose short-pulse induction of remission (R-mNHL-BFM-90) in combination with the prolonged administration of medium doses (R-EPOCH) was crucial in achieving a successful result. The inclusion of lenalidomide in the "PML-19" program made it possible to achieve complete remission in 100 % of cases after 4 courses. The possibility of using DNA analysis to assess MRD in patients with PML was shown.Copyright © 2022 Izdatel'stvo Meditsina. All rights reserved.
ABSTRACT
Introduction. Primary mediastinal lymphoma (PML) is an aggressive lymphoid tumor treatment success of which is determined by induction therapy. To date, none of the standard chemotherapy regimens (CT) have demonstrated an advantage in efficacy. Intensive therapy programs are associated with high toxicity. Aim - to evaluate the efficacy and toxicity of two pilot prospective treatment protocols PML-16 and PML-19 as well as the possibility of using the analysis of freely circulating tumor DNA (ctDNA) to assess MRD in patients with PML. Materials and methods. From January 2016 to January 2022, 34 previously untreated PML patients were included in the study;average age - 32;stage > I - in 60 %;extramediastinal lesions - in 14.7 %;bulky disease - in 73.5 % of patients. Positron emission tomography combined with computed tomography (PET- CT) was performed;ctDNA was determined to assess the completeness of remission. Results. Eighteen patients received treatment according to the PML-16 protocol (6 courses of chemotherapy;2 blocks of R-mNHL-BFM-90 + 4 courses of R-EPOCH). After the end of therapy, all 18 patients achieved PET-negative remission. The next 16 patients received treatment according to the PML-19 protocol (4 courses of chemotherapy;2 blocks of R-mNHL-BFM-90 + 2 courses of R-EPOCH) in combination with lenalidomide. After the end of therapy, 9 (56 %) patients achieved PET-negative remission;7 (44 %) retained pathological activity (D4-5 points). After 3 and 6 months 15 (94 %) patients achieved normalization of metabolic activity. Considering the high frequency of false-positive results in patients with PML, a ctDNA study was performed to determine the depth of remission in 15 patients. After the end of therapy, all 15 patients had complete elimination of ctDNA. Of these, 5 (33 %) remained PET-positive at the end of treatment. During further observation, after 3-6 months, in 4 patients the level of metabolic activity decreased to physiological without the use of consolidating therapy. After the end of therapy, one patient suffered the new coronavirus infection, COVID-19. A month later, residual formation of SUVmax 14.2 remained in the mediastinum. The patient is currently under observation. With a median follow-up of 36 months (9 to 76 months) all 34 patients are in remission. Conclusion. The effectiveness of PML-16 made it possible to abandon the consolidation therapy and refuted the idea of the need for 6 courses of CT. The combination of programs based on the application of the principle of high-dose short-pulse induction of remission (R-mNHL-BFM-90) in combination with the prolonged administration of medium doses (R-EPOCH) was crucial in achieving a successful result. The inclusion of lenalidomide in the "PML-19" program made it possible to achieve complete remission in 100 % of cases after 4 courses. The possibility of using DNA analysis to assess MRD in patients with PML was shown.
ABSTRACT
Background: In the largest study of Baliakas et al. (2019) the presence of at least 5 abnormalities, was associated with dismal clinical outcome, independently of the somatic hypermutation status and TP53 status. The presence of 3 or 4 aberrations is defined as clinically relevant in the absence of TP53. Studies by Kittai (2021) and Al-Sawaf (2020) showed the impact of karyotypic complexity on survival in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib or venetoclax. The complex karyotype (CK) is a topic that is being intensively researched, both in the aspect of increasing karyotypic complexity stratification and clonal evolution. Optimal therapy for patients with CLL has not yet been developed. The combination therapy of ibrutinib and venetoclax was superior to chlorambucil and obinutuzumab in terms of undetectable minimal residual disease (MRD) responses according to data from the GLOW trial (Tunir, 2021). The importance of achieving a complete response with undetectable MRD as the goal of therapy in CLL was proposed (Montserrat, 2005). Aims: The aim of our study is to evaluate the effectiveness of therapy with ibrutinib and venetoclax in combination for the patients with CLL and CK. Methods: This ambilinear observational study included patients with CLL with high genetic complexity (high-CK), defined as >=5 aberrations or CK (>=3 aberrations) in combination with a 17p deletion (CK+del17p). The first retrospective cohort included patients treated with ibrutinib monotherapy (Imono) to progression or intolerable toxicity since May 2015. The second prospective cohort included patients receiving ibrutinib in combination with venetoclax (IVen) since July 2019. Venetoclax therapy was started at the 3rd month of ibrutinib (from the escalation phase). Combination therapy was continued until a complete response, defined as three consecutive PET-CT-negative and MRD-negative results 3 months apart. If this criterion was not achieved at 24th month of therapy, venetoclax was discontinued and ibrutinib continued indefinitely. Results: Seventy-nine patients are included in the study. Twenty-nine patients in the first cohort and 50 patients in the second cohort. The characteristic is presented in Table. At the current follow-up periods, there were no significant differences in PFS and OS regarding a follow-up period <= 24 months (with the exception of death from COVID-19, since patients were not observed at parallel time intervals). In the group of patients treated with Imono, the majority of patients achieved partial remission or partial remission with lymphocytosis by 12 months. In 21 patients from Iven group, with a median follow-up of 7.4 months, a complete remission was achieved (72.4%);of these, 8 had unmeasurable MRD. Four patients did not complete the escalation period. There was a significant difference in the median MRD response achieved between 3 (log10>10) and 12 (log10<0,1) months in IVen group (p=0,03). In 2 patient from the IVen group progression of the disease was noted. Summary/Conclusion: Combination therapy with ibrutinib and venetoclax is an effective oral regimen for high-risk patients with complex karyotype disorders. PFS in both groups is currently not significantly different, which is obviously due to the short follow-up period. Patients receiving the IVen regimen achieve a significantly better response, which paves the way for allogeneic transplantation in these patients.
ABSTRACT
Background: High-grade B-cell lymphoma double-hit (HGBL DH) can arise from follicular lymphoma (FL). In the case of transformation of FL it accumulates a large number of additional mutations and secondary c-MYC gene rearrangement, which can make it resistant to standard immunochemotherapy. Aims: To evaluate an efficacy of induction regimen R-CHOP/R-DAEPOCH and modified BFM chemotherapy with rituximab in treatment of HGBL DH raised from FL. Methods: We studied13 FL pts with double- (9 - with c-MYC/8q24 and BCL2/18q21;4 - with c-MYC/8q24 and BCL6/3q27) and one pt with triple translocations involving c-MYC/8q24, BCL2/18q21 and BCL6/3q27 genes and deletion of17p13.10 pts had morphological signs of transformation into aggressive lymphoma;4 pts had FL 3A. There was 8 women and 6 men aged from 30 to 60 y. o. (median 47 y.o.). Lymph node with the highest FDG-accumulation according to PET-CT was chosen for biopsy and consequent immunohistochemistry and cytogenetics. The majority of pts had high12/14 and 2/14 - high-intermediate FLIPI score. All pts had advanced (III-IV) stage according to Ann-Arbor classification. 3 out of14 pt had a history of low-grade FL (16-96 months) without c-MYC rearrangement in primary biopsy samples, in other11 cases - anamnesis varied from 0,5 to 4,0 months. Lymphoma manifested by rapidly spread aggressive tumor with bulky disease: 2 pts had leukemic presentation of FL;1 pt had FL cells in cerebrospinal fluid;12/14 out of pts had several extranodal sites of involvement such as ovaries (2/8), kidneys or adrenals (6/14), paranasal sinuses (1/14);bones (3/14);soft tissues (4/14);lungs (3/14);stomach or intestine (4/14);spleen (4/14);liver (1/14). Ki-67 varied from 40 to 90%. An expression of c-MYC protein higher than 40% in11/13 of FL pts. We didn't revealed TP53 mutation within 7 out of 7 analyzed pts. Results: None of pts had previous therapy. 4 pts were treated with R-CHOP-21. 3/4 (75%) out of pts died due to progressive disease (PD),1/4 (25%) had partial remission (PR) after consequent therapy including obinutuzumab. 7 pts underwent modified BFM-protocol with Rituximab. 6/7 (86%) out of pts achieved complete remission (CR) after first-line treatment,1 pt died due COVID-19 in PD status (14%). Autologous stem cell transplantation (auto-SCT) was performed in 4 out of 7 pts. 3 pts underwent R-DA-EPOCH.1 pt achieved a CR after 6 courses,1 pt - after second-line 2 R-DHAP;auto-SCT was performed for consolidation.1 pt (33%) had PD after R-DA-EPOCH and another therapy. Rituximab supportive treatment was administrated only in 4 cases due to epidemiological situation. Median of observation was 9 months (1,0-59,5). We couldn't study TP53 mutation status in pts with PD, but we observed PD in one case with deletion of17p13. Summary/Conclusion: For better diagnostics of FL transformation into HGBL DH we should perform biopsy of lymph node with the most active FDG accumulation according to PET-CT. We observed a higher rate of CR in this pts cohort when treated with intensive induction immunochemotherapy (modified BFM chemotherapy with rituximab) in comparison with R-CHOP/R-DA-EPOCH (86% vs 25% and 33%, respectively), and lower rate of primary resistance/PD (14% vs 75% and 33%). Our data needs consequent confirmation or consideration within metanalysis due to rare diagnostics of FL with double translocations of c-MYC and BCL2/BCL6. We should initiate a randomized study to estimate if auto-SCT had any benefits in comparison with a new immunotherapy modalities in FL transformed into HGBL DH.